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ANNUAL REPORT 2014 | 1 CELL BIOLOGY

Aetiology and pathogenesis the children across the first year of life, employing 16S rRNA deep sequencing. of atopy and asthma in The resultant data base of >193 children million sequence reads was utilized in characterizing dynamic changes in the The role of bacterial during NPM associated with viral infections, infancy in asthma development and linking these with asthma risk at 5 and 10yrs. Salient findings include: aMok D, aKusel MMH, aSerralha M, aTroy (i) the steady state NPM is dominated N, aHolt BJ, aHales B, aHollams EM aHolt by commensals Corynebacterium, PG, in collaboration with bSly PD, cGern Staphylococcus, and/or Alloiococcus JE, cBochkov YH, cGrindle L; dJohnston sp. which are largely supplanted by the SL; eTeo SM, ePham K, eWalker ML pathogens Haemophilus, Streptococcus eHolt KE and/or Moraxella sp. during viral aTelethon Kids Institute, University of ; (ii) the same pathogens are selected for by day-care and antibiotic bQueensland Children’s Medical treatment; (iii) rhinovirus (HRV) and Research Institute, University of RSV are independently associated with ; symptoms during acute respiratory illness (ARI), but after controlling for c University of Wisconsin School of virus, Haemophilus, Streptococcus Medicine and Public Health and/or Moraxella remained strongly dImperial College of London associated with ARI symptoms and with infection spread to the lower airways; e Depts of Pathology, Microbiology (iii) these bacterial pathogens plus & Immunology, and , RSV (but not HRV) were additionally University of , Australia associated with febrile lower respiratory illness (fLRI), which was itself a major risk factor for asthma development Respiratory viral infections during across the whole cohort; (iv) HRV-C infancy, particularly against a infection was associated with acute background of early allergic wheezing (w)LRI and with subsequent sensitization, have been implicated as asthma development, but only in “high risk factors for asthma development. risk” children who displayed early Recent findings suggest that bacterial aeroallergen sensitization; (v) early fLRI pathogens may also contribute to and wLRI operated independently and pathogenesis but definitive data are additively in promoting asthma risk; (vi) lacking. We have addressed this time to first LRI also appears important question in our Childhood Asthma with earlier fLRI occurring amongst (CAS) birth cohort study, as part of children who developed asthma; which we have characterized the relevant to this, early colonization with nasopharyngeal microbiome (NPM) in

2 | TELETHON KIDS INSTITUTE Streptococcus (which was again more The majority of school children with common in the sensitized group) was inflammatory airway disease(s) are strongly associated with both earlier sensitized to aeroallergen(s), and first LRI, and risk for subsequent asthma. symptom frequency and intensity We conclude that dynamic changes associates positively with IgE titres. in the constituents of the infant NPM However only a minority of sensitized/ contribute independently to driving exposed children are symptomatic, asthma development, and also play key suggesting that the pathogenic effects modulatory role(s) in the parallel asthma of IgE are normally attenuated by causal pathway driven by interactions endogenous control mechanisms. between virus-driven and allergen- We hypothesized that aeroallergen- driven inflammatory mechanisms. specific IgG that is co-produced with These studies are continuing into 2015, IgE, contributes significantly to this during which analyses of NPM samples attenuation. To address this question, collected during years 2-5 in the cohort we have pooled data from our CAS will be performed. and RAINE birth cohorts from , together with data from the Manchester This project is funded by the National Asthma and Allergy cohort from UK. In Health and Medical Research Council of these three independent community Australia. cohorts we have analysed relationships between serum aeroallergen-specific Distinguishing benign from pathologic IgE and IgG titres and associated immunophenotypes, and susceptibility Th2-immunity in atopic children to asthma and rhinitis. a a Patrick Holt, Deborah Strickland, Amongst atopic children with elevated a a a Anthony Bosco, Belinda Hales, Elysia aeroallergen-specific IgE, levels of a a Hollams, Barbara Holt, Merci Kusel, in corresponding specific (total) IgG or b c collaboration with Peter D Sly, Adnan IgG1 (and hence IgG:IgE ratios) were c Custovic, Danielle Belgrave, and inversely related to the presence, d Staffan Ahlstedt severity and persistence of airway aTelethon Kids Institute, The University symptoms, responsiveness to of Western Australia intradermal allergen challenge, and the potency of their sera in basophil bQueensland Children’s Medical triggering in vitro. Genome wide Research Institute, University of expression profiling of underlying Queensland; aeroallergen-specific Th-memory cUniversity of Manchester, UK responses revealed strong positive associations between IgG:IgE ratios dCentre for Allergy Research, Karolinska and IL-10-dependent (regulatory) gene Institute, Stockholm, Sweden signatures, and the converse for Th2- effector signatures.

ANNUAL REPORT 2014 | 3 These findings suggest that following Australia sensitization, aeroallergen-specific Th- dQueensland Children’s Medical memory matures over time driven by Research Institute, Brisbane, Australia. ongoing environmental exposure. The balance that develops between effector We tracked vitamin D levels from birth and regulatory mechanisms controlling to age 10y in over 100 CAS cohort the strength of the immediate (IgE- members; we used a highly specific, mediated) and ensuing late phase internationally-standardised method (T-cell-mediated) reactions collectively developed by Metabolomics Australia determine resistance/susceptibility to (University of Western Australia) to aeroallergen-induced airway symptoms. measure the storage form of vitamin Allergen-specific IgG1, production of D (25(OH)D) from cryobanked CAS which is likely driven via IL-10, plays plasma samples collected at birth a hitherto unsuspected “gatekeeper” (cord blood), 6 months and 1, 2, 3, 4, 5, role in this process via limiting the & 10 years. Our findings suggest that intensity of the acute phase response low 25(OH)D in infancy is linked to that initiates the atopic inflammatory higher numbers of severe respiratory cascade. These findings in atopic infections up to age 5 years. We have children have implications for design also observed that children with low of prognostic and immunotherapeutic vitamin D at a high proportion of the 8 strategies for controlling airway disease follow-up ages had increased risk of development/progression. asthma, allergy and eczema at age 10y, suggesting a continuing requirement for This project is funded by the National adequate vitamin D beyond infancy and Health and Medical Research Council of throughout childhood. Australia. This project is funded by Asthma Australia in conjunction with the Investigating relationships between National Health and Medical Research vitamin D status and asthma and Council of Australia. allergy development throughout childhood. Prediction of asthma in childhood Hollams EMa, Hart PHb, Zhang Gc, Holt from wheezing phenotypes up to age BJa, Sly PDd, Holt PGa. 3 years: findings from the Western Divisions of Cell Biologya and Australian Pregnancy Cohort (Raine Inflammationb, Telethon Kids Institute, Study). University of Western Australia, Perth, Hollams EMa , de Klerk Nb, Holt BJa, Sly Australia PDc, Holt PGa. cSchool of Paediatrics and Child Health, Division of Cell Biologya and Centre for University of Western Australia, Perth, Biostatisticsb, Telethon Kids Institute,

4 | TELETHON KIDS INSTITUTE University of Western Australia, Perth, cQueensland Children’s Medical Australia Research Institute, Brisbane, Australia. cQueensland Children’s Medical Late onset and persistent (early onset) Research Institute, Brisbane, Australia. asthma in young adults are generally recognised as distinct phenotypes Increased number of wheezing that are likely to be driven by different episodes by age 3 years (with or mechanisms; they are therefore likely without a cold) was associated with to need different treatments, but increased risk of asthma at age 14 underlying details are sparse. We have years in the Raine cohort. Measures of recently received funding to address lung function and airway calibre were these important issues within the reduced in 14-year-olds who had ever Western Australian Pregnancy Cohort wheezed by age 3 (with or without (Raine Study). A follow-up examining a cold) compared to those who had the respiratory health of ~1000 not. Furthermore, a higher number of 22-year-old Raine Study participants episodes of wheezing with a cold by has recently been completed, age 3 predicted poorer lung function at complementing a similar follow-up that age 14; there was no such association took place at age 14 years. In addition for wheezing without a cold, suggesting to collecting clinical data relating to that it is increased respiratory infections asthma, both follow-ups created an rather than wheezing alone that is likely archive of viable immune cell samples to have a persistent detrimental effect (peripheral blood mononuclear cells) on lung function. These analyses are that were collected from subjects at ongoing. the time of clinical assessment, at both This project is funded by the National 14 and 23 years. This enables us to Health and Medical Research Council of strategically examine immune function Australia. at both ages to identify immunological markers associated with remitting asthma, persistent asthma, and late- Uncovering the immunological onset asthma. mechanisms determining whether This study will commence early in 2015 asthma waxes or wanes between and is funded by the National Health adolescence and adulthood. and Medical Research Council of Hollams EMa, Bosco Aa, Strickland Da, Australia. de Klerk Na, Sly PDc, Holt PGa.

a Division of Cell Biology and Centre for Developmental-associated b Biostatistics , Telethon Kids Institute, dysregulation of innate anti- University of Western Australia, Perth, microbial immunity in early life as Australia a determinant of susceptibility to

ANNUAL REPORT 2014 | 5 atopic asthma pathogens and includes detailed assessment of inflammasome- Holt PG, Mok D, Bosco A, Hollams EM associated functions resulting in Telethon Kids Institute, The University of secretion of pro-inflammatory cytokines. Western Australia Using cryobanked peripheral blood mononuclear cells (PBMCs) from the We have established previously CAS cohort to address this hypothesis, that children most likely to develop we examined age-associated changes persistent asthma are those who in regulation of inflammasome- experienced repeated/intense lower associated functions. One hundred and respiratory tract infections (LRIs) sixty cord blood samples, 166 PBMCs during infancy, especially if they also obtained at age 4 and 126 PBMCs at show early signs of atopy. The marker age 10 were cultured and examined for for asthma risk in these children inflammatory and regulatory cytokine was associated with the severity of responses, including IL-1 following the accompanying - activation with innate stimuli (LPS or associated respiratory symptoms, poly(I:C)), which we have shown to up- suggesting that their antimicrobial regulate IL-1 production and secretion. responses are dysregulated to the Cells from these cultures were extent that they contribute directly cryobanked to measure transcriptional to airway tissue damage. Findings in levels of genes associated with the the Childhood Asthma Study (CAS) inflammasome complex. A case:control birth cohort indicate that the most subset of cord blood samples, asthmatogenic infant LRIs are those comprising those who did not exhibit associated with fever, a classical marker fever during an LRI against those who of acute inflammation and a specific had multiple fevers during an LRI, marker of the underlying activation was assessed by flow cytometry for of the inflammasome complex, which caspase-1 activity, a critical component mediates production of the active form of the inflammasome complex. of the fever-inducing cytokine, IL-1. Analysis of these data are ongoing We postulate that children at maximum in 2015, which will be correlated with risk of developing persistent asthma documented clinical outcomes in are those in whom postnatal maturation relation to asthma, particularly where of innate immune functions are individuals with an LRI showed a febrile developmentally delayed, leading response. to transient dysregulation of their This project is fully funded by an antimicrobial defence mechanisms NHMRC Project Grant during infancy. This project focuses on cell populations within the innate arm of the immune system that mediate initial defence against respiratory

6 | TELETHON KIDS INSTITUTE Role of IRF7 gene networks in asthma In the second approach, we utilized a exacerbations mouse model of rhinovirus infection (attenuated mengovirus model), to a a a b Jones A, Troy N, Holt PG, Wiehler S, determine if IRF7 regulates antiviral b a Proud D, Bosco A responses in vivo. The data showed aTelethon Institute for Child Health that neutrophilic airways inflammation Research, The University of Western was increased in IRF7 knockout mice Australia, Perth, Australia in comparison to wild type controls. Taken together, these data show b Department of Physiology and that IRF7 controls the expression of Pharmacology, University of Calgary, innate antiviral genes and regulates Alberta, Canada airways inflammation during rhinovirus Human rhinovirus (HRV) infections infections. These data highlight the are a major trigger for asthma potential utility of the IRF7 pathway exacerbations and are a frequent cause to develop new treatments that of hospitalization among children. Very modulate inflammation during asthma few treatment options exist for asthma exacerbations. exacerbations, and little progress has This research is supported by a been made towards the development Medical Research Fellowship from the of new treatments because the Brightspark Foundation and McCusker underlying disease mechanisms are Charitable Foundation. poorly understood. We previously utilized a systems biology approach to characterize the gene networks that Gene network patterns in sputum underpin the pathogenesis of asthma underlying asthma-related traits exacerbations in children. Our findings suggested that a gene called IRF7 was Jones A, Troy N, White E, Hollams EM, a master regulator of these networks. Holt PG, Hall GL, Bosco A However, the data were based on a Telethon Kids Institute, The University of computational analysis and do not Western Australia, Perth Australia constitute direct proof. In this study, we used two approaches to further Asthma is a chronic and heterogeneous our understanding of the role of IRF7 inflammatory disease that is strongly in asthma. First, siRNA technology was associated with sensitization to used to knockdown IRF7 expression allergens, but the underlying in airway epithelial cells, and then mechanisms are poorly understood. the epithelial cells were infected with Previous studies have largely relied rhinovirus. Using microarray profiling we on animal models or human challenge demonstrated that knockdown of IRF7 studies to elucidate the underlying reduced the expression levels of genes mechanisms, but these approaches involved in innate antiviral responses. employ high doses of allergen, and

ANNUAL REPORT 2014 | 7 there is a lack of data in the context Department of Pathology, Oslo of natural allergen exposure. In this University Hospital Rikshospitalet study we collected induced sputum and University of Oslo, PO Box 4950 samples from participants of the 23 Nydalen, Oslo 0424, Norway year follow-up of the Raine cohort The incidence of allergic diseases has study. We hypothesized that normal reached epidemic proportions over the domestic exposure to dust mite last few decades in the industrialized allergens could be leveraged to reveal world. Detailed molecular studies of asthma-associated inflammatory memory T cell responses in disease- mechanisms via comparative profiling relevant tissues in humans in vivo of the sputum transcriptome at will be essential to understand the baseline in symptomatic/asymptomatic pathogenesis of allergic diseases. The mite sensitized subjects. The data objective of this study is to develop showed that hundreds of genes were new methods to isolate highly purified differentially expressed in house dust CD4 T cells from allergen challenge mite allergic subjects with or without sites in humans for systems biology asthma. These findings demonstrate studies. Patients with allergic rhinitis are that transcriptomic profiling of sputum- recruited out of season and challenged derived cells can unveil biological with allergen in the nasal cavity for pathways and networks underlying seven days. Biopsies are obtained from the pathogenesis of asthma-related the nasal mucosa before and after the traits in the context of natural allergen allergen challenge. The biopsies are exposure. enzymatically digested into single cell This project is supported by funding suspensions and sorted into CD4 T cells from the Asthma Foundation of WA and antigen presenting cells. Molecular and the National Health and Medical profiling technologies are then Research Council of Australia. employed to measure gene expression levels. The data showed that CD4 T cells isolated from allergen challenge Identification of allergen-driven T sites are characterized by upregulation cell memory gene networks during of Th2- and FoxP3-associated gene experimental allergic rhinitis in expression signatures. We are now humans conducting a follow-up study to repeat the experiments at multiple time points aBosco A, bDollner R, bMelum G, in a larger number of patients. bLexberg M, aJones A, bBækkevold E, This project is funded by the National aHolt PG, bJahnsen F Health and Medical Research Council of aTelethon Kids Institute, The University Australia. of Western Australia, Perth, Australia bCentre for Immune Regulation

8 | TELETHON KIDS INSTITUTE Genomic responses during acute to healthy controls. Notably, these human anaphylaxis are characterized modules contain multiple hub genes, by upregulation of innate which are known to play a central role inflammatory gene networks in the regulation of innate inflammatory responses. Bioinformatics analyses bStone S, aBosco A, aJones A, bCotterell show that the data are enriched for V, bvan Eeden P, bArendts G, bFatovich TNF activation signatures. Our findings DM, aHolt PG, bBrown S. indicate a central role for innate immune aTelethon Institute for Child Health pathways in the pathogenesis of Research, The University of Western human anaphylaxis, and the hub genes Australia, Perth, Australia identified in this study represent logical candidates for follow-up mechanistic b Centre for Clinical Research in studies. Emergency Medicine, Harry Perkins Institute of Medical Research This project is supported by a grant from the US Food Allergy and The pathogenesis of anaphylaxis in Anaphylaxis Network. humans involves the systemic spread of immune activation and mediator release. Anaphylaxis in adults Epigenetic changes underpinning represents an extreme example of the allergen sensitization: a twin-based inflammatory responses which drive the study. early phase of severe atopic asthma exacerbations in children, and we are aSaffrey R,b Read J, bHolt PG, bStrickland studying this syndrome in adults to DH gain additional insight into the range of aMurdoch Children’s Research Institute genes involved. The aim of this study and Dept Paediatrics, University is to investigate genomic responses Melbourne during acute anaphylaxis in peripheral blood leukocytes. Peripheral blood bTelethon Kids Institute, The University samples are being collected from of Western Australia, Perth Australia patients presenting to the Emergency Allergic diseases are one of the most Department with acute anaphylaxis common chronic inflammatory disorders and from healthy controls. Gene afflicting humans. In genetically expression patterns are profiled on susceptible individuals, dysfunctional microarrays, differentially expressed immune responses cumulatively result genes are identified, and network in the adaptive generation of IgE to analysis is employed to characterize specific environmental antigen(s). the underlying mechanisms. The data Defining the molecular pathways show that innate inflammatory gene that are disrupted in IgE mediated modules are upregulated in patients antigen sensitization has proven to during acute anaphylaxis in comparison be one of the most elusive aspects

ANNUAL REPORT 2014 | 9 in our understanding of how to better through a within-pair comparison of direct approaches towards preventive the epigenetic and gene expression or improved treatment strategies profiles of cells of the adaptive immune targeting allergic disease. Genetics system (CD4+ T and APC cells). We and environmental factors alone do not have used flow cytometry to sort purify independently explain development of subsets of immune cells from PBMC allergic disease. Rather, allergy appears of twin pairs and are currently in the to involve a complex interplay between process of examining genome wide genetic susceptibility and environmental methylation profiles. Additionally we exposure. Recent findings suggest a have characterized PBMC samples role for epigenetic change, in particular to determine frequency, activation DNA methylation, in the causal pathway. state and function of the immune cell Using allergic asthma as an archetypal subpopulations and are currently in the allergic disease, the central aim of process of data analysis. this study is to identify differences This project is funded by the National in epigenetic profile specifically Health and Medical Research Council of associated with environmentally Australia. induced allergen sensitization in humans. Recent unequivocal data in inducible mouse models of Finding the cellular explanation for asthma have demonstrated specific recurrent asthma exacerbations disruption of DNA methylation profile in the peripheral T cell compartment. Leffler J, Laing I, Le Souef P, Holt PG, Equivalent data in humans is lacking Bosco A*, Strickland DH due to the difficulties associated with Telethon Kids Institute, The University of teasing out the relative roles of genes Western Australia, Perth Australia and environment in the modulation of epigenetic state. An elegant approach SPACH*** to overcome such issues, which mirrors Asthma is a complex chronic animal models, is to study human inflammatory disease affecting the twins in childhood. This study aims to airways. It develops mainly in young definitively test the link between altered children and presents as several DNA methylation in CD4+ T cells and disease phenotypes of different allergy in genetically identical twins underlying pathogenesis, severities discordant for allergic sensitization to and health care requirements. One house dust mite. The first aim of this particular subgroup of patients study is to Identify methylation sensitive manifests with recurrent severe genes (MSG) associated with gene exacerbations, requiring frequent expression differences in monozygotic hospitalization. These patients have a twins discordant for house dust mite high risk of developing irreversible loss (HDM) sensitization (SPT+ and SPT-) of lung function and, in addition, do not

10 | TELETHON KIDS INSTITUTE respond well to available treatments. To Aetiology and pathogenesis date, there is only limited knowledge regarding mechanisms governing of asthma: Animal Model recurrent exacerbations in this subset of Studies susceptible individuals. Defective aeroallergen surveillance In this project we are testing the by airway mucosal dendritic cells as hypothesis that specific unique a determinant of risk for persistent patterns of cellular and molecular airways hyper-responsiveness in inflammatory responses are associated with the recurrent severe exacerbation experimental asthma disease phenotype. To achieve aStrickland DH, aThomas JA, aMok D, this we are employing state of the bBlank F, aLarcombe AN, aHolt PG art technology to characterize the a cellular and molecular signatures Telethon Kids Institute, The University of peripheral blood mononuclear of Western Australia, Perth, Australia cells (PBMC) collected from healthy bDivision of Respiratory Medicine, individuals, and from patients University Hospital of Bern, Inselspital, presenting at hospital during acute Bern Switzerland asthma exacerbations across a range Atopic asthma contributes significantly of exacerbation frequency scores, to the overall community disease and in same individuals at follow-up. burden. Sensitization to aeroallergens We are performing multi-parameter during early life years is a major risk flow cytometry and transcriptome factor associated with the development profiling (RNA-Sequencing) of PBMC of atopic asthma. However of all samples to determine proportions sensitized individuals only a subset go of cellular subsets, activation status on to develop clinically relevant airways and corresponding gene expression. symptoms, suggesting important roles These studies will improve our current for additional cofactors in disease understanding of the inflammatory pathogenesis. This study aims to map responses in this hard-to-treat patient the cellular immune mechanisms that group and may unveil novel therapeutic underlie expression of clinically relevant targets leading to improved treatment persistent forms of allergic asthma. options for these children. We have developed an experimental model system featuring rat strains at the two extremes of the spectrum of susceptibility to allergic airways disease: 1) high-IgE-responder (HR) BN rats (analogous to symptomatic human atopic asthmatics) in which sensitization with aeroallergen leads to high-level

ANNUAL REPORT 2014 | 11 Th2-responses and subsequent aerosol mechanism that determines antigen challenge triggers rapid onset of severe uptake capacity in HR rats in more and persistent airways inflammation detail, in the expectation that this and airways hyperresponsiveness knowledge will point to new targets (AHR), versus 2) low-IgE-responder (LR) for design of asthma treatment and PVG rats (analogous to the majority of prevention therapies. aeroallergen-sensitized atopics) which This project is funded by the National are by comparison, refractory to aerosol Health and Medical Research Council of challenge. In dissecting the cellular Australia. responses in the two rat strains we have identified that high susceptibility to aeroallergen-induced persistent Respiratory viral infections as triggers airways disease in HR animals is a of acute severe asthma exacerbations direct result of a specific deficit in the in atopic individuals: mechanistic capacity to generate mucosal-homing Treg cells in airway draining lymph studies in an experimental model nodes (ADLN). The two key findings Strickland DH, Thomas JA, Lauzon- from our study are (i) the deficit in Joset JF, Jones A, Bosco A, Holt PG Treg induction in HR animals is linked to reduced capacity of their resident Telethon Kids Institute, The University of airway mucosal dendritic cells (AMDC) Western Australia, Perth, Australia for in situ antigen uptake, and (ii) this Asthma is one of the most common defect in AMDC function is a direct chronic diseases in the world. Of the result of signals from the local airway different pathological phenotypes mucosal tissue microenvironment. We associated with this disease, atopic have demonstrated that this deficit asthma contributes most to the can be therapeutically manipulated overall community disease burden. via intranasal transfer of in vitro Sensitization to aeroallergens during aeroallergen-loaded AMDC from naïve early life is recognized as a potent risk animals into AHR-susceptible animals factor driving development of atopic during prolonged aerosol challenge, asthma in children and young adults. which markedly boosts subsequent Sensitization to these allergens is now accumulation of iTregs in the airway extremely common and occurs in half of mucosa and rapidly resolves their the Australian population, however, less chronic AHR. This suggests that than 20% of at-risk sensitized subjects compromised antigen surveillance by develop clinically relevant airways AMDC results in defective functional symptoms, suggesting that additional programming of iTreg, which may be cofactors are required to drive disease causally related to AHR susceptibility. pathogenesis. The role of respiratory Our future studies will characterize viral infections as a cofactor contributing the tissue-specific immunomodulatory to allergic asthma pathogenesis, in

12 | TELETHON KIDS INSTITUTE particular Rhinovirus (RV), is currently the airway mucosa to impact disease one of the most active areas in pathogenesis. Our findings indicate that asthma research. It is thought that in concurrent RV infection/aeroallergen susceptible individuals, respiratory viral exposure results in significant infections can operate independently of worsening of airways inflammation and atopy and/or interact synergistically with that genetic susceptibility and gender the effects of atopy to maximise asthma play important roles in the process. risk. It is additionally suggested that This project is funded by the National the atopic state may itself predispose Health and Medical Research Council of to viral infections in the airways and Australia. this “reverse causality” may also be sufficient to explain the association. Our own investigations in this context Targeting the mucosal immune have indicated that the connection system in a mouse model to prevent between respiratory viral infection pregnancy complications following and atopy may be more intimate. To best compliment the findings in maternal bacterial infection children showing strong associations Scott NM, Lauzon-Joset JF, Mincham between RV infection and acute KT, Prescott SL, Robertson SA, Holt PG, asthma exacerbation and to mimic Strickland DH the essential characteristics of human disease, we have developed a model Telethon Kids Institute, The University of unique in the international literature. Western Australia, Perth Australia This model compares the extremes Robinson Institute, University of of the spectrum of susceptibility to Adelaide, . symptomatic allergic airways disease Maternal exposure to microbial seen in humans using rat strains pathogens during pregnancy is expressing high (HR) versus low (LR) frequently associated with exaggerated atopic responder phenotypes. We have inflammatory responses and examined the inflammatory response accompanying high intensity acute to RV infection over a time course symptoms, and in some cases more in naïve male and female HR and LR profound follow-on effects ranging from rat strains, including determination the extreme of premature termination of viral titre, airways inflammatory of pregnancy, to growth restriction in responses, cytokine production and the offspring. Preterm birth is the single cellular immunology profiles of T cell most important health care issue in and DC subsets. In addition, we have fetal-maternal medicine, with a high investigated how allergic responses prevalence in Australia and other interplay with existing viral infection to developed countries. Children born influence local Th2 (allergic) immune with low for gestational age weight responses to aeroallergen challenge in have an increased susceptibility to

ANNUAL REPORT 2014 | 13 subsequent development of a range This project is funded by the National of persistent diseases, exemplified by Health and Medical Research Council of atopic asthma. Safe effective treatments Australia that can be used to protect against infection-induced complications would provide exciting new opportunities for Long-term derangement of antigen improving maternal, fetal and neonatal presenting cell populations in the health. We have developed preclinical respiratory tract following A mouse models to study mechanisms infection underlying infection induced pregnancy complications. In one model we are Stumbles PA, Smith M, Bozanich E, Fear using exposure of pregnant mice to V, Wikstrom M, Thomas J, Napoli S, Lipopolysaccharide (LPS), the major Zosky GR, Larcombe AN, Sly PD, Berry pathogenic component of gram- C, von Garnier C, Holt PG and Strickland negative bacteria to induce preterm DH. delivery, growth retardation, embryonic Telethon Kids Institute, The University resorption and reduced fetal survival. of Western Australia, Perth, School of We are investigating the therapeutic Pathology, Murdoch University, Perth potential of an immune modulating Western Australia. agent, OM85BV – (a bacterial extract) delivered via the gut mucosa, to protect The respiratory tract (RT) is continually against complications induced by LPS exposed to a plethora of environmental administration during late gestation. antigens of pathogenic and non- Our results have shown that treatment pathogenic nature within inhaled air. To of pregnant mice with OM85BV for one best maintain the crucial normal function week prior to LPS exposure provides of the respiratory tissues the respiratory significant protection against preterm immune system must constantly screen birth and fetal growth retardation, these antigens for their potential danger potentially via modulation of immune to the host and rapidly neutralize the cell populations in gestational tissues. threat, or alternatively must effectively This pre-clinical study has also ignore harmless antigens to effectively demonstrated the safety of OM85BV minimize unnecessary inflammation. A during pregnancy and may represent balanced network of antigen presenting a novel, safe effective treatment cells (APC) play an important role in this strategy to protect against bacterial process and are capable of regulating infection-induced complications during tolerance or immunity as required. pregnancy. The project is progressing Respiratory viral infections can pose with a detailed analysis of the cellular a serious threat to immunological and molecular mechanisms associated homeostasis in the RT via the induction with OM85BV mediated protection. of potent inflammatory and cytotoxic responses in local tissues. Disruption to the balance of immunity in the RT can

14 | TELETHON KIDS INSTITUTE last for a prolonged period following environment. infection, and this may potentially result This project is funded by the National in modified immune responses to other Health and Medical Research Council of antigens during this time frame. This Australia. includes increasing the risk of allergic sensitization or decreasing resistance to secondary infections. In this study, Targeting the mucosal immune we have used an experimental mouse system in a mouse model to prevent model of H1N1 Influenza Type A Virus pregnancy complications following (IAV) infection in adult and juvenile animals to examine the dynamics maternal Influenza A infection and activation states of APC in airway Lauzon-Joset JF, Scott NM, Mincham mucosal (AM) and parenchymal lung KT, Holt PG, Strickland DH (PL) tissue of the RT following a time course post IAV. We found marked Telethon Kids Institute, The University of differences in the selective depletion Western Australia, Perth Australia and reconstitution of dendritic cells (DC) Following from the study above, subsets in the AM and PL environments. we are also studying the impact of In adult mice, DC in the AM were Influenza A infection during pregnancy shown to have a generally more acute on maternal and fetal health, and the response to infection that resolved potential of OM85BV to protect against by day 7, versus a more delayed complications induced by maternal response with persistent depletion respiratory viral infection. We have of PL DC subsets lasting for up to 3 developed a pre-clinical mouse model weeks following infection. Tissue- that mimics human disease to study resident macrophages populations in the cellular and molecular mechanisms the PL were also significantly altered associated with infection induced well after viral clearance, being poor maternal/fetal health. In pregnant significantly depleted and remaining mice, clinical disease symptoms in a persistent state of activation. In following Influenza A infection are more juvenile mice, persistent changes in PL severe compared to non-pregnant DC and macrophages were found for animals, mediated in part by enhanced up to 5 weeks following IAV infection. activation of immune cell populations These data demonstrate that IAV has in respiratory tissues. Fetal health is differential effects on APC populations also compromised in infected pregnant in different micro-environmental tissue mice with significantly reduced weights compartments of the RT, leading to for gestational age. Pretreatment long-term derangement in the numbers of pregnant mice with OM85BV and activation states of these cells, demonstrates significant protection which likely disrupt the fine balance against clinical disease in 60% of of immunological protection in this infected pregnant mice. Furthermore,

ANNUAL REPORT 2014 | 15 in this subset the fetuses are protected elevated compared to sensitized and against growth retardation. This project challenged wild type mice. Inhaled will progress with an investigation into allergen capture and trafficking by the underlying cellular and molecular dendritic cell subsets in the airways mechanisms associated with OM85BV of CD103-/- mice was also altered, as mediated protection and how this well the generation and trafficking impacts neonatal immune function. to the lungs of allergen-induced effector, memory and regulatory T cell This project is funded by OM PHARMA subsets when compared to wild-type (Geneva). mice, with preliminary studies also suggesting that CD103-/- mice show Role of CD103 in the regulation of modified lung physiological responses to methacholine following allergen immunity to inhaled allergens challenge. These data suggest a pivotal Fear V, Wikstrom M, Lai SP, Zosky GR, role for CD103 in the early stages of Stumbles P, Strickland DH systemic allergic sensitization and generation of allergen-specific IgE, as Telethon Institute for Child Health well as at later stages in the initiation Research, The University of Western and regulation of the local lung immune Australia, Perth Australia responses to allergen rechallenge. CD103 is the α chain of integrin αEβ7, an This project is funded by the National adhesion molecule that mediates cell Health and Medical Research Council of binding to epithelial cells via E-cadherin. Australia. This molecule is expressed by subsets of dendritic cells and T cells, and is important in T cell homing to epithelial Mechanisms of IgE sensitization barriers and marks a subset of dendritic cells that can mediate tolerogenic Leffler J, Mincham KT, Holt PG, T cell responses to environmental Strickland DH allergens. In these studies we are Telethon Kids Institute, The University of examining the role of CD103 in the Western Australia, Perth Australia development of allergic asthma using mouse models of sensitization Increasing rates of atopic (IgE mediated) followed by inhaled-allergen challenge sensitization has been identified as to induce allergic airways disease. a key risk factor associated with the CD103 knock-out (CD103-/-) mice rising prevalence of allergic asthma. developed a range of hallmark features The nature of the immunological of atopy and allergy, including OVA- mechanisms that underlie generation specific IgE and elevated eosinophils of mucosal IgE sensitization, as in bronchoalveolar washings, opposed to the normal response of although these were markedly protective tolerance to aeroallergens,

16 | TELETHON KIDS INSTITUTE remains unclear. The induction of high dose antigen results in earlier “mucosal tolerance” to aeroallergen development of IgE tolerance and that represents one of the established this is associated with earlier increased paradigms in lung immunology and induction of iTreg in the DLN. involves the selective attenuation of This project is funded by the National Th2 skewed immunity, particularly Health and Medical Research Council of production of IgE. This can be can Australia. be attained by repeated exposure to an allergen via the respiratory route with accompanying induction Targeting the mucosal immune of a phenotypically heterogeneous system in a mouse model to prevent population of T cells with “regulatory” pregnancy complications activity. Notably, in animals with hyper- susceptibility to allergic disease and Scott NM, Mincham KT, Prescott SL, development of high IgE responses Robertson SA, Holt PG, Strickland DH (high responder; HR) generation of mucosal tolerance required log Telethon Kids Institute, The University of fold higher levels of exposure to Western Australia, Perth Australia aeroallergen compared to than their Maternal infection has been associated low-responder (LR) counterparts. No with pregnancy complications including satisfactory explanation exists to explain increased mortality and morbidity this profound difference in efficiency for mother and fetus. Bacterial and of mucosal tolerance mechanisms. viral infections can induce preterm Recent novel and counterintuitive delivery and are associated with epidemiological findings suggesting low birth weight, which can have that risk for IgE sensitization to inhalant detrimental impact on child growth allergens may be inversely related to and development during early life and allergen exposure levels. The core represent significant risk factors for hypothesis of this project is derived development of non-communicable from these studies and our own diseases in later life. Preterm birth is findings that indicate that variations in the single most important health care the functional capacity of respiratory issue in fetal-maternal medicine, with a immune cell surveillance mechanisms high prevalence in Australia and other results in a spectrum of susceptibility developed countries. Safe effective to development of protective IgE treatments that can be used to protect tolerance to aeroallergens. Our HR/LR against infection-induced complications rat model provides unique opportunities would provide exciting new to systematically test this hypothesis. opportunities for improving pregnancy Our preliminary studies align well with health for all women. Rodent models our core hypotheses and suggest that are well validated to study mechanisms in LR rats, intranasal exposure to daily underlying infection induced pregnancy

ANNUAL REPORT 2014 | 17 complications. Lipopolysaccharide In common with a number of chronic (LPS), the major pathogenic component diseases, a significant proportion of of gram-negative bacteria can induce risk for development of potentially preterm delivery, growth retardation, chronic atopic asthma is pre-set embryonic resorption and reduced before birth, via a combination of fetal survival, when delivered to inherited genetic factors operating in pregnant mice. In this study we conjunction with environmental factors, are investigating the therapeutic which collectively impact negatively potential of an immune modulating upon the health of the mother during agent (OM85BV – a bacterial extract) pregnancy. These include common delivered via the gut mucosa, to protect respiratory infections such as influenza, against complications induced by LPS and atopic asthma exacerbations. It administered during late gestation. is recognised that in atopic mothers, Our preliminary results have shown intercurrent asthma exacerbations, that treatment of pregnant mice in particular severe episodes, pose with OM85BV for one week prior a significant threat to the health of to LPS exposure provides a level of the mother and to the pregnancy, protection against the LPS induced exemplified through preterm delivery changes to fetal growth and survival, and fetal growth restriction leading potentially via modulation of immune to low birth weight babies. Maternal cell populations in the intrauterine asthma during pregnancy has been tissues. This pre-clinical study suggests linked to an increased likelihood of the that treatment with OM85BV during neonate developing allergic asthma. pregnancy may represent a novel, safe This study uses an experimental model effective treatment strategy to protect of allergic asthma during pregnancy against bacterial infection-induced to examine the mechanisms that lead complications during pregnancy. to worsening maternal atopic asthma, fetal complications and increased risk This project is funded by the National of neonates to develop allergic asthma. Health and Medical Research Council of Additionally we will investigate the Australia and OM Pharma (Geneva). therapeutic potential of an immune modulating agent (OM85BV – a Maternal allergic asthma: pregnancy bacterial extract) delivered via the gut mucosa, to protect against these complications induced in mother and pregnancy health complications in fetus asthmatic women. This pre-clinical Mincham KT, Scott NM, Prescott SL, proof-of-concept study is aimed at Robertson SA, Holt PG, Strickland DH providing the rationale for future translational studies in humans, where Telethon Kids Institute, The University of the proposed target group for treatment Western Australia, Perth Australia in the first instance is atopic mothers

18 | TELETHON KIDS INSTITUTE whose offspring are known to be at such as preterm birth and small for high risk of asthma. Furthermore, it is gestational age infants. To further our now recognized that the exacerbations understanding of the types and roles of in human atopics which are associated immune cells in gestational tissues in with the most severe inflammation healthy pregnancy this study is focused are those triggered by concomitant on identifying the subsets of immune exposure to viral pathogens and cells in gestational tissues (placenta, aeroallergens, and accordingly we are decidua, uterus, lymph nodes) and in a developing a pregnant mouse model to cross-section of other peripheral tissues mimic this. over a time course of a normal healthy pregnancy. This data will serve as an This project is funded by the National invaluable guideline of normality, which Health and Medical Research Council of will be used to better understand the Australia and OM Pharma (Geneva). mechanisms underlying pregnancy complications. Mapping changes in immune cell populations in gestational tissues Differential activity of Type I over the course of pregnancy. Interferons on airways response to Study M, Scott NM, Lauzon-Joset JF, allergen. Holt PG, Strickland DH Fear VS, Holt PG, Strickland DH. Telethon Kids Institute, The University of Telethon Institute for Child Health Western Australia, Perth Australia Research, The University of Western For a successful pregnancy, the Australia, Perth Australia maternal immune system must make Asthma is a significant and increasing significant adaptions to tolerate the health burden, impacting on personal semi-allogeneic fetus. This process quality of life, lost work productivity involves selective alterations to number, and the health service. Recent activity and function of immune cells in studies implicate early life respiratory gestational tissues, in a tissue specific viral infection and concomitant IgE manner and dependent on gestational sensitisation to allergen as strong risk age. To date there remains much to be factors in the development of atopic learned, but it is clear that imbalances asthma. One hypothesis is that signals in number and function of immune cells elicited in response to respiratory viral within gestational tissues could be infection cross stimulate responses critical and even fatal to the developing to allergen, leading to sensitization fetus. Maternal inflammatory responses and subsequent allergic asthmatic of pathogenic and non-pathogenic responses. The early innate immune origin can disturb this balance and response to respiratory viral infection result in adverse pregnancy outcomes is high level Type I IFN production from

ANNUAL REPORT 2014 | 19 dendritic cells and airway epithelial Mrs B.J. Holt, BSc - Research Officer cells. Therefore, this family of cytokines Ms A. Jones - Research Assistant may potentially play a key role in the viral induction of inappropriate Dr D. Mok, PhD – Research Fellow responses to airway allergen, which Mr R. Ng – Graduate student contribute to the development of asthma. Two key cell types involved Ms N Scott, B.Biomed Sci (Hons) PhD – in the development, progression Research Officer and resolution of allergic asthma Mr M. Serralha, BSc (Hons) - Research exacerbations include airway mucosal Assistant DCs and T regulatory cells. This project examines the effect of IFN2 and IFN Dr D.H. Strickland, PhD - Senior intranasal delivery on airway dendritic Research Fellow cells, T cells and T regulatory cells. We †Dr P.A. Stumbles, PhD - Senior Lecturer, demonstrate the influence of IFN2 Murdoch University and IFN intranasal delivery on the Mrs J. Tizard - Research Assistant development of sensitization and/or tolerance to allergen. Ms N. Troy – Research Assistant This project is funded by the National †Honorary Fellow at Telethon Kids Health and Medical Research Council of Institute; all research activities remain Australia. based within this Division.

PhD Students

Mr K. Mincham – Graduate Student Staff and Students (Hons) Ms A Jones – Graduate Student Head of Division

Patrick G Holt DSc,FAA Visiting Research Fellows Telethon Kids Institute Mr J Lauzon-Joset, University of Centre for Child Health Research, UWA Quebec, Canada Mr J. Leffler, Lund University, Sweden Research Staff Dr A. Bosco , PhD - Research Fellow Theses Passed Dr V. Fear - Research Fellow Laurence Chung, PhD, University of Dr E.M. Hollams, PhD - Research Fellow Western Australia

20 | TELETHON KIDS INSTITUTE External Committees Institute of Pathology, Rikshospitalet, Oslo, 2014 (Professor Frode Jahnsen): Prof Patrick Holt Role of allergen specific IgG1 in Australian Academy of Science: modulation of allergic inflammation. Sectional Committee for Medicine and Prof Patrick Holt-Respiratory Centre, Public Health University of Arizona, Tucson, 2014 MAAP External Advisory Board, Henry (Prof F Martinez): Distinguishing benign Ford Health System, Detroit versus pathological atopy in children. Scientific Consultant; Christine-Kühne Center for Allergy Research and National Education (CK-CARE), Munich Dr Anthony Bosco, DOHaD Society of ANZ meeting, Perth, oral presentation, Dr Deborah Strickland 2014. National Health and Medicaa Research Dr Deborah Strickland: Council Early Career Fellowship – Panel Oral Presentation; Society Reproductive Member Biology; Melbourne. ACS National Conference Organising Prof Patrick Holt: Aetiology and Committee Member pathogenesis of asthma. Queensland Childrens Medical Research Institute, Brisbane. Invited Presentations

International Local Prof Patrick Holt-Symposium Speaker: Dr Deborah Strickland: The role of T-cell immunity in the Seminar Series; inception of allergy and asthma – EAACI Congress, Copenhagen, 2014. Chair, Immunology Working Group Workshop Symposium Speaker: Distinguishing benign from pathological Th2 immunity Dr Anthony Bosco: Grand Round in atopic children – Collegium TICHR presentation. Princess Margaret Internationale Allergologicum Congress, Hospital. Development of a framework Petersberg, 2014. for Translational Systems Immunology. Prof Patrick Holt-Symposium Speaker: Dr Anthony Bosco: University of Update on the Origins of Asthma: Western Australia Workshop on Insight from birth cohort studies – Complex networks: a perspective for Nemacolin Asthma Conference, understanding real-world problems Pittsburg, 2014. Dr Anthony Bosco: Asthma Foundation

ANNUAL REPORT 2014 | 21 of Western Australia: A new approach to Medicine, USA elucidate asthma endotypes. Steve Durham, Dept Allergy & Clinical Dr Anthony Bosco: Plenary lecture: Immunology, National Heart & Lung 24th Annual Scientific Meeting of Institute, UK the Australasian Society of Clinical Sebastian Johnston, Imperial College, Immunology and Allergy (ASCIA). Using School of Medicine at St. Mary’s, network graph theory to understand National Heart and Lung Institute, UK allergy and asthma. Steffan Ahlstedt, Karolinska Institute, Dr Anthony Bosco: Lung Institute of Sweden WA (LIWA) Medical Research Seminar Series: Role of gene networks in Christophe von Garnier, Bern University asthma. Hospital, Bern Switzerland Dr Anthony Bosco: Rottnest Annual John Upham, Director of Lung and Scientific Respiratory Meeting. Using Allergy Research Centre, School network graph theory to understand of Medicine, The University of asthma. Queensland. Louis Rosenthal, National Institutes of Health, USA ACTIVE collaborations Dr Christian Pasquali, OM PHARMA, Prof Patrick Holt Switzerland Fernando Martinez, Respiratory Sciences Center, University of Arizona, Dr Deborah Strickland USA Prof Sarah Robertson, University James Gern, Clinical Science Centre, of Adelaide. Preventing poor fetal University Of Wisconsin Medical School, outcomes associated with maternal USA infection during pregnancy. Robert Lemanske, Division of Pediatric Prof Susan Prescott, Perth, Australia. Allergy, Immunology and Rheumatology, RCT- egg allergy; Preventing poor fetal Wisconsin University, USA outcomes associated with maternal Adnan Custovic, University Hospital of infection during pregnancy. South Manchester, UK Prof Peter Sly, Queensland. Peter Sly, Queensland Children’s Protection against allergic asthma by Medical Research Institute, Australia immunomodulation. Hugh Sampson, Department of Prof Richard Saffrey,, Dr David Martino, Pediatrics, Division of Allergy & Melbourne, Australia. Epigenetics in Immunology, Mount Sanai School of allergic asthma- a twin study.

22 | TELETHON KIDS INSTITUTE Prof Mark Kendall, Dr Michael Crichton, cohort) Queensland, Australia. Immunotherapy Assoc Prof Charlene Kahler, UWA, for allergy using nanopatches. animal models for bacterial infections Prof Lou Rosenthal, Virology Division, Prof Frode Jahnsen, Oslo, Norway. University Wisconsin, US. Respiratory Dendritic cells in human allergy. viral infection and asthma David Proud, University of Calgary, Dr Phil Stumbles, Murdoch Uni Perth, Alberta, Canada Australia. Respiratory viral infections Active collaborations with industry Dr Christophe von Garnier, Bern University Hospital, Switzerland, Dr Deborah Strickland and Prof Patrick Nanoparticles; Respiratory viral Holt, OM PHARMA, Geneva, Switzerland infections Active community involvement Dr Fabian Blank, Bern University Hospital, Switzerland, Nanoparticles; Dr Deborah Strickland, secondary Respiratory viral infections school student laboratory projects Dr Matt Linden, CMCA UWA, immune development- Awards Prof Mark Hogarth, Melbourne, Australia. Fc-Gamma Receptors and Dr. Elysia Hollams received a Merit immune responses in allergic asthma Award (Near-miss, $75,000) from the W.A. Department of Health in Dr Anthony Bosco, Perth- viral infection recognition of a well-scored NHMRC and asthma pathogenesis (animal project grant application in 2013, to model) enable the application to be made more Dr Debbie Palmer, School Paediatrics competitive in the 2015 funding round. and Child Health (SPACH)- allergic Dr Deborah Strickland diseases/VitaminD WA Department of Health Fellowship Prof Mark Everard, SPACH, Perth. RSV Award infection ARC Linkage Infrastructure and Dr Christian Pasquali, OM PHARMA, Equipment Fund (LIEF): Mass cytometry Switzerland, studies on protection - a breakthrough in multidimensional against inflammatory mediated disease. systems biology. 2014. Co-chief Assoc Prof Alex Larcombe- Clinical Investigator, $440,000; Sciences, Lung physiology group, Telethon Kids Dr Ingrid Laing, Perth- acute asthma exacerbation and viral infection (human

ANNUAL REPORT 2014 | 23 CHILDHOOD

Cancers in children comprise many screening. Our experimental systems different diseases. More than half of comprise many leukaemia and cancer them affect cells of the immune system cell models, and they are ideal tools and the central nervous system, and for testing potential new drugs for the thus, the most common malignancy treatment of patients. in children is leukaemia, followed by brain tumours. In contrast, the most common types of cancer in adults are Leukaemia carcinomas, and they begin in cells that line the surface of the body and High levels of connective tissue internal structures. Despite marked growth factor can accelerate disease improvements in the cure rates for in a model of acute lymphoblastic paediatric , leukaemia and leukaemia. brain tumours account for half of the deaths. In order to find better therapies Investigators: JE Wells, M Howlett, HM for children with cancer, our Division Halse, J Heng, J Ford, LC Cheung, AL at the Institute and the Oncology Total Samuels and UR Kees, in collaboration Care Unit at Princess Margaret Hospital with CH Cole, M Crook and AK Charles, (PMH) are both members of the US- Princess Margaret Hospital. based Children’s Oncology Group Acute lymphoblastic leukaemia (ALL) (COG). COG is the largest study group is the most common form of cancer in of this kind, and 240 hospitals around children. Despite major improvements the globe participate in evaluating in cure rates, a significant number of better treatments for children with patients relapse and their prognosis cancer. The major goal is to improve remains dismal. ALL originates in the our understanding of paediatric cancers bone marrow, and cell-cell interactions and leukaemia, and work towards in this microenvironment can alter curative therapy for patients. disease progression and treatment The Division focuses on research into efficacy. childhood leukaemia, brain tumours Connective tissue growth factor (CTGF/ and a very rare disease in children, a CCN2) is expressed at significantly form of carcinoma. The main aims are higher levels in approximately 75% the identification of genetic alterations of pre-B ALL specimens compared that lead to childhood cancers, and the to normal cells. CTGF is a secreted application of this knowledge to the protein with functions in mesenchymal prognosis and improved therapeutic stem cell differentiation, fibrosis and approaches for patients. In order to cancer. Mechanisms of action include examine the genetic lesions present in neo-vascularisation, migration and the various types of cancer, we make proliferation. The role of CTGF in ALL use of whole-genome sequencing is currently unknown. Addition of CTGF technologies and high-throughput drug to two bone marrow stromal cell lines

24 | TELETHON KIDS INSTITUTE enhanced their proliferation rate, while Median survival of control PER-371 cells it had no effect on the proliferation was 67 days, while survival of mice of four pre-B ALL cell lines. Using injected with distinct shPER-371 cells lentiviral technology we modified a was extended to 78 days and 81 days, patient-derived pre-B ALL cell line, respectively (p=0.0002). These in vivo PER-371 to express and secrete high studies demonstrate that modulation levels of CTGF, which did not alter their of CTGF expression levels significantly proliferation rate in vitro. However, influences survival. when xenografted in NOD/SCID This work was supported by NHMRC mice, high CTGF-expressing PER-371 and the Children’s Leukaemia and cells showed accelerated leukaemic Cancer Research Foundation, WA. development. The median survival was 70 days, compared to 89 days (p=0.03) Novel CT domain-encoding splice for mice injected with PER-371 control forms of CTGF/CCN2 are expressed cells that express basal levels of CTGF. in B-lineage acute lymphoblastic We determined whether high gene leukaemia. expression led to distinct cell homing in xenografted mice. Investigators: MD Welch, M Howlett, HM Halse and UR Kees, in collaboration Leukaemic cell infiltration was with WK Greene, Division of Health measured in haemopoietic organs of Science, Murdoch University, Perth. mouse cohorts at three time points during disease development. There Connective tissue growth factor (CTGF/ were no significant differences CCN2) has been shown previously in leukaemic cell infiltration early to be aberrantly expressed in a high in disease, however, high CTGF- proportion of paediatric precursor B expressing PER-371 cells were cell acute lymphoblastic leukaemia significantly increased in the bone (pre-B ALL), suggesting a potential marrow approximately two weeks oncogenic role in this tumour type. before full development of disease We therefore assessed CTGF mRNA compared to control PER-371 xenografts transcript diversity in B-lineage ALL (44% vs 8%; p=0.01). This suggests using primary patient specimens and that high levels of CTGF in these cells cell lines. CTGF mRNA expression was confer a growth advantage within the evaluated by quantitative real-time PCR bone marrow. Using lentiviral shRNA and Northern blotting. Northern blot technology, we recently generated analysis of pre-B ALL cell lines revealed pre-B ALL cell lines with reduced non-canonical CTGF transcripts that levels of secreted CTGF, resulting were expressed in association with in significantly reduced proliferation the active phase of cellular growth. in vitro. Knocking down CTGF in the We performed a structural analysis same PER-371 cell line we observed of CTGF mRNA by nested reverse- corresponding disease outcomes. transcriptase PCR and observed the

ANNUAL REPORT 2014 | 25 synthesis of several novel CTGF mRNA and in fibroblasts, chondrocytes isoforms in B-lineage ALL cell lines and endothelial cells. Our previous that were uniformly characterised by studies showed that CTGF was highly the retention of the coding sequence upregulated in acute lymphoblastic for the C-terminal (CT) domain. One of leukaemia of pre-B type (pre-B ALL). these novel spliceforms was expressed CTGF also plays a role in osteoblast in a majority (70%) of primary pre-B ALL proliferation and differentiation, and patient specimens positive for canonical these cells are known to control CTGF mRNA. These alternative haematopoietic stem cells (HSCs) transcripts appear to have coding via production of factors essential potential because immunoblots using for renewal and maturation. The anti-CTGF antibodies revealed bands balance of HSC self-renewal and of predicted size. This study identifies differentiation is highly regulated by for the first time alternative splicing of intrinsic factors together with cues from the CTGF gene and shows that a short the surrounding microenvironment, CTGF splice variant associated with cell including growth factors. Hence, we proliferation is expressed in most cases hypothesize that CTGF plays a role in of primary CTGF-positive pre-B ALL. haematopoiesis. We studied mice with This novel variant encoding only the targeted disruption of the Ctgf gene. CT domain may play a role in pre-B ALL Using multi-colour flow cytometric tumorigenesis and/or progression. analyses, different lineage populations in various haematopoietic organs from This work was supported by the Cancer Ctgf-/- and wild type (WT) mice were Council of WA and the Children’s enumerated. Because Ctgf-/- mice die Leukaemia and Cancer Research perinatally, the haematopoietic potential Foundation, WA. of cells from Ctgf-/- and WT fetal The role of connective tissue growth livers was compared using a chimera factor (CTGF) in haematopoiesis. transplantation models. Furthermore, mRNA expression of Ctgf was examined Investigators: LC Cheung , M Howlett in the bone marrow compartment. and UR Kees in collaboration with DH Strickland, Division of Cell Biology, and While adult Ctgf+/- mice appeared CH Cole, AK Charles, Princess Margaret to have normal haematopoiesis, Hospital, Perth and WS Alexander, Ctgf-/- newborn mice exhibited Walter and Institute of Medical impaired haematopoiesis. Using Research, Melbourne, and KM Lyons, chimeric transplantation models, we UCLA, Los Angeles, USA. demonstrated that absence of Ctgf had an impact on B-cell development, Connective tissue growth factor in particular from pro-B to more (CTGF) is a member of the CCN mature stages, which was linked to a gene family, whose protein products requirement for Ctgf in bone marrow have critical roles in bone formation, stromal cells (BMSCs). Additionally,

26 | TELETHON KIDS INSTITUTE sorted BMSCs were found to have strongest predictors of outcome. high Ctgf expression, and this was However, patients relapsing with T-cell evident in newborn and adult mice. In ALL (T-ALL) face a dismal outcome. The contrast, Ctgf was barely detectable in aim of this study was to identify new unfractionated adult bone marrow cells markers of drug-resistance and clinical and no Ctgf expression was detected response in T-ALL. We measured in isolated B-cell subpopulations, gene expression and drug sensitivity indicating BMSCs are the major in 15 paediatric T-ALL cell lines to find source of Ctgf in the bone marrow signatures predictive of resistance microenvironment. Using in vitro culture to ten drugs used in therapy. These systems, Ctgf-/- BMSCs led to impaired were used to generate a model for B-cell differentiation from pro-B to more outcome prediction in patient cohorts mature B cells, further demonstrating using microarray data from diagnosis Ctgf is required in BMSCs to maintain specimens. In three independent T-ALL B-cell function. Lastly, CTGF potentiated cohorts the ten-drug model was able B-cell proliferation and promoted to accurately identify patient outcome, pro-B to pre-B differentiation in the indicating that the in vitro derived drug- presence of IL-7. Further investigations gene profiles were clinically relevant. are in progress to elucidate the exact Importantly, predictions of outcome mechanism. within each cohort were linked to distinct drugs, suggesting that different This work was supported by the mechanisms contribute to relapse. Children’s Leukaemia and Cancer Sulphite oxidase (SUOX) expression Research Foundation, WA. and the drug-transporter ABCC1 (MRP1) Pharmacogenomic modelling in were linked to thiopurine sensitivity, vitro reveals the clinical importance suggesting novel pathways for targeting of 6-mercaptopurine therapy for resistance. This study advances our outcome in paediatric leukaemia. understanding of drug resistance in T-ALL and provides new markers for Investigators: AH Beesley, A Samuels, J patient stratification. The results suggest Ford and UR Kees in collaboration with potential benefit from the earlier use D Anderson and MJ Firth, Division of of 6-mercaptopurine in T-ALL therapy Biostatistics and Genetic Epidemiology. or the development of adjuvants that Children with acute lymphoblastic may sensitize blasts to this drug. The leukaemia (ALL) are treated with methodology developed in this study complex chemotherapy regimens of could be applied to other cancers to up to ten different drugs according to achieve patient stratification at the time risk stratification at diagnosis. Around of diagnosis. 80% of patients achieve continuous This work was supported by the complete remission with early response Children’s Leukaemia and Cancer to drug therapy being one of the Research Foundation, WA.

ANNUAL REPORT 2014 | 27 Whole exome sequence and gene- FP is cytotoxic in PER-255 cells with expression analyses of an in vitro 50% inhibitory concentration (IC50) model of T-cell acute lymphoblastic observed of 37.9 nM. The resistant leukaemia drug resistance. clones ranged in IC50 from 72.1-82.8 nM flavopiridol (n=4). Comparison of Investigators: MN Cruickshank, J Ford, FP-resistant and parental exome data AH Beesley and UR Kees. identified 378 SNVs among resistant Detection of chromosomal clones that were undetectable in abnormalities in leukaemia can provide parental T-ALL cells (n=2). Of the prognostic markers used to guide common variants associated with treatment. However, genetic alterations FP-resistance, 40 were predicted to predicting response to chemotherapy cause damaging mutations. These in paediatric T-cell acute lymphoblastic included six novel variants. A total of leukaemia (T-ALL) are poorly defined. 212 predicted damaging variants in We are investigating mechanisms of 181 unique genes were shared in two T-ALL resistance to Flavopiridol (FP), or more FP-resistant clones. Gene an isoflavone compound with cyclin- ontology analyses of shared variants dependent kinase inhibitor activity. suggested enrichment of genes involved in immune responses and We generated FP-resistant T-ALL drug metabolic processes. Differential clones by long-term drug exposure expression analysis identified 143 of PER-255 cells followed by limiting differentially expressed genes following dilution. Exome-sequencing was FP-treatment (adjusted p<0.05; Log2- performed on FP-resistant clones and fold change>1.5) enriched for genes parental T-ALL cells. Burrows-Wheeler encoding catalytic enzymes. Comparing Aligner (BWA) was used for alignment exome-seq data and microarray data, (hg19, GRCh37), PCR duplicates were we found two distinct UGT-family genes removed with SAMTools, and single (UDP-glucuronosyltransferase enzyme nucleotide variants (SNVs) were called encoding genes) associated with FP using a GATK pipeline according to treatment. These genes are involved best practices guidelines. Exonic, in isoflavone metabolism and may non-synonymous SNVs were filtered be involved in FP-response or drug- to identify variants with at least five resistance. identical non-reference genotypes from at least 20 total reads. Gene expression We provide proof of principle for in vitro profiling was performed using the selection and exome-sequencing to Affymetrix Human Gene ST Array on identify sequence alterations associated untreated PER-255 cells and 8 hours with drug-resistance. Our results after FP treatment with five biological identified candidate genetic variants in replicates. T-ALL cells resistant to a CDK-inhibitor currently under trial to treat various cancers, including acute and chronic

28 | TELETHON KIDS INSTITUTE leukaemias and carcinoma. Further development of new strategies to target studies to explore if these variants arise them. in T-ALL or FP-treated patients who Importantly, our research recently develop drug-resistance may reveal the identified that glucocorticoid resistant clinical relevance of genetic alterations leukaemia cells alter their glucose identified in this model system. energy metabolism. We found that This work was supported by the drug-resistance is associated with Children’s Leukaemia and Cancer an increased glycolytic phenotype Research Foundation, WA. and protection from metabolic crisis in T-ALL. Using a unique panel of Modulation of energy metabolism leukaemia cell lines we were able to pathways associated with overcome drug resistance by targeting glucocorticoid resistance in T-cell these unique pathways (Samuels et al., acute lymphoblastic leukaemia 2014, British Journal of Haematology). (T-ALL). Collectively, our findings suggest that dual targeting of bioenergetic pathways Investigators: AL Samuels, J Heng, AH in combination with glucocorticoids may Beesley and UR Kees in collaboration offer a promising therapeutic strategy with KW Carter and RW Francis, Division to overcome drug resistance in ALL. To of Biostatistics and Bioinformatics. further investigate how these metabolic Leukaemia is the most common cause pathways mediate drug resistance of cancer in children. Steady progress we have developed novel profiling has pushed the cure rate in paediatric approaches to identify the proteins and patients to >80% in some subtypes of metabolites specifically deregulated the disease. The outlook, however, for in steroid resistant leukaemia. patients with T-cell acute lymphoblastic Metabolomic and proteomic analysis leukaemia (T-ALL), particularly drug- identified significant alterations in key resistant patients is dismal, with event bioenergetic pathways associated free survival rates <15%. Current with drug resistance. The function treatment regimens are harsh involving of these proteins and pathways is a combination of up to 10 different currently being investigated to identify drugs, which are frequently associated therapeutic approaches to target with both long- and short-term side steroid resistance. These experiments effects. But resistance to agents used in aim to identify novel targeted proteins the initial phase of therapy, particularly that can overcome glucocorticoid steroids (glucocorticoids) is one of resistance, thereby addressing a critical the strongest predictors of adverse unmet need in the clinical management outcome. Improving the outcome of of T-ALL. these patients requires the identification This work was supported by the Cancer of specific molecular mechanisms that Council of WA and the Children’s drive resistance to therapy and the

ANNUAL REPORT 2014 | 29 Leukaemia and Cancer Research developed drug resistant phenotypes Foundation, WA. associated with distinct changes in gene expression, including, changes Targeting drug resistance in paediatric to lipid and carbohydrate metabolism, acute lymphoblastic leukaemia. an observation that led us to focus Investigators: D Anderson, AL on a number of agents that modulate Samuels, AH Beesley and UR Kees in these pathways as a proof-of-concept collaboration with B Yadav and R Lock, approach to overcome resistance in Leukaemia Biology, Children’s Cancer ALL. Institute Australia for Medical Research, We are currently extending this study . to larger numbers of ALL xenografts to Drug resistance continues to be a capture a greater diversity of relapsing significant problem in childhood T-cell profiles. The molecular alterations acute lymphoblastic leukaemia (T-ALL), driving acquired drug resistance yet few novel therapies have emerged will provide important clues for the over the last decades. To identify genes development of new therapeutic and pathways deregulated in drug strategies for the treatment of T-ALL. resistance, as well as small molecule This work was supported by the inhibitors that could synergise with NHMRC, Australia and the Children’s current therapies, we have established Leukaemia and Cancer Research and validated a powerful preclinical in Foundation, WA. vivo model of ALL induction therapy that allows for the investigation of Pharmacological and molecular mechanisms of resistance. Using a analysis of high-risk infant acute clinically relevant four-drug treatment lymphoblastic leukaemia. regimen we have demonstrated that Investigators: MN Cruickshank, J this model accurately recapitulates the Ford, J Heng, RS Kotecha, and UR in vivo development of drug resistance. Kees, in collaboration with CH Cole, This approach identified biological Haematology-Oncology, Princess signatures associated with the Margaret Hospital. development of resistance in vivo and determined, that patterns of resistance The overall cure rate for children with are different amongst tumours derived acute lymphoblastic leukaemia (ALL) from individual patients. In two of the has improved significantly with time, four leukaemia lines tested, no drug and currently exceeds 90%. However, resistance emerged after repeated infants less than one year of age at drug treatment, and this correlates diagnosis remain an exception to this with the clinical course of the patients success. Risk factors predictive of in question since these individuals an inferior outcome for infants with remain in clinical remission. However, ALL (iALL) include the presence of a the two other leukaemia lines mixed lineage leukaemia (MLL) gene

30 | TELETHON KIDS INSTITUTE rearrangement (MLL-r), which occur in and genetic analyses of the cell lines up to 80% of cases, hyperleukocytosis and matched primary leukaemia at presentation, age less than 90 days specimens to characterize molecular at diagnosis and poor response to initial concordance and divergence. Drug prednisone therapy. Contemporary sensitivity was assessed in vitro therapeutic protocols use combinations comprising drugs currently used to of drugs, including steroids, alkaloids treat iALL, FDA-approved cancer drugs and anti-metabolites, administered in and pre-clinical therapeutics targeting dose-intensive schedules. However, features of MLL-r disease, including 5-year event-free survival remains chromatin, NF-κB, cyclin dependent at 16% for infants with MLL-r disease kinase 9 and BCL2 function. We report who are diagnosed before they are a comprehensive molecular comparison 3 months old, highlighting the need of a panel of iALL cell lines with their to identify novel drugs to improve corresponding primary material. Our outcome. high-throughput drug screens identified several classes of drugs with consistent Cell lines established from ALL efficacy, including histone deacetylase patients with MLL-r disease provide inhibitors (HDACi), cyclin dependent an indispensable resource to examine kinase inhibitors (CDKi) and proteasome drug responses. However, in respect inhibitors (PROTi). Moreover, we found to commercially distributed cell lines, that Romidepsin, an FDA-approved there are limited reports that compare HDACi drug, synergises with ARAC their features to those of the matched across this panel of patient-derived primary patient specimens, to verify MLL-r cell lines and also can reduce their utility in pre-clinical studies. We leukaemia burden in a mouse xenograft previously generated two iALL cell model of iALL disease. lines with MLL-r and reported their responses to ten currently used This work was supported by the chemotherapeutic drugs. These Children’s Leukaemia and Cancer two cell lines demonstrated vastly Research Foundation, WA. different responses to drugs such as Dose-dependent effects of histone Cytarabine (ARAC), 6-Mercaptopurine, Dexamethasone, Methylprednisone deacetylase inhibitors on high-risk and L-aspariginase. Identification of infant acute lymphoblastic leukaemia novel drug candidates for iALL therapy cells. therefore requires assessment across Investigators: MN Cruickshank, J Ford, several patient-derived specimens. J Heng, and UR Kees, in collaboration We established additional ALL cell with D Anderson, Division of lines from high-risk infants, diagnosed Biostatistics and Bioinformatics, and CH with MLL-r disease before 90 days Cole, Haematology-Oncology, Princess of age, and performed transcriptome Margaret Hospital.

ANNUAL REPORT 2014 | 31 The survival rate of infants with acute but did not induce changes to histone lymphoblastic leukaemia (iALL) with a acetylation or methylation. High dose translocation at the MLL-locus (MLL-r) Vorinostat treatment was associated is less than 40%. MLL encodes a with accumulation of cells in S-phase histone methyltransferase (H3K4) that and an increased frequency of cells is part of the trithorax complex, an with high levels of H3K27-acetylation evolutionarily conserved developmental and H3K79-trimethylation. Conversely, regulator of chromatin structure. sub-toxic low dose Vorinostat treatment Since this aggressive leukaemia caused a reduction in global H3K27- is an exemplary tumour driven by acetylation and H3K79-trimethylation, epigenomic dysfunction, we have at 24 hours and also after 8-days investigated the effects of drugs treatment. The inhibitor of DOT1L targeting epigenetic processes, such histone H3K79-trimethylation caused as histone regulators. Drug actions a dramatic reduction in both H3K27- were examined by flow cytometry to acetylation and H3K79-trimethylation. measure cell cycle and chromatin state These results reveal contrasting alterations at single-cell resolution. Cells effects of low and high doses of HDAC were harvested, permeabilised and inhibitors on the chromatin state of stained with antibodies against H3S10- iALL cells. Intriguingly, the effects phosphorylation and either H3K27- of low dose Vorinostat treatment acetylation or H3K79-trimethylation. Cell resembled effects of inhibiting the cycle was assessed using propidium H3K79-methylatrasferase, DOT1L. iodide staining. Further studies are required to define We examined chromatin state following the therapeutic implications of these exposure of iALL cells to drugs that findings. function as inhibitors of histone This work was supported by the modifying enzymes. Vorinostat, a pan- Children’s Leukaemia and Cancer histone deacetylase (HDAC) inhibitor, Research Foundation, WA. was assessed at low and high doses (625 nM and 3 M respectively). We Transcriptome and exome analyses also tested effects of an inhibitor of MLL-rearranged infant acute of the DOT1L H3K79-histone lymphoblastic leukaemia identifies methyltransferase (3 M), and Vincristine gene variants involved in DNA repair. (10 mg/ml) - a microtubule inhibitor used as a control cytotoxic compound. Cells Investigators: AM Gout, RS Kotecha, were incubated for 24 hours. Cells J Ford, AH Beesley, RW Francis, treated with the low dose of Vorinostat MN Cruickshank and UR Kees, in (625 nM) or DOT1L inhibitor were also collaboration with T Lassmann, assayed after 8-days treatment. As Computational Biology. expected, Vincristine induced H3S10- Acute lymphoblastic leukaemia (ALL) phosphorylation indicative of mitosis; occurring in the first year of life is rare,

32 | TELETHON KIDS INSTITUTE accounting for 2-5% of paediatric ALL allele frequencies (dbSNP, 1000 cases. Infant ALL (iALL) is distinguished Genomes and HapMap) and presence by unique clinical and biological in the Catalogue of Somatic Mutations characteristics, with an aggressive in Cancer (COSMIC variants). course. The mixed lineage leukaemia We used a conservative “majority rule (MLL) gene, located on chromosome approach” described recently, whereby 11q23, is involved in 80% of cases. candidate non-synonymous variants Currently, 79 different MLL-fusion are prioritized based on overlap of partner genes have been molecularly loss-of-function called by at least four of characterised with t(4;11), t(9;11) and these computational methods. Ingenuity t(11;19) the most frequent translocations Pathway Analysis was performed on in iALL. The survival of patients gene lists associated with predicted diagnosed before they are 90 days old damaging SNVs. This revealed an over- remains poor at only 16%. Given the representation of DNA-repair genes advent of next generation sequencing, harbouring putative damaging SNVs further insight into the biology of the in iALL patient samples compared to disease may identify potential targets controls. Further studies are required for novel therapies and ultimately to determine the role of these SNVs in improve outcome. infant leukaemogenesis. We investigated ten iALL patients This work was supported by the diagnosed with MLL-rearranged ALL, Children’s Leukaemia and Cancer including the common t(4;11) and Research Foundation, WA. t(9;11) rearrangements, and a pair of monozygotic twins with a rare MLL- Analysis of tandem E-box motifs translocation partner gene, t(1;11). We within human complement receptor performed RNA-seq (Illumina, 100bp 2 (CR2/CD21) promoter reveals cell paired end) on the ten leukaemia specific roles for RP58. specimens, and exome-seq for seven matched remission bone marrow Investigators: MN Cruickshank, in biopsies. RNA-seq and exome-seq collaboration with Lawrence J Abraham reads were mapped to reference and Daniela Ulgiati, University of sequences (including genome, splice Western Australia. junction and transcriptome sequences E-boxes serve as binding sites for for RNA-seq data) and variants were E-proteins, including E2A, which play identified using a pipeline utilizing a role in executing B-lineage-specific Genome Analysis ToolKit (GATK) gene expression programs. However, functions. Variants were annotated the mechanisms that restrain E2A using seven functional prediction activity during lymphoid development algorithms, including PolyPhen2, Sift, are poorly defined. We have previously MutationTaster, likelihood ratio test, characterized the basal requirements GERP, PhyloP and CADD, population for transcription of the CR2/CD21

ANNUAL REPORT 2014 | 33 gene and identified tandem E-box leukaemia, raising the possibility elements that are crucial for cell- and that this gene may be involved in B-cell stage-specific expression. Here normal B-cell development and we investigate tandem E-box motifs, leukaemogensis. spaced 22 bp apart and within 70 This work was supported by the bp of the transcription initiation site, Children’s Leukaemia and Cancer revealing a critical role in controlling Research Foundation, WA. CR2/CD21 transcription. These two motifs show opposing function and Focused transcription from the appear only to be active depending human CR2/CD21 core promoter is on the cellular context. Furthermore, regulated by synergistic activity of we have identified E2A transcription TATA and initiator elements in mature factors as binding to one of the E box B cells. motifs using EMSA and ChIP analyses; however, as yet unidentified proteins Investigators: MN Cruickshank, in are also binding these functionally collaboration with Lawrence J Abraham important elements. Utilizing a and Daniela Ulgiati, University of proteomics approach to identify Western Australia. unknown components interacting with Complement receptor 2 (CR2/CD21) E-box site 2 motifs, we successfully is predominantly expressed on the isolated and identified RP58 (encoded surface of mature B-cells where it by RP58/ZNF238/ZBTB18); and forms part of a coreceptor complex reconstituted its binding activity in vitro. that functions, in part, to modulate Further, in vitro transfection studies B-cell receptor signal strength. CR2/ confirmed repression specifically CD21 expression is tightly regulated through the E-box site 2 repressor throughout B-cell development such element. Conversely, CR2-expression that CR2/CD21 cannot be detected in B cells was associated with E2A and on pre-B or terminally differentiated USF binding via E-box sites 1 and 2 plasma cells. CR2/CD21 expression is respectively and localized chromatin upregulated at B-cell maturation and hypersensitivity. Analysis of gene can be induced by IL-4 and CD40 expression compendia in humans signalling pathways. We have previously and mice reveals co-expression of characterized elements in the proximal RP58, E2A and CR2/CD21 in B-cells, promoter and first intron of CR2/CD21 supporting a role for these factors that are involved in regulating basal in controlling B-cell development and tissue-specific expression. We or function. Furthermore, RP58 has now extend these analyses to the CR2/ been defined within a signature gene- CD21 core promoter. We show that in expression profile distinctive of a mature B-cells, CR2/CD21 transcription translocation t(1;19)(q23;p13.3) present proceeds from a focused TSS regulated in paediatric B-cell acute lymphoblastic by a non-consensus TATA box, an

34 | TELETHON KIDS INSTITUTE initiator element and a downstream of cancers and this work thus also promoter element. Furthermore, contributes to our understanding of occupancy of the general transcriptional other diseases. To study this disease machinery in pre-B versus mature we have a rare panel of NMC cell B-cell lines correlate with CR2/CD21 lines grown from patients diagnosed expression level and indicate that at Princess Margaret Hospital and at promoter accessibility must switch from other centres around the world. This inactive to active during the transitional now stands a total of 12 such cell B-cell window. lines – to our knowledge, the most comprehensive collection of NMC This work was supported by the cell lines in the world. To increase Children’s Leukaemia and Cancer our understanding of the oncogenic Research Foundation, WA. mechanism in these NMC cells we have performed next-generation transcriptome and whole-exome Carcinomas sequencing. The NUT Midline Carcinoma Research To look for the expression of gene Program: understanding the biology fusions, we developed an in-house of a fatal disease. program called FusionFinder, designed to detect transcripts containing Investigators: A Stirnweiss, J Oommen, sequences from two different genes. RW Francis, UR Kees and AH Beesley, Analysis of the data from the NMC in collaboration with AK Charles and CH cell line PER-624 identified a novel Cole, Princess Margaret Hospital, Perth. transcript in which Exon 15 of BRD4 NUT midline carcinoma (NMC) is a was fused to Exon 2 of NUT, therefore rare but extremely aggressive cancer differing from all previously published that arises in various tissues along the NMC fusion transcripts. Through these midline of the body (e.g. thymus, thorax studies we now know that there are or abdomen) and can affect people of several other breakpoint positions that any age, including infants. Currently feature in this disease and that each of there is no effective therapy for NMC these gives rise to alternative isoforms and median survival is less than seven of the fusion protein. Thus, there are at months. The hallmark of the disease least six different molecular subtypes of is a rearrangement of DNA that joins NMC and this is likely to have important two genes (called BRD4 and NUT) to implications for patient stratification create a new hybrid gene that initiates and clinical outcomes. For example, and drives the cancer. Resolving how we have data to indicate that the NMC this BRD4-NUT fusion causes cells to subtypes may respond differently to grow out of control is a major aim of currently used chemotherapies. We are our research. Importantly, the BRD4 now mining the sequencing data from gene is now implicated in a wide range these lines to identify their common

ANNUAL REPORT 2014 | 35 GROUP NAME

(and unique) genetic features and in NMC, we have performed a high- understand the signalling pathways throughput drug screen against NMC driving the disease. Such knowledge cell lines in collaboration with the ACRF is an important step towards finding Drug Discovery Centre of Childhood therapeutic targets for a disease that is Cancer (CCIA, Sydney). This involved refractory to current treatments. comparative testing of a chemical library of > 1200 FDA-approved compounds in This work was supported by the NMC vs. non-NMC cell lines. Children’s Leukaemia and Cancer Research Foundation, WA. From this we have identified a shortlist of effective compounds that we are Drug screening in NUT midline now testing in an expanded panel carcinoma: the search for a cure. of NMC cell lines. These represent Investigators: AH Beesley, A Stirnweiss, a number of distinct drug classes J Oommen, UR Kees in collaboration including microtubule inhibitors, with CH Cole, Princess Margaret anthracyclines, topoisomerase Hospital, Perth. inhibitors, antimetabolites, aurora-kinase inhibitors and anti-inflammatory agents, NUT midline carcinoma (NMC) is a rare as well as BET inhibitors and the CDK9 but extremely aggressive cancer for inhibitor flavopiridol. Our data show that which there is no effective therapy; anthracyclines, topoisomerase inhibitors patient survival is less than one year and microtubule poisons are among the from diagnosis. Lack of progress most cytotoxic drug classes for these in the development of treatment cells in vitro, but the efficacy of aurora protocols for NMC is attributable kinase and bromodomain inhibitors both to the voracity of the disease varies considerably between NMC cell and, until recently, difficulties in its lines. The CDK9 inhibitor flavopiridol diagnosis. Clinical protocols have is consistently effective at nanomolar essentially been adapted without concentrations in vitro and inhibits systematic assessment, and so far tumour growth in a subset of NMC with little success, from those used to mouse xenografts. The microtubule treat other solid tumours. The hallmark inhibitor vincristine also inhibits tumour of the disease is a chromosomal growth and increases survival in translocation that disrupts a member of these mouse models, supporting the the bromodomain and extra-terminal continued use of this class of agent to (BET) protein family known as BRD4. treat patients with NMC. Such pre- Inhibitors that target BET proteins clinical drug screening is an essential are currently in clinical trial for NMC step towards finding effective treatment but data from our laboratory indicate strategies for an orphaned disease that these drugs are unlikely to be that is refractory to current therapy effective in all subtypes of the disease. approaches. To identify agents likely to be effective

36 | TELETHON KIDS INSTITUTE This work was supported by the Laurence Cheung, BPharm (Hons), PhD Children’s Leukaemia and Cancer Research Support Research Foundation, WA and the Telethon Adventurers. Stewart Cattach

Staff and Students Theses passed

Head Laurance Cheung, PhD UWA. The role of connective tissue growth factor in Ursula R Kees PhD hematopoiesis. Supervisors: Professor Adjunct Professor University of Western UR Kees, Professor CH Cole, Dr D Australia Strickland and Dr A Charles. Consultant, Department Haematology/ Rishi S Kotecha, PhD UWA. Rare Oncology, Princess Margaret Hospital childhood tumours: Clinical challenges for Children and genetic alterations. Research Staff Supervisors: Professor CH Cole, Professor UR Kees and Dr N Gottardo. Alex Beesley, PhD Jette Ford, BApplSc, Grad Dip Comp Amy Samuels, PhD, BSc (Hons) Awards Meegan Howlett, PhD Ursula Kees, Raelene Endersby, Nick Gottardo, Jason Waithman and others. Alex Gout, PhD Cancer Council WA / BHP Billiton Mark Cruickshank, PhD Infrastructure Grant (2014), $500,000. Anja Stirnweiss, PhD Anja Stirnweiss, Raine Priming Grant (2015-2016): ‘Protein signalling networks Jasmin Heng, BSc (Hons) in NUT Midline Carcinoma (NMC).’ Joyce Oommen (Hons) Alex Beesley, Children’s Leukaemia Laurence Cheung, BPharm (Hons) PhD and Cancer Research Foundation Heloise Halse, BSc (Hons) (CLCRF) Research Fellowship (2013- 2015): ‘Targeting therapy and disease Sajla Singh, BSc, MsC outcomes in NUT Midline Carcinoma’. Postgraduate Students Alex Beesley, CLCRF Project Grant (2014-15): ‘Morpholino therapy for Rishi Kotecha, MB ChB(Hons), MRCPCH, childhood cancer’. PhD candidate Julia Wells, BSc (Hons), PhD candidate

ANNUAL REPORT 2014 | 37 Alex Beesley, CLCRF Project Grant and molecular genetics of leukaemia in (2014-5): ‘Finding the most effective infants. therapies for midline carcinoma’. Mark Cruickshank, Children’s Leukaemia and Cancer Research External Committees Foundation Travel Grant. International Laurence Cheung, Children’s Ursula Kees, Chair COG-B969 Study Leukaemia and Cancer Research Committee (Children’s Oncology Foundation Travel Grant. Group), Arcadia, CA USA. Ursula Kees, The Kids Cancer Project Ursula Kees, Co-investigator COG- (2014): Improving the treatment for AALL10B1 Study Committee (Children’s infants with leukaemia, $100,000. Oncology Group), Arcadia, CA USA.

Ongoing Awards Local Ursula Kees, Alex Beesley, Adrian Ursula Kees, The Cancer Council Charles, NHMRC Project Grant of Western Australia, Research and ID1007586 (2011-2014): Role of Scientific Advisory Committee. connective tissue growth factor in the pathobiology of lymphoid tumours and response to therapy. Invited Presentations Ursula Kees, Richard Lock, Alex Beesley, NHMRC Project Grant Stirnweiss A, Beesley AH, Kees UR et ID1011499 (2011-2015): Targeting al (2014). NUT Midline Carcinoma – The drug-resistance in paediatric acute search for therapy options to improve lymphoblastic leukaemia. the outcome of a fatal disease. EORTC- NCI-AACR Symposium on Molecular Nick Gottardo, Raelene Endersby and Targets and Cancer Therapeutics, Ursula Kees, NHMRC Project Grant Barcelona, Spain. APP1033720 (2012-2014, 3 years) Testing novel therapies using paediatric Beesley AH (2014). NUT Midline brain tumour models. Carcinoma: What is it, and why should you care? iVEC Supercomputing Annual Ursula Kees, Children’s Leukaemia and Symposium, Perth, Western Australia. Cancer Research Foundation (CLCRF): Recognition Award (2012-2017): Beesley AH (2014). NUT Midline Molecular genetics of childhood cancer. Carcinoma - A pre-clinical assessment of therapy options for a fatal disease. Ursula Kees, Children’s Leukaemia and ASMR Scientific Symposium, Perth, Cancer Research Foundation (CLCRF) Western Australia. Research Program (2012-2015): Therapy

38 | TELETHON KIDS INSTITUTE Beesley AH (2014). Researching South Wales, Australia. Childhood Cancer. Rotary-Lions Club Dr G. Arndt, ACRF Drug Discovery South West Bike Trek Fundraiser, Centre for Childhood Cancer, Children’s Pinjarra, WA. Cancer Institute Australia for Medical Kees UR (2014). Pathophysiology Research, Sydney. of CTGF expression in acute Prof C. Cole, Dr M Phillips, Dr T lymphoblastic leukaemia. University Carter and Dr A Charles, Department Medical Center Utrecht, The of Paediatric and Adolescent Netherlands, October 2014. Haematology and Oncology, Princess Margaret Hospital for Children. ACTIVE collaborations Novartis Pharma AG, Basel, Switzerland, NMC Carcinoma Project. Prof M Norris & Prof M Haber. GlaxoSmithKline R&D, Brentford, UK, Experimental Therapeutics Program, NMC Carcinoma Project. Children’s Cancer Institute Australia for Medical Research. Dr Christopher French, Women and Brigham’s Hospital, Boston. Prof R Lock, Leukaemia Biology Program, Children’s Cancer Institute Dr A Murch, Cytogenetics Department, Australia for Medical Research. King Edwards Memorial Hospital, Perth. Dr Richard Lipscombe, Proteomics Dr Bernard Callus, School of Chemistry International, Perth, Australia. and Biochemistry, University of Western Australia, Perth. Metabolomics Australia, University of Western Australia, Perth, Australia. Prof Peter Leedman and Dr Keith Giles, Western Australian Institute of Medical Prof C Mullighan St Jude Children’s Research, Perth. Research Hospital, Memphis TN, USA. Prof Terry Johns, Monash Institute for Prof W Alexander and Dr R Dickins, Medical Research, Melbourne. Walter and Eliza Hall Institute of Medical Research, Melbourne. Pfizer Inc, New York, USA. Prof D Brigstock, Children’s Research Professor Steve Wilton, Foundation Institute, Columbus OH, USA. Chair in Molecular Therapies, Centre for Comparative Genomics, Murdoch Dr M Garnett, Cancer Genome Project, University. Wellcome Trust Sanger Institute, Hinxton, UK. Dr James Bradner, Dana-Farber Cancer Institute, Harvard Medical School, Dr Antoinette Anazado & Dr Kristy Boston USA. McCarthy, Kids Cancer Centre, Sydney Children’s Hospital, Randwick, New Dr Ester Falconer, Terry Fox Laboratory, BC Cancer Research Centre, Vancouver

ANNUAL REPORT 2014 | 39 BC, Canada. rates and quality of life for patients. Prof Ryan Lister, University of Western Team BT leaders Nick Gottardo and Australia, Perth, WA. Raelene Endersby both began their independent research careers at Dr Alistair Forrest, Ricken, Facility the Telethon Kids Institute following Director / Unit Leader - LSA mentored training programs at St Bioinformatics Core Facility, Yokohama Jude Children’s Research Hospital Institute, Japan. (link) in the USA. In recent years, we have established a strong national and international reputation and Brain Tumour Research are recognised as being the largest Program research team in Australia primarily focussed on paediatric brain tumours. Cancer is a battle too many children The major goals of our group are and teenagers face every day. It is the intensely focussed on improving the leading cause of death by disease well-being of children with cancer. With among Australian children from birth strong ties between Princess Margaret to age 15. The Brain Tumour research Hostpial (PMH) (link) and Telethon program is a group of dedicated Kids, leaders Nick & Raelene are researchers striving to improve cure acutely aware of what it takes to get a rates for young people affected by new treatment into the clinic and our brain tumours. To ensure our research research goals are sharply focussed is grounded in clinical practice we have on providing the preclinical evidence forged strong partnerships between required to form the basis of new laboratory researchers and paediatric clinical trials. oncologists, pathologists, surgeons, imaging specialists and radiation The skills of our team members are oncologists. These clinicians share diverse and include laboratory scientists their observations from the clinic with from academia and industry, clinical laboratory colleagues and researchers oncologists and neuro-surgeons. plan their research direction with Each member of the team brings their patients in mind. unique and varied experience to tackle our research questions. Moreover, Brain tumours are the most common we collaborate with others who bring paediatric solid cancer, affecting valuable expertise. These include, but 200 children in Australia each year. are not limited to, radiologists (clinical The BTRP, also known as Team and mouse models), medical physicists BT, is a collaborative group of (cell and animal imaging), chemists researchers dedicated to improving (drug screening), pharmacologists our understanding of paediatric brain (preclinical testing in mouse models) tumour biology and finding more and bioinformaticists (large scale effective treatments to improve survival

40 | TELETHON KIDS INSTITUTE analyses of brain tumour genomics). genotyping of a larger cohort of human ependymoma specimens (n=230) Development of a mouse ependymoma revealed frequent focal deletions in the model. tumour suppressor gene PTEN. Array Investigators: R Endersby, M Ancliffe, H comparative genomic hybridisation Hii and NG Gottardo. analysis of mouse ependymomas Ependymoma is the third most common demonstrated numerous large brain tumour affecting children and chromosomal copy number alterations remains incurable in 40% of patients. (CAN) as well as focal CAN, common As is often the case with paediatric to all tumours, which included the brain tumours, survivors are frequently Pten locus. Thus, to more faithfully left with devastating long-term neuro- recapitulate the human disease, we are cognitive sequelae. There is an modifying the existing ependymoma urgent need for more effective and mouse model by additionally deleting safer therapies. Transgenic mouse Pten. The development of such a model tumour models are important tools to will be an important tool to enhance facilitate the study of tumour initiation our understanding of the biology of and progression and are invaluable this disease and facilitate pre-clinical for pre-clinical studies. A genome- studies of novel targeted therapies. wide analysis of human ependymoma This work is supported by the John Lillie specimens demonstrated that all Cancer Research Fellowship (RE and cerebral ependymomas exhibited NGG). activated NOTCH signaling and INK4A/ARF deletion and that radial Characterisation of a Novel Fabp7- glia (RG) were the putative cell of CrePR Mouse. origin of ependymoma. Based on Investigators: M Ancliffe, H Hii, NG these observations we generated the Gottardo, R Endersby first mouse model of ependymoma, which phenocopies the human Ependymomas are the third most disease precisely by over-expressing common brain cancer in children. NOTCH1 in RG cells using the Blbp Attempts to determine optimum promoter and concurrent deletion of therapies of ependymoma have been Ink4a/Arf. However, the penetrance hindered by the low incidence of of ependymoma formation was low disease and a poor understanding of (1 to 5%) with a long latency (6 to 18 the disease’s biological characteristics months), suggesting that additional and lack of in vivo and in vitro models. genetic mutations are required for A Fabp7-CrePR mouse is being used ependymoma formation, making the to generate a spontaneous mouse current model unsuitable for pre-clinical model for paediatric ependymoma. testing. A more extensive genomic This model mimics human disease by analysis using high resolution SNP alterations in commonly mutated genes

ANNUAL REPORT 2014 | 41 Notch1, Pten, and Cdkn2a. Genetic characterisation is required for this events are controlled by an inducible study Cre/loxP system (CrePR), which is This work is supported by the NHMRC, activated by a synthetic steroid RU486. Telethon Adventurers, Australian This occurs specifically in radial glia Postgraduate Award (MA), and Raine (Fabp7), the candidate stem cell for Clinician Research Fellowship (NGG). ependymoma. Repurposing approved drugs to treat This is the first report of temporal and spatial regulation of Cre activity in childhood brain cancer. Fabp7-CrePR mice. Therefore, the Investigators: TD Schoep, R Endersby, characterisation of this inducible system JP McGlade, PB Dallas, NG Gottardo. is necessary to determine if CrePR is being activated by RU486 in radial glia. Brain tumours are the second most To characterise Fabp7-crePR mice, common cancer in children and are a reporter Rosa26-LSL-LacZ mouse the major cause of childhood cancer was bred with Fabp7-crePR knock- related mortality. This highlights the fact in mice to generate offspring where that although survival for children with transcription of β-galactosidase does brain tumours has improved over the not occur until activation of CrePR using last 30 years, survival rates for the past a synthetic steroid RU486. Cre activity decade have reached a plateau well was induced at postnatal day 0 (P0) and below that of other childhood cancers, 7 (P7). Brain tissue from mice was then such as leukaemia. Moreover, children assessed for Beta-galactosidase using that do survive brain tumours suffer histochemisty and immunofluorescence debilitating long-term side effects, which for Cre mediated recombination. significantly impact on their quality of life. After surgery, residual tumour is Beta-Galactosidase staining was treated with a combination of intensive observed in cells of the radial glia chemotherapy and whole brain and lineage including astrocytes, Bergman spine radiation. However, this approach glia and neural progenitor cells. The is devastating to children under three expression and activity of CrePR in years of age as the radiation kills these mice was found to be higher normal brain cells as well as tumour at postnatal day 0 than postnatal cells, which has a major impact on day 7, which is consistent with subsequent brain development. For the known patterns of expression this reason, children under three years of the endogenous Fabp7 gene. old are not treated with radiotherapy. Histochemistry assays were possibly However, chemotherapy alone is rarely underestimating the amount of effective and the tumours in most Cre-mediated recombination when of these patients grow back. There compared to immunofluorescence is therefore a clear need for novel staining. Therefore further therapies that increase survival rates.

42 | TELETHON KIDS INSTITUTE We are identifying drugs that when the best molecules proceed to clinical combined with conventional brain trial in the shortest amount of time. tumour therapies improve the outcomes This work is in part supported by the for the most common childhood brain NHMRC, John Lillie Fellowship (RE cancer, medulloblastoma (MB), and the and NGG), Raine Clinician Research rarer, but highly lethal brain cancer, Fellowship (NGG), Elliot Parish Research pineoblastoma (PB). To achieve this, Fellowship and Telethon Adventurers. we are performing a high-throughput screen (HTS) using state of the art New and effective combination robotic technology, of thousands of therapies identified in a mouse model compounds including existing FDA- of paediatric medulloblastoma. approved drugs, other pharmaceuticals and known bioactive compounds Investigators: R Endersby, JP with the aim of repurposing drugs for Whitehouse, M Kuchibhotla, T Schoep, the treatment of these cancers. The H Hii and NG Gottardo. advantage of repurposing existing Background:Medulloblastoma is a drugs is that the pharmacokinetic metastatic paediatric brain tumour profiles and toxicities have been arising in the cerebellum. It is classified extensively characterised, promoting into four major subgroups based rapid translation into the clinic. on clinical and molecular profiles The efficacy of compounds will be and current standard of care is to evaluated alone and in combination treat patients similarly regardless of with currently used conventional classification. The clinical interventions chemotherapeutics in vitro to identify of surgery, chemo- and radiotherapy optimal combinations. Their activity can result in cures buts come at a price will then be validated in vivo using not obvious by the reported survival sophisticated animal models of MB statistics due to the collateral damage and PB established in our laboratory to of healthy tissue by these treatments, closely mimic the disease in children. As which negatively impact patient quality part of an international drug discovery of life. network, in addition to our HTS Objective:Identify new effective approach for drug discovery we are therapeutic approaches for also validating promising therapeutics medulloblastoma patients. identified at our drug discovery partner institution, St Jude Children’s Research Results:Using high-throughput, cell- Hospital, in our unique animal models based assays human medulloblastoma of MB and PB. Our dual approach of cells (n=6) were screened against repurposing existing, FDA approved a library of approximately 3200 drugs for the treatment of childhood compounds, including US FDA- brain cancer, and validating new drugs approved drugs. Fifty effective discovered internationally ensures that compounds were identified and

ANNUAL REPORT 2014 | 43 further in vitro assessment identified Investigators: B Patterson, JP several drugs that enhanced the Whitehouse, TD Schoep, NG Gottardo, cytotoxic activity of the clinically-used R Endersby therapeutic: cyclophosphamide (CPA). Pineoblastoma is an invasive paediatric A checkpoint kinase inhibitor (CHKi), brain tumour of the pineal gland. was further assessed in vivo using Only 50% of patients will survive with mice bearing cortical implants of current treatments which include human medulloblastoma cells. When surgery, radiotherapy and intensive combined, CPA and CHKi reduced chemotherapy. However, survivors tumour burden as measured by IVIS can suffer from long-term detrimental imaging and significantly increased side effects. Our laboratory performed survival of tumour-bearing animals. a high-throughput drug screen on Immunohistochemical assessment of paediatric pineoblastoma cell lines tumours the combination treatment to identify potential new treatments, significantly decreased the percentage which identified several inhibitors of of proliferating (Ki67-postive) cells the phosphatidylinositol 3-kinase (PI3K) compared to control or CPA-treated pathway as effective. Dysregulation of tumours. The combination treatment the PI3K pathway has been identified also significantly induced apoptosis in many human cancers including (measured by cleaved caspase 3 the brain tumours medulloblastoma, positivity) compared with controls. ependymoma and glioblastoma. Conclusion:These data demonstrate The aim of this study was to evaluate our experimental approach has robustly the effect of BKM120 on PI3K pathway identified effective new therapies activity in, and proliferation of, for paediatric medulloblastoma, and pineoblastoma cells, and whether our findings strongly suggest that the BKM120 may enhance the anti-cancer combination of CPA with CHKi may action of current chemotherapeutics. be a promising new treatment for this disease. The effect of BKM120 on PI3K pathway activity in three pineoblastoma cell lines This work is supported by the NHMRC, (PER-452S, PER-452A, and PER-453) a Telethon-Perth New Children’s was determined using immunoblotting. Hospital Research Grant, the Telethon Dose-response assays were performed Adventurers, Raine Clinician Research to determine the sensitivity of these Fellowship (NGG) and the Telethon Kids cells to BKM120, or the conventional Institute. chemotherapeutics cisplatin, The PI3-kinase inhibitor BKM-120 cyclophosphamide, and vincristine enhances the anti-cancer effects using alamar blue assays. Drug- of vincristine in in vitro paediatric interaction assays were performed pineoblastoma models. to examine the effect of combining BKM120 with these conventional

44 | TELETHON KIDS INSTITUTE chemotherapeutics. Investigators: Aya Anaout, JP Whitehouse, H Hii, T Schoep, NG BKM120 resulted in a dose-dependent Gottardo, and R Endersby. reduction of AKT phosphorylation in pineoblastoma cells indicating One in five childhood cancers arise pathway inhibition. Furthermore, within the central nervous system. proliferation was blocked in all three Primitive neuroectodermal tumours lines at concentrations comparable (PNETs) including medulloblastoma and to conventional drugs. Combination pineoblastoma are the most common assays with mathematical modelling malignant brain tumours of childhood revealed that BKM120 did not and survival rates are low compared interfere with the anti-cancer effects of to other paediatric cancers such as cisplatin and cyclophosphamide, but leukaemia. Current treatment protocols reduced the effect of vincristine when often fail and can leave children with administered simultaneously. devastating long term side effects, consequently there is a clear need for BKM120 effectively inhibited the PI3K novel treatments for PNET. pathway and blocked pineoblastoma proliferation. Interaction assays Several high-throughput screens have suggested that BKM120 does not been performed recently to identify new enhance the action of current drugs that might be effective against chemotherapeutics when administered PNET. One of these drugs was MK-2206 simultaneously. This study reveals that that targets the phosphatidylinositol- drug screening and assessment of 3-kinase (PI3K) pathway, a ubiquitous novel compounds in pineoblastoma and evolutionarily conserved signalling cells can identify therapies with a lack cascade influencing numerous cellular of efficacy, avoiding lengthy and costly functions and frequently deregulated in-vivo experiments. Assessment of in human cancer. This drug targets the other compounds identified in the effector AKT. AKT isoform expression high-throughput screen using a similar and the effects of MK-2206 on pathway pipeline will expedite the discovery activity in three pineoblastoma cell lines of a favorable drug-interaction, which were evaluated using immunoblotting, will hopefully lead to improved patient which confirmed the drug inhibited outcomes of pineoblastoma patients. the three AKT isoforms present in human cells. MK-2206 was also This work is supported by a Telethon- effective at inhibiting pineoblastoma Perth New Children’s Hospital Research cell proliferation as measured by Grant, the Cancer Council of WA (BP), alamar blue assay. Moreover, the ability Raine Clinician Research Fellowship of MK-2206 to modulate the anti- (NGG) and the Telethon Adventurers. cancer activity of several conventional Testing Novel Treatments for chemotherapeutics used in PNET Primitive Neuroectodermal Tumours. treatment, such as cisplatin and

ANNUAL REPORT 2014 | 45 vincristine, was assessed using drug Investigators: S Rogers, S Lee, NG interaction assays and biostatistical Gottardo, and R Endersby calculations. These studies revealed Background: Biopsy is performed MK-2206 synergises with cisplatin to kill clinically to conclusively diagnose pineoblastoma cells in vitro. a cancer and elucidate the severity In addition, the combination of of disease. It is often used to tailor pemetrexed (a folate antimetabolite) treatment to known vulnerabilities in and gemcitabine (a DNA poison) was the tumour, such as cancer-specific also recently identified as a potential “targeted” agents. Like human new treatment for PNET using in tumours, spontaneous cancers in vitro high-throughput screening. genetically modified mice carry a range This combination is a promising new of potentially targetable secondary treatment for non-small cell lung cancer. mutations. Biopsy would greatly To evaluate the activity of this drug enhance the utility of mouse models for combination in PNET, immunodeficient preclinical studies using molecularly- mice were orthotopically implanted targeted therapies. with human medulloblastoma cells. Objectives: Develop a novel method of Bioluminescence was used to monitor serial biopsy in mice, assess morbidity xenograft growth and treatment associated with the technique and administered once tumours were well determine the quality and utility of established. Outcome was assessed tissue samples obtained. using immunohistochemistry, which revealed increased apoptosis in drug- Results: To determine the feasibility of treated tumours compared to controls. brain biopsy, we utilised an intracranial implant model of glioblastoma, driven These studies demonstrate that high- by activation of EGFR. We previously throughput drug screening and in vitro showed that EGFR can be inhibited assessment of novel drugs in paediatric in brain tumours using the pan-ERBB brain tumour cells can identify inhibitor dacomitinib and that inhibition potential new therapies for PNET and prolongs animal survival. We developed assessment of new drug combinations a micro-dissection technique that using preclinical models will inform retained structural and molecular which new treatments validate features of the brain tumour. We were translation into novel clinical trials for able to able to successfully detect childhood brain cancer. active EGFR in the biopsy sample and This work was supported by the measure the intratumoural response Telethon Adventurers. following systemic administration of dacomitinib. Neurological impairment A novel technique of serial surgical of animals following the procedure was biopsy in a mouse brain tumour minimal and reversible. model. Conclusions: Serial brain biopsies in

46 | TELETHON KIDS INSTITUTE mouse models are possible with little resistance to anti-cancer therapies. impairment. Tissue samples can be cFLIP has been shown to be down obtained reliably and retain enough regulated by the compound CDDO, and histological features for reliable its derivatives CDDO-Imidazolmide and assessment of tumour histology and CDDO-methyl. This study proposes that molecular pathology. Analysis of tumour the CDDO-based compounds inhibit samples could identify the presence of proliferation of medulloblastoma cell drug-targetable alterations in murine lines, and that these drugs are additive cancers and serial biopsy can monitor with conventional chemotherapies. the magnitude and duration of response To assess the effect of CDDO on to treatment in a single animal. three human medulloblastoma cell This work is supported by the Ethan lines the assay conditions for cellular Davies Scholarship for Brain Cancer proliferation were optimized. We Research, the Telethon Adventurers and confirmed that three medulloblastoma Raine Medical Research Foundation cell lines produced cFLIP and were (NGG). sensitive to CDDO based compounds at effective doses between 0.27 and Combination of novel drugs with 1.05 µM. It was also observed that at conventional chemotherapies for the concentrations below 0.22 µM these treatment of medulloblastoma. drugs stimulated cellular growth. The Investigators: K Smith, T Schoep, P combined effect of each CDDO based Dallas, R Endersby, NG Gottardo. compound with the conventional chemotherapies used to treat Medulloblastoma is a malignant medulloblastoma, cisplatin, vincristine, embryonal brain tumour, and is the most cyclophosphamide, was assessed in significant cause of paediatric cancer cell line based drug interaction assays. mortality. A plateau in survival rates Using three different algorithms for the for children with medulloblastoma has analysis of drug interaction: the Chou- been reached and novel therapies are Talalay, BLISS independence and, urgently needed to improve cure rates Loewe additivity method, it was shown and minimize the treatment related that all combinations of the CDDO- side effects. Gene expression profiling based molecules and the standard of human medulloblastoma primary chemotherapeutics were antagonistic. samples revealed the over-expression of a gene known as cellular FAS-like As a result, results from this study IL-1β-converting enzyme-inhibitory suggest that the CDDO and the protein (cFLIP) that normally functions derivatives CDDO-Imidazolmide and to prevent apoptosis by inhibiting the CDDO-Methyl, are not suitable for activation of caspase 8. This protein is preclinical evaluation in animal models also over-expressed in other cancers of medulloblastoma in combination with and is thought to be involved in either of the standard chemotherapies.

ANNUAL REPORT 2014 | 47 This work is supported by the NHMRC, model (glioblastoma). This pilot grant Princess Margaret Hospital Foundation will enable CI Whitehouse to extend Translational Research Grant, Raine this model to medulloblastoma. This Clinician Research Fellowship (NGG), study will provide for the first time and the Telethon Adventurers. a direct test of whether previously identified candidate genes are Oncogenic transformation of human involved in causing the development of neural stem cells. medulloblastoma. In addition, this study Investigators: JP Whitehouse, R will generate unique mouse models Endersby, C George, PB Dallas and NG and identify potential new targets for Gottardo. therapy. Medulloblastoma is a malignant brain This work is supported by the tumour that is the most common cause Brain Foundation, and the Telethon of cancer-related death in children. Adventurers Recent studies have described Molecular genetics of novel at least four distinct subgroups of paediatric brain tumour models. medulloblastoma based on their genetic characteristics. However, Investigator: R Endersby, M Kuchibhotla, while specific genes have been H Hii, S Lee, N Gottardo associated with the development and Brain tumours are the leading cause progression of medulloblastoma, a of death among paediatric neoplasms. direct causal relationship has yet to The commonest malignant brain be established. Furthermore, the cell tumours of infancy and childhood are type(s) from which this cancer arises medulloblastoma (MB), pineoblastoma has yet to be identified. Evidence from (PB) and ependymoma (ED). Despite animal models of medulloblastoma recent therapeutic advances, the suggest that neural stem cells are a tumours in many patients relapse and good candidate for investigating the are incurable. Moreover, survivors cellular origin of this disease. The aim often have significant treatment- of this pilot study is to transform normal related sequelae. To develop more human neural stem cells into cancer- effective therapies, identifying and causing cells by altering the expression understanding the genetic events of five specific genes implicated in that drive these tumours is critical, as medulloblastoma. is deducing factors that contribute to These cancerous cells will then be therapeutic resistance. implanted into the brains of mice and MB, ED and possibly PB, are each we will examine their potential to comprised of multiple subgroups form medulloblastoma tumours. This defined primarily by gene expression methodology has been successfully profiling. Additionally, a number of achieved in another brain tumour recent high-profile publications have

48 | TELETHON KIDS INSTITUTE further dissected the genetic complexity This work is supported by the Telethon of MB using whole-genome (WGS) or Kids institutional small grants scheme whole-exome sequencing (WES). These and The Telethon Adventures. data provide important new insights into Investigating the role of DACH1 the pathogenesis of MB and highlight targets for therapeutic development. and miR-200b in Group 4 However, whilst many targeted anti- medulloblastoma pathogenesis. cancer agents have recently been Investigators: C George, J Bearfoot, and developed, evaluation of their efficacy PB Dallas. is delayed due to a lack of model systems that accurately reflect the Medulloblastoma is the most common various subtypes of these diseases in malignant childhood brain tumour, and children. the most significant cause of childhood cancer-related mortality. Four core To address this, we have generated a molecular sub-groups exist, with distinct panel of unique cell lines representative features and responses to treatment. of various primary and relapsed The current clinical management of paediatric brain tumours. Furthermore, patients does not account for this to more closely resemble their natural molecular variation, and many patients microenvironment, we have established may receive sub-optimal treatment. mouse models for these diseases by To address this, targeted therapies orthotopic transplant providing a unique for each molecular sub-group would resource in the preclinical analysis be ideal. Unfortunately, for the more of novel therapies. However, the aggressive Group 3 and Group 4 sub- preclinical utility of these new models groups, the underlying mechanisms requires full characterization of their of pathogenesis remain poorly underlying genetic alterations such understood. The current challenge is that molecularly targeted therapies to identify the key tumour suppressors are assessed in the most appropriate or oncogenes involved in Group 3 systems. and Group 4 pathogenesis, which may Our study aim is to identify mutations ultimately lead to the development of across the coding regions of several new therapeutic targets. Transcriptional new models of paediatric brain tumours profiling studies of medulloblastoma using whole-exome capture and deep have identified numerous genes sequencing. With our models and the commonly affected in other cancers, results of this study we will be poised to which may also contribute to study critical questions about malignant medulloblastoma pathogenesis. brain tumour biology and be better One potential candidate is Dachshund able to test novel therapies in the most Homolog 1 (DACH1), which has up- appropriate context. regulated expression across all medulloblastoma sub-groups, relative

ANNUAL REPORT 2014 | 49 to normal cerebellum. Oncogenic target Smoothened (SMO), which is over-expression of DACH1 has been a component of the sonic hedgehog demonstrated in both ovarian and (SHH) pathway, have shown great colorectal cancers, and is associated promise for the treatment of MB. with cancer progression and However, there are drawbacks with invasiveness, but has not previously these new SMO targeting drugs, been linked to medulloblastoma particularly associated with the pathogenesis. MicroRNAs (miRNAs) development of resistance. Phylomers have been implicated in the initiation are a unique type of peptide-based and progression of many cancers and drug developed by the drug discovery may mediate the abnormal expression company Phylogica, which may be of DACH1 in medulloblastoma. Analysis particularly suitable for avoiding the of the DACH1 3’UTR using TargetScan drug resistance problem, and may revealed potential binding sites for open new avenues for effective MB nine individual/clusters of miRNAs. One therapeutics that have yet to be putative miRNA is miR-200b, belonging exploited. In addition, Phylomers to the highly conserved microRNA-200 that are effective for the treatment of family (miR-200). We identified an MB may also be effective for other association between high levels of types of cancer, including basal cell DACH1 expression and low level of carcinomas, the majority of which are miR-200b and further assessed the associated with altered SHH pathway regulation of DACH1 by this miRNA in activity. Preliminary data suggest that medulloblastoma cell lines. several Phylomers we have identified are capable of blocking SHH pathway This work was supported by the activity in vitro. If the inhibitory activity of Telethon Adventurers (PD) and Cancer these Phylomers can be recapitulated in Council of Western Australia (CG). vivo, Phylomers may ultimately provide Novel peptide based drugs for a new treatment option for MB patients. the treatment of sonic hedgehog This research is supported by the dependent medulloblastoma. Telethon Adventurers. Investigators: PB Dallas, TD Schoep, R Endersby, NG Gottardo, in collaboration with N Milech, B Longville, P Watt, R Hopkins, Drug Discovery Group, Telethon Kids Institute. Medulloblastoma (MB) is the most common malignant brain tumour in children, and a leading cause of paediatric cancer related mortality and morbidity. Recently, drugs that

50 | TELETHON KIDS INSTITUTE Staff and students Aya Arnaout (BSc), Honours thesis, Murdoch University. Testing Novel Co-heads Treatments for Primitive

Raelene Endersby, PhD Neuroectodermal Tumours. Nick Gottardo, MB ChB FRACP PhD Supervisor: Dr Raelene Endersby Research Staff Brett Patterson (BSc), Honours thesis, University of WA. The PI3K inhibitor, Peter Dallas, PhD NVP-BKM120, does not interact Tobias Schoep, PhD synergistically with cisplatin, 4-HPC or vincristine in in vitro paediatric Jacqueline Whitehouse, PhD pineoblastoma models. Hilary Hii, BSc Hons Supervisors: Dr Raelene Endersby, Dr Mani Kuchibhotla, BSc MSc Jacqueline Whitehouse, Dr Fiona Pixley Postgraduate Students Courtney George (BSc), Honours thesis, Edith Cowan University. Mathew Ancliffe, BSc, PhD candidate Investigating the role of DACH1 and Sasha Rogers, BSc(Hons) MBBS miR-200b in Group 4 medulloblastoma MRCS(ed), MPhil student pathogenesis. Aya Arnaout, BSc, Honours student Supervisors: Dr Peter Dallas, Dr Mel Ziman Kathyln Smith, BSc, Honours student Kathyln Smith, (BSc), Honours thesis, Brett Patterson, BSc, Honours student Murdoch University. Targeting Apoptotic Courtney George, BSc, Honours Pathways in Medulloblastoma. student Supervisors: Dr Tobias Schoep, Dr Peter Other Students Dallas, Dr Garth Maker

Brooke Strowger, Murdoch University Awards Theses passed Ursula Kees, Raelene Endersby, Nick Gottardo, Jason Waithman and others. Rishi S Kotecha, PhD UWA. Rare Cancer Council WA / BHP Billiton childhood tumours: Clinical challenges Infrastructure Grant (2014), $500,000. and genetic alterations. Nicholas Gottardo, Raelene Endersby, Supervisors: Professor CH Cole, Anang Shelat, Telethon-Perth Children’s Professor UR Kees and Dr N Gottardo. Hospital Research Fund (2014-2016), $198,344.

ANNUAL REPORT 2014 | 51 GROUP NAME

Ongoing Awards Raelene Endersby, national conference organising committee, Nick Gottardo and Raelene Endersby, Science Pathways: Effective science John Lillie Cancer Research Fellowship communication for EMCRs. April 2015. (2011-2014, 3 years). Adelaide, Australia. Nicholas Gottardo, Raine Clinician Raelene Endersby, national conference Research Fellowship (2013 – 2015). organising committee, EMBL Australia Nick Gottardo, Raelene Endersby and PhD Program. June 2015. Perth, Ursula Kees, NHMRC Project Grant Australia. APP1033720 (2012-2014, 3 years) Testing novel therapies using paediatric brain tumour models. Local Nicholas Gottardo, Member of WA Health Department Rare Diseases External Committees Strategy Advisory Group.

International Raelene Endersby, Australian Cancer Research Foundation Cancer Imaging Nicholas Gottardo, international Facility, Management Committee. conference convenor, Global Symposium on Childhood Brain Tumours. February 11-14, 2013. Bunker Bay, Australia. Invited Presentations Nicholas Gottardo. Study Chair for Raelene Endersby (June 2014) the upcoming COG Average Risk High-throughput drug screening for Medulloblastoma front-line clinical trial. childhood brain tumours: translating hits into the clinic. The Children’s Hospital at Westmead, Kids Research Institute. National Sydney, Australia. Nicholas Gottardo. Co-chair on currently Raelene Endersby (July 2014) High- open paediatric phase I/II clinical trial throughput drug screening for conducted through the ACCT entitled: childhood brain tumours: translating hits A Phase I/II Study of Valproate in into the clinic. Peter MacCallum Cancer Combination with Interferon alpha in Centre. Melbourne, Australia. Relapsed, Recurrent or Progressive Raelene Endersby (November 2014) Neuroblastoma. Understanding childhood brain cancer Nicholas Gottardo. Executive Councillor and finding new ways to improve on the Australian and New Zealand patient outcomes. Curtin University. Children’s Haematology/Oncology Bentley, Australia. Group Executive (2012-present). Nick Gottardo (January 2014) Update

52 | TELETHON KIDS INSTITUTE on the upcoming Children’s Oncology Research Hospital, USA. Group’s (COG) frontline average Dr Suzanne Baker, St Jude Children’s risk medulloblastoma clinical trial Research Hospital, USA. Medulloblastoma In the Mountains, St Moritz, Switzerland. Dr Charles Eberhart, Johns Hopkins Medicine, USA. Nick Gottardo (May 2014) Clinical trials in the Children’s Oncology Group - the Dr Anang Shelat, St Jude Children’s past and the future Perth Cancer Club, Research Hospital, USA. Perth, Australia. Dr Christa Nath, Children’s Hospital at Nick Gottardo (June 2014) Summary talk Westmead, NSW, Australia. for PNET and Rare Tumours Session. International Symposium Paediatric Neuro-Oncology (ISPNO), Singapore. Nick Gottardo (June 2014) Paediatric Oncology, from Bench to Bed. Cure Brain Cancer Foundation International Scientific Meeting, Sydney, Australia. Nick Gottardo (October 2014) Princess Margaret Hospital and Telethon Kids Institute Annual Research Symposium, Perth.

ACTIVE collaborations

Brain Cancer Discovery Collaborative (BCDC). Members: Prof Terrance Johns (MIMR-PHI Institute of Medical Research, VIC), Prof Andrew Boyd (QIMR Berghofer Medical Research Institute, QLD), Dr Kerrie McDonald (Lowy Cancer Research Centre, NSW), Dr Nicholas Gottardo (Telethon Kids Institute, WA), Associate Prof Stephen Rose (CSIRO, QLD), Associate Prof Geraldine O’Neill (Children’s Hospital at Westmead, NSW). International Medulloblastoma Working Group (50 members). Prof Amar Gajjar, St Jude Children’s

ANNUAL REPORT 2014 | 53 CYSTIC FIBROSIS

Imagine a world where you often have EARLY SURVEILLANCE to miss school, playing sport and fun times with friends because your lungs PROGRAM (ESP) don’t work properly. You have to spend The ESP is the platform upon which the hours each day having treatments and AREST CF research program is based. getting a cold could potentially mean Children attending CF clinics in Perth having to be admitted to hospital. and Melbourne participate in the ESP This is what life can be like if you are from the time of diagnosis onwards. The child with cystic fibrosis (CF). CF is the ESP includes bronchoalveolar lavage most common chronic, life-shortening (BAL, to assess airway inflammation, genetic condition affecting Australians. infection and other markers of disease), Approximately 1 in 25 people carry a imaging (CT scan, to measure structural CF-causing gene, resulting in around lung disease) and lung function 1 in 2000 babies being born with measurements. Researchers are able the disease. CF affects many body to track the progress of lung disease systems, but is most devastating in the through a comprehensive longitudinal lungs, reducing a child’s quality of life, set of biological samples, images and eventually leading to premature and data archives. The ESP is now death. AREST CF is a collaborative embedded in standard clinical practice group of over 30 doctors, allied in both Australian centres, and is in the health professionals and researchers process of being adopted by centres in dedicated to improving the respiratory the Netherlands and Switzerland. Since health of children with CF by translating 2012, Professor Stick and A/Prof Sarath scientific research into tangible clinical Ranganathan (VIC) were supported outcomes. The WA arm of the Australian by a US Cystic Fibrosis Foundation Respiratory Early Surveillance Team Therapeutics grant to maintain and for Cystic Fibrosis (AREST CF) is based expand this precious resource. at the Telethon Institute and is led by Professor Stephen Stick. Research by Funded by: NHMRC, US Cystic Fibrosis our group and others has shown that Foundation Therapeutics infants and children with CF exhibit EARLY DISEASE reduced lung function and evidence of inflammation and infection at a very MECHANISMS early age. This highlights the need for A better understanding of the significant new treatments that can be given from contributing factors to the establishment time of diagnosis to prevent and/or and progression of CF lung disease reverse the damage. will enable researchers to identify key targets for new treatments. Our research into early disease mechanisms combines data and samples from the ESP with cutting edge technologies for

54 | TELETHON KIDS INSTITUTE measuring airway biology and infection. in clinical trials of new therapeutics. New research projects initiated since In 2013, in a landmark paper, we 2012 include investigations into mucus, published the first data demonstrating hypoxia and the respiratory microbiome that a biomarker measured at 3 months in progressive CF lung disease with can predict structural lung disease the University of North Carolina, USA outcomes at 1 and 4 years of age. We and the role of bioactive lipids in have also developed the first outcome resolution of inflammation and tissue measure (a quantitative CT method) remodelling with Erasmus Medical to accurately reflect early structural Centre, Netherlands. Many factors disease in CF that can pave the way to contribute to exaggerated inflammatory regulatory studies of new therapies in responses observed in the CF lung; we young children with CF. A/Prof Graham have observed dysfunctional immune Hall’s paediatric Respiratory Physiology responses to common viruses and team is a key element of this research, using systems biology approaches, we and partnering with A/Prof Sarath are identifying responses to viruses Ranganathan (Vic) and Professor Harm and bacteria that are pro-inflammatory Tiddens (Erasmus MC, Netherlands) the and modifiable with existing and novel team has been successful in obtaining agents. Our data confirm that these funding from various sources since are present soon after diagnosis, 2012 to investigate different aspects associated with disease progression of lung structure/function and disease and present a range of therapeutic progression. targets. Funded by: NHMRC, NIH, UWA, Lung Funded by: NHMRC, NIH Institute of WA, US Cystic Fibrosis Foundation Therapeutics PREDICTORS AND ENDPOINTS DEVELOPING AND TRIALING NEW The premise that underpins this research area is the identification of TREATMENTS AND early predictors of adverse pulmonary INTERVENTIONS outcomes in children with CF. This will allow treatments to be targeted at those A new research area for the group who will benefit the most. Development is the development of a stem cell of objective novel, safe and potentially program aimed at producing respiratory more informative methods will allow epithelial cells. These cells could be clinicians to identify progressive lung used to test candidate therapeutic disease earlier and prevent or delay compounds as well as a therapy to the onset of abnormal lung structure replace defective epithelial cells in and function. These methods can then CF patients. This program is being led be incorporated as outcome measures by Dr Anthony Kicic, in partnership

ANNUAL REPORT 2014 | 55 with researchers from UWA, Monash Staff and Students University and WEHI. HEAD OF GROUP Funded by: NHMRC, US Cystic Fibrosis Therapeutics Professor Stephen Stick PSYCHOSOCIAL EFFECTS Research Strategy Leader, Telethon OF EARLY INTERVENTIONS Kids Institute Senior Principal Investigator, Telethon Little is known about the psychological, Kids Institute social and economic effects on families of children undergoing early Professor, School of Paediatrics and interventions for CF. Examination of the Child Health, risks, burdens and benefits for families University of Western Australia will inform improved future strategies Head, Department of Respiratory for appropriate clinical and pastoral Medicine, care. Translation of this research will also impact on content and delivery Princess Margaret Hospital of education, nature of support NHMRC Practitioner Fellow services offered and development of relationships between families and providers, improving service delivery CHIEF INVESTIGATORS and potentially health outcomes for children with CF. Collection of Professor Nicholas de Klerk qualitative and quantitative data from (Biostatistics) parents and care-givers of children Professor Graham Hall (Paediatric participating in the ESP commenced Respiratory Physiology) in 2012 at Princess Margaret Hospital. Our psychosocial data have begun to Dr André Schultz, (CF Centre Director, identify significant impacts on children Princess Margaret Hospital) with CF and their families. These data provide important, unique opportunities to assess child and family psycho- RESEARCH STAFF social distress, quality of life, anxiety A/Prof Anthony Kicic – Research Officer, on academic achievement and other Associate Principal Investigator outcome measures and to develop effective interventions. Dr Ingrid Laing – Research Officer, Associate Principal Investigator Funded by: NHMRC, WA Department of Health Dr Barry Clements – Paediatric Respiratory Physician, Department of Respiratory Medicine

56 | TELETHON KIDS INSTITUTE Mr Andrew Chong – Program Manager Mr Kevin Looi - PhD candidate Mr Marc Padros-Goossens - Data Manager THESES PASSED Dr Lidija Turkovic – Biostatistician Lauren Mott – PhD Dr Kathryn Ramsey - Research Officer, Paediatric Respiratory Medicine Dr Shannon Simpson - Research Officer, AWARDS Paediatric Respiratory Medicine Dr Erika Sutanto - Research Officer Kathryn Ramsey Ms Kak Ming Ling – Research Assistant North American Cystic Fibrosis Conference Young Investigator Award Mr Luke Berry – Research Assistant Dr Louisa Alessandri Memorial Fund Dr Elizabeth Starcevich – Research Prize for Scientific Publication Officer/study coordinator 2014 AJRCCM publication editorialised Ms Georgia Banton – Research Assistant, Paediatric Respiratory Luke Garratt Medicine TSANZ Ann Woolcock Young Ms Anneli Robbshaw – Clinical Trials Investigator Award Coordinator Poster Prize - Child and Adolescent Ms Lucy McCahon – Clinical Trials Health Research Symposium Coordinator Tim Rosenow Ms Annemarie Naylor – Project Officer TSANZ CF SIG Prize Ms Nicole Shaw - Research Assistant Vertex Cystic Fibrosis Research Award Ms Kelly Martinovich - Research Lauren Mott Assistant UWA Most Cited Articles Ms Pari Tackle - Research Assistant

EXTERNAL COMMITTEES POSTGRADUATE STUDENTS International Mr Tim Rosenow – PhD candidate Steve Stick Mr Luke Garratt – PhD candidate Scientific Board - Sophia Foundation, Ms Cindy Branch-Smith – PhD Rotterdam candidate Graham Hall Mr Thomas Iosifidis - PhD candidate

ANNUAL REPORT 2014 | 57 ERS College of Experts Ireland. Symposium Early CF Lung Disease. TSANZ Adelaide. National Symposium Imaging and Structural Steve Stick Lung Disease. North American CF Grant Review Panel – NHMRC Conference Atlanta, USA. Graham Hall Local Laying the foundations in childhood for Nick de Klerk healthy or disease adult lungs. Joint New Zealand TSANZ and ANZSRS Clinical Drug Trial Committee, Sir annual meeting. Charles Gairdner Hospital Tim Rosenow / Conor Murray Western Australian Mesothelioma Register Committee What’s around the corner in chest CT. CHESTRAD Melbourne 2014. Busselton Population Medical Research Institute Inc, Board Cindy Branch-Smith Busselton Population Medical Research Arresting’ psychological issues for Institute Inc, Research Committee better health outcomes in parents of infants and young children with cystic Director, Western Australian Twin fibrosis. European Cystic Fibrosis Register Conference Psychosocial Special Expert Reference Group, Australian Interest Group. Twin Registry Western Australian Medical Radiation and Cancer Working Party ACTIVE research Data Safety Monitoring Committee Collaborations - RCT Intragastric Balloon in Obese NATIONAL Adolescents A/Prof Sarath Ranganathan – Murdoch Patron, Perth and Districts Multiple Birth Children’s Research Institute Association Dr Phil Robinson – Royal Children’s Hospital, Melbourne INVITED PRESENTATIONS Professor Peter Sly – Queensland Children’s Medical Research Institute Steve Stick Professor Ed Stanley – Monash Plenary Early Cystic Fibrosis Lung University Disease. Irish Thoracic Society Dublin,

58 | TELETHON KIDS INSTITUTE Dr Ian Street – Walter and Eliza Hall funding Institute Cystic Fibrosis Australia - CF community Professor Linda Shields – James Cook engagement, funding University Dr Lynn Priddis – Curtin University Translation Dr Yuben Moodley - UWA The COMBAT CF clinical trial, the first interventional trial for prevention of lung INTERNATIONAL disease in infants, is ongoing. This is a Professor Richard Boucher multi-centre study to test the efficacy of azithromycin for the primary prevention Dr Charles Esther of bronchiectasis in children with CF. Dr Marianne Muhlebach Recruitment on the study is ongoing, with more than half of the target 130 Professor Mike Knowles – University of subjects recruited from sites in Australia North Carolina and New Zealand. Our goal is to Professor Bob Hancock – University of eventually ensure that a clinical trial is British Columbia available to every child born with CF. Professor Harm Tiddens – Erasmus University Medical Centre, Rotterdam Bob Scholte - Erasmus MC, Rotterdam Professor Marcus Mall - University of Heidelberg ACTIVE collaborations with industry

Ataluren – USA Boehringer-Ingelheim Parion – USA Vertex – USA ACTIVE involvement with the community

Type of involvement, organisation, state or country Cystic Fibrosis WA – CF community engagement and research update,

ANNUAL REPORT 2014 | 59 DIABETES AND OBESITY

Overview (methods paper), microvascular function in and the management The team conducts research in of obesity. The group has also recently collaboration with the Department been recognised for its work with the of Endocrinology and Diabetes in award of the jointly funded NHMRC/ Princess Margaret Hospital for Children JDRF Centre of Research Excellence. Perth, the School of Sports Science and Exercise Health, Psychology, University of Western Australia; the Western Australian Institute for Type 1 Diabetes Medical Research, the Juvenile Clinical Prof TW Jones Diabetes Research Foundation and collaborators from diabetes research Associate Clinical Prof EA Davis centres interstate and overseas. Our primary research is in the field of Type 1 diabetes. We are also increasingly EPIDEMIOLOGY involved in research into childhood onset Type 2 diabetes and obesity Epidemiology of childhood diabetes with the aim of improving the lives of in Western Australia children and adolescents affected by these conditions. Our research Investigators: Liz Davis, Aveni Haynes, addresses relevant clinical questions Matt Cooper, Carol Bower, Tim Jones and encompasses epidemiology, Funding Source: Department of clinical investigations, clinical trials, new Endocrinology & Diabetes, PMH technology in disease management and The objectives of this study are: prevention studies. • To study the epidemiology of In the year 2014, type 1 diabetes childhood diabetes in Western research has seen the advancement in Australia from 1985 onwards a series of clinical trials with the ultimate aim of implementing the closed- • To look for differences in incidence loop system to improve glycaemic rates by year of diagnosis, age of management in Type 1 diabetes using diagnosis, sex, month of diagnosis, pump therapy. birth month and place of residence at diagnosis. The Group has published papers in the areas of exercise and type 1 diabetes, • To identify modifiable risk factors psychological impact of hypoglycaemia that may be contributing to the in type 1 diabetes, pump therapy in type increasing number of children 1 diabetes, sensor augmented pump being diagnosed with diabetes therapy in type 1 diabetes, mortality • To characterise the clinical course risk in type 1 diabetes, environmental of diabetes in this population-based determinants of type 1 diabetes cohort of childhood diabetes and

60 | TELETHON KIDS INSTITUTE the development of complications is reported that over the past decade of diabetes the overall incidence of severe hypoglycemic events has declined • To analyse the effects of changes relative to the previous decade. In this in treatment regimens and clinical study we investigate the demographic, management strategies on the lifestyle and diabetes management rates of complications of diabetes factors associated with the incidence • To periodically evaluate the of severe hypoglycemia to provide completeness of ascertainment of clinicians and diabetes educators with the Western Australian Children’s knowledge our which patients may be Diabetes Database at higher risk of severe hypoglycemia. These aims will be achieved by analysis The aims of this study are: of data from the Western Australian • Report the incidence of severe Children’s Diabetes Database, together hypoglycemia over the past decade with data linkage to other core data in the WA childhood T1D onset resources in the Western Australian cohort Data Linkage Unit. The study population will be all children diagnosed with • Calculate the relative risk for childhood diabetes under the age of the association of demographic, 15 years, who were resident in Western lifestyle and management factors Australia at the time of diagnosis. The (including but not limited to age, study period is from January 1985 to the length of diagnosis, BMI, insulin most recent years available. There are regime) with the incidence of over 1500 cases in the diabetes register severe hypoglycemia. at Princess Margaret Hospital that meet Investigating mortality rates and the these inclusion criteria. incidence and risk factors of diabetes complications and co-morbidities Epidemiology of hypoglycaemia in during early adult life in a population childhood-onset diabetes in Western based childhood onset diabetes Australia cohort

Investigators: Tim Jones, Liz Davis, Matt Investigators: Liz Davis, Matt Cooper, Cooper Aveni Haynes, Tim Jones Funding Source: Internal Funds Funding Source: Diabetes Research Fund Hypoglycemia and the subsequent effects of hypoglycemia remain the The education and treatment regimes primary fear for children and their for children with Type 1 Diabetes parents in adequately managing the (T1D) are constantly evolving, and the treatment of Type 1 Diabetes (T1D). It introduction of and improvements to new technologies adds to the

ANNUAL REPORT 2014 | 61 complexity of the management of age and sex matched controls) T1D. Studies have been done in for incidence of diabetes the past to provide insight into the complications and co-morbidities complications and co-morbidities in in early adulthood (<40 years) adulthood for this with childhood onset associated with childhood onset type 1 diabetes, but little is known T1D in a population-based cohort. about how the changes to diabetes • To compare the all-cause mortality management affect the incidence of rate, and cause of death in these complications and co-morbidities, early adulthood (<40 years) in a as this is something that can only childhood onset T1D population- be revealed with time. This project based cohort to general population will use the Western Australian Data age and sex matched controls. Linkage System (WADLS) to provide novel information of the incidence and • To examine the impact of risk relative risk of T1D co-morbidities and factors observed during childhood mortality during early adulthood in a on the incidence of diabetes modern clinical setting. The primary complications, co-morbidities and source of the study population is the cause of death in early adulthood Western Australian Children’s Diabetes (<40 years) in a childhood onset Database. The WADLS contains data T1D population-based cohort. uploaded from the Hospital Morbidity TrialNet: Pathway to Prevention Data Collection; the Emergency Department Data Collection; the Mental Local Investigators: Tim Jones, Liz Davis Health Information System; the Birth, Study Staff: Julie Dart, Heather Roby; Death and Marriages Registry and the Adam Retterath; Western Australia Electoral Commission records. The WADLS will enable the Funding Source: The National Institute selection of matched controls from of Diabetes and Digestive and Kidney the birth registry. All subjects in WA Diseases (NIDDK), the National Institute diagnosed with T1D prior to age 16 who of Allergy and Infectious Diseases were 18 years or older at 30th June (NIAID), the National Institute of Child 2010 (n=1,376) are considered eligible Health and Human Development for entry into this analysis. (NICHD), the National Center for Research Resources (NCRR), the The aims of this study are: Juvenile Diabetes Research Foundation • To identify the incidence of International (JDRF), and the American diabetes complications and co- Diabetes Association (ADA) morbidities seen in early adulthood The overall objective of this multi- (<40 years) in a childhood onset centre international study is to perform T1D population-based cohort. baseline and repeat assessments over • To calculate the risk (relative to time of the metabolic and immunologic

62 | TELETHON KIDS INSTITUTE status of individuals at risk for type 1 about immunologic and metabolic diabetes (T1D). This is in order to:(a) factors related to the pathogenesis characterize their risk for developing of T1D and validate new methods or T1D and identify subjects eligible tests that mark disease progression or for prevention trials, (b) describe the response to therapy. pathogenic evolution of T1D, and (c) 8. To accrue additional information increase the understanding of the about genomic markers associated with pathogenic factors involved in the risk for the development of T1D. development of T1D. 9. For those participants who The specific objectives of this study are: participated in the DPT-1 study, to 1. To determine the risk for the examine associations of characteristics occurrence of T1D according to glucose (e.g. demographics, immunologic, tolerance tests, C-peptide levels, islet metabolic, etc.) assessed during the autoantibodies, HbA1c levels, markers DPT-1 study with characteristics and of cell-mediated immunity, and genetic outcomes assessed in TrialNet. markers associated with T1D. The primary outcome of this 2. To examine the accuracy of TrialNet prospective cohort study is the measures in predicting future T1D. development of diabetes as defined by the American Diabetes Association 3. To characterize the progression (ADA) based on glucose testing, or the of immunologic abnormalities in the presence of symptoms and unequivocal development of T1D by serially studying hyperglycaemia. islet autoantibodies and immune mechanistic studies. Participant eligibility: (1) Having a first degree relative (parent, sibling, child) 4. To characterize the progression with T1D, and aged 1 – 45 years; (2) of metabolic decompensation in the having a second and third degree development of T1D by serially studying relative (nieces, nephews, aunts, uncles, insulin, C-peptide, other islet hormones, grandparent, cousins, half-siblings) with HbA1c and glucose levels, and to T1D and aged 1 – 20 years. identify immunologic and other factors associated with this decompensation. Early environmental determinants 5. To determine the incidence of severe of pancreatic islet : a acute metabolic decompensation as the pregnancy to early life cohort study initial clinical presentation in individuals in children at risk of type 1 diabetes who have been identified as being at (T1D) increased risk for T1D. Local Investigators: Tim Jones, Liz Davis 6. To identify individuals who qualify for Study Staff: Wayne Soon, Alexandra TrialNet T1D prevention trials. Tully 7. To accrue additional information

ANNUAL REPORT 2014 | 63 Funding Source: NHMRC 1025082 Local Investigators: Liz Davis; This is a multi-centre study involving Study Staff: Megan Evans researchers in South Australia, Funding Source: Pfizer APEC Research , New South Wales, Western Grant Australia and Queensland. The study is coordinated by Prof Jenny Couper in This dual-site study is investigating the South Australia. effect of fat and protein content of a standardized carbohydrate meal, on This prospective cohort follows children the post-prandial glycaemic response who are at risk of developing T1D from in children with type 1 diabetes who the gestational period into the first 3 are on multiple daily injections or years of life. Pregnant women who have insulin pump therapy. The study design type 1 diabetes or where their unborn is a randomised 4 armed cross-over child has a first degree relative with trial, where the glycaemic fluctuations T1D are recruited to the study. The in the 180min following the meal infants are monitored for genotype, is traced using a continuous sub- weight gain, insulin sensitivity, changes cutaneous glucose monitoring system. in the metabolome and microbiome, investigating the vitamin D and omega 3 fatty acid status, and the timing and frequency of viral 58 children between the two infections. This is in order to determine participating sites having the following the relationship between weight gain, inclusion criteria, will be recruited: insulin sensitivity, nutritional status and aged- 7-18 years inclusive; on 4 or more viral infection, and the development of insulin injections per day, or on insulin persistent islet autoimmunity in these pump therapy; diagnosed with type 1 children. diabetes, at least over 6 months ago; with HbA1c ≤ 8.0% at last clinic visit. The primary outcome measure is islet Exclusion criteria are: ; autoimmunity defined as persistent Hyperlipidaemia; history of poor elevation of > 1 islet autoantibodies on compliance or attendance; Unable to consecutive 6 monthly tests, including commit to full study protocol. the most recent. This will exclude transient, low titre autoantibodies. Low glucose suspend study

Investigators: Tim Jones MANAGEMENT Study Staff: Jennifer Nicholas, Adam Retterath How do high protein and/or high fat Funding Source: Juvenile Diabetes meals affect postprandial glycaemic Research Foundation control in children using intensive insulin therapy? A new pump has just been released, the Paradigm Veo pump. This pump

64 | TELETHON KIDS INSTITUTE has the new feature of detecting low Adam Retterath, Heather Roby; Ray glucose levels (hypoglycaemia) and Davey; automatically switching off insulin Funding Source: Internal infusion for 2 hours if the blood glucose level is low. This will be helpful in Current recommendations for reducing the severity of an episode of carbohydrate supplementation hypoglycaemia. to prevent exercise-induced hypoglycaemia in individuals with type 1 The aim of this study is to see if using diabetes (T1D) do not take into account the Paradigm Veo pump for a period of blood glucose levels during exercise. 6months can reduce the rate of severe Our objective was to investigate the hypoglycaemia, particularly for patients effect of blood glucose levels on who have lost some of the symptoms carbohydrate requirements to maintain that would normally alert them to a low stable glycaemia during exercise in blood glucose level. In a subgroup individuals with T1D at basal insulin of 16 adolescents, we will also look at levels and to determine the underlying their hormone and symptom responses glucoregulatory mechanisms. during hypoglycaemia. We subjected eight healthy Patients aged between 4 years and individuals with T1D to a euglycaemic 50 years with T1D on insulin pump clamp, whereby euglycaemia was therapy with impaired awareness maintained by infusing insulin at basal of hypoglycaemia will be eligible to rates with concomitant infusion of participate. deuterated glucose for determining Patients will be randomised to either glucose kinetics. Participants were the Paradigm Veo (low glucose then randomized to undergo either suspend feature and continuous euglycaemic or hyperglycaemic clamp, glucose monitoring) or continue on following which they performed 40 their standard pump (no low glucose minutes of exercise at 50% VO2peak, suspend capability and no continuous on 2 separate days using a randomised glucose monitoring). counterbalanced study design. The glucose levels maintained during Effect of blood glucose levels on euglycaemic and hyperglycaemic the amount of glucose needed to clamp was 4.5-6.0 and 9.5-10.5mmol/L maintain stable blood glucose levels respectively. The glucose infusion during and after moderate intensity rate (GIR), levels of glucoregulatory exercise in young people with type 1 hormones and rates of glucose diabetes. appearance (Ra) and disappearance (Rd) were compared between Investigators: Vinutha Shetty, Paul conditions. Fournier, Tim Jones, Liz Davis Effect of exercise intensity on the rate Study Staff: Nirubasini Paramalingam,

ANNUAL REPORT 2014 | 65 of glucose administration required intensity and how this relationship to maintain stable glycaemia when responds to confounding factors such plasma insulin is at basal levels in as prevailing insulin and glucose levels. individuals with type 1 diabetes This study will involve ten healthy, mellitus active type 1 diabetic individuals (male and female) aged between 13 and 25 Investigators: Vinutha Shetty, Paul years old. All participants will undergo Fournier, Tim Jones, Liz Davis four testing sessions involving cycling on a stationary bike at four different Study Staff: Nirubasini Paramalingam, workloads – 35%, 50%, 65% and 80% Adam Retterath, Heather Roby; Ray VO2 peak. Davey; Kaitie McNamara Primary outcome: Calculation of the Funding Source: Pfizer APEC Research glucose requirements to maintain stable Grant; PMH Foundation Grant glucose levels during and after exercise Regular exercise provides a number over a range of exercise intensities of well documented health benefits under basal insulin conditions. for individuals with type 1 diabetes. Secondary outcome: Determining the Unfortunately for individuals with type extent to which changes in glucose 1 diabetes, particularly those in good requirements result from changes in glycaemic control, exercise increases glucose production and utilisation rates. the risk of severe hypoglycaemia. This increased risk of hypoglycaemia Effect of antecedent hypoglycaemia occurs not only while exercising, but on the hyperglycaemic effect of a also for several hours during recovery. short 10-second sprint in type 1 One approach to reduce the risk diabetes of hypoglycaemia associated with exercise is to reduce insulin dose Investigators: Paul Fournier, Ray Davey; before exercise. Another is to consume Tim Jones, Liz Davis extra carbohydrates during and/after Study Staff: Nirubasini Paramalingam, exercise, but the current guidelines Heather Roby for treatment of hypoglycaemia do not provide practical information about the Funding Source: NHMRC amount of CHO necessary to prevent To investigate whether experiencing hypoglycaemia during exercise. a low blood glucose event prior to a This proposed study aims to determine 10-second sprint reduces the capacity more precisely the amount of glucose of the sprint to increase blood glucose intake that is required to prevent levels in people with type 1 diabetes. hypoglycaemia during exercise; under Individuals with type 1 diabetes aged basal insulin conditions. In addition, between 15 and 25 years will be we will investigate how glucose recruited from the general population requirements are affected by exercise and from the population of individuals

66 | TELETHON KIDS INSTITUTE regularly attending diabetes clinics Davey at Princess Margaret Hospital. All Funding Source: NHMRC participants must be free of any complications associated with type 1 The aims of this are (1) To determine diabetes. if hyperglycaemia prior to and during exercise, affects the amount of glucose All participants will be asked to visit our necessary to maintain stable blood laboratory on four separate occasions. glucose levels (BGL) during moderate On two of these visits, the participants intensity exercise, will be fitted with glucose and activity monitors to record data in the lead (2) To determine if hyperglycaemia prior up to the study days. Each of the two to and during exercise, affects specific study days will follow these preliminary hormonal responses during and after data collection periods. On these visits, moderate intensity exercise. glucose and insulin will be infused to The hypothesis is that under basal control the participants’ blood glucose insulin conditions, the amount of levels. On one occasion, their blood intravenous glucose required to glucose will be lowered and kept at maintain stable BGL during moderate- a low level for 90 minutes before it intensity exercise is increased during is returned to normal levels. On the hyperglycaemia compared with other occasion, their blood glucose euglycaemia. will be kept at normal levels during this 90-minute period and afterwards. All participants, with T1DM, aged Following each treatment, the between 13 and 25 years old (n=10), participants will perform a 10-second HbA1c < 9.5% and diagnosis of diabetes sprint on an exercise bike. The >1yr, will have two testing sessions and participants will then rest for 2 hours an initial session to determine their and their blood will be taken at regular maximum exercise capacity. Testing intervals to monitor their blood glucose sessions begin at 8am, and participants levels and to measure hormone levels. arrive having fasted overnight. A cannula is inserted in the back of one The effect of hyperglycaemia on hand for blood sampling, and the elbow the rate of glucose administration for infusion of insulin and glucose. In required to maintain stable glycaemia one session participants are asked during moderate intensity exercise to exercise at 50% of their VO2peak in individuals with type 1 diabetes (moderate intensity exercise) after mellitus a stabilisation period during which their BGL is maintained between 4.5 Investigators: Vinutha Shetty; Paul to 5.5mmol/L (euglycaemia). In the Fournier, Tim Jones, Liz Davis alternate condition participants are Study Staff: Adam Retterath; Nirubasini asked to exercise at 50% of their Paramalingam, Heather Roby; Ray VO2peak (moderate intensity exercise)

ANNUAL REPORT 2014 | 67 after a stabilisation period which Study Staff: Nirubasini Paramalingam, includes a period where their BGL is Heather Roby maintained between 8.5 - 9.5mmol/L Funding Source: NHMRC (hyperglycaemia). Their BGLs are maintained at these specified levels during exercise To determine if performing a 10-second (euglycaemia or hyperglycaemia) by sprint in the morning lessens the infusing 20%(w/v) dextrose solution. release of hormones to afternoon Urine will also be collected throughout hypoglycaemia. these testing session in order to Both male and female participants measure any glucose spill over, and with type 1 diabetes, aged between 13 this result will be used to track how and 30 years old will be recruited to the body uses the glucose infused. this study. They will be in reasonable The amount of glucose oxidised to good control of their diabetes and during exercise is determined by the they will be aware of the symptoms of rate of oxygen consumption and CO2 hypoglycaemia. production obtained by analysing samples of expired air collected All participants will have two testing from the subjects before, during and sessions and two pre-testing visits. after exercise, at regular intervals Three days prior to each testing using indirect calorimetry. Finally, session, the participants will briefly visit since all these processes are under the laboratory to have a glucose sensor tight hormonal regulation, blood will and accelerometer fitted. These devices be sampled at timed intervals for will measure their glucose levels and hormone assay. Participants will be activity levels for 3 days before each provided a late lunch before leaving the study. Testing sessions will begin at laboratory, and will carry carbohydrates 8am and the participants will arrive for hypoglycaemia treatment on the having fasted overnight. Two drips will way home. They will also be asked to be inserted; one to sample blood and closely monitor their blood glucose the other to infuse glucose and insulin. levels for a day following the testing Blood glucose levels will be kept at session. 5.5 mmol/L by varying the infusion rates of insulin. When blood glucose The effect of a 10-second sprint on levels are stable, the participants will the counterregulatory responses perform either a 10-second sprint or to a subsequent episode of rest. Then, approximately 4 hours later, hypoglycaemia in males and females the participants will have their blood with type 1 diabetes mellitus. glucose level lowered over 30 minutes to 2.8 mmol/L by adjusting the infusion Investigators: Ray Davey; Paul Fournier, rate of glucose; at a higher rate of Tim Jones, Liz Davis insulin. This blood glucose level will

68 | TELETHON KIDS INSTITUTE be maintained for a further 40 minutes basal insulin delivery for a pre- before it will be increased to 5.5 mmol/L determined period if patients do not once more. At certain times before and respond to alarms. Whilst this is a major after the sprint (or rest) and before and step forward, the capacity to suspend during the lowering of blood glucose insulin delivery when impending levels, blood samples will be collected hypoglycaemia is predicted offers the to measure blood glucose, insulin additional advantage of reducing the and key hormones that are released actual time spent hypoglycaemic. If in response to hypoglycaemia. After effective and safe this system is likely to this, the participants will have the drips reduce the burden of diabetes care as removed and will be provided with well as allow more intensive attempts to lunch before they leave the laboratory. improve glycaemic control. At least 2 weeks later, the participants This study will aim to test a novel will return to the laboratory to perform algorithm for hypoglycemia prediction, the alternate condition such that all under conditions of excess insulin participants perform both the morning and moderate intensity exercise, to sprint and the morning rest before they determine if the response of insulin undergo afternoon hypoglycaemia on suspension to these different conditions both occasions. which predispose hypoglycaemia differs. Crucial to the effectiveness of a preventive system and the prevention TECHNOLOGICAL of post suspend hyperglycemia will be a ADVANCES complimentary algorithm that activates the resumption of insulin delivery. Predictive low glucose suspend study By studying post suspend glucose – Stage2 values under controlled conditions we will generate such data. In addition, Local Investigators: Liz Davis; Tim although previous studies have utilized Jones; Mary Abraham increased basal insulin delivery as a Study Staff: Ray Davey; Jennifer method of inducing hypoglycaemia, in Nicholas; Nirubasini Paramalingam; our study we will utilize increased bolus Adam Retterath; Julie Dart; insulin delivery-the scenario more likely to be encountered in a real-life setting. Funding Source: JDRF Study participants will be: adolescents The availability of continuous glucose and young adults age from 12 to 26 monitoring systems is an important years with type 1 diabetes; duration of advancement in the pursuit of a fully diabetes > 1 year and on treatment with automated closed-loop system. An an insulin pump; HbA1c < 8.5% initial stage in the development of such a system has been the availability of The aims of this study are: (1) a system that automatically suspends To determine the blood glucose

ANNUAL REPORT 2014 | 69 profile with a predictive low glucose how much insulin to give by a special suspend (PLGS) algorithm versus no mathematical formula. The Blackberry insulin suspension (control) following receives a signal from the sensors and hypoglycemia induced by a bolus of then tells the pump how much insulin to subcutaneous insulin; (2)To determine give. the blood glucose profile with a PLGS At night, the PCGS will do everything for algorithm versus no insulin suspension the patient. During the day, it will only (control) following hypoglycemia work if the blood glucoses are very high induced by moderate intensity or very low. The patient still continues exercise; (3) To determine the blood to operate the pump as they normally glucose profile with a predictive low would. We will also compare how well glucose management (PLGM) algorithm the system works with a night in hospital versus no insulin suspension (control) when the patient would manage their following hypoglycaemia induced by diabetes as they do at home. an increased basal insulin infusion overnight; There are 3 parts to this study and there will be 8 patients recruited to each part. (4) To analyse the pattern of blood Patients may take part if they have type glucose and ketone levels following 1 diabetes, be aged between 12-50 pump suspension in these scenarios, years and be on insulin pump therapy. and use these to assist with determination of parameters for insulin For the first part, we want to see how pump resumption. well the system manages patients going about their normal routine (Part 1). We Closed Loop Study – Treat To Range will then go on to test how well the Local Investigators: Martin de Bock; Tim system manages high blood glucose Jones; Liz Davis; levels when a dose of insulin is missed (Part 2). Study Staff: Julie Dart; Adam Retterath; Jennifer Nicholas Part 1 and part 2 are complete and have presented at international meetings in Funding Source: NHMRC 2014. The aim of this study is to see if the Overnight glucose control with Portable Glucose Control System an Android-based Automated (PGCS), a portable artificial pancreas, is Ambulatory Glycemic Controller safe and accurate in managing blood glucose levels for a patient with type 1 (AAGC) in patients with type 1 diabetes during the day and night. The diabetes PGCS consists of 2 glucose sensors Local Investigators: Martin de Bock; Tim that sit under the skin, an insulin pump Jones; Liz Davis; that delivers insulin and a BlackBerry phone. The Blackberry works out Study Staff: Julie Dart; Adam Retterath;

70 | TELETHON KIDS INSTITUTE Funding Source: NHMRC Overnight glucose control with hybrid The aim of this study is to see if the closed loop system in patients with Automated Ambulatory Glucose type 1 diabetes Controller (AAGC), a portable artificial Local Investigators: Martin de Bock; Tim pancreas, is safe and reduces the time Jones; Liz Davis; (Colaboration with St spent with low blood glucose levels in Vincents hospital in Melbourne) patients with type 1 diabetes at night in the patient’s home environment. The Study Staff: Julie Dart; Carolyn Berthold; AAGC consists of a glucose sensor Funding Source: NHMRC that sits under the skin, an insulin pump that delivers insulin and an Android- The aim of this study is to see if the based smartphone that contains the Medtronic hybrid closed loop system, AAGC controller software. The AAGC a portable artificial pancreas can be works out how much insulin to give by safely used in the home. The system a special formula. The AAGC receives consists of a glucose sensor that a signal from the sensors and then tells sits under the skin, an insulin pump the pump how much insulin to give. that delivers insulin and an Android- The maximum amount of insulin that based smartphone that contain the would be given per hour would not be maths program to calculate the insulin any greater than the pre-programmed needed. Patients will use the closed rates that patients are already giving loop system at home, after they have themselves. spent one night in the hospital getting used to the equipment. Apart from Patients will firstly wear a glucose blood glucose levels, we will see how sensor for one week whilst they it benefits sleep quality, cognition, and continue their standard diabetes care. quality of life. This records their blood glucose values continuously and will give us a time to Feasibility of 24-hour hybrid closed compare how well the AAGC works in loop insulin delivery in free living reducing hypoglycaemia. conditions

Patients will then be admitted for one Local Investigators Martin de Bock; Tim night in hospital. They will have the Jones; Liz Davis; AAGC system fitted and the system Study Staff Julie Dart Carolyn Berthold will manage their blood glucose levels overnight. This will allow them to check Funding source JDRF to see if the glucose sensor is reading The aim of this study is to see if the accurately. If it is, the system will Medtronic hybrid closed loop system, continue to manage glucose levels till a portable artificial pancreas is feasibly the morning. to use in the home. The system Patients will be discharged home the consists of a glucose sensor that following morning. sits under the skin, an insulin pump

ANNUAL REPORT 2014 | 71 that delivers insulin and an Android- This study will aim to recruit 500 based smartphone that contain the adolescents with the following criteria: maths program to calculate the insulin adolescents aged 11-16years; with type 1 needed. Patients will learn to use the diabetes of >1year duration; identified as device for 2 days in hospital, and then being at high risk for the development for 5 days at home. Their results will be of DN and CVD as predicted by compared to when they use their insulin albumin excretion in the upper tertile pump as normally. This study is now afterappropriate adjustment for age, complete and has been presented at an sex, age at diagnosis and duration international conference of disease. Recruitment closed in December 2012. It is a four-armed randomised clinical trial involving: (1) COMPLICATIONS Quinapril: starting dose 5mg increased to 10mg daily after 2 weeks ,(2) Adolescent type 1 diabetes cardio- Atorvastatin, 10mg daily, (3) Quinapril + renal Intervention trial Atorvastatin, (4) Placebo.

Local Investigators: Tim Jones; Liz Davis Aussi-AdDIT Study Staff: Alison Roberts; Vinutha Local Investigators: Tim Jones; Liz Davis Shetty; Mary Abraham; Martin de Bock; Study Staff: Julie Dart; Alison Roberts; Adam Retterath; Jennifer Nicholas; Julie Adam Retterath Dart Funding Source: NHMRC Grant Funding Source: JDRF; BHF #632521 This is an international clinical trial with This multi-centre study is investigating the primary objectives of determining the changes in retinopathy, aortic whether intervention with Angiotensin intima media thickness (aIMT) and heart Converting Enzyme Inhibitors (ACEI), rate variability which are indicators of Statins, or a combination of both, when macrovascular disease and autonomic compared with placebo, will: (1) reduce neuropathy respectively; which are albumin excretion as assessed by six complications of type 1 diabetes. monthly measurement of albumin/ creatinine ratio (ACR) in 3 early morning The study’s aims are: (1)To determine urines; (2) reduce the incidence of whether adolescents with T1DM found microalbuminuria (MA) (ACR log mean > to be at high risk of microalbuminuria 3.5 mg/mmol (males) or > 4 mg/mmol have evidence of accelerated atherosclerosis, retinopathy and (females) in 2 out of 3 urines) at the autonomic neuropathy as compared end of the study period; (3) reduce the to adolescents at lower risk of incidence of MA during the six month microalbuminuria. (2) To determine run out period following the completion whether ACE inhibition and or statin of intervention phase.

72 | TELETHON KIDS INSTITUTE therapy during puberty will slow the history and cognitive ability on a progression of microvascular and number of cognitive domains including macrovascular disease in T1DM verbal IQ, verbal memory short-term memory and attention. These findings The study population is adolescents are not always replicated and, as aged 11.0y to 16.9y, and with type yet, there is no consensus as to how 1 diabetes mellitus; screened as episodes of severe hypoglycaemia being at low risk or high risk for affect the developing brain. Our developing diabetic nephropathy and previous study however indicated that cardiovascular disease. Throughout performance on tasks of executive Australia 370 adolescents deemed at function and fluid intelligence was high and 200 adolescents deemed at significantly poorer in individuals low in the Microalbuminuria Screening with T1DM, and there is a suggestion Study were recruited into the study. The of associated differences in frontal study duration is 6 years, and includes a functioning as indicated by ERP (event- two year recruitment period and a 4year related potential) studies. follow-up period. The study endpoints are changes in retinal images, aIMT and The main aim of the Neurocognitive heart rate variability measures, after 4 Outcomes study is to conduct an years duration from baseline. analysis of children with TIDM’s cognitive profile at an age in Neurocognitive outcomes of children which both cognition and cortical with type 1 diabetes mellitus development are still maturing (7- Investigators: Tim Jones; Mike 11 years). This will be achieved Anderson; Liz Davis through the use of neurocognitive assessment, electroencephalogram Study Staff: Kaitie McNamara; Nooshi (EEG) technology and magnetic Rath resonance imaging (MRI) screens. Funding Source: PMH Foundation; We are also analysing the cognitive APEG grant profile of a healthy sibling comparison group. In particular we will test the Previous research has indicated that hypothesis that if there are cognitive children with type 1 diabetes mellitus deficits associated with T1DM, they are (T1DM) may experience deficits in their more likely to be found in measures neurocognitive development compared of fluid intelligence and executive with healthy children. Whilst the impact (frontal) functions. This study is run in that T1DM has on the developing collaboration with the Neurocognitive brain remains controversial, evidence Development Unit at the School of suggests that these deficits may reflect Psychology, UWA. the occurrence of episodes of severe hypoglycaemia. Previous studies have found a link between hypoglycaemia

ANNUAL REPORT 2014 | 73 PREVENTION developing diabetes and be eligible to enter this trial. Testing for this study is Intranasal Insulin Trial II free and can be done either at PMH or at the local blood collection centre. Local Investigators: Liz Davis; Tim Jones Oral Insulin Trial Study Staff: Alison Roberts; Vinutha Shetty; Mary Abraham; Martin de Bock; Local Investigators: Tim Jones; Liz Davis Jacqueline Curran; Adam Retterath; Study Staff: Julie Dart; Heather Roby; Funding Source: NHMRC; JDRF Adam Retterath The Type 1 Diabetes Prevention Trial, Funding Source: NIDDK; NIAID; NICHD; also known as the Intranasal Insulin Trial NCRR; JDRF; ADA (INIT II), is part of a coordinated global The TrialNet Oral Insulin Diabetes effort to develop a vaccine for type Prevention Study is being conducted 1 diabetes. The trial, which began in internationally, to see if giving insulin 2006, is jointly funded by the National by mouth (in a capsule) will delay or Health and Medical Research Council prevent T1DM in people at increased (NHMRC) and the Juvenile Diabetes risk of developing diabetes. Research Foundation, through the Diabetes Vaccine Development Centre. Participants attend the hospital for an initial, a baseline (Randomization), a If successful, this vaccine could 3-month follow-up visit and then follow- prevent type 1 diabetes and the need up visits 6-monthly for the rest of the for daily insulin injections in people study. At each study visit, participants at risk. Over the past 5 years, over are asked questions about their health, 6,500 people have been screened activity, diet and about diabetes in their in Australia. Before someone is family and will also have a physical diagnosed with diabetes, there is a examination and blood tests. At the period of time, often many years, when Baseline Visit, participants are randomly there are no symptoms, but the body’s assigned to receive either active immune system has already begun treatment with insulin capsule (7.5 mg attacking the insulin-producing cells insulin) or an inactive dummy capsule in the pancreas. This time provides a called placebo. potential opportunity to prevent further destruction of the beta cells and thus the onset of type 1 diabetes. INITII is recruiting relatives of people with type 1 diabetes. Relatives have an increased risk of developing diabetes, which can be assessed by a simple blood test. Only 2% of the people tested will be considered at high risk of

74 | TELETHON KIDS INSTITUTE Type 2 Diabetes glucose, the effects of which can cause other major health problems such as Associate Clinical Prof EA Davis heart or kidney disease. However studies have shown that we may be EPIDEMIOLOGY able to avoid the effects of constant high blood glucose by improving blood Epidemiology of T2DM in childhood glucose control within the first few years and associated disease complications of diagnosis. One way of improving Investigators: Liz Davis; blood glucose control is through exercise. Study Staff: Rachelle Kalic; Jacqueline Curran; Aveni Haynes We are studying how exercise in young people with T2DM, and obese young Funding Source: Departmental people at risk of developing type 2 This study is investigating the incidence diabetes, affects: (1) The function of of childhood Type 2 Diabetes in small and large blood vessel, and the Western Australian community, whether an exercise training program and the incidence of diabetes- can improve function, (2) How well the related complications and related body uses insulin, and (3) Whether cardiovascular risk factors such as exercise training can improve blood hypertension and hyperlipidaemia in glucose control. that population

Obesity MANAGEMENT Associate Clinical Prof EA Davis Can exercise training Improve The 2007-2008 Australian National health in young people with type 2 Health Survey found that 25.1% of diabetes? children aged 5-17 years in Western Australia are overweight or obese (ABS, Investigators: Liz Davis; Danny Green; 2011). The Obesity Research Team Louise Naylor at Telethon Institute for Child Health Study Staff: Norhaida Mohd Yusuf; Research together with the Department Nirubasini Paramalingam; Mary of Endocrinology and Diabetes at the Abraham; Rachelle Kalic Princess Margaret Hospital for Children, Funding Source: Pfizer APEC grant # are researching the causes of obesity WS1836718 and interventions to combat obesity. Over the last few years, T2DM and Investigators are collecting DNA and obesity is becoming more common in serum to investigate the genetic factors young people. Individuals with T2DM and biomarkers that are potential risk and obesity often have high blood factors for weight gain in children

ANNUAL REPORT 2014 | 75 and adolescents, the development compliance is often poor and drug of obesity-related complications, choices are limited. and protective factors against these Studies of bariatric surgery highlight complications. By collecting information the potential weight loss that can on the development of obesity and be achieved in obese patients with successful interventions, investigators the subsequent improved health, hope to alleviate the burden of complication rates unfortunately remain childhood obesity high. In obese adolescents who fail to The team is also investigating physical, lose weight with lifestyle alone surgery psychological and dietary factors is increasingly being considered. contributing to sustainable weight However there are currently no loss and improved health in children predictors to determine which and adolescents participating in the adolescents will get complications Department’s lifestyle intervention from Laparoscopic Adjustable Gastric programs, and participants in the trial of Banding or bypass surgery. Likewise a new weight loss device. there are no reliable predictors to determine which adolescents will have a good response from surgery, there is INTERVENTION no available risk benefits data. A less invasive option is the gastric Bioenteric Intragastric Balloon balloon, achieving a temporary Investigators: Jacqueline Curran; Liz restriction of food intake in combination Davis; Colin Sherrington; Tim Jones with lifestyle and behavioural changes the aim being to achieve long term Study Staff: Leticia Good; Rachelle Kalic; weight loss. This has been achieved in Luise Russel; Deanna Messina; Anna adults with the use of a gastric balloon Tremayne that floats in the stomach giving the Funding Source:: NHMRC # 634308; individual the sensation of continued Pfizer APEC Grant satiety, reducing their requirement and desire for food. While there have Weight loss treatments for adolescents been large studies on the successful who are overweight or obese include use of the BIB in obese adults. Only lifestyle changes that includes diet, one small (n=5) retrospective study has exercise, parental involvement, been performed in adolescents with reinforcement, stimulus control and self- the use of the BIB. The purpose of this monitoring as targeted interventions. randomized clinical trial is to determine These lifestyle interventions in children whether the use of the BIB aids weight have found to result in a mean loss in obese adolescents. sustainable excess weight loss of 8%. Pharmacotherapy has a very limited role Specifically, that: in the treatment of adolescent obesity, 1.The BIB aids weight loss in obese

76 | TELETHON KIDS INSTITUTE adolescent patients. 2. We investigated the factors which could impact on guidelines 2.The BIB will be well tolerated in obese provided to patients with type 1 adolescent patients. diabetes in reducing the risk of 3.The BIB will reduce the severity hypoglycaemia associated with and frequency of obesity related co- exercise. The potential management morbidities in obese adolescents. strategies that could be implemented 50 adolescent patients (male and to enable type 1 diabetes patients to female), age 12-17 years attending exercise safely, will now be tested in Princess Margaret Hospital (PMH) will free-living clinical trials. recruited to the study. 3. The effect of varying macronutrient content of a meal on subsequent glycaemic excursions, was Translational Research tested with the goal of later quantifying the insulin requirements and the pattern Clinical Prof TW Jones of insulin requirements for meals that Associate Clinical Prof EA Davis vary in their protein and fat content, when the carbohydrate content is kept The year 2013 saw the progress in constant. This will enable reduction of our research from purely lab-based post prandial glycaemic excursions and studies towards taking a step closer to improve the management of patients translational research. This is especially with Type 1 diabetes in regards to the following areas of research into ways of improving the life To help us move forward into of consumers with type 1 diabetes. translational research, we have initiated a consumer participation working party The areas in focus are: to evaluate the needs of patients with 1. The in clinic technology regards to their health care and sharing studies using sensor-augmented of health research information with pump therapy, closed-loop insulin them. At this early stage, the first step delivery systems and predictive low has been an evaluation of the preferred glucose management were aimed at method of communication with patients reducing glycaemic excursions and and their families about the information hypoglycaemic events. This will be a from the clinical and research areas of boon to patients as hypoglycaemia our group. negatively impacts on health and quality of life. The next milestone is to test the efficacy and safety of these systems Consumer Participation with real life variables in the home environment. Study Staff: Barbara Sheil; Kaitie McNamara; Melanie Baker; Rachelle Kalic; Ray Davey; Sonia Johnson; Alison

ANNUAL REPORT 2014 | 77 Roberts; Heather Roby; Mark Shah; Matt connections with: Diabetes WA, Cooper JDRF, DRF Consultant: Anne McKenzie Funding Source: Unfunded RESEARCH RESOURCE Our overall aim is to promote the REPOSITORIES AND DATABASES development and engagement of a wider diabetes and obesity community. Tim Jones; Liz Davis Specifically, we aim: Type 1 and Type 2 Diabetes DNA bank • To increase consumer input in to research Investigators: Tim Jones; Liz Davis • Input in to information and consent Study Staff: Adam Retterath forms Funding Source: Departmental • Consumer driven research A prospective population-based proposals diabetes register that conforms to • More effective result dissemination international standards, and which stores demographic and clinical data • Wider knowledge about available on all patients attending the diabetes research projects clinic at Princess Margaret Hospital. • To increase consumer input in to The database also records family clinical matters history, in the first degree relative, of and atopic • Input on clinic design & scheduling disease As PMH is the only tertiary • Input on camp format and structure paediatric referral centre in Western Australia, the case ascertainment of • Consumer driven education this register has consistently been over resources & materials 99%. This complete, population-based • Facilitation of opportunities for data source is invaluable for studying families to meet the epidemiology of childhood onset Outcomes: diabetes in Western Australia. • A diabetes and obesity community Australian Childhood Diabetes DNA Repository • Greater consumer satisfaction • Positive research experiences Investigators: Grant Morahan; Tim Jones; Liz Davis • Positive clinic experiences Study Staff: Heather Roby • Increased social opportunities for families to meet and network Funding Source: NHMR Enabling Grant • Heightened partnership Both types of diabetes tend to run

78 | TELETHON KIDS INSTITUTE in families. This means that certain established to provide a store of genes we inherit from our parents samples from subjects with diabetes may increase or decrease the risk of as well as their families. This resource developing diabetes. will allow researchers to carry out scientific studies looking at the genetic By testing DNA samples from families causes for diabetes. The ultimate affected by diabetes, we can identify aim is to improve on current practice genes which increase the risk of this for prevention and monitoring of disease. Identification of diabetes complications related to diabetes. genes is important as it will help us to Samples can only be accessed by understand better why some people research teams with appropriate ethics become diabetic, and help researchers approval and sample details can only to develop new treatments. be accessed by authorised personnel. The Australian Childhood Diabetes DNA Repository (ACDDR) is aiming to Western Australian Children’s collect DNA samples from Australian Diabetes Database families affected by diabetes. Families Investigators: Tim Jones; Liz Davis with a child with either type 1 or type 2 diabetes are invited to participate. DNA Study Staff: Jennifer Brooks; Madeleine for the Repository is collected once Lowe; Adam Retterath; Helen via saliva samples. To participate, both Clapin; Vinutha Shetty; Nirubasini biological parents and the child with Paramalingam; Matthew Cooper diabetes provide about a teaspoon of Funding Source: Departmental saliva in a special pot that we supply and can be collected in clinic or at This diabetes register was established home. at Princess Margaret Hospital (PMH) in 1987 which stores data on all The Repository stores samples of DNA, consenting patients attending the so that Diabetes researchers, with the hospital’s diabetes clinic. In Australia, approval of relevant Ethics Committees, all children diagnosed with type 1 can then apply to access this Repository diabetes (T1DM) are admitted to hospital rather than asking your child and you at the time of diagnosis. As PMH is for more blood samples. the only children’s teaching hospital Longitudinal Type 1 and 2 Diabetes in Western Australia (WA), all children Plasma and Serum Repository diagnosed with diabetes are seen by the diabetes department at this hospital. Investigators: Tim Jones; Liz Davis Since the diabetes register was set up, over 99% of children newly diagnosed Study Staff: Adam Retterath with T1DM have consented to being Funding Source: Internal Funds registered in the register. This means The Serum & Plasma bank was that the register contains data on almost all children diagnosed with T1DM under

ANNUAL REPORT 2014 | 79 the age of 15 years in WA, and can complications of children with obesity be used to accurately describe their who present to treatment at Princess characteristics. Margaret Hospital, in an on-site database. The database records A history of T1DM in the parents demographic and anthropometric data and siblings of children diagnosed about participants in the study, as well with T1DM has been collected by as features of complications of obesity. the diabetes clinicians since 1992. Complications of obesity include an Since 2005, this data collection has abnormal lipid profile, hypertension, extended to include type 2 diabetes glucose intolerance, fatty liver, and other diseases associated with musculoskeletal issues and obstructive T1DM. This population based database sleep apnoea, among others. Analysis for childhood is a valuable resource of this data quantifies the complications which will allow us to investigate the of obesity in children who are relationship between associated overweight and obese, and will be used diseases may add to the understanding to develop guidelines for investigation of their underlying mechanisms. and treatment. The data is collected using a questionnaire, either at the time Western Australian DNA and of diagnosis for newly diagnosed Longitudinal Serum Bank for Weight patients, or during routine follow-up Regulation appointments, for patients attending Investigators: Liz Davis; Tim Jones; the diabetes clinic. Data access will Jacqueline Curran; be restricted to relevant clinical and authorised research staff only. Consent Study Staff: Rachelle Kalic; Adam is obtained from newly diagnosed Retterath patients or their parents prior to the Funding Source: NHMRC Enabling collection and storage of incidence data Grant & Internal Funds and family history data in the diabetes register. Patient confidentiality is The establishment of this resource will maintained. allow researchers in the future to carry out scientific studies which will look at A Database of the Complications of the genetic causes of excessive weight Obesity in Children gain (how excessive weight gain runs in families), and to identify biomarkers Investigators: Liz Davis; Jacqueline (special molecules) in blood that help Curran predict individuals at risk of becoming Study Staff: Rachelle Kalic overweight or at risk of developing Funding Source: Departmental obesity related diseases. Eventually the aim is to improve on current practice The Obesity Database records for prevention and monitoring of the characteristics and medical complications related to obesity.

80 | TELETHON KIDS INSTITUTE The individuals that will be eligible Staff and Students for recruitment to the study will be overweight children their siblings and Head of Division parents seen for their weight problem Tim Jones MBBS, DCH, FRACP, MD at Princess Margaret hospital, and families enrolled in the Growth and Clinical Professor, The University of Development study through Institute of Western Australia Child Health research. Practitioner Fellow, National Health & DNA will be extracted from blood/ Medical Research Council saliva; serum & plasma from the blood Head, Department of Endocrinology samples The samples collected will be and Diabetes, Princess Margaret coded so that no one outside the PMH Hospital for Children research team will be able identify who the sample belongs to. Faculty Member - Senior Principal Investigator, Centre for Child Health Fractions of DNA and protein results Research, Telethon Institute of Child may be provided to properly qualified Health researchers, with PMH ethics approval, to identify susceptibility genes and Adjunct Professor, Institute for Health & biomarker results may be provided Rehabilitation Research, The University to properly qualified researchers, of Note Dame Australia with PMH ethics approval, to identify Senior Team Leader susceptibility genes and biomarkers related to obesity and its complications. Liz Davis MBBS , FRACP, PhD Clinical Associate Professor, University of Western Australia Head, Diabetes and Obesity Services, Princess Margaret Hospital for Children Associate Professor, School of Paediatrics and Child Health, The University of Western Australia Faculty Member - Senior Principal Investigator, Telethon Institute for Child Health Research, The University of Western Australia Research Staff (TKI)

Davey, Raymond PhD Evans, Megan APD, BSc, Post-Grad Dip

ANNUAL REPORT 2014 | 81 (Nutrition and Dietetics) MPH Haynes, Aveni BA (Hons), MBBChir, PhD Postgraduate Students

Kalic, Rachelle BPsych, MApp Econ Cooper, Matthew- PhD candidate candidate Curran, Jacqueline- PhD candidate Tully, Alexandra BN, Post-Grad Dip (Midwifery) Kalic, Rachelle – M App Econ Candidate Berthold, Carolyn BSc (Nursing) Nicholas, Jennifer- MSc Candidate Cole, Carol BN, CDE Shetty, Vinutha- PhD candidate Nicholas, Jennifer BSc (Nursing), CDE, Soon, Wayne BSc (Hons); PHD MSc (Diabetes Education), Nurse candidate Practitioner Trainee Hamidi, Ana MBB; PhD candidate Paramalingam, Nirubasini HDip Research Support (Children’s Nursing), Grad Cert (Diab Edu), BSc(Hons) Tina Commisso – B.Business (Marketing / Tourism Man) Good, Leticia BPsych, MSocRes (Social research methods) Roby, Heather BSc Awards Czank, Charles BSc (Hons), PhD Dr Vinutha Shetty – RACP Trainee Makin, Janet BBus (info processing) Research Award, 2013 Research Staff (PMH) APEG New investigator award 2014

Dr Abraham, Mary Pfizer Reasearch APEC Grant 2015 Dr Curran; Jacqueline Dr Mary Abraham – RACP Advance Trainee; WA, 2013 Dart, Julie; CRN Telethon Fellowship, 2013 Dr de Bock, Martin Dr Aveni Haynes - 2014 Australasian Roberts, Alison; CRN; MSc candidate Paediatric Endocrinology Group Dr Shetty, Vinutha Travel bursary Dr Siafarikas, Aris Dr Mary Abraham –Telethon Fellowship, Dr Chetty, Tarini 2013 Dr Rath, Nooshi Trainee Research Award of the WA state branch of RACP 2013 Dr Kiranjit Joshi Trainee Research Award of the WA Clapin, Helen BSc. Grad Dip Comp; state branch of RACP 2014

82 | TELETHON KIDS INSTITUTE External Committees Meeting – local organiser - 1997 Liz Davis. Australasian Paediatric International Endocrine Group - 2011-Member of Tim Jones. International Journal Executive Council 2011 - 2013 of Diabetes and Clinical Research- Liz Davis. Australasian Paediatric Editorial Board - 2015 Endocrine Group - 2005- Tim Jones. JDRF PEAK Expert Panel - Member Diabetes Database Committee Member 2014 – Ongoing – 2005 Tim Jones. International Hypoglycemic Liz Davis. Australasian Paediatric Study Group – Member 2013-ongoing Endocrine Group – 2013 – Vice Tim Jones. JDRF Artificial Pancreas President – 2013- Consortium – Member 2011-ongoing

Tim Jones. JDRF Artificial Pancreas National Consortium – Member 2011 Tim Jones. Diabetes Australia Research Tim Jones. Medtronic Advisory Board Trust - Member Scientific Review Clinicians – Member 2011 Committee 2004- Tim Jones. Australasian Paediatric Tim Jones. National Diabetes Services Endocrine Council Research Grant Scheme Diabetes Expert Reference Review Body – Chairman 2011-12. Group- Youth advisory Committee – Tim Jones. Australasian Paediatric Member 2013 Endocrinology Group Council - Tim Jones. Diabetes Australia – Member - 2001-2005 development of the National Diabetes Tim Jones. Royal Australasian College Strategy and Action Plan – National of Physicians – Clinical Examiner - Expert Advisory Committee Member 2002,2004 2013. Tim Jones. JDRF International - Tim Jones. NHMRC Research Scientific Review Committee Member Translation Faculty – Member 2012 - 2001- 2004 Tim Jones. JDRF – Type 1 Diabetes Tim Jones. JDRF Professional Advisory Clinical Network Steering Committee Panel- 2007 2012 Liz Davis. Consensus Guidelines on Tim Jones. Type 1 Diabetes Guidelines Insulin resistance in children - Invited Expert Advisory Group – Member 2011- member of International committee 2012. 1998 Tim Jones. Diabetes & Endocrine Liz Davis. Australasian Paediatric Health Networks Advisory Group – Endocrine Group’s Annual Scientific Member 2011-2012

ANNUAL REPORT 2014 | 83 Tim Jones. Best Practice in Paediatrics Liz Davis. Endocrine training and Committee. Organising Committee – curriculum development subcommittee, 2010 APEG - Member 2009 - 2012 Tim Jones. Royal Australasian College Liz Davis. Birth Defects Registry - of Physicians - Clinical Examiner Advisory member – 2004 - 2002,2004 Liz Davis. Royal Australian College Tim Jones. Diabetes Australia Research of Physicians - Written Examination Trust - Member Scientific Review committee - 2000-2007 Committee 2004- Liz Davis. Diabetes Research Tim Jones. Australian Growth Hormone Foundation – board member 2004 Advisory Committee Member 2000, Liz Davis. Brightspark Foundation Chairperson 2003-2005 (formerly Child Health Research Tim Jones. JDRF Australia, Scientific Foundation) Board Member 2005 Advisory Committee – Member - 1999- 2004 Local Tim Jones. Australian National Association of Diabetes Centres - Tim Jones. New Children’s Hospital WA Paediatric Representative 1999-2005 Advisory Group – Member 2011 Liz Davis. APEG annual scientific Tim Jones. Paediatric Medical Clinical Meeting – member of scientific Care Unit WA Medical Advisory organising committee 1998-2011 Committee – Member 2011 Liz Davis. Consensus Guidelines on Tim Jones. Diabetes Research Insulin resistance in children - Invited Foundation of Western Australia - member of International committee Member Medical Advisory Panel, 2002- 1998 New Children’s Hospital WA Advisory Liz Davis. Australian Consensus Group – Member 2011 Guidelines on Polycystic Ovary Liz Davis. PMH-KEMH - Accreditation Syndrome - Invited member of national committee - 2001-02 committee – 2010 Liz Davis. Australian Paediatric Endocrine Council Research Grant Invited Presentations Review Body – Chairman – 2011 - 2012 INTERNATIONAL Liz Davis. SAC Endocrinology, RACP - Member – 2010 - 2012 Tim Jones. Risks of hypoglycemia in childhood Australian Diabetes Liz Davis. Australian Tertiary Obesity Association. Investigators Research Clinical Network - Member of Executive Symposium, New Mexico, 1997. committee – 2009 - 2012

84 | TELETHON KIDS INSTITUTE Tim Jones. International Diabetes of Paediatric Endocrinology. South Federation Congress, Mexico 2000. Africa 2008. Tim Jones. NZSSD Annual Scientific Tim Jones. Intensive Insulin Therapy. Meeting, May 2001. Lawson Wilkins Paediatric Endocrine Society/European Society for Pediatric Tim Jones. Risks of Hypoglycaemia Endocrinology, New York NY USA, in Type 1 diabetes, International September 2009. Conference of Paediatric Endocrinology, Montreal, Canada July 2001 Tim Jones. Barriers to Achieving Glycaemic Targets and Risks of Tim Jones. New Zealand Diabetes Hypoglycaemia, Session A1C Targets Conference, “Challenges in managing in Pediatric Diabetes – Ideal vs Real. diabetes in the young”, September American Diabetes Association 70th 2004. Scientific Sessions, Florida, June 2010. Tim Jones. International Society of Tim Jones. Diabetes in Children Paediatric & Adolescent Diabetes (Plenary); Technology in Type 1 Diabetes Congress, Singapore 2004. Therapy; Pediatric Care (Discussions) Tim Jones. Growth in children born Diabetes Asia 2010, Kuching, Malaysia SGA, Symposium, Magdeberg Oct 2010. Germany, June 2005. Tim Jones. Insights into the Future Tim Jones. Hypoglycaemia in of Glucose Management - Managing Early Diabetes. American Diabetes Hypoglycemia: a prospective view of Association, Washington, USA 2006. GCM technologies. at 5th International Tim Jones. Hypoglycemia in Children. Conference, Advanced Technologies Presented at the American Diabetes & Treatments for Diabetes, Spain. Feb Association, Washington USA 2006. 2012 Tim Jones. Neurocognitive Findings Tim Jones. CME Symposium: Waiting for Do Not Provide Evidence for Upper Closed Loop – tapping the full potential and Lower Glucose Targets in Children. of advanced diabetes technology in Presented at the American Diabetes today’s clinical practice. American Association 67th Annual Scientific Diabetes Association, 72 Scientific Meeting, Chicago IL, June 2007. Sessions, Philadelphia PA, USA June 2012. Tim Jones. Treatment of Paediatric Diabetes. Presented at the China Tim Jones. Technology in Diabetes Paediatric Endocrinology Association Therapy. Australasian Paediatric Annual Meeting, Huan Gsang, 14th Endocrine Group: Annual Scientific November 2007. Meeting, New Zealand, July 2012. Tim Jones. Workshop. Exercise in Tim Jones. The use of an automated Diabetes Children. International Society glucose control system for overnight

ANNUAL REPORT 2014 | 85 glucose control in adolescents with Adelaide November, 1995. Type 1 Diabetes. The Annual Rachmiel Tim Jones. Challenges and Advances. Levine Diabetes & Obesity Symposium. Asia Pacific Paediatric Endocrinology Pasadena, California, USA March, 2013. Workshop, Sydney, March 1996. Tim Jones. China National Pediatric Tim Jones. Achieving Metabolic control Endocrine Conference. Xia men, China, in adolescent with IDDM. Invited lecture, October 2013 ADS Annual Scientific Meeting, Sydney Tim Jones. Hypoglycemia in Diabetes: 1996 risks, management and prevention. Tim Jones. Childhood Diabetes. Invited 34th Annual Meeting of the Australasian Lecture. Diabetes Australia Symposium, Neuroscience Society. Adelaide, Sydney 1997. Australia, January, 2014. Tim Jones. Hypoglycaemia, JDF Tim Jones. Managing Exercise in Type 1 Research Seminar, Perth, Australia, Diabetes. Joslin Seminar 2014. Boston, 1998. February, 2014. Tim Jones. Hot topics in Diabetes. Tim Jones. Technology to Prevent Annual Scientific Meeting of the Hypoglycemia. 2014 American Diabetes Australian Paediatric Endocrine Group, Association Scientific Sessions. San 1999. Francisco, California, June, 2014. Tim Jones. Pump Therapy in Children Tim Jones. Exercise and Hypoglycemia. and adolescents. Directions in Diabetes. 2014 American Diabetes Association Invited speaker, Queensland. March Scientific Sessions. San Francisco, 2002. California, June, 2014 Tim Jones. Hypoglycaemia in Children. Tim Jones. Exercise in Children with Invited speaker. JDRF Seminar. Diabetes. 2014 American Diabetes Melbourne, March 2002. Association Scientific Sessions. San Francisco, California, June, 2014 Tim Jones. Management of diabetes in Children. Invited speaker. JDRF Type 1 Tim Jones. Hypoglycemia Prevention in Seminar. Adelaide, September 2002. Children with Type 1 Diabetes. ISPAD. Toronto, September, 2014 Tim Jones. Glucose Sensing Invited speaker. Australian Diabetes Society Tim Jones. Hypoglycemia and Annual Scientific Meeting, Adelaide, Glycemic Targets. Panel Discussion and September 2002 Presentation. EASD Annual meeting. Vienna, Austria 2014 Tim Jones. Research Advances: hypoglycemia. Invited speaker. NATIONAL Australian Diabetes Society Annual Tim Jones. Hypoglycaemia in Children Scientific Meeting, Adelaide, September and Adolescents. Invited Lecture. 2002.

86 | TELETHON KIDS INSTITUTE Tim Jones. Australian Diabetes GP Weekend- Great Southern GP Educators Association Annual Scientific Network. Albany, Western Australia, Meeting, September 2003. Invited February 2008. speaker. Meet the Expert: CGMS it has Tim Jones. Advances in Insulin Therapy. a place in diabetes management. Pumps and CGMS. Presented at the 9th Tim Jones. Australasian Paediatric Annual Directions in Diabetes Regional Endocrine Group, Melbourne, Medical Conference, Melbourne September 2003. Invited Speaker: Australia, Sebel Albert Park Hotel, 23- Hypoglycaemia in children - ?an 25 May 2008. uncommon problem. Tim Jones. Insulin Pump Services. Best Tim Jones. Australian Association of Practice in Diabetes Centres. 2008. Clinical Biochemists Annual Scientific Tim Jones. Exercise in Diabetes. ADEA/ Conference. September 2003. Invited ADS. Melbourne 2008. Speaker: In vivo continuous glucose monitoring. Tim Jones. Kimmelsteil meeting, Improving standards of care for children Tim Jones. Consequences of with Type 1 Diabetes. Melbourne, hypoglycaemia. Presented at the October 2008 Australasian Paediatric Endocrine Group Annual Meeting, , Australia Tim Jones. Prefer to Improve, Exercise September 2006. and Glucose and Practical Pump Therapy, Queensland, November 2008. Tim Jones. Hypoglycaemia. Presented at the Diabetes Twenty Meeting, Tim Jones. Advances in the Treatment Melbourne, Australia 2006. of Type 1 Diabetes in Children. JDRF Symposium. Australian Paediatric Tim Jones. Transitioning type 1 from Endocrinology Group Annual Scientific childhood to young adult. Presented at Meeting, November 2008. the, Diabetes Association of Western Australia Annual General Meeting, Tim Jones. Insulin Pump Therapy. Subiaco Oval, 25th October 2007. Australian Paediatric Society, 3rd Annual Insulin Pump Workshop, Newcastle, Tim Jones. Effects of exercise on NSW. March 2009. glucose. Australasian Paediatric Endocrine Group 2007. Tim Jones. Paediatric Endocrine Disorders and Fertility. Fertility Nurses Tim Jones. Paediatric Endocrine Cases. Association of Australia, Perth, WA. Presented at the 2008 Chemical October 2009. Pathology Course. Fremantle Western Australia, February 2008. Tim Jones. Closing the Loop – Australian perspectives on Artificial Tim Jones. Common and Uncommon Pancreas Project. ADS Medtronic Presentations. Presented at the Symposium. Adelaide, 2009. Continuous Professional Development

ANNUAL REPORT 2014 | 87 Tim Jones. Intensive Insulin Therapy of Paediatric Diabetes. “Directions in Type 1 Diabetes and Hypoglycaemia. Diabetes” Symposium. Sydney May Novo Nordisk Diabetes Nurse 2012. Educators Symposium, Perth, May 2010. Tim Jones. Tots and Technology. Tim Jones. Lilly 11th Annual Diabetes NHMRC Clinical Trials Centre Master Regional Medical Conference, Sydney, Class, 4th Update on Diabetes & May 2010. Vascular Disease Sydney July 2012. Tim Jones. Diabetes in Youth, Aboriginal Tim Jones. Use of data in diabetes Health Conference, Perth, July 2010. therapy. Australian Paediatric Society: Plenary Talks, July 2012. How to Achieve tight controls without Hypoglycaemia. Australian Paediatric Tim Jones. Invited Speaker: Preventing Society 5th Annual Diabetes Workshop nocturnal hypoglycaemia. Australian Jul 2011. Paediatric Society: Plenary Talks, July 2012. Tim Jones. Exercise in Diabetes. Australian Paediatric Society 5th Annual Tim Jones. Hypoglycaemia prevention Diabetes Workshop Jul 2011. with predictive suspension of insulin delivery. Australian Type 1 Diabetes Tim Jones. Hypoglycaemia and Clinical Research Network Meeting, Exercise in Diabetes. 9th Australian Sydney, Mar 2013. Paediatric Endocrine Group – Clinical Fellows School. Aug 2011. Tim Jones. Update on Diabetes in Children in transition. Rural Health West Tim Jones. Assessing Glycaemic Symposium. Perth, Mar 2012. Variability: Does it Make a Difference in Paediatrics? Sanofi Diabetes Expert Tim Jones. Success in the Next Steps Forum, Melbourne, Oct 2011. to Prevent Hyperglycemia. ADS / ADEA Scientific Meeting. Sydney. August 2013. Tim Jones. Artificial Pancreas: Myth or Reality? Australian Diabetes Educators Tim Jones. Getting better Glycemic Association WA Branch Conference, Control with Vulnerable Patients. ADS Perth, May 2012. / ADEA Scientific Meeting. Meet the Professor. Sydney. August 2013. Tim Jones. Numbers: Use of data in Diabetes Management and Clinical Tim Jones. Numbers – The Importance Research. Melbourne & Sydney, May of Data Sets for Diabetes Research. 2012. Telethon Institute for Child Health Research Seminar. Perth Aug 2013. Tim Jones. Exercise and its prevention in Type 1 Diabetes. “Directions in Tim Jones. Closing the loop. 2013 Lilly Diabetes” Symposium. Sydney, May Directions in Diabetes - Endocrinologist, 2012. Sydney, October, 2013. Tim Jones. Regional Differences in Tim Jones. New Technologies in

88 | TELETHON KIDS INSTITUTE Diabetes Therapies. Western Australian Endocrine Group ASM, Symposium Endocrine Weekend. November 2013. speaker: Insulin pumps in children, September 2003. Tim Jones. Exercise and Hypoglycemia in diabetes. Annual Scientific Meeting Liz Davis. Obesity - current trends: 2014 of the Australian Diabetes Society. annual scientific update WA Dental Melbourne. Australia. August 2014. Society, May 2004 Tim Jones. Hypos - sugar, suspend or Liz Davis. The neonate of the diabetic sprint? 8th Annual Australian Paediatric mother: WA branch of Perinatal Society Society Meeting. Canberra. Australia. of Australia and New Zealand, August October 2014. 2004 Tim Jones. World Diabetes Day NSW. Liz Davis. Development of a multisite Australia. November 2014 protocol for bisphosphonate treatment of children with Chronic neurological Tim Jones. AstraZeneca Post Graduate disability, August 2004 Weekend. March 2015 Liz Davis. Childhood Obesity: Have Liz Davis. Obesity and Type 2 diabetes Physiotherapists missed the boat? in adolescents, Kimberley Regional Presentation and panel discussion. APA Medical Conference, 2002 WA Biennial State Conference, May Liz Davis. Obesity in Children and 2005 Adolescents, RACGP Annual Seminar, Liz Davis. Obesity, super size me in the 2002 under 18’s. Endocrine Nurses Society of Liz Davis. Obesity – prevalence, Australia, September 2005 investigations and management, Annual Liz Davis. Diabetes thru the ages. RACP update, May 2003 Australian Diabetes Educator Liz Davis. Diabetes and hypoglycaemia: Association State Conference- Keynote Australasian Association of Clinical speaker, March 2006 Biochemists, May 2003 Liz Davis. Obesity and T2DM in Liz Davis. Childhood overweight and Children: South Metro Region Diabetes obesity: Australian Pediatric Review Update, Invited speaker, March 2007 Training Program, June 2003 Liz Davis. Obesity and T2DM in Liz Davis. Management of Type 2 childhood: WA Annual Scientific diabetes in Childhood, West Australian meeting of Pharmacologists, Perth, May Diabetes Forum, June 2003 2007 Liz Davis. Diabetes: What’s new? Liz Davis. Clinical Aspects of Childhood Institute for Child Health Research Obesity: Childhood Obesity: Prevention Seminar Series, June 2003 and Treatment Seminar, WA, May 2007 Liz Davis. Australasian Paediatric Liz Davis. T 2 Diabetes in Indigenous

ANNUAL REPORT 2014 | 89 Youth. Australasian Paediatric Endocrine Professional update meeting, Perth Group 25th Annual Scientific Meeting, 2010 Broome. October 2007 Liz Davis. Endocrine Society of Liz Davis. Obesity and Emerging Policy: Australia-Australasian Paediatric Community Health Nurses Clinical Endocrine Group, Liz Davis. Combined Practice Update. Invited speaker. Feb ESA-APEG orals – Diabetes (Clinical – 6 2008 presentations). Invited Session Chair - Annual Meeting, 2011. Liz Davis. European Society for Paediatric Endocrinology Conference, Liz Davis. Australian Diabetes Society Turkey, 2008 ASM Symposium speaker: Clinical significance of genetics in Diabetes, International Society of Paediatric and 2011 Adolescent Diabetes Conference, Durban 2008 Liz Davis. Novo Nordisk WA Endocrine Weekend 2012. Monogenic Diabetes Liz Davis. European Association for the – Case presentations and Clinical Study of Diabetes Conference, 2008 Relevance. Nov 2012 Australasian Paediatric Endocrine Group Liz Davis. International Diabetes Annual Meeting, Canberra 2008 Federation: World Diabetes Congress Liz Davis. T2DM in Youth – (Basic and Clinical Science Stream) Management: Rural Health West Annual Invited Speaker: Role and Impact of Conference. Invited speaker. May 2008 Exercise in Type 1 diabetes. Australia, Liz Davis. T2DM in WA – Annual 2013. meeting of WA Diabetes Educator Liz Davis. Endocrine Society Paediatric Association. Invited speaker, May 2009 Endocrinology, 9th Joint Meeting of Liz Davis. Lawson Wilkins Paediatric Paediatric Endocrinology, Chair - Free Endocrine Society/European Society for Communication Session FC17 – Obesity, Pediatric Endocrinology in New York, Milan, Italy. Sept 2013. NY USA, September 2009 : Invited Liz Davis. The University of Western symposium speaker. Australia & the Continuing Professional Liz Davis. Management of Diabetes Development Program - Diabetes: Mellitus in Isolated Aboriginal Priorities, targets and the Annual Cycle Populations. of Care Seminar. Diabetes in Children – Risk Factors, Presentation and Liz Davis. Australasian Paediatric Treatment. Perth, June 2013. Endocrine Group Annual Meeting, Symposium speaker: Insulin Resistance Consensus Update: 2009

Liz Davis. Maturity Diabetes of The Young: Diabetes Nurse Educators

90 | TELETHON KIDS INSTITUTE ACTIVE collaborations Dr Lim Ee Mun: Clinical Biochemistry, PathWest, Sir Charles Gairdner Prof Geoff Ambler: Children’s Hospital Prof Grant Morahan: Western Australian at Westmead, NSW Institute for Medical Research Winthrop Prof Mike Anderson: School of Dr David O’Neal: St Vincent’s Hospital, Psychology, UWA NSW Prof Fergus Cameron: Royal Children’s Dr Carmel’ Smart: John Hunters Hospital, VIC Hospital for Children, NSW Prof Jennifer Cooper: Women’s and Prof Ranjaney Thomas: Diamantina Children’s Hospital, SA Institute, Qld A/Prof Andrew Cotterill; Mater Hospital, Prof Donna Cross:”Telethon Kids Insitute Qld Associate Prof Liz Geelhoed: University A/Prof Maria Craig: Australian Clinical of Western Australia Trials Network; NSW Professor Bill Tamborlane: Yale Dr Dennis Daneman: Hospital for Sick University Children, Toronto, Canada Professor Margaret Grey: Yale University Prof Kim Donaghue: Children’s Hospital at Westmead, NSW Professor Stuart Weinzmer: Yale University Prof David Dunger: Addenbrooke’s Hospital, Cambridge, UK Dr Jan Fairchild: Women’s and Children’s Hospital, SA Prof Paul Fournier: School of Sports Science and Exercise Health, UWA A/Prof Kym Geulfi: School of Sports Science and Exercise Health, UWA Winthrop Prof Danny Green: School of Sports Science and Exercise Health, UWA Prof Len Harrison: Royal Children’s Hospital, VIC Dr Joey Kaye: Sir Charles Gardiner Hospital, WA Prof Bruce King: John Hunters Hospital for Children, NSW

ANNUAL REPORT 2014 | 91 GENETICS AND HEALTH

Our research focuses on using expression of host genes in a pathway genomics and transcriptomics to influencing mitochondrial dysfunction understand complex diseases, helping that could relate directly to congenital us to find better drugs and vaccines. clinical signs being focused in the eye Highlights of our research for 2014 and brain. This provides support for include: repurposing of drugs currently used to treat genetic eye and brain diseases Visceral leishmaniasis is a parasitic that are associated with mitochondrial disease found in resource poor tropical dysfunction. countries and is life-threatening in susceptible individuals. Drugs are toxic, and no vaccines are available. We employed genomics to identify the major genetic risk factor for visceral leishmaniasis in India and Brazil, and have now used biochemical techniques to identify parasite antigens that bind to the molecules encoded by this major histocompatibility complex gene for presentation to the immune system. We also used a genome-wide approach on Raine Study data to show that the same gene determines response to the pneumococcal surface protein C of gram positive Streptococcus pneumoniae pneumococci, invasive forms of which are capable of causing life-threatening pneumococcal sepsis and meningitis. Both studies are helping us to design vaccines that will specifically aid in protecting susceptible individuals. Toxoplasma parasites are common globally, with 30-40% of Australians infected. The parasite causes serious problems if mothers become infected for the first time during pregnancy and pass the parasite across the placenta to the developing baby. Using transcriptomics we have demonstrated that Toxoplasma causes changes in

92 | TELETHON KIDS INSTITUTE ANNUAL REPORT 2014 | 93 INFLAMMATION

Members of the Inflammation group but more data are accumulating that are studying both the positive and there are a large range of benefits for negative effects of UV exposure. Dr health from sensible safe exposure to Jason Waithman’s group is studying moderate sun. With further research, melanoma development (UV exposure we believe that the right balance of is the strongest risk factor for sun exposure will be determined for melanoma development) and potential public health advice. We believe that immunotherapeutic approaches to we are studying issues important to the destroy it. Drs Prue Hart and Shelley health of children and we would like to Gorman are leading teams to study develop, in time, guidelines tailored for the positive effects of UV exposure sun exposure of children. on reducing several significant health In 2014 with the award of a large issues, namely autoimmune diseases NHMRC grant, we began translational and obesity, respectively. studies of the effect of UVB exposure Sunlight is one of the most important on the development of autoimmunity in environmental agents to which man humans. The trial involves participants is exposed. The ultraviolet B (UVB) with an early form of . wavelengths are the most powerful They have had a first demyelinating and cause not only melanoma and event but are not classified as clinically non-melanoma skin cancers, but also definite multiple sclerosis until they suppression of immune responses to have had a second event. We propose antigens introduced at distant body that phototherapy with UVB light can sites. We have previously shown that dampen or reverse their disease UVB light administered to the shaved course. Using preclinical models, in dorsal skin of mice can suppress 2014 we began studies of the effect models of allergic airways disease of UVB on reducing the pathology of and models of multiple sclerosis. This another immune-mediated disease, suggested that UV-induced changes namely Crohn’s Disease. in the skin could signal downstream The effects of sun exposure can be systemic responses to allergens in long-lived for several weeks. With respiratory tissues, and neural antigens immune cells regularly turned over, in brain and spinal cord. Further in we believe that signals must be sent 2013 and 2014, we demonstrated that from UV-irradiated skin to the bone exposure of the shaved skin of mice marrow which is the powerhouse for to UV radiation could also reduce immune cell development. In 2014, weight gain of mice on a high fat diet studies continued to focus on the and that this effect was not due to effects of UV irradiation of skin on UV-induced vitamin D. All our studies blood precursor cells in the bone are important as they tell us that a marrow. Erythemal UVB irradiation of balance of sun exposure is required. skin stimulated the production from We hear a lot about avoiding sun

94 | TELETHON KIDS INSTITUTE bone marrow of poorly functioning the skin of mice with normal levels of dendritic cells and macrophages (ie vitamin D3) and in deficiency (mice myeloid cells). Further, UV-induced were fed diets restricted in vitamin prostanoids were responsible for the D3). We discovered that male vitamin effects of UV irradiation of skin on D3-deficient mice were unable to myeloid cell precursors in the bone respond to UVB irradiation of skin marrow. This result suggested that for vitamin D3 production. Thus, if UV-induced inflammation per se was the male mice responded to UVB for responsible for this effect and that regulation of immunity, this was not via it was a homeostatic response that the modulatory properties of vitamin ensured that the inflammation in the D3. This finding has given us an exciting skin was restricted and did not progress and ongoing approach to analyse out of control. We have also tested the relative contribution of vitamin D3 these bone marrow cells in controlling and other UV-induced mediators to models of established inflammation. the immunomodulatory properties of Dendritic cells generated from the bone UV irradiation. This finding will help marrow of UV-irradiated mice actively us determine the relative role of UV suppressed ongoing responses in and vitamin D3 in regulating Crohn’s antigen-sensitised mice and suggested Disease. Furthermore, we have shown that the dendritic cells were not only that vitamin D3 and UV irradiation of poor in function but actively regulatory. skin have different effects on reducing We have continued to study large the symptoms associated with obesity. numbers of chimeric mice, i.e. mice During 2014, we continued to analyse engrafted with bone marrow cells from the impact of maternal vitamin D levels UV-irradiated mice or mice implanted on health outcomes in children born to for 3 days with pellets releasing the those mothers. The Raine cohort study prostanoid, prostaglandin E2. In these has allowed studies of the impact of chimeric mice, immune responses vitamin D in pregnancy on bone, lung initiated by dendritic cells and and brain developmental outcomes macrophages were minimal. in the children in childhood and In parallel studies we have investigated adolescence. the effects of UV-induced vitamin D3 Dr Jason Waithman, an NHMRC Career in control of immune cell activity and Development Fellow, is focusing on asthma and obesity models in mice. harnessing the power of the immune Humans obtain 90% of their vitamin system to eradicate primary and D3 from UV irradiation of skin so it has metastatic melanoma. T cells play a been proposed by us, and others, that pivotal role in the control and clearance UV-induced Vitamin D3 may contribute of tumours such as melanoma. Dendritic to the immunomodulatory effects of cells control these T cell responses UV. We have examined the effect of and he is interested in the type of vitamin D3 in excess (painted onto

ANNUAL REPORT 2014 | 95 instructions specific dendritic cells are believe that a lack of UV-induced providing to T cells during melanoma. vitamin D is responsible, but vitamin D His team has recently identified supplementation trials have not shown the dendritic cells that are involved the reduced disease progression that in coordinating T cell immunity to was hoped for. We propose that UV cutaneous melanoma. They are actively via vitamin D-independent pathways developing a vaccine that specifically may be responsible. We have initiated a targets these dendritic cells in order to trial of narrow band UVB phototherapy stimulate and activate T cells to expand for participants diagnosed with their and attack established tumours. first demyelinating event in the last 120 days. Participants are randomised Another focus of the lab is to improve to receive, or not receive, UVB existing immunotherapies that have phototherapy (24 sessions over 8 enormous potential to transform how weeks). Blood is taken for phenotyping oncologists treat patients with cancer. of immune cell subsets in their blood, Adoptive T cell therapy was recently and biobanking, over a 12 month selected by the journal Science as one period. We believe that this is the first of the most important breakthroughs in trial in the world of UVB phototherapy cancer immunotherapy. However, this for participants with Clinically Isolated treatment doesn’t help everyone and Syndrome. The trial is called PhoCIS as further refinements will improve patient it is Phototherapy for participants with outcome. His team is investigating Clinically Isolated Syndrome. whether type I interferon can enhance the therapeutic efficacy of adoptive T Funded by NHMRC cell therapy. The effect of vitamin D and UV UVB phototherapy for participants radiation on a preclinical model of with an early form of multiple Crohn’s disease sclerosis Simon Ghaly, Prue Hart Sian Geldenhuys, Prue Hart, Robyn Low vitamin D levels have been Lucas, Allan Kermode, Bill Carroll, David associated with increased incidence Nolan, David Booth, Judy Cole of Crohn’s disease. However Latitude gradients for the incidence of supplementation trials have not multiple sclerosis are well established, generally been successful. It is possible with more disease at higher latitudes that low vitamin D levels merely reflect when there is reduced sun. Exposure low sun exposure and that exposure to to sun has been linked with the UV may be a more realistic treatment initiation and progression of MS, and strategy. A preclinical model of Crohn’s there is evidence that sun exposure Disease was established using dextran is important at all stages of life for MS sulphate delivered in drinking water. pathogenesis, even in utero. Many Mice were fed deficient, sufficient and

96 | TELETHON KIDS INSTITUTE excessive levels of vitamin D in their that the cells differentiated from the diets, and this was superimposed bone marrow of UV-irradiated mice with UV phototherapy (low dose twice versus those from non-irradiated weekly). The preliminary results show control mice have increased glycolytic that UVB irradiation was protective activity, with no difference observed in for the pathology of Crohn’s Disease mitochondrial respiratory function. This in mice on a vitamin D-deficient suggests that metabolism and function diet. However the mice on the diet of dendritic cells may be linked. Mice containing the highest levels of vitamin were also given the demethylating D had the worst pathology. Assessment agent, 5-Aza-2-deoxycytidine, at the of all the tissues removed from the mice time of UV irradiation of skin. As the is ongoing. function of bone marrow-derived dendritic cells was restored in mice Funded by special grant to Simon given 5-Aza-2-deoxycytidine, we Ghaly by Gastroenterology Society of believe that an epigenetic event was Australia involved. Effect of UV irradiation of skin on Funded by Asthma Foundation WA, the glycolytic activity of dendritic Scott Kirkbride Melanoma Research cells generated by culture from the Foundation bone marrow. Is an epigenetic event involved? Effect of a short Prostaglandin E2 pulse on bone marrow cells engrafted Terry McGonigle, Royce Ng, Prue Hart into chimeric mice We have previously shown that signals Terry McGonigle, Will Kermode, Naomi sent from skin irradiated with erythemal Scott, Prue Hart. UV to the bone marrow stimulate the development of dendritic cells that Regulatory dendritic cells are generated are poorly immunogenic and cannot by culture of bone marrow cells from induce a strong immune response. UV-irradiated mice or mice exposed Similar responses have been detected to subcutaneous pellets releasing following multiple exposures to sub- prostaglandin E2. To determine whether erythemal UV radiation. The phenotype prostaglandin E2 acts directly on bone and function of cells generated marrow cells, or indirectly via an effect by culture from the bone marrow on other cells, the outcome of a 60 of animals administered a single minute pulse of bone marrow cells with inflammatory dose of UV, or multiple a stabilised derivative of prostaglandin lower doses of UV radiation, were E2, namely 16,16-dimethyl prostaglandin analysed. We studied that metabolism E2 (dmPGE2) , was investigated. of dendritic cells generated from the Dendritic cells differentiating from bone marrow of UV-irradiated mice. bone marrow given a dmPGE2-pulse Contrary to our hypothesis, we believe were similarly poor at inducing new

ANNUAL REPORT 2014 | 97 immune responses. Then, to remove is blocked by the administration of the potential artificial effect of bone indomethacin and again suggests marrow cell culture, we established that inflammation-induced PGE2 chimeric mice with bone marrow cells is responsible. We also gave mice pulsed with dmPGE2. The efficiency the demethylating agent, 5-Aza-2- of the engrafted dendritic cells was deoxycytidine, at the time of allergen sought with increasing time after bone airways challenge. This removed the marrow cell engraftment (CD45.1 into effect of inflammation-induced PGE2 CD45.2 mice). After 2-3 weeks, the on bone marrow-derived dendritic differentiating dendritic cells had poor cell function, and suggested the priming ability but after 16 weeks, this involvement of an epigenetic event. We effect was no longer detected. This propose that the formation of regulatory suggested that the effect of PGE2 may dendritic cells in the bone marrow be dose-dependent and reversible. In is part of a homeostatic mechanism experiments in which the recipient mice, to limit the destructive properties of not the donor mice, were UV-irradiated, respiratory inflammation. no differences were detected and Funded by Asthma Foundation WA suggested that the effect of PGE2 was direct on haemopoietic progenitors in The effects of vitamin D deficiency on the bone marrow. inflammation and the microbiome of Funded by Asthma Foundation WA, the lungs Scott Kirkbride Melanoma Research Shelley Gorman, Denise Anderson, Foundation, Multiple Sclerosis Research Claire Weeden, Luke Berry, Vanessa Australia Fear, Martin Feelisch, Sian Geldenhuys, Effect of experimental allergic airways Alex Larcombe, Anthony Kicic, Prue disease on bone marrow-derived Hart dendritic cells In 2014 we continued to examine the effects of vitamin D deficiency on lung Naomi Scott, Royce Ng, Terry inflammation, with a new focus on McGonigle, Prue Hart. the role of the microbiome. In these In response to UV-induced inflammation studies, we compared the effects of of the skin, bone marrow-derived dietary vitamin D with of gestational dendritic cells and macrophages are and neonatal vitamin D deficiency regulatory. To determine whether the induced by feeding female mice and effect is unique to skin inflammation, their offspring a diet deficient in vitamin the effect of inflammation at other tissue D. Our published studies suggest that sites has been examined. In response the severity of allergic airway disease to inflammation in the airways, bone is worse in the vitamin D-deficient mice marrow derived dendritic cells are supporting the hypothesis that vitamin regulatory. Further their development D has a regulatory role in systemic

98 | TELETHON KIDS INSTITUTE immune diseases such as asthma. Diabetes. Exposure to low-dose UVR In addition we found that vitamin D also had beneficial effects on weight controls asthma-inducing inflammatory gain, adipose tissue accumulation, cells in the lungs in a gender-specific glucose intolerance and insulin fashion through the regulation of resistance and other risk factors for respiratory bacteria. In more recent the metabolic syndrome in mice fed a studies, we observed increased high diet. The effects of UV irradiation inflammation and bacteria levels in the were independent of any change in lungs of naïve vitamin D-deficient male vitamin D status. We also demonstrated mice. These effects could be reversed that some of the UV-related effects on by vitamin D supplementation. In obesity development occurred through studies with researchers from Denmark a nitric oxide dependent pathways. (Dr Kenneth Barford, National Research These studies involved collaborations Centre for the Working Environment; with British researchers, Professors Dr Michael Roggenbuck, University Richard Weller (University of Edinburgh) of Copenhagan) we have used high and Martin Feelisch (University of throughput sequencing to examine Southampton). how vitamin D deficiency may affect the Funded by the Brightspark Foundation type of bacterial species that compose and the Telethon Kids Institute the microbiome of the lungs. We are now examining whether changes Cross-presentation of cutaneous to the microbiome and structure of melanoma antigen by migratory the lung epithelium may contribute XCR1+CD103- and XCR1+CD103+ towards the increased lung microbiota dendritic cells and inflammation observed in vitamin D-deficient mice. Ben Wylie, Elke Seppanen, Kun Xiao, Rachael Zemek, Damien Zanker, Sandro Funded by the Brightspark Foundation Prato, Bree Foley, Prue H. Hart, Richard Ultraviolet radiation suppresses A. Kroczek, Weisan Chen and Jason obesity and symptoms of metabolic Waithman syndrome independently of vitamin D The question of which dendritic cells (DCs) cross-present peripheral Sian Geldenhuys, Prue Hart, Raelene tumor antigens remains unanswered. Endersby, Peter Jacoby, and Shelley We assessed the ability of multiple Gorman skin-derived and lymphoid resident In 2014 we published our studies DCs to perform this function in a investigating the suppressive effects novel orthotopic murine melanoma of skin exposure to ultraviolet radiation model where tumor establishment on the development of signs of and expansion is within the skin. obesity and the metabolic syndrome Two migratory populations defined in the leading endocrinology journal, as CD103-XCR1+ and CD103+XCR1+

ANNUAL REPORT 2014 | 99 efficiently cross-presented melanoma- immunosurveillance program that derived antigen, with the CD103-XCR1+ can protect and treat individuals with DCs surprisingly dominating this cancer. It has been shown that distinct process. These results are critical for dendritic cell subpopulations have the understanding how anti-tumor CD8+ T potential to drive specific specialized cell immunity is coordinated to tumor CD4+ T cell responses. We intend to antigens present within the skin. describe which subtypes are involved in MHC II presentation during melanoma Funded by NHMRC, Cancer Australia, progression and elucidate whether Cure Cancer Australia Foundation and individual subtypes are promoting UWA Postgraduate Award to BW distinct CD4+ T cell responses. We Identification of the cell types hope to find that certain dendritic cells involved in MHC class II presentation drive a more productive response of cutaneous melanoma-derived and that this knowledge provides the antigens and characterization of the foundations for translational studies ensuing T cell response targeting maximal antitumour CD4+ T cell responses. Ben Wylie, Prue Hart and Jason Funded by NHMRC, Cancer Australia, Waithman Cure Cancer Australia Foundation and The role of CD4+ T cells in anti- UWA Postgraduate Award to BW melanoma remains controversial and poorly understood. This lack of clarity type I interferon enhances the is due to multiple factors that include therapeutic efficacy of adoptive T cell the models used to interrogate their therapy response and the complexity of their Anthony Buzzai, Vanessa Fear, Willem biology. Upon antigen recognition, Lesterhuis, Raelene Endersby, Andreas CD4+ T cells can differentiate into Behren, Prue Hart and Jason Waithman diverse subsets defined by a specific phenotype. Although this plasticity Immunity commonly observed during is well documented, the historic acute viral infection is identical to what description focuses on their role as a we would like to induce and sustain helper cell in enhancing and sustaining against cancer. Type I interferons the “more important” CD8+ T cell (IFN-I) are one of the first cytokines response, which eliminate cancer produced during a viral infection by direct cytotoxicity. While this help and are responsible for directly and is still extremely important, recent indirectly modulating the anti-viral studies show that CD4+ T helper cells immune response. Thus, it is logical that can mediate tumor regression on IFN-I has the potential to enhance anti- their own and such cells are termed tumour immunity. However, systemic cytolytic CD4+ T cells. Thus, CD4+ T administration of IFN-I to melanoma cells can orchestrate a comprehensive patients has not improved overall

100 | TELETHON KIDS INSTITUTE survival. This treatment has been Thomas Gebhardt and Jason Waithman limited to the use of only one subtype, Until recently, it has been widely IFN-2. Considering 13 additional accepted that memory T cells are a subtypes exist, we asked whether other heterogeneous population, comprised IFN-I subtypes have an effect against of two subsets: central memory (TCM) melanoma and if they could be used to and effector memory (TEM) CD8 T cells. increase the efficacy of adoptive T cell TCM cells circulate within secondary therapy. lymphoid organs, where they lack Funded by NHMRC and UWA immediate effector function, instead Postgraduate Award to AB having the capability to proliferate and differentiate into cytotoxic T cells. Personalised therapeutic peptide TEM cells are excluded from the lymph vaccination targeting mutated cancer nodes and unlike TCM cells, have antigens immediate effector functions. Recently, Paul Watt, Mark Cruickshank, Justine a third subset of memory T cells has Mintern, Shane Stone, Timo Lassmann, been recognised, known as tissue- Raelene Endersby, Anthony Bosco, resident memory T cells (TRM). TRM Alex Gout, Bree Foley, Katrin Hoffmann, cells are found primarily at barrier sites Robyn Lucas and Jason Waithman including skin, gut, lungs and genital tracts, as well as the brain where they The paradigm for cancer treatment is provide superior protection against evolving from non-specific cytotoxic local viral challenge. Research on TRM agents to selective, mechanism-based cells has mainly centred on their role therapies. A successful example is in viral infections. It has been observed immunotherapy, with this modality that post-viral infection; the TRM subset now proving to be an effective adjunct remains resident at the site of pathogen therapy for patients with cancer. Indeed, entry, where they can efficiently control the journal Science recently named secondary challenge. For example, TRM cancer immunotherapy ‘The 2013 cells have demonstrated the ability to Breakthrough of the Year’. The most confer immediate protection in the skin promising and effective immune-based of herpes simplex virus infected mice therapies harness the activity of helper when presented with viral re-challenge. and killer T cells. The overall aim of this We are investigating whether these project is to use a novel therapeutic TRM cells are present after tumour peptide vaccine strategy to generate T clearance or remission and if they are of cell immunity directed against mutated a similar phenotype to those observed cancer antigens. in viral infections. Funded by NHMRC Funded by NHMRC The role of tissue-resident memory T cells in cutaneous melanoma

ANNUAL REPORT 2014 | 101 Staff and Students Theses passed

Research Staff Samantha Winter BSc Honours

Prue H Hart BSc (Hons) MSc PhD, Ayesha Dhillon-LaBrooy BSc Honours Principal Research Fellow Jason Waithman BSc (Hons) PhD, Awards NHMRC Career Development Fellow Shelley Gorman BSc (Hons) PhD, Prue Hart: Research Fellow NHMRC: Robyn Lucas BSc MBCHB MPH&TM 1067209Narrow band UVB PhD MHE FAFPHM, Institute Strategy phototherapy for patients with Clinically Leader Isolated Syndrome: A phase 1 trial Terence McGonigle BSc (Hons), PH Hart, DR Booth, A Kermode, Research Assistant D Nolan, R Lucas, W Carroll, J Cole $660,558.00 2014-2016 Postgraduate Students Other: Ben Wylie (Hons), PhD candidate SEDS: Sun exposure versus vitamin D Sian Geldenhuys, PhD candidate supplementation for human health R Lucas, R Neale, PH Hart, Anthony Buzzai (Hons), PhD candidate $582,911 2013-2015 Rachel Foong BSc (Hons), PhD Cancer Australia Candidate Epigenetic changes to dendritic cell Elouise Greenland BSc (Hons), PhD progenitors in the bone marrow of mice Candidate, Dept Pharmacology with inflammatory airways PH Simon Ghaly MBBS, FRACP, PhD Hart $26,175 2013-14 Asthma Fdn Candidate, Dept Medicine WA Tenielle George (Hons), PhD candidate A novel immune component of the susceptibility formula for melanoma Honours Students PH Hart Chelsea Wilson BSc S Gorman $75,000 2014 Scott Kirkbride Melanoma Foundation MSRA Vacation Scholar (10 weeks) Shelley Gorman: William Kermode National Health and Medical Research Council Project Grant (2013-2015: Zosky, Henry, Gorman, LeCras; $618,108, The link between vitamin D deficiency

102 | TELETHON KIDS INSTITUTE and chronic lung disease is due to to melanoma”; Sole CIA Waithman; increased airway smooth muscle, Funding Source: NHMRC; Duration: 4 #1042235). years (2014-2017); Amount: $404,884 Department of Health (Western Linkage Infrastructure, Equipment Australia) Merit Award Project and Facilities Grant: LE150100066 – Fellowship (2014: $5,000: Harnessing “A breakthrough in multidimensional ultraviolet radiation to curb the systems biology”; PI Waithman; Funding development of obesity) Source: ARC; Duration: 1 year (2014); Amount: $440,000 Asthma Foundation of Western Australia Grant (2015: Gorman, Project Grant: APP1052141 – “Induction Matthews, $24,821). Exploring the of adaptive immunity during melanoma”; effects of maternal obesity on asthma Sole CIA Waithman; Funding Source: pathogenesis. Cancer Australia and Cure Cancer Australia; Duration: 2 years (2013-2015); UWA, Faculty of Medicine, Dentistry Amount: $199,245 and Health Science Near Miss Grant (2014: Gorman, Mori, Lucas, Matthews, Siafarikas, Oddy, Jakoby; $70,000). Could sunlight be harnessed for the Invited Presentations control of obesity and metabolic Prue Hart: syndrome? June: Invited speaker, Endocrinology Scott Kirkbride Melanoma Research Forum, SCGH, Nedlands Centre Priming Grant (2014: Hart, Gorman; $75,000). A new component of August: Invited speaker, Lung Club, the susceptibility formula for melanoma. SCGH, Nedlands Princess Margaret Hospital Foundation Speaker, Raine meeting. Seed Grant (2014: Oo, Gorman, Le September: International Photobiology Souef, Zhang $20,000). Analysis Congress, Cordoba, Argentina, Invited of vitamin D and cathelicidin levels Symposium speaker (free registration) in children with acute asthma exacerbations in relation to viral October: Invited speaker, National analysis. SKMRF Melanoma Conference, Perth Jason Waithman: November: Invited symposium speaker, MEPSA/AHMRC, Melbourne Project Grant: CIA Waithman; “Paediatric brain tumour immunotherapy”; Funding Invited speaker, Endocrinology Source: Telethon Adventurers; Duration: symposium for M Maclean from 3 years (2015-2017) Amount: $375,000 Westmead Hospital Career Development Fellowship Shelley Gorman: Level 1: APP1066869 – “Immunity

ANNUAL REPORT 2014 | 103 The Inaugural Developmental Origins of Health and Disease Society of Australia and New Zealand Meeting (Perth, April 2014). Does vitamin D really have any role in autoimmunity or allergy? The Annual Scientific Meeting of the Australian Endocrine Society (Melbourne, August 2014). Tissue- specific effects: Vitamin D action in the immune system. Jason Waithman: Invited national speaker: Cure Cancer Australia Researcher Symposium (2014) Invited national seminar: Melanoma WA (2014), Perth Cancer Club (2014)

External Committees

Prue Hart: Invited Member, NHMRC Academy Sole External Member, Deputy Chair, Royal Perth Hospital Medical Research Foundation Scientific Committee. Member, Organising Committee, Australasian Society for Dermatology Research Annual conference, Adelaide, May 2015. Shelley Gorman: Molecular and Experimental Pathology Society of Australia (Hon. Secretary)

104 | TELETHON KIDS INSTITUTE ANNUAL REPORT 2014 | 105 LUNG GROWTH AND RESPIRATORY ENVIRONMENTAL HEALTH

We have three major research themes (Collaborators: Prof Steve Stick, PMH; 1) early life determinants of lung growth, Prof Peter Sly, UQ, Prof Barry Marshall, 2) respiratory environmental health and UWA) and environmental exposure 3) mechanisms of airway dysfunction studies (Collaborators: Dr Peter Franklin, in asthma. These research themes WA Department of Health, A/Prof Ben overlap in several areas and underpin Mullins, Curtin). We also combine our our overall goal to understand the measures of lung function with structural early life factors that contribute to (stereology and in vivo imaging) and respiratory disease. These factors genetic studies (Collaborators: Dr include environmental exposures, Anthony Bosco, Telethon Kids Institute) viral infection, allergic sensitization, with a view to understanding critical nutritional deficiencies and genetic pathways involved in lung growth and variability in innate lung function development and how these may be responses. It is becoming increasingly altered by early life insults resulting clear that early life exposures make a in a predisposition for disease. These substantial contribution to respiratory studies on early life factors that impact morbidity and by understanding key on lung growth and disease are lung development processes we aim to complemented by our ongoing work design interventions that will ultimately examining the mechanisms of airway prevent the onset of respiratory hyper-responsiveness in obstructive disease and improve lung health in the disease. These studies are largely community. driven by A/Prof Peter Noble’s in vitro and in vivo (human/animal model) work This research relies heavily on which tests new concepts of airway mouse models and the state of the smooth muscle physiology and how art techniques for assessing lung these impact airway function in health function and structure that have and disease (Collaborators: A/Prof Alan been developed in our laboratory James, SCGH; Prof Howard Mitchell, through ongoing collaborations with UWA; Dr Peter McFawn, UWA; Prof Prof Zoltan Hantos (University of David Sampson, UWA; A/Prof Robert Szeged, Hungary) and Prof Peter Sly McLaughlin, UWA). (University of Queensland). These studies involve a multi-disciplinary approach whereby epidemiological and clinical studies inform the design Early life determinants of of mechanistic animal studies; which lung growth are in turn used to identify issues that require further investigation in terms Vitamin D deficiency and lung growth of clinical outcomes and public health. Rachel Foong, Shelley Gorman, Prue This approach is facilitated through Hart, Tim LeCras (Cincinnati) Graeme collaborations with researchers Zosky (University of Tasmania) examining clinical outcomes

106 | TELETHON KIDS INSTITUTE There has been a dramatic increase in the role of vitamin D deficiency airway recent decades in the prevalence of remodelling in chronic lung disease. vitamin D deficiency in Australia and Rachel has published work showing worldwide. Vitamin D deficiency is that vitamin D deficiency causes airway associated with a number of diseases hyperresponsiveness and increases including, 1) the bone disorder rickets airway smooth muscle mass in female (due to the importance of vitamin D in mice. These are central features of calcium homeostasis), 2) autoimmune many chronic lung diseases and may disorders and 3) cardiovascular explain the link between vitamin D disease. Recent prominent publications deficiency and chronic lung diseases. have also implicated vitamin D in the She has also found that in utero pathogenesis of obstructive lung vitamin D deficiency was sufficient to diseases such as asthma and COPD. alter lung structure and function and Additionally, epidemiological studies differentially regulate genes important have shown a strong association in lung development. Finally, she has between serum vitamin D levels and also demonstrated in a mouse model lung function suggesting an important of chronic allergic asthma that vitamin link between vitamin D status and lung D can modulate asthma-related genes health. However, there had been no and contribute to asthma symptoms. study showing a direct lung between Rachel will include this work in her PhD vitamin D deficiency and lung growth/ thesis, which will be submitted in 2015. structure/function. In 2010 we published Funding: NHMRC Project Grant (2013- a study in the leading respiratory journal 2015). (American Journal of Respiratory and Critical Care Medicine) on the lung structure and function of mice raised on vitamin D deficient and replete Respiratory environmental diets. We showed for the first time health that vitamin D deficiency alters lung structure resulting in significant deficits Environmental health of remote in lung function. This study received Aboriginal communities considerable public interest resulting Holly Clifford, Graeme Zosky (University in an international media release by of Tasmania), Roz Walker, Glenn the American Thoracic Society and Pearson interviews for ABC Radio National. These studies are ongoing and we There is a significant gap in health now plan to identify the mechanism between Aboriginal and non-Aboriginal of vitamin D deficiency induced Australians. This is particularly true for alterations in lung growth. This work respiratory health and in individuals is being pursued by Rachel Foong living in remote communities. In who began a PhD in 2011 examining 2011 we commenced a research

ANNUAL REPORT 2014 | 107 program designed to assess the role mouse model of acute diesel exhaust of the environment, with a focus on particle (DEP) exposure using intra- water quality and dust exposure, in nasal instillation of DEP (ie small contributing to poor lung health in amounts of DEP in solution are placed these communities. We have travelled on the nose of mice and inhaled). We to several communities of the Martu followed this by establishing a more people in the eastern Pilbara as well realistic mouse model of whole diesel as Bidyadanga in the Kimberley region. exhaust exposure by exposing mice We have collected water and dust to exhaust generated by a Euro 1 samples for analysis of heavy metal diesel engine under partial load. In contamination and we have now begun 2013 we performed a comparative expanding this program to conduct study investigating the effect of real-time monitoring of the inhalable route of exposure on the respiratory dust with a view to estimating exposure consequences of diesel exhaust levels in the communities. We have also exposure. We exposed mice to diesel begun investigating the role of iron in exhaust via inhalation and to identical dust and how this contributes to the particles in solution via instillation. severity of the response to respiratory Exposure via either route elicited infection. This year, we plan to examine pulmonary inflammation and changes in the specific effects of dust on the cells lung function. We identified significant of the human airway, and to investigate differences in response between the how dust exposure contributes to the two routes of exposure, with mice severity of common bacterial infections exposed via inhalation generally seen in Aboriginal children. displaying more realistic dose-response relationships. Mice exposed via Funding: BrightSpark Foundation; intranasal instillation responded more Thoracic Society of Australia and New variably, with little influence of dose. Zealand; The Raine Foundation Our results suggest that selection Diesel exhaust exposure and of the route of exposure is of critical its effects on lung function and importance in studies such as this. exacerbations of airways disease Further, inhalation exposure, while more methodologically difficult, resulted in Alexander Larcombe, Ben Mullins responses more akin to those seen in (Curtin), Ryan-Mead Hunter (Curtin), humans. These data were published in Anthony Kicic 2014 in Inhalation Toxicology. This ongoing project is designed to Biodiesel exhaust exposure and investigate the mechanisms behind respiratory health air pollution (specifically diesel exhaust and woodsmoke) induced Alexander Larcombe, Ben Mullins exacerbation of airways disease. In (Curtin), Anthony Kicic 2009 and 2010 we established a Biodiesel is a renewable fuel made

108 | TELETHON KIDS INSTITUTE from a variety of plant or animals oils. It type (canola) there were significant is often seen as a “green” or healthier differences in response to different alternative to finite sources of mineral blends. In general, exposure to exhaust diesel, however, recent studies show from B100 or B20 combustion resulted that biodiesel exhaust has certain in greater inflammation and reduced physical and chemical characteristics viability compared to exposure to that also make it dangerous to health. mineral diesel exhaust. Apoptosis was This ongoing study employs a range of highest in cells exposed to mineral in vitro and in vivo exposure studies, diesel exhaust. These data were detailed physical and chemical published in 2014 in Environmental assessment of exhaust characteristics Toxicology. and gene expression profiling to Funding: Thoracic Society of Australia identify what characteristics make and New Zealand, Friends of the a “healthy” or “unhealthy” biodiesel Institute. and understand the mechanisms of biodiesel exhaust induced disease. The respiratory health effects of In 2012 we made and combusted our electronic cigarettes own canola biodiesel, and measured a Alexander Larcombe, Peter Franklin range of physico-chemical properties (Department of Health, Western of the exhaust. We found that canola Australia), Ben Mullins (Curtin) biodiesel combustion produced a greater number of particles <1μm in Electronic cigarettes (“e-cigarettes”) diameter and particles with a higher heat and atomize a liquid solution surface area to volume ratio compared (“e-juice”) producing an aerosol to mineral diesel particles. We also which is inhaled. They are a very new showed that canola biodiesel exhaust technology and their use is widespread contained greater amounts of oxides and increasing rapidly especially in of nitrogen, carbon monoxide, carbon adolescents. In many countries, the dioxide and oxides of sulfur compared number of people regularly using to mineral diesel. In late 2012 we also e-cigarettes is doubling annually, exposed human airway epithelial cell and there are an estimated 200,000 cultures to diluted exhaust generated current Australian users. Despite this, by combusting mineral diesel, 100% the potential for e-cigarette use to canola biodiesel, 20% canola biodiesel impact health is virtually unknown. This or pure canola oil in an unmodified knowledge gap has been recognized diesel engine under partial load. We as a research priority by international assessed cell viability and apoptosis 24 medical associations and it is this hrs after exposure, and inflammation knowledge gap that our proposed (IL-6, IL-8 and RANTES) 6, 12 and 24 research aims to help fill. The limited hours after exposure. We found that, data on e-cigarettes that exist suggest even using the same renewable oil that: (i) they are likely to have a negative

ANNUAL REPORT 2014 | 109 impact on health, especially in situations were also hyper-responsive to of pre-existing respiratory disease, (ii) methacholine (similar to tobacco pregnant women are more likely to smoke exposed mice) regardless of use them compared with conventional the presence or absence of nicotine. cigarettes and (iii) the type of e-cigarette This study shows, for the first time, e-juice can significantly influence that chronic exposure to e-cigarette health outcomes. In Australia, the laws vapour is not harmless to the lungs, and surrounding the importation, sale and results in significant impairments in lung use of e-cigarettes are vague, and hard- function. They also indicate that the data on their potential to impact health e-cigarette excipient used is important, are urgently required to guide policy with the most severe impairments seen makers. in mice exposed to vegetable glycerin based vapour. Our results suggest In 2014 we received Department of that caution should be exercised Health, Western Australia funding to when advocating e-cigarettes as a perform the first study investigating safe alternative to tobacco smoking, the long term respiratory health and that further research in this field is effects of electronic cigarette vapour warranted. exposure. We employed our expertise in pre-clinical exposure models In 2014 we also received an Asthma to expose mice to either tobacco Foundation of Western Australia smoke, medical air (control) or one Project Grant to study the potential of 4 different types of e-cigarette for e-cigarettes to exacerbate asthma. vapour from week 4 to week 12 of life. These studies are ongoing. E-cigarette vapours varied depending Funding: Asthma Foundation of Western on nicotine content (0 or 12mg/mL) Australia, Department of Health, and the main excipient (propylene Western Australia. glycol or vegetable glycerin). We then measured lung volume, lung mechanics, responsiveness to methacholine and pulmonary inflammation. Mice exposed Mechanisms of airway to tobacco cigarette smoke showed hyperreponsiveness in increased pulmonary inflammation asthma and responsiveness to methacholine, compared to air controls. Mice exposed Viral induced airway to e-cigarette vapour did not have hyperresponsiveness increased inflammation, but did display decrements in parenchymal lung Alexander Larcombe, Jennifer Phan, function at both functional residual Rachel Foong, Anthony Kicic, Steve capacity and high transrespiratory Stick, Peter Sly, Peter Noble (UWA), pressures. Mice exposed to vegetable Graeme Zosky (University of Tasmania) glycerin based e-cigarette vapours

110 | TELETHON KIDS INSTITUTE These studies span a number of disease in adult mice and that early different projects and involve infecting life infection plus allergic sensitization mice with respiratory viruses (primarily would enhance airway hyper- rhinovirus and influenza) at different responsiveness (AHR) in adulthood. To ages and under different conditions test these hypotheses, BALB/c mice (e.g. in the presence of other respiratory were inoculated with house dust mite insults). In 2010 and 2011 we focused and/or HRV before measurement of on 2 aspects; the role of neutrophil lung function and responsiveness to elastase in the progression of influenza methacholine. We also assessed viral induced airway hyperresponsivness load, cellular inflammation and serum (AHR) and the impact of diesel exhaust antibodies. The greatest effects were particle (DEP) exposure during acute seen in HDM exposed mice which influenza infection. In 2011 we published had altered lung mechanics, AHR and studies on the sexual dimorphism increased inflammation. There were in response to influenza infection limited effects of HRV alone, however in mice, and in 2012 we published in adult mice, additive effects of HDM a methodological study on the best and HRV contributed to neutrophilic technique to assess lung function in inflammation and there was an mice with influenza induced respiratory interaction between HDM and HRV disease. in some parameters of lung function. These data, which formed the basis In 2012 and 2013 we made significant of a 1st class honours project and progress in our studies on how were published in PLoS One in 2014 rhinovirus infection alters the In neonatal mice, more macrophages development of pathogenesis of were seen in mice exposed to both allergic airways disease. This was respiratory insults compared with either prompted by recent studies which show insult alone. Exacerbation of some that rhinovirus (HRV) infections account allergic airways disease symptoms was for ~90% of asthma exacerbations, seen due to the combination of HDM however our understanding of HRV- and HRV. Our manuscript on this topic is induced disease is incomplete. We currently under review. infected mice with HRV in early life and studied the effects of this infection Funding: UWA Research Development on lung function, and responsiveness Award (2010), ARC Discovery Grant to methacholine in adulthood. We (2011-2013), NHMRC Project Grant (2012- also superimposed a mouse model of 2014) allergic airways disease (house dust Airway smooth muscle as an mite) onto HRV infection to assess whether early life HRV infection independent predictor of asthma potentiates asthma development. Peter Noble, Alexander Larcombe, We hypothesised that HRV infection Graeme Zosky, Alan James (SCGH), would exacerbate allergic airways Timothy LeCras (Cincinnati), Kimberley

ANNUAL REPORT 2014 | 111 Wang in mice that are Egr-1 deficient. We now have preliminary data in Egr-1 deficient The primary airway structure/function mice exposed to doxycycline for 10 abnormalities in asthma include days demonstrating greater ASM mass, increased airway smooth muscle increased airway narrowing and lung (ASM) mass and exaggerated airway resistance to methacholine challenge. narrowing. Importantly, recent data We also found that ASM mass also show that ASM mass is increased correlates to baseline resistance. early in the natural history of asthma and remains relatively constant In 2014, we have combined this non- throughout life. This argues against inflammatory transgenic mouse model the conventional paradigm whereby of ASM remodelling with an established repeated allergic inflammation allergic mouse model. We found that drives the remodelling process. We allergic inflammation does not enhance hypothesise that the mechanism airway hyperresponsiveness produced producing increased ASM in asthma is by thickening of the ASM layer. Findings independent of allergic inflammation bring into the question the perceived and that the combination of increased causal relationship between allergy ASM mass and allergy is required to and remodelling which may instead be produce allergic asthma. The specific independent features of asthma. aim of the project is to combine a newly Funding: NHMRC Project Grant (2012- developed mouse model of increased 2014) ASM mass with an existing model of allergic airway disease to assess the Impact of intrauterine growth relative contributions of ASM mass and restriction on airway smooth muscle allergic inflammation to the asthmatic and the development of asthma phenotype. Kimberley Wang, Peter Noble, This NHMRC funded project began Alexander Larcombe, Sandra Davidge in 2012. The first stage of the project (Alberta) was to have the required mouse genotypes re-derived and sent to our Epidemiological studies have Perth laboratory. The mouse models demonstrated that growth restriction in were charactered by our collaborator the womb (termed intrauterine growth Professor Timothy Le Cras in his Ohio restriction; IUGR) is associated with (USA) based laboratory. The required respiratory disease (including asthma) mouse genotypes have now been in childhood and persistent chronic successfully re-derived and the mouse lung disease in adulthood. However, it colony established at TICHR. In 2012- is still not known why growth restriction 2013 we exposed mice to doxycycline, in early life can lead to respiratory which upregulates TGFalpha expression disease. Our hypothesis is that IUGR in the airways, producing ASM growth is associated with increased airway smooth muscle at birth and this

112 | TELETHON KIDS INSTITUTE represents an independent risk factor Research, The University of Western for the development of asthma. Australia In this study, we collaborated with Kimberley Wang PhD Professor Sandra Davidge (University Research Officer, Telethon Kids Institute of Alberta) and together we have established a BALB/c mouse model Lecturer, Centre for Child Health of maternal hypoxia-induced IUGR. In Research, The University of Western 2013, we have determined the optimum Australia oxygen concentration to house the Peter Noble PhD pregnant dams during the period of embryonic airway development to Research Assistant Professor, University induce IUGR on the offspring. Our of Western Australia (Honorary member) preliminary data show that offspring to Graeme Zosky PhD dams exposed to hypoxic conditions are 19% lighter at birth but displayed Lecturer, University of Tasmania “catch up growth” at 2 weeks old, which (Honorary member) is often seen in IUGR offspring. Luke Berry BSc In August 2014, we managed to secure Laboratory Manager, Telethon Kids the Asthma Foundation Western Institute Australia New Investigator Grant to fund Maxine Janka BSc(Hons) this study. We will be increasing the sample size of this study in 2015. Research Assistant Rachel Foong BSc(Hons) Staff and Students Part-time Research Assistant, Telethon Kids Institute Head of Group Postgraduate Students

Alexander Larcombe PhD Rachel Foong BSc(Hons) PhD Senior Research Fellow, Telethon Kids Candidate Institute Research Support Associate Professor, Centre for Child Health Research, The University of Ms Marina Stubbs, Administration Western Australia Officer Research Team

Holly Clifford PhD Awards Research Officer, Telethon Kids Institute Alexander Larcombe - Telethon-Perth Children’s Hospital Research Fund 2013 Lecturer, Centre for Child Health

ANNUAL REPORT 2014 | 113 (Round 2) $217,000 External Committees Alexander Larcombe - Department of National Health, Western Australia $49,000 Alexander Larcombe - NH&MRC Early Alexander Larcombe - Australasian Career Fellowships Panel Society of Clinical Immunology and Allergy (ASCIA) Annual Conference Best Alexander Larcombe - NH&MRC Poster (Allergy) Postgraduate Scholarships Panel Alexander Larcombe - TSANZ Alexander Larcombe - Safe Work Annual Meeting, Occupational and Australia Expert Work Health & Safety & Environmental Lung Disease Best Workers’ Compensation Panel Presentation Alexander Larcombe – Rebecca L Alexander Larcombe - TSANZ Janet Cooper Medical Research Foundation Elder International Travel Award Scientific Review Committee Kimberley Wang - Friends of the Institute - Provision of Financial Support Local for Researchers and Research - $2,500. Holly Clifford - Thoracic Society Kimberley Wang – TSANZ Travel Grant of Australia & New Zealand (WA) - $540. Associates Committee. Kimberley Wang – Barbara May Alexander Larcombe - University Scholarship, Telethon Kids Institute - of Western Australia Animal Ethics $4,900. Committee. Holly Clifford - The Raine Foundation Kimberley Wang - Australian Society Priming Grant $200,000 for Medical Research (WA) committee Holly Clifford - Robert Pierce Grant-in- member. Aid for Indigenous Lung Health Award $15,000 Holly Clifford - TSANZ/Japanese Invited Presentations Respiratory Society Early Career Alexander Larcombe - Curtin Health Development Award Innovation Research Institute, Perth, July Rachel Foong - Perron Performance 2014. “Biodiesel Exhaust – the Need for Award Health Effects Research”. Rachel Foong - Asthma Foundation Alexander Larcombe - Thoracic Society of Western Australia PhD Scholarship of Australia and New Zealand, Western Top-Up Australia Branch Annual Meeting. Perth, July 2014. “Biodiesel Exhaust – the Need for Health Effects Research”.

114 | TELETHON KIDS INSTITUTE Alexander Larcombe - University of Western Australia Western Australia - School of Anatomy, Physiology and Human Biology, Perth, May 2014. “Ventilation systems - how to make a decent gas exchange system”. Alexander Larcombe - Ondek Pty Ltd. Perth, February 2014. “Measuring Lung Function and AHR in Mice …and results to date”.

ACTIVE collaborations

Prof Alan James, Sir Charles Gairdner Hospital, WA Prof Zoltan Hantos, University of Szeged, Hungary Prof Peter Sly, University of Queensland, QLD Prof Steve Stick / Dr Anthony Kicic, Princess Margaret Hospital, WA Assoc Prof Ben Mullins / Dr Ryan Mead- Hunter, Curtin University, WA Dr Alma Fulurija / Prof Barry Marshall, University of Western Australia Professor John Mamo, ATN Centre for Metabolic Fitness, Curtin University, WA Assoc Prof Timothy LeCras, Cincinnati Children’s Hospital, USA Professor Sandra Davidge, University of Alberta, Canada Professor Peter Henry, University of Western Australia Prof Peter Richmond/Dr Ruth Thornton, University of Western Australia Dr Peter Franklin, Department of Health,

ANNUAL REPORT 2014 | 115 ORIGINS PROJECT

ORIGINS is a new birth cohort study, (such as nutrition, physical activity, based upon the Developmental sleep, time spent indoors and outdoors, Origins of Health and Disease (DOHaD) smoking and pollutants, microbial hypothesis: preventive intervention diversity, water, air and food quality) strategies are best targeted in early are the most logical, large scale life. The Project is the result of strong and effective long-term strategies expertise and experience in the to improve all aspects of physical DOHaD Field in WA, an initiative led by and psychological wellbeing, both UWA and the Telethon Kids Institute. in childhood and in later life. Nested The Project is designed to collect within the main observational cohort detailed information about how the will be a series of intervention studies. early environment influences the risk Building upon the success of the Raine of a broad range of early and later Study, this new birth cohort will have onset diseases including asthma, detailed data and sample collection, allergies, diabetes, obesity, renal including detailed environmental and disease, mental health disorders and biological profiling using cutting edge their many complications. We will recruit technologies such as metagenomics, women (and the father of their baby) immune profiling, metabolomics, and early in pregnancy and collect data genomics. on their health, diet, physical activity The ORIGINS Project encompasses patterns and a range of factors in their a wide engagement of clinicians, environment. We will then assess how researchers, and the community. these early life exposures influence We have collaborations with other their child’s growth, development, and national and international longitudinal health (including neurodevelopment, studies, ensuring harmonisation of evidence of allergies, infections, and research methods. ORIGINS is a large other medical history). collaboration of clinical disciplines, The greatest potential for improving all focused on taking a more future health lies in early intervention integrated approach from the outset and there is already substantial to ensure optimal capacity and inbuilt evidence that initiatives to promote interventions through translational a ‘healthy start to life’ can reduce research. the risk of both early and later non- ORIGINS is a new birth cohort study, communicable diseases with wide designed to collect detailed information social and economic benefits. about how the early environment The Project is grounded in making influences the risk of a broad range meaningful changes that will reduce of early and later onset diseases the risk of common health conditions. including asthma, allergies, diabetes, Interventions to improve modifiable obesity, renal disease, mental health aspects of the early life environment disorders and their many complications.

116 | TELETHON KIDS INSTITUTE We will recruit women (and the father of their baby) early in pregnancy and collect data on their health, diet, physical activity patterns and a range of factors in their environment. We will then assess how these early life exposures influence their child’s growth, development, and health (including neurodevelopment, evidence of allergies, infections, and other medical history). Funders: Joondalup Health Campus, Telethon Kids Institute

ANNUAL REPORT 2014 | 117 PAEDIATRIC RESPIRATORY PHYSIOLOGY

The Paediatric Respiratory Physiology unknown. The goals of this study are research group was established in to evaluate objective measurements of mid 2010 with the appointment of respiratory function and their combined Prof Graham Hall by the Telethon Kids ability to detect and monitor the Institute. The primary aim of the group presence of lung disease early in the is the assessment of lung growth and life of infants and young children with development in both health and in cystic fibrosis. respiratory disease, including asthma, This project is funded by the National cystic fibrosis and chronic lung disease Health and Medical Research Council of prematurity. of Australia and the USA Cystic Fibrosis Foundation Cystic Fibrosis Long term outcomes of infant lung function in cystic fibrosis Evolution of airway function and inflammation in early CF lung disease Investigators: Graham Hall, Stephen Stick, Sarath Ranganathan (VIC), Kathryn Investigators: Graham Hall, Stephen Ramsey, Caroline Gallagher, Tim Stick, Sarath Ranganathan (VIC), Rosenow and Rachel Foong as part Kathryn Ramsey, Caroline Gallagher, of the AREST CF collaboration (www. Jasmine Grdosic, Tim Rosenow and arestcf.org) Rachel Foong as part of the AREST CF As part of the AREST CF collaboration collaboration (www.arestcf.org) we have developed a unique and Cystic Fibrosis (CF) is a condition of internationally recognised early chronic inflammation and infection surveillance program for the detection resulting in destruction of lung of lung disease in CF that includes architecture eventually leading to death. complex measurements of lung function We and others have shown that infants obtained in infants newly diagnosed and young children with CF show with CF following newborn screening evidence of early inflammation and (NBS). We are the only group in the infection and reduced lung function. world to have comprehensively studied This highlights this period of life as a population-based cohorts of children critical period for the development of diagnosed by NBS using such tests. new treatments to prevent progression In this project we aim to evaluate or even reverse lung disease. the longer term lung structural and However, the development of lung functional outcomes associated with disease in early infancy is poorly lung function measurements made understood and ongoing relationships during infancy. These data will inform between peripheral lung function the clinical importance of measuring and measurements of pulmonary lung function during infancy in CF and inflammation or infection remain also the role of the tests in proposed

118 | TELETHON KIDS INSTITUTE early intervention studies in CF. Such Investigators: Graham Hall, Peter data are eagerly anticipated by the Franklin, Zoltan Hantos, Shannon global CF community. This project is Simpson, Mark Tan and Naomi Hemy funded by the National Health and with the Peel Child Health Study (www. Medical Research Council of Australia peelchildhealthstudy.com.au) Viral Pathogenesis of Early Cystic This project aims to assess the impact Fibrosis Lung Disease of prenatal environmental exposures on lung function in infancy. In particular we Investigators: Graham Hall, Stephen wish to: Stick, Sarath Ranganathan (VIC), Kathryn Ramsey, Caroline Gallagher and • Determine the impact of air Rachel Foong as part of the AREST CF pollution, particularly indoor air collaboration (www.arestcf.org) pollution, during the prenatal period on lung function in infancy. Infectious insults can profoundly change the trajectory of CF lung • Investigate the different measures disease. Virus infections can lead to of infant lung function for detecting significant morbidity, but their effect on early lung changes in response to the early origins and progression of CF prenatal environmental exposures. pulmonary disease is ill-defined. In this • Assess the impact of early life project, powerful nucleic acid-based exposure to air pollution on detection approaches will be used to respiratory symptoms during prospectively characterize infections infancy in infants, and determine the impact of This project is funded by the National viruses on bacterial colonization, airway Health and Medical Research Council of inflammation, physiological measures, Australia and structural changes, thus elucidating early pathogenic events in CF lung disease. This project is funded by the National Institutes of Health (USA) and Preterm birth and National Health and Medical Research Bronchopulmonary Council of Australia. dysplasia

Bronchopulmonary Dysplasia: Indoor air pollution and lung Identifying Cardiorespiratory health Consequences and Targets for Prevention and Intervention. Impact of exposure to air pollutants during the prenatal period on lung Investigators: Jane Pillow, Graham Hall, function in infancy Andrew Wilson, Zoltan Hantos, Shannon Simpson, Andrew Gill, Naomi Hemy,

ANNUAL REPORT 2014 | 119 Nada Townsi of cardiovascular, chest wall or respiratory muscle contributions to BPD Bronchopulmonary dysplasia (BPD) will provide novel data that will inform remains the most significant chronic planning for health service delivery lung complication of preterm birth and including identification of infants at the most common form of chronic lung high risk who may benefit from early disease in infancy. Although BPD is intervention, and development of often assessed in relation to the lung guidelines for additional screening and alone, the clinical picture is more of monitoring of extrapulmonary disease. a complex multisystem disorder with multiple antecedent contributory factors This project is funded by the National and extrapulmonary manifestations Health and Medical Research Council of including abnormal cardiac, pulmonary Australia vascular, chest wall and respiratory Investigation of the influence preterm muscle development as well as neurodevelopmental impairment. There birth on lung structure and function are few data to indicate the frequency in school age children or severity of abnormal cardiac, Investigators: Graham Hall, Andrew pulmonary vascular, chest wall and Wilson, Jane Pillow, Andrew Maiorana, respiratory muscle outcomes after very Shannon Simpson, Karla Logie, Chris preterm birth, and their contributions O’Dea, Maureen Verheggen. to respiratory problems in very preterm infants are unknown. Bronchopulmonary dysplasia (BPD) remains the most significant chronic We will approach BPD as a clinical lung complication of premature birth. disorder resulting from abnormal Contemporary BPD is dominated function of the integrated thoracic by peripheral lung abnormalities unit. We will quantify contributions of including failed alveolarisation with cardiovascular, respiratory muscular a decreased number of large and and pulmonary contributions to the simplified alveoli and abnormal development and persistence of the pulmonary vascular development. The new BPD clinical phenotype in a large few studies to examine the long term (n=500) regional cohort of very preterm respiratory outcomes in new BPD have infants by performing comprehensive demonstrated impaired gas transfer lung, cardiac and diaphragmatic reduced cardiopulmonary exercise function testing prior to initial hospital capacity, gas trapping and increased discharge and again at 12 months. Risk respiratory morbidity. None of these indices for perinatal adverse exposures studies undertook a comprehensive and abnormal function of each system assessment of lung structure, peripheral will be used to develop a predictive lung function and respiratory morbidity model for moderately severe BPD. The and examined the influence of neonatal identification of a significant incidence history on the long term outcomes of

120 | TELETHON KIDS INSTITUTE new BPD. Studies of this nature are Health and Medical Research Council essential and will provide an improved of Australia, Raine Foundation and understanding of the pathology of new Princess Margaret Hospital Foundation BPD and its long term outcomes and allow a more targeted approached to the treatment and management of Congenital Diaphragmatic infants with BPD through the neonatal period and into childhood. Hernia Key outcomes include Long-Term Respiratory, - Nearly all preterm children Cardiovascular and Quality of Life have abnormal lung structure, Outcomes of Neonatal Congenital irrespective of the presence of BPD. Diaphragmatic Hernia Patients in More structural abnormalities on chest Western Australia CT are associated with lower lung Investigators: Dr Jason Tan, Dr Corrado function in preterm children at 9-12 Minutillo, Prof Graham Hall, Prof Jan years of age. Dickinson, Mrs Maureen Verheggen, Dr - Children with a history of BPD Jim Ramsey and Georgia Banton more likely to exhibit exercise flow Babies born with a congenital limitation when compared to preterm diaphragmatic hernia are at risk of children without BPD and healthy significant morbidity and mortality. children. Acute problems generally arise from - All pre-term children have a pulmonary hypoplasia or agenesis, reduced exercise capacity, and children pulmonary hypertension and surgical with BPD have an altered ventilator intervention. Long-term complications pattern to exercise. have been documented however vary between units as management options - Preterm children (with and differ. There are no long-term data without BPD) had reduced lung function. available for the Western Australia Specifically, significant reductions in cohort at present. This study is a pilot spirometry, gas trapping and altered study to summarize the long-term peripheral lung mechanics. respiratory, cardiovascular, quality of life - Respiratory Symptoms and psychological well-being outcomes are increased in preterm children in our cohort of CDH patients. The irrespective of a diagnosis of BPD. baseline information will be used to Children with respiratory symptoms in develop a framework for a follow-up the last year had worse lung function program in Western Australia to improve outcomes than children without recent long-term outcomes and enable future symptoms. research in this area. This project is funded by the National This project is funded by the CH 7

ANNUAL REPORT 2014 | 121 Telethon Trust several risk factors for persistent and later-onset asthma in the cohort, and found that some asthma diagnosis tests Asthma do not work as well as current literature would suggest in community groups. Risk factors for the development of This project is funded by the National late onset and persistent asthma in Health and Medical Research Council of young adults: A longitudinal birth Australia cohort study Measurement of bronchial hyper- Investigators: Prof Graham Hall, Prof responsiveness in young children: Patrick Holt, Dr Elysia Hollams, Prof Mannitol and exercise challenge Zoltan Hantos, Prof Nick de Klerk, Dr testing Anthony Bosco, Elisha White and the Raine study team (www.rainestudy.org. Investigators: Prof Graham Hall, Dr au) Shannon Simpson, Prof Stephen Stick, Dr Afaf Albloushi and Ms Georgia Australia has one of the highest Banton Mr Mark Kendall incidences of asthma in the world, with 14-16% of children and 10-12% of adults Summary: The addition of objective diagnosed as asthmatic. Early-life measures of bronchial hyper- factors involved in the development responsiveness (BHR) to current of childhood asthma have been well clinical practice may result in explored however it remains largely improved diagnosis and management unknown whether these risk factors, of young children with exercise or other yet unidentified factors, related symptoms. This project aims are involved in the development of to determine the feasibility of BHR later onset asthma or persistence of testing using the forced oscillation childhood asthma into adulthood. While technique (FOT) as a primary outcome many children with asthma continue to of the mannitol challenge test in have asthma as adolescents and young pre-school children with exercise adult, some children grow out of their induced symptoms. In addition we aim asthma, equally some people develop to determine the agreement of the asthma for the first time as young mannitol challenge test and exercise adults. This study aims to examine challenge test in these children. the risk factors for the remittance and We found that 85% of children aged persistence of childhood asthma, as three to seven years and 100% of well as the development of later-onset children aged 4-7 years were able to asthma within 23 year old participants complete the mannitol challenge using of the Raine study birth cohort. Data FOT as the outcome measure. The collection for this project is now three children that failed to complete complete. We have already identified the test were three years of age and did

122 | TELETHON KIDS INSTITUTE not complete due to difficulty sustaining Early results have demonstrated that attention. exhaled nitric oxide can predict adverse events during anaesthesia, but that it Further research comparing mannitol is no better than asking children and and exercise challenge tests and to their parents a detailed medical history. define appropriate cut off levels to Other current work is looking at the support the diagnosis of excise induced best way to administer anaesthetic bronchoconstriction in young children is agents and if using salbutamol (for ongoing. example Ventolin) before surgery This project is funded by the Asthma reduces adverse events. Foundation of WA and Australian and This project is funded by the National New Zealand Society of Respiratory Health and Medical Research Council Science of Australia, State Health Research Risk Assessment and prevention Advisory Council and Princess Margaret of respiratory complications in Hospital Foundation paediatric anaesthesia

Investigators: Graham Hall, Britta Prediction and prevention Regli-von Ungern-Sternberg, Anoop Ramgolam, Lliana Slevin, Lara Oversby of peri-operative respiratory and Debbie Cooper adverse events (PRAE) Background: Despite the development of anaesthesia management guidelines, Obesity: the mechanics of lung perioperative respiratory adverse function impairment and risks related events (PRAE) remain a major cause to PRAE of morbidity and mortality during Background: In paediatric anaesthesia paediatric anaesthesia causing more obesity is a significant problem with than three quarters of critical incidents obese children not only having and nearly one third of all perioperative anaesthesia-relevant co-existing cardiac arrests. Perioperative diseases like asthma or hypertension, respiratory adverse events include but also having a higher incidence of laryngospasm, bronchospasm, stridor, anaesthesia related complications. severe coughing, oxygen desaturation Perioperative Respiratory Adverse and airway obstruction. Improving the Events (PRAE) are amongst the most identification of children at risk of PRAE common complications observed during the pre-anaesthetic assessment in this population and a previous and developing perioperative observational study has demonstrated preventive strategies incorporated into an increased likelihood of these an optimised anaesthetic management events occurring in these children. would reduce the occurrence of PRAE. Many factors encountered during

ANNUAL REPORT 2014 | 123 GROUP NAME

general anaesthesia such as supine injury, including atelectasis (collapse positioning (lying down, face up), of lung tissue), pneumonia (disease anaesthetic agents and the type of marked by inflammation of the lungs), surgery affect the functioning of the pneumothorax (presence of air within respiratory system and in particular lung the pleural cavity leading to lung volumes and respiratory mechanics. collapse), Acute Lung Injury (ALI) and These anaesthesia related changes in Acute Respiratory Distress Syndrome lung function are expected to be even (ARDS). Anaesthetic management can more significant in obese patients. contribute to these injuries, exacerbate Since PRAE remains the main cause any underlying lung conditions or even of perioperative morbidity, especially improve outcomes, depending on the in this population, a better knowledge specific situation. Moreover, several of both the changes in lung function studies have shown that pulmonary caused by anaesthesia and the complications, more specifically impairment of the respiratory mechanics respiratory failure requiring ventilation, by obesity will help to improve the are associated with high morbidity management of this high risk category and mortality along with increased of patients. This study thus aims at health-related costs and greater length assessing the lung function changes as of hospital stay. Ventilation mode well as the incidence of PRAE in healthy (volume, pressure or dual), modality and overweight/obese children with an (controlled, assisted, support ventilation) expectation that the incidence of PRAE and respiratory parameters (e.g. tidal will be higher in the obese/overweight volume and respiratory rate) are the children. The state of consciousness most important factors of mechanical and body position is expected to affect ventilation. An important aspect of the functional residual capacity while ventilation strategies is to optimise respiratory resistance is expected to be respiratory mechanics. A critical part significantly higher in the overweight/ of this process is knowing the normal obese children too. range of respiratory mechanics during ventilation. This allows clinicians Normal values of lung resistance; to define ventilation such that the an evidence-based guideline for respiratory mechanics can be paediatric anaesthesia maintained at a level expected for that Background: Paediatric patients particular patient and therefore protect undergoing elective or emergency against over- or under ventilation and surgery, or who have been admitted thus minimise potential harm. While the to the Neonatal/Paediatric Intensive normal ranges of a variety of respiratory Care Unit (NICU/PICU), often require outcomes during mechanical ventilation mechanical ventilation. During the have been assessed in adults, there are perioperative period, these patients no normal reference ranges of values are at risk of several types of lung available for the paediatric population.

124 | TELETHON KIDS INSTITUTE This precludes the formulation of Australia; Christchurch, New Zealand; clear evidence-based ventilation London, England; Berne, Switzerland guidelines in children. We are thus and Utrecht, The Netherlands) and aiming at collecting lung function equations were successfully derived for outcomes (respiratory resistance and a rage of static lung volume outcomes. pulmonary compliance) in healthy Assessing the accuracy of the hypoxia children aged between 1 and 15 years old undergoing surgery under general challenge test to predict in-flight anaesthesia and requiring mechanical hypoxia in infants ventilation. The data and demographic Investigators: Graham Hall, Maureen information collected will then be Verheggen, Evelyn Low, Wendy Lim and used to develop robust prediction Lisa Chau equations and nomograms that define the values of physiological parameters Each year many infants born to be programmed in the mechanical prematurely undertake air travel to ventilators for optimal lung function in return home after treatment at KEMH anaesthetised children having surgery. or PMH or for holiday travel. Air travel exposes babies to reduced oxygen levels on the aircraft. Whilst for most of Clinical us this is well tolerated, the effect of this reduced oxygen level on babies born Collation of multi centre prematurely has not been scientifically plethysmographic lung volumes data evaluated. The hypoxia challenge test, to derive reference equations for which is used to assess fitness to fly in patients with respiratory disease, has Caucasian children. shown to replicate in-flight hypoxia Investigators: Maureen Verheggen, in adults but in newborn infants has Graham Hall demonstrated to be inaccurate. It is not known if it is accurate in predicting Knowing what a normal result is for the need for in flight oxygen in preterm any medical test is essential. Equally infants up to 12 months corrected age. this applies for the interpretation of The aim of this study is to determine the any lung function test. We are working accuracy of the Hypoxia challenge test towards a global multicentre normal in predicting in-flight hypoxia in pre-term range for lung volumes in children. The and healthy term infants. aim of this study is to derive reference ranges for static lung volumes based on age height and sex, for contemporary health Caucasian children as a multi centre project with collaborators in Europe and New Zealand. We have collated data from five centres (Perth,

ANNUAL REPORT 2014 | 125 Staff and Students Respiratory Physician Postgraduate Students Head of Division Ms Karla M Logie BSc(Hons) - PhD Graham L. Hall; BAppSci, PhD, CRFS, Candidate FANZSRS Mr Ash Mortavazi Research Strategy Leader, Telethon Kids Institute Mr Chris O’Dea PhD, B. Med Sci (Resp Sci) Hons - PhD Candidate Professor (Adjunct), Centre for Child Health Research, University of Western Mr Tim Rosenow BSc Grad Cert Paed Australia Resp Sci – PhD Candidate Associate Professor (Adjunct), Faculty of Mr Mark Tan MSc - PhD Candidate Health Sciences, Curtin University Ms Elisha White - MHltSci, CRFS. Research Staff Ms Jasmine Grdosic – Honours Student Ms Georgia L Banton BSc - Research Mr Mark Kendall – Honours Student Assistant Evelyn Low, Wendy Lim and Lisa Chau Mrs Debbie Cooper - Research Assistant Ms Rachel Foong – Research Officer Theses passed

Ms Caroline Gallagher – Research Dr Karla M Logie BSc (Hons) Assistant “Structural and Functional Respiratory Ms Naomi Hemy - Research Assistant Abnormalities in a Contemporary Cohort of 9 – 11 Year Old Children Born Mr Chris O’Dea B. Med Sci (Resp Hsci) Very Preterm” Hons – Senior Respiratory Scientist Dr Anoop Ramgolam - Research Officer Dr Kathryn Ramsey BSc (Hons) PhD – Awards Research Officer Kathryn Ramsey Dr Shannon Simpson PhD – Research NHMRC CJ Martin Early Career Officer Biomedical Fellowship Ms Lliana Slevin BSc (Hons) - Clinical Vertex Cystic Fibrosis Research Award Trial Coordinator North American Cystic Fibrosis Ms Maureen Verheggen - M Med Sci / Conference Young Investigator Award Senior Respiratory Scientist Dr Louisa Alessandri Memorial Fund Dr Andrew Wilson - Paediatric Prize for Scientific Publication

126 | TELETHON KIDS INSTITUTE Shannon Simpson Kathryn Ramsey Thoracic Society of Australia and New • Joint American Thoracic Zealand Janet Elder Award Society – European Respiratory Society Working Group for the Standardisation TSANZ Travel Award; Awarded to of Inert Gas Washout Technique (2013 - attend the annual scientific meeting ongoing)

External Committees National International Graham Hall Graham Hall Member Medical and scientific advisory committee, Asthma Australia (2013 – ) • Joint American Thoracic Society - European Respiratory Society Andrew Wilson Working Party on Infant Lung Function Co-ordinator of Paediatric Training, Testing (2003-Ongoing) Specialist Training Committee for • Joint American Thoracic Thoracic and Sleep Medicine, Royal Society - European Respiratory Society Australasian College of Physicians Task Force for Provocation testing (RACP) (2008 – ) guidelines (2010 -Ongoing) • European Respiratory Society Local Annual Congress Paediatric Respiratory Physiology Abstract review committee Graham Hall • Editorial Advisory Panel; Expert Asthma Foundation of Western Australia Review of Respiratory Medicine (Oct Board member (2010 – ) 2006 – Ongoing) Chair, Medical and scientific advisory • Secretary; Paediatric committee, Asthma Foundation of Respiratory Physiology Group, Western Australia European Respiratory Society (Sep 2012 Kathryn Ramsey – Ongoing) Postdoctoral Council, Telethon Kids • Jan 2014 – Ongoing Series Institute Editor; Respirology Human Biology Advisory Board, Curtin • May 2014 ERS 2014 University of Technology Paediatric Respiratory Physiology Abstract review committee Shannon Simpson • Oct 2014 – Ongoing ERS Postdoctoral Council, Telethon Kids College of Experts Institute

ANNUAL REPORT 2014 | 127 GROUP NAME

2013-2014 Telethon Kids Leadership Shannon Simpson course member TSANZ 2014 (Adelaide) Talk “Lung function decline in school-age Invited Presentations children with a neonatal classification of bronchopulmonary dysplasia (BPD)” Graham Hall • Joint ANZSRS and TSANZ: Tim Rosenow Laboratory Accreditation workshop PRAGMA: a new method of quantifying • TSANZ: “Oxygen Therapy structural lung disease in young Symposium: Oxygen therapy in children with cystic fibrosis. Thoracic Children” Society of Australia and New Zealand, • Joint WA TSANZ and ANZSRS Adelaide, South Australia. Annual scientific meeting: The global PRAGMA: Further support for use as a challenge of reference ranges: The quantitative CT outcome measure. 28th new Global Lung Function Initiative Annual North American Cystic Fibrosis equations. Conference, Atlanta, USA. • Joint New Zealand TSANZ A new gold standard for assessing CT and ANZSRS annual meeting: “Normal in early CF lung disease? European Perturbations in respiratory physiology Respiratory Society International at rest” Conference, Munich, Germany. • Joint New Zealand TSANZ and TSANZ Cystic Fibrosis SIG Prize ANZSRS annual meeting: “Laying the foundations in childhood for healthy or Anoop Ramgolam disease adult lungs” 2014: Thoracic Society of Australia and • Hong Kong Society of New Zealand, WA scientific meeting Paediatric Respirology: Lung Function Presentations : Workshop “Lung function testing in children” • Can exhaled nitric oxide be used to predict children at higher risk • Hong Kong Society of of perioperative respiratory adverse Paediatric Respirology: “Using events. measurements of respiratory resistance in clinical paediatric respiratory • Salbutamol – does it go where medicine” we want it to? • Asthma Foundation WA, World 2014: Child and Adolescent Health Asthma Day Symposium: “Making Symposium spirometry work for you” • Can exhaled nitric oxide be used to predict children at higher risk

128 | TELETHON KIDS INSTITUTE of perioperative respiratory adverse University of Szeged, Hungary events Prof Zoltan Hantos • Can’t intubate can’t oxygenate Erasmus University, Rotterdam, The scenario – rabbits II Netherlands • Can’t intubate can’t oxygenate Prof Philip Quanjer scenario – rabbit III Hospital for Sick Children, Toronto Dr Sanja Stanojevic ACTIVE collaborations University Medical Centre, Utrecht Royal Perth Hospital, Respiratory Prof A Arets Medicine, Perth Christchurch Hospital, Christchurch Dr Kevin Gain Dr Maureen Swanney King Edward Memorial Hospital, Neonatology, Perth Centre for Lung diseases, Berne Prof Jane Pillow Prof Richard Kraemer Assoc Prof Noel French Dr Ronnie Hagan Dr Mary Sharp University of Western Australia, Perth A/Prof Dr Peter Franklin A/Prof Sunalene Devadason Royal Children’s Hospital, Melbourne A/Prof Sarath Ranganathan University Children Hospital, Zurich Switzerland Dr Alex Moeller University Children Hospital, Vienna Austria Dr Fritz Horak Institute for Child Health, London UK. University College London Prof Janet Stocks

ANNUAL REPORT 2014 | 129 POPULATION SCIENCES

Alcohol & Pregnancy & in health, justice and education for implementation of strategies FASD Research for prevention and for managing Fetal Alcohol Spectrum Disorders children and young people with FASD. (FASD) are preventable and our Aboriginal communities have been at research will reduce the risks and the forefront of these calls and have effects of prenatal alcohol on child been proactive in seeking strategies to health through prevention, diagnosis address educational and employment and therapy interventions. potential, and cultural integrity which is threatened by the learning and FASD are characterised by brain behavioural consequences of FASD. damage from prenatal alcohol exposure and the effects are lifelong. Resultant Our current program of research neurodevelopmental disabilities encompasses the following projects: include developmental delay, poor Epidemiology of FASD in WA – executive functioning, and problems prevalence rates using data from with learning, behaviour, and social and the WA Register of Developmental adaptive functioning. These can lead Anomalies to secondary outcomes such as poor school performance, unemployment, Investigators: Raewyn Mutch, Rochelle substance abuse, mental health Watkins, Carol Bower problems and justice system Telethon Kids Institute, The University of engagement. Without intervention Western Australia, Perth, Australia this may lead to a cycle of welfare dependency and privation which has Data on notified cases of FASD born significant intergenerational social and in Western Australia 1980 – 2010 were economic impact. For example, Fetal identified from the WA Register of Alcohol Syndrome has been calculated Developmental Anomalies. Tabulated at $USD5bn per annum, with a lifetime denominator data were obtained from cost for individuals ranging from the Midwives Notification System. $USD1.6m to $2.5m. Prevalence rates per 1000 births were calculated by demographic variables. The Alcohol & Pregnancy & FASD Prevalence ratios (PRs) and 95% Research Group has led research and confidence intervals (Cis) of Aboriginal policy development in the area of FASD compared with non-Aboriginal for over a decade, has influenced policy prevalence rates were calculated. PRs and practice across a range of health were also calculated to compare rates professions and has engaged with for births 2000 – 2010 with 1980 – consumers in the research process. 1989. Together with inquiries and plans calling for action, there is strong support from 210 cases of FASD were identified: a advocacy groups and professions birth prevalence of 0.26/1000 births

130 | TELETHON KIDS INSTITUTE (95% CI 0.23-0.30). The majority of health service use, among notified cases reported were Aboriginal (89.5%), Fetal Alcohol Syndrome (FAS) cases, a rate of 4.08/1,000, compared with including emergency department 0.03/1,000 in notified non-Aboriginal encounters, hospital admissions, cases, giving a PR of 139 (95% CI 89- intellectual disability, contact with 215). The prevalence of FASD in 2000 – mental health services, school 2010 was over twice that in 1980 – 1989 performance, and interactions with for both Aboriginal (PR 2.37, CI 1.60-3.51) the WA criminal justice system. Health and non-Aboriginal (PR 2.13, CI 0.68- and adverse life outcomes among 6.69) children. Population surveillance individuals with FAS will be compared data such as these are valuable in with a population based comparison advocating for and monitoring the group. Comparative analysis of effectiveness of preventive activities outcomes among individuals with FAS and diagnostic and management and those in the comparison group will services. enable identification of the population- level attributable risk for adverse life Findings from this study have been outcomes associated with FAS. A published in: Mutch RC, Watkins R, health economic analysis will also be Bower C. Fetal alcohol spectrum undertaken. disorders: Notifications to the Western Australian Register of Developmental Funding: Foundation for Alcohol Anomalies. Journal of Paediatrics and Research and Education Child Health. 2014. doi:10.1111/jpc.12746 Prenatal alcohol use & educational Funding: This project was supported by outcomes the NHMRC Program Grant 572742 and Research Fellowship 634341 Investigators: Carol Bower, Steve Zubrick Health and adverse life outcomes among individuals notified with FAS Project staff: Kirsten Hancock1, Nadia Cunningham in Western Australia: implications for policy, service delivery and Telethon Kids Institute, The University of prevention Western Australia, Perth, Australia

Investigators: Rochelle Watkins, Carol In this project, we are using linked data Bower to examine the educational outcomes for children of women with a record Telethon Kids Institute, The University of of an alcohol-related condition in Western Australia, Perth, Australia the hospital morbidity data system, A retrospective population-based compared with the educational study of FAS diagnoses in WA will outcomes of children of women with no be conducted to describe health such record. and adverse life outcomes, and Funding: ARC Grant DP140101573 and

ANNUAL REPORT 2014 | 131 Research Fellowship 634341 screening tool (47.5%) or conduct brief interventions when indicated (70.4%). Alcohol and pregnancy and fetal Most midwives endorsed professional alcohol spectrum disorder: Midwives’ development about screening tools knowledge, attitudes and practice (93.5%) and brief interventions (92.9%). Investigators: Jan Payne1, Rochelle These findings support the need for Watkins1, Heather Jones1, Tracy Reibel1, further professional development and Raewyn Mutch1,2, Amanda Wilkins1,2, support for midwives. Julie Whitlock1, Carol Bower1 Findings from this study have been 1Telethon Kids Institute, The University published in: Payne JM, Watkins RE, of Western Australia, Perth, Australia Jones HM, Reibel T, Mutch R, Wilkins A, Whitlock J, Bower C. Midwives’ 2 WA Government Department of Health, knowledge, attitudes and practice Child and Adolescent Health Services, about alcohol exposure and at risk of Perth, Australia fetal alcohol spectrum disorder. BMC This cross sectional study was Pregnancy and Childbirth 2014, 14:377 conducted at 19 maternity sites across Funding: This project was supported by the seven health regions of WA. A the NHMRC Program Grant 572742 and questionnaire was designed following Research Fellowship 634341 a review of the literature and other relevant surveys. Midwifery managers 3M FASD Prevention Project: Marulu, of the maternity sites distributed the Mass Media, Midwives questionnaires to all midwives working Investigators: James Fitzpatrick1, in their line of management. A total Rochelle Watkins1, Carol Bower1, Glenn of 334 midwives were invited to Pearson1, Jonathan Carapetis1, Mike participate in the research and 73.4% of Daube2, Kaashifah Bruce1, Elizabeth these were eligible. Chester1 The response rate was 67.8%. Nearly all Project staff: Kaashifah Bruce1, Martyn the midwives (93.2%) asked pregnant Symons1, Tracy Reibel1 women about their alcohol consumption during pregnancy and 99.4% offered 1Telethon Kids Institute, The University advice about alcohol consumption of Western Australia, Perth, Australia, in accordance with the Australian 2 McCusker Centre for Action on Alcohol Guideline, which states “For Alcohol and Youth, Curtin University, women who are pregnant or planning Perth, Australia. a pregnancy, not drinking is the safest option.” While informing women about The objective of the 3M FASD the effects of alcohol consumption Prevention Strategy is to implement in pregnancy (64.2%), they did not and evaluate a community designed always use the recommended AUDIT FASD prevention strategy for the Fitzroy

132 | TELETHON KIDS INSTITUTE Valley and surrounding communities where high-risk drinking is prevalent. that if effective can be translated to At the regional level across the other settings in Western Australia. Kimberley and Pilbara, the media This overarching Strategy comprises campaigns will raise awareness of the three distinct but interrelated initiatives NHMRC guidelines relating to alcohol responding to high FASD prevalence use in pregnancy. Complementary rates in Western Australia through communication strategies will seek a whole of community prevention to ensure a further state-wide impact. strategy: Marulu, Midwives and Mass Additionally, health workforce benefits Media. will be significant in that the AUDIT-C Marulu: An exemplar high-impact FASD (a screening tool for alcohol use in prevention strategy in the communities pregnancy) intervention will have been of the Fitzroy Valley, where high FASD developed. Training resources will prevalence has been documented; be developed for the implementation of this intervention throughout Midwives: A workforce intervention up- other communities in regional and skilling midwives in the documentation metropolitan Western Australia. and brief intervention around alcohol use in pregnancy, to reinforce the Funding: WA Department of Health community-wide interventions; and Marulu FASD Prevention Strategy Mass Media: A mass media strategy targeting regional and remote Investigators: James Fitzpatrick1, communities throughout the Kimberley Maureen Carter2, June Oscar3, Glenn and Pilbara, with a further aim of Pearson1, Jonathan Carapetis1, Carol ensuring state-wide impact for the Bower1, Rochelle Watkins1, Kaashifah program and its messages. Bruce1 Local impacts among the Fitzroy Valley Project staff: Kaashifah Bruce1, Martyn communities include an increased Symons1 knowledge of the harms of drinking 1Telethon Kids Institute, The University while pregnant, altered social norms of Western Australia, Perth, Australia about the acceptability of drinking while pregnant, and reduced rates of alcohol 2Nindilingarri Cultural Health Services, use in pregnancy and FASD. The social, Fitzroy Crossing, Australia health and justice system benefits for 3Marninwarntikura Fitzroy Women’s the Fitzroy Valley communities will be Resource Centre, Fitzroy Crossing, significant and enduring. Documenting Australia the Marulu strategy as an exemplar of a community-initiated response to There is a humanitarian crisis in the a significant public health issue will Fitzroy Valley region of remote North- enable this approach to be adopted in western Australia, which has amongst other communities in Western Australia the highest rates of Fetal Alcohol

ANNUAL REPORT 2014 | 133 Spectrum Disorders (FASD) in the world. Spectrum Disorder prevention that: However, Fitzroy Valley communities 1. Works in the Fitzroy Valley. have shown strong leadership and commitment to tackling FASD through 2. Can be adapted for FASD prevention the initiation of a comprehensive and in other communities. multifaceted program: the Marulu FASD This project will develop a model Strategy that has the bold goal to “Make for FASD prevention that can be FASD History” by driving down rates of transferred to other sites. The drinking in pregnancy. development of transferable ‘Marulu’, meaning ‘precious, worth interventions and strategies is also a nurturing’ in the Bunuba language, priority for the community. has three priorities: to prevent FASD, Funding: WA Department of Health WA, to diagnose FASD and to support WA Department of Aboriginal Affairs, affected families. The initial phase of McCusker Charitable Foundation the Marulu FASD Strategy (2008-2013), saw the establishment of a locally-led Multidisciplinary Team governance structure, the successful (MDT) Evaluation: Evaluating implementation of alcohol restrictions multidisciplinary team-based (University of Notre Dame, 2010), and early intervention for children the collection of FASD prevalence data with complex needs, in a remote through the Lililwan Study (Fitzpatrick et community setting al. 2012). Investigators: James Fitzpatrick1, Now, the Telethon Kids Institute has Maureen Carter2, Catherine Elliot3,4, been invited by the communities in Kaashifah Bruce1 the Fitzroy Valley to partner with them in developing, implementing and Project staff: Gayle Segar2, Martyn evaluating a prevention arm of the Symons1, Kaashifah Bruce1 Marulu FASD Strategy. 1Telethon Kids Institute, The University Aim: of Western Australia, Perth, Australia To develop, implement and evaluate 2Nindilingarri Cultural Health Services, The Marulu FASD Prevention Strategy Fitzroy Crossing, Australia to increase the proportion of women 3Chair of Allied Health, Western abstaining from alcohol while pregnant Australian Child and Adolescent Health in the Fitzroy Valley. Services, WA Health, Perth, Australia Objectives: 4Princess Margaret Hospital for Children To work with local health promotion Department of Paediatric Rehabilitation organisations (Nindilingarri Cultural This project aims to evaluate the Health Services) to develop and effectiveness of a multi-disciplinary implement a model for Fetal Alcohol

134 | TELETHON KIDS INSTITUTE team (MDT) model in improving health education services in the future. and developmental outcomes in a Finally, the research will have cohort of children with complex health national relevance by measuring and needs residing in the Fitzroy Valley, documenting a best practice approach West Kimberley; and to document of the to delivering child health services in experience and perceptions of families remote Indigenous contexts. who participate in the MDT model. Funding: CAGES Foundation, Royalties Objectives: for Regions WA • The primary objective of this Evaluating the evidence-practice research project is to develop an effective model for delivering gap between the NHMRC alcohol health care services to children and breastfeeding guideline (2009), with complex needs in remote clinician application and maternal Indigenous Australia. uptake • The secondary objective is to Investigator: Roslyn Giglia deliver the MDT model in a manner Telethon Kids Institute, The University of that engages local people and Western Australia, Perth, Australia families in the health and education support networks established for Alcohol consumption is the cultural the benefit of their children. norm in Australia but alcohol in breast milk will disrupt the hormonal milieu • The outcomes of this research required for successful lactation and will benefit the Fitzroy Valley result in a lower milk yield by the baby, communities by improving the a factor rarely considered in the early effectiveness of health services to cessation of breastfeeding. In 2009 the children in their region, and in the NHMRC released the revised alcohol longer term, improving the health guidelines and a national first was the and education outcomes of these inclusion of a guideline exclusively children. A more effective health for breastfeeding women (4B)(http:// service delivery model will be of www.nhmrc.gov.au/_files_nhmrc/ value to families, by providing publications/attachments/ds10-alcohol. evidence-based therapy that is pdf). With limited promotion of this coordinated and outcome focused, guideline it is not known whether relative to standard care currently maternal health practitioners such as available in the Fitzroy Valley. GPs and midwives, educate women on By including families in the MDT this guideline in their daily practice. It is model, the treatment and language also not known whether breastfeeding relating to their child’s health will be women are practising safe alcohol de-mystified. This will build families’ consumption during lactation. Given the confidence to engage more proven, but not well-known negative proactively with the health and

ANNUAL REPORT 2014 | 135 impact of alcohol on breastfeeding, Elizabeth Russell8, Colleen O’Leary9, and the importance of extending Jane Halliday10, Lucinda Burns11, Lorian the positive short (e.g. immunity) and Hayes12, Maureen Carter13 long term effects (e.g. decrease in Project staff: Heather Jones1 cancer, diabetes and adult obesity) of breastfeeding, it is important that 1Telethon Kids Institute, The University the awareness and utilisation of this of Western Australia, Perth, Australia guideline be evaluated. 2Discipline of Paediatrics and Child Dr Roslyn Giglia was successful in being Health, Sydney Medical School, awarded a Translational Research Into University of Sydney, Sydney Australia Practice (TRIP) Fellowship which will 3The Children’s Hospital at Westmead, support her to conduct the evaluation Sydney, Australia of guideline 4B. Building on her PhD 4 research, Dr Giglia has found that WA Government Department of Health, anecdotally there is little awareness of Child and Adolescent Health Services, guideline 4B or of the adverse effect Perth, Australia of alcohol on breastfeeding. The 5The George Institute for Global Health, translation of the evaluation of guideline Sydney Medical School, University of 4B into a practical and targeted Sydney, Sydney, Australia awareness raising and education 6 campaign for practitioners and women National Organisation for Fetal Alcohol of child bearing age is not supported Spectrum Disorders, Australia by the TRIP Fellowship. Potentially the 7Menzies School of Health Research, promotion and uptake of this public Charles Darwin University, Darwin, policy guideline has the capacity to Australia promote long term breastfeeding which 8Russell Family Fetal Alcohol Disorders in turn translates into a decrease in Association, Australia infant illness and the prevention of adult chronic diseases. 9Centre for Population Health Research, Curtin University, Perth, Australia Funding: NHMRC Translational Research Into Practice (TRIP) Fellowship 10Public Health Genetics, Genetic Disorders, Murdoch Children’s Research Development of a diagnostic Institute, Melbourne, Australia instrument for FASD in Australia 11National Drug and Alcohol Research Investigators: Carol Bower1, Elizabeth Centre, University of New South Wales, Elliott2,3, Rochelle Watkins1, Jan Payne1, Sydney, Australia Raewyn Mutch1,4, Amanda Wilkins1,4, 12Centre for Chronic Disease, School James Fitzpatrick1, Jane Latimer5, of Medicine, University of Queensland, Sue Miers6, Elizabeth Peadon2, Anne Brisbane, Australia McKenzie1, Heather D’Antoine7,

136 | TELETHON KIDS INSTITUTE 13Nindilingarri Cultural Health Services, Australian context, and can be updated Fitzroy Crossing, Australia to include new diagnostic technologies or diagnostic classifications when The Australian FASD Diagnostic appropriate. Instrument was developed to facilitate and standardise the identification of As reported in previous Telethon FASD in Australia. This guide provides Kids Institute Annual Report Scientific clinicians with the background supplements, a Final Report was information needed to apply standard submitted to the Commonwealth national diagnostic criteria for Department of Health in 2012. Five FASD in the Australian context. The papers were published in 2012 – 2013 recommended clinical diagnostic and a final paper published in 2014. assessment methods are based on Watkins RE, Elliott EJ, Wilkins A, Latimer the University of Washington (UW) J, Halliday J, Fitzpatrick JP, Mutch RC, 4-Digit Diagnostic Code1 method of O’Leary CM, Burns L, McKenzie A, interdisciplinary team assessment, and Jones HM, Payne JM, D’Antoine H, the Australian diagnostic categories Miers S, Russell E, Hayes L, Carter and criteria combine elements of the M, Bower C. Fetal alcohol spectrum UW and Canadian Guidelines for the disorder: development of consensus diagnosis of FASD.2 Although the referral criteria for specialist diagnostic actual 4-Digit Diagnostic Code does assessment in Australia. BMC Pediatrics not need to be routinely derived during 2014, 14:178 the diagnostic assessment, it can be Funding: Commonwealth Department of derived from information recorded Health and Ageing on the Australian FASD Diagnostic Assessment Form. FASD Diagnostic Instrument for The diagnosis of FASD is complex, Australia Trial and Implementation and ideally requires an interdisciplinary Investigators: Carol Bower1, Elizabeth team of clinicians to evaluate individuals Elliott2, Rochelle Watkins1 for a range of potential outcomes 1 that are associated with, but not Project staff: Juanita Doorey unique to, prenatal alcohol exposure. 1Telethon Kids Institute, The University In addition, alternative diagnoses of Western Australia, Perth, Australia must be excluded and the potential 2 Discipline of Paediatrics and Child influence of other adverse exposures Health, Sydney Medical School, assessed. Diagnostic criteria used University of Sydney, Sydney Australia internationally are based on criteria developed in North America. Research The Telethon Kids Institute, in is required to ensure that diagnostic collaboration with the University of criteria and methods recommended Sydney, developed a diagnostic for use in Australia are validated in the instrument for FASD for use in Australia,

ANNUAL REPORT 2014 | 137 on contract from the Commonwealth Investigators: Rochelle Watkins1, Carol Department of Health and Ageing. Bower1, Raewyn Mutch1 , Rhonda Following its development, the Marriot2, Steve Zubrick1, Carmella Commonwealth Department of Health Pestell3, James Fitzpatrick1, Peter contracted the Telethon Kids Institute in Collins4, Jonathan Carapetis1 2014 to trial the implementation of the Project staff: Roslyn Giglia1, Candice diagnostic instrument for FASD, again Rainsford1, Jacinta Freeman1, Natalie in collaboration with the University of Kippin1, Bernadette Safe1 Sydney. 1Telethon Kids Institute, The University The specific objectives of the project of Western Australia, Perth, Australia are to: 2 Murdoch University, Perth, Australia • Develop guidelines for health professionals on how to use the 3 University of Western Australia, Perth, diagnostic instrument; Australia • Develop guidelines for support and 4 Aboriginal Legal Service, Perth, referral pathways for families when Australia a family member is diagnosed with In 2013 the Alcohol and Pregnancy and FASD; FASD Research Group were successful • Finalise the diagnostic instrument in obtaining a $1.4M grant from the for release Australia-wide; National Health and Medical Research Council (NHMRC) to assess how many • Develop training resources for juvenile offenders in detention are health professionals to support the affected by FASD. The aim of this national implementation; and, research is to determine how common • Establish a mechanism for the FASD are in young people in detention, evaluation of the use of the develop a FASD screening tool diagnostic instrument. appropriate for young people entering the juvenile justice system, and develop An Expert Review Panel and project appropriate management strategies for Steering Group have been established, these young people. recruitment of clinicians across Australia has commenced and ethics applications 2014 saw the bulk of the foundation have been submitted. work for the implementation of the research project at Banksia Hill Funding: Commonwealth Department of Detention Centre (Banksia Hill DC). Health and Research Fellowship 634341 Most often referred to as the ‘Banksia FASD in the juvenile justice Hill’ project, work has progressed to system: a feasibility study of include: screening, diagnosis and workforce • The conferment of ethics from the development WAAHEC and UWA HREC.

138 | TELETHON KIDS INSTITUTE • The establishment and meeting of team move forward and build upon the a Steering Group, and a Community strong foundation of collaboration and and Consumer Representative commitment that has been developed Group. during 2014. • The advertising for the employment Funding: NHMRC Targeted Call for of a research officer, speech Research: Fetal Alcohol Spectrum pathologist and occupational Disorder among Aboriginal and Torres therapist who will be based at Strait Islander Peoples 1072072 and Banksia Hill DC as part of the Research Fellowship 634341 diagnostic assessment team. Understanding FASD – a guide for • The advertising for two research justice professionals positions (PhD or Postdoc) supported by the project to Investigators: Heather Jones, Raewyn investigate; 1) a qualitative case Mutch, Rochelle Watkins, Carol Bower study of the entire research Telethon Kids Institute, The University of process, and 2) a workforce Western Australia, Perth, Australia development project to provide staff with support in managing In 2011 and 2012 we conducted the young people (detainees) with ‘Fetal Alcohol Spectrum Disorder: FASD. Knowledge, attitudes and practice within the Western Australian Justice • The enrolment of a System’ project with the aim of neuropsychologist (PhD/Masters assessing justice professionals’ (judicial student with supervision) as part of officers, lawyers, corrections staff, police the diagnostic assessment team. officers) awareness and knowledge of • The engagement of Banksia Hill DC FASD, the perceived impact of FASD staff in the research program and on practice within the justice system, the establishment of a dedicated and to identify the information needs work space at the centre. relating to FASD for the justice system in WA. When asked if they would like • The development of a final more information about FASD 93% of research protocol for the judicial officers responded positively. Department of Corrective Services which when approved will allow the Our research on FASD knowledge, research pilot to take place. attitudes and practice of justice professionals in WA identified: In bedding down the research protocol there were many challenges which • what information is required by needed to be overcome to ensure justice professionals; and project rigor, acceptance, and clear • how this information should be research outcomes articulated to all delivered key stakeholders. 2015 will see the

ANNUAL REPORT 2014 | 139 GROUP NAME

The purpose of this project is to Funding: Department of the Attorney translate this research into educational General Criminal Confiscation of resources for justice professionals so Property Grants Program that they can: The Alert Program: An evidence • recognise cognitive impairments based treatment program for and possible FASD in young Aboriginal children living with FASD people engaging with the criminal justice system whether as a victim, Investigators: James Fitzpatrick1, Karen witness or offender; or otherwise Edmond2, Jane Latimer3, Branko Celler4, engaged in, or the subject of legal Trevor Mazzucchelli5 Glenn Pearson1, proceedings Heather Carmichael Olsen6, Rochelle Watkins1, John Boulton7, Maureen • identify legal implications Carter8 • consider referral for assessment if Project staff: Bree Wagner1, Kaashifah the disability is suspected Bruce1, Martyn Symons1 • consider decision making with 1Telethon Kids Institute, The University respect to orders, sentencing and of Western Australia, Perth, Australia management 2Winthrop Professor of Aboriginal In 2014 a Steering Group with Clinical Child Health, The University of representation from the courts, legal Western Australia, Perth, Australia organisations and the community was formed to provide high level advice 3 The George Institute for Global Health, and expertise into the development of University of Sydney, Sydney, Australia FASD educational resources for justice 4 Digital Productivity and Services professionals: Flagship, CSIRO, New South Wales, • 5 short videos for judicial officer Australia (judges and magistrates) and 5Psychology and Speech Pathology, lawyers Curtin University, Perth, Australia • On-line CPD module for lawyers 6Department of Psychiatry and • Information on FASD for the WA Behavioral Sciences, University of Bench Book which is used by all Washington School of Medicine, Seattle, judges and magistrates in WA USA • Presentations at conferences and 7 Professor of Paediatrics, Kimberley seminars + training and education Paediatric and Child Health Team sessions 8Nindilingarri Cultural Health Services, • FASD and Justice section on the Fitzroy Crossing, Australia Alcohol and Pregnancy and FASD Children with FASD and early life website trauma can experience difficulties with

140 | TELETHON KIDS INSTITUTE their self-regulation and executive • Identify children with impairments functioning. This can impact on in self-regulation and executive children’s ability to plan, organise, functioning by screening and maintain attention and choose an assessing school-aged children in appropriate level of alertness to suit a the Fitzroy Valley, and accessing particular task or situation. The Alert results of prior assessments Program® is based on the analogy (including those conducted during of the body being like a car engine the Lililwan FASD prevalence to teach self-regulation and improve study). executive functioning. The body can • Conduct consultation with run at different levels of alertness community, schools, and child such as high, low or just right. Children health services to tailor the Alert are taught five ways to change their Program® and select measures level of alertness through listening, of self-regulation and executive moving, touching, looking or putting functioning to ensure cultural something in their mouth. The program appropriateness and local also supports families, teachers and relevance. therapists to develop strategies to change or maintain states of alertness • Conduct training with teachers, to optimise student functioning. Whilst Aboriginal school support staff and initially designed for children with child health service providers in attention and learning disabilities, the the delivery of the tailored Alert program can be tailored to meet the Program®. needs of a specific population, such • Determine the effectiveness of as children in the Fitzroy Valley, so that the tailored Alert Program® using the concepts can be most effectively a step wedged randomised taught. controlled study design. This The goal of this research project is design introduces the Alert to develop, implement and evaluate Program® to different schools the Alert Program® to improve self- at different times and compares regulation and executive functioning outcomes for students before and skills of primary school aged children in after the program is implemented the Fitzroy Valley. at each school. Quantitative data (numbers) will be collected to Alert Program® study objectives measure the effectiveness of the • Establish a therapeutic program program at improving children’s governance structure, representing self-regulation and executive community/families, schools, and functioning. Qualitative (stories) child health services within the data will determine provider/family existing Marulu FASD Strategy satisfaction with the program. Leadership Team. • Provide parent/carer education and

ANNUAL REPORT 2014 | 141 training to increase their knowledge Funding: National Disability Insurance of how strategies utilised in the Agency tailored Alert Program® can assist Staff and Students children to self-regulate Funding: NHMRC Program Grant Head of Alcohol & Pregnancy & FASD 1086145 Research Group Fetal Alcohol Spectrum Disorders Professor Carol Bower MBBS, MSc, (FASD) in the National Disability PhD, FAFPHM, DLSHTM, FFPHA Insurance Scheme (NDIS) Senior Principal Research Fellow, Investigators: James Fitzpatrick, Telethon Kids Institute Tanyana Jackiewicz, Carol Bower Professor, Centre for Child Health, The Project staff: Angela Dudley University of Western Australia Telethon Kids Institute, The University of Leadership Group Western Australia, Perth, Australia Dr James Fitzpatrick BSc (Physiology In 2014 we received funding to conduct and Psychology), MBBS, PhD candidate a comprehensive review of the McCusker Clinical Research Fellow in available information, both published Aboriginal Child Health, Telethon Kids and unpublished on services and Institute supports for people living with FASD to inform the development of draft best Dr Rochelle Watkins BAppSc practice guidelines for NDIA planners. (Physiotherapy), PhD, Grad Dip Mgnt The work which will commence in 2015 Senior Research Fellow, Telethon Kids will: Institute • develop a draft functional severity Dr Roslyn Giglia BAppSc index for people with FASD to assist (Nutr&FoodSci), Grad Dip Dietetics, planners in decision making around MPH, PhD, the level and type of services and supports required Senior Research Fellow, Telethon Kids Institute • estimate service cost estimates including workforce requirements Advanced Practicing Dietitian for evidence based and promising Group Members services and supports Kaashifah Bruce – Marulu FASD • present these draft guidelines Prevention Strategy Coordinator and functional severity index for assessment by the NDIA Expert Juanita Doorey – Senior Research Panel Officer Heather Jones – Manager FASD

142 | TELETHON KIDS INSTITUTE Projects were invited to contribute to a 2014 special edition of Seminars in Fetal and Associate Professor Raewyn Mutch – Neonatal Medicine titled “IVF – Impact Clinical Research Fellow on Fetal and Neonatal Outcomes.” Our Candice Rainsford – Project Officer paper on intrauterine growth and birth Dr Tracy Reibel – Senior Research defects summarised current evidence Fellow and the implications for future research in this field. Gayle Segar – Patches Fitzroy Valley Paediatric Clinic Coordinator Dr Martyn Symons – Senior Research There have been substantial changes Fellow to IVF clinical practice in the last 10 years but little is known about child Bree Wagner – Alert Program health outcomes following these shifts Coordinator in treatment. Specifically, there are *Dr Jan Payne – Honorary Research no reliable birth defects data available Fellow internationally subsequent to the use of recent techniques such as extended *Dr Amanda Wilkins – Honorary Clinical embryo culture (blastocyst transfer) and Research Fellow rapid embryo freezing (vitrification). This information is essential for appropriate pre-treatment counselling and to Assisted Reproductive inform best practice in Australian ART Technology and Birth clinics. Western Australia (WA) is the only State with a statutory Register of Defects all ART treatment that exists alongside Investigators: Dr Michele Hansen, Prof an extensive system of population- Elizabeth Milne, Prof Carol Bower, Prof based health datasets. In 2014 we Roger Hart, Prof Adrian Charles, Dr Lyn were successful in obtaining a 3-year Colvin NHMRC project grant to continue our work examining intrauterine growth and Assisted Reproductive Technologies birth defects in a more recent cohort (ART) are commonly used; 1 in 25 of ART births (2003-2013). Our project children in Australia are born as a result will link several WA datasets together of ART treatment such as IVF and this with information from the national figure rises to 1 in 7 for women over 37 Pharmaceutical Benefits Scheme (PBS). years of age. Hence it is important to This will allow us, for the first time, to evaluate the safety of ART treatment identify not only naturally conceived by examining health outcomes in the children and those born following children born. We have been studying ART, but also those born outside health outcomes with a particular the fertility clinic setting following focus on birth defects since 2002 and

ANNUAL REPORT 2014 | 143 controlled ovarian hyperstimulation and multiple birth rates highlight the need intrauterine insemination or ovulation for strategies that encourage single induction alone. embryo transfer. We also collaborated with Dr Georgina Funding: NHMRC Project Grant #211930; Chambers and colleagues at the NHMRC Program Grant #572742; National Perinatal Epidemiology and NHMRC Fellowship #634341 (CB). New Statistics Unit to conduct an economic funding obtained in 2014: NHMRC assessment of the frequency, duration Project Grant #1086530; NHMRC Early and cost of hospital admissions during Career Fellowship #1090648 (MH). the first 5 years of life for singleton, twin and higher order multiple (HOM) children, and to examine the Autism Research Team contribution of ART to the incidence and cost of multiple births. The study, The Autism Team conducts cutting- published in JAMA Pediatrics, included edge research into the causes of all children born in Western Australia autism, and discovering new ways to 1994-2003 with follow up to 2009 help people with autism live the most (226,624 singletons, 6941 twins and fulfilling life possible. 285 higher order multiples (HOMs)). We The two research aims of our team are: found that 1.0% of singletons, 15.4% of twins and 34.7% of HOM children were • To identify the causes of Autism conceived following ART. Compared Spectrum Disorders(ASD) and with singletons, twins and HOMs related conditions; and were 3.4 and 9.6 times more likely to • To discover new and innovative be stillborn, and 6.4 and 36.7 times ways to help individuals with ASD more likely to die during the neonatal period. Twins and HOMs were 18.7 Overall we wish to create a better future and 525.1 times more likely to be for individuals with ASD. preterm, and to be small for gestational The Autism Research Team is age. The average hospital cost of continuing to conduct a range of singleton, twin and HOM children to 5 significant and diverse studies including years was $2730, $8993 and $24,411 Randomized Controlled Trials (RCT’s)… (USD 2009/10) respectively, with In 2014, we started a national project cost differences concentrated in the in collaboration with the Autism neonatal period and during the first year Cooperative Research Centre (www. of life. Our results indicated that 15% of autismcrc.org.au) to create an Australian hospital costs for multiple births could Autism Biobank. A ‘biobank’ is simply have been avoided if ART twins and a storehouse of biological information, HOM were born as singletons. This such as blood and DNA. It is now widely paper was particularly aimed at a US thought that ASD is not one condition audience where persistently high ART

144 | TELETHON KIDS INSTITUTE with one cause, but many different to any community therapy a child is conditions with many different causes. receiving, and This means that to identify all of the 2) To examine parent different causes of ASD (and there are empowerment as a result of using the likely dozens of these, if not hundreds!), TOBY Playpad App. we need to study the genetics of as many individuals with ASD A total of 100 children will be recruited from two sites: 50 participants from the and their families as possible. Australia Telethon Kids Institute, University of has never had such a resource, and Western Australia and 50 participants so we’ve decided to create one! Many from the secondary trial site that is families will have participated in our located in Victoria, a collaboration team’s Western Australian Autism between Deakin, La Trobe and Monash Biological Registry (WAABR), which has Universities. been an enormous success. Now, with funding from the Autism Cooperative Recruitment for this project finished on Research Centre, we are collecting the 31st of October, 2014. TOBY families this same information from families in will be followed for the next 6 months three other states: Victoria, New South with data analysis and preliminary Wales and Queensland. This national results to follow in late 2015. project is led by our research team, Funder of the project: Australian and we believe that it will bring about Children’s Trust a revolution in Australian research into the causes of ASD. You can see an Fluoxetine: Fluoxetine for the article about this exciting project here: Treatment of Autistic Repetitive Behaviours (FAB Trial) http://goo.gl/kmxo2x Clinical Trials This is a multi-site randomised double- blind controlled trial of Fluoxetine TOBY Playpad App (Selective Serotonin Reuptake Inhibitor, SSRI) versus placebo. It aims to This is a multi-site single blinded clinical investigate the efficacy of low dose trial of an early intervention program Fluoxetine on the frequency and named TOBY (Therapy Outcomes By severity of restricted, repetitive and You) Playpad App for children 4 years or stereotyped behaviours among 146 younger with a recent diagnosis of an participants aged 7.5-17 years with Autism Spectrum Disorder (ASD). The a confirmed diagnosis of an Autism TOBY is delivered as an educational Spectrum Disorder. Telethon Kids App on the iPad. Institute is one of three sites with The aims of the TOBY Trial are: Murdoch Children’s Research Institute, and the Royal Children’s Hospital 1) To determine the effectiveness in Melbourne as well as Children’s of TOBY Playpad as a complement

ANNUAL REPORT 2014 | 145 Hospital at Westmead in Sydney being fatty acids are essential for normal the other trial sites. brain development, but some evidence suggest that children with This trial will finish recruitment in early an Autism Spectrum Disorder (ASD) 2015. have lesser amounts compared with Funder of the project: NHMRC non-affected children. The use of fish Oxytocin Nasal Spray oil supplementation among families who have a child with an Autism This is a multi-site double-blinded Spectrum Disorder is common despite clinical trial investigating whether little evidence for its benefits and an oxytocin (OT) nasal spray is an associated costs. A double blinded effective treatment for impaired social randomised controlled trial of fish oil communication and behaviours in supplementation aims to determine children aged 3-6 years with an Autism whether the high-dose of fish oil for six Spectrum Disorder (ASD). A total of months is able to improve behavioural, 100 young children with ASD will be cognitive or language outcome recruited from two sites: 50 participants in children aged 2-6 years with a are expected to be recruited from the diagnosed ASD. Telethon Kids Institute, University of Funder of the project: NHMRC Western Australia and 50 participants from the Brain and Mind Research Other Autism related research we’ve Institute, University of Sydney. been conducting includes: Funder of the project: NHMRC • Brain processing of pictures and words Bright Light-box therapy • Dental Health About 50% of individuals with an Autism • Lung Function Spectrum Disorder (ASD) experience sleeping difficulties such as falling • Face Structure asleep or frequent awakenings at night. • Prenatal Brain Development An intervention trial named ‘Bright Light Therapy’ is investigating whether scheduled exposure to daily bright light early in the morning may aid in a better The natural history of sleep at night time among children who the CDKL5 disorder: are 8-11 years old with a diagnosed development of an ASD. international register Autism and Fish Oil Supplementation Trial Investigators: Stephanie Fehr, Helen Leonard, John Christodoulou, David Omega -3 long chain polyunsaturated Forbes, Simon Williams and Jenny

146 | TELETHON KIDS INSTITUTE Downs the treatment and pattern of epilepsy. Stephanie Fehr submitted her PhD on The CDKL5 disorder is caused by the database and its outcomes to date mutations on the cyclin-dependent in November 2014. kinase-like 5 (CDKL5) gene. Clinical features include early-onset seizures Funders of the project: International (generally within the first three CDKL5 Foundation, NHMRC Program months of life), global developmental Grant (572742), NHMRC Senior delay, abnormal muscle tone, hand Research Fellowship Helen Leonard stereotypies, gastrointestinal problems (572568), Australian Postgraduate and bruxism. In the past this disorder Award, University of Western Australia was considered an atypical form of Safety-Net Top-Up Scholarship, the Stan Rett syndrome, however our research and Jean Perron Top-Up Scholarship published in 2012 and other articles and the Stan and Jean Perron Award for published since conclude that it is an Excellence (Stephanie Fehr). independent disorder. Since our 2012 publication, which included the largest cohort of Childhood Cancer individuals with the CDKL5 disorder, we Epidemiology worked on developing an International database for the CDKL5 disorder. Australian Study of Causes of Acute This was done in collaboration with Lymphoblastic Leukaemia in Children the International Foundation for CDKL5 Research. Data collection Investigators: Elizabeth Milne, Carol commenced in September 2012 and Bower, Nick de Klerk, Ursula Kees, in involved families of individuals with collaboration with Bruce Armstrong, the CDKL5 disorder completing a Frank van Bockxmeer, Michelle Haber, questionnaire either online or on Rodney Scott, John Attia, Murray paper. The questionnaire has also Norris, Lin Fritschi, Margaret Miller, been translated into French, German Judith Thompson, Frank Alvaro, and Spanish. By year end 253 families Catherine Cole, Luciano Dalla Pozza, had been recruited and over 80% John Daubenton, Peter Downie, Marie had provided data. In June 2014 we Kirby, Liane Lockwood, Glenn Marshall, presented findings to families and Elizabeth Smibert, Ram Suppiah . clinicians at the 2nd International Researchers in the Childhood Cancer CDKL5 Research Symposium and Epidemiology program have been Family Conference in Washington analysing the data collected between DC. We presented information on the 2003 and 2007 in this national case- functional abilities of individuals with the control study of the causes of childhood CDKL5 disorder, the occurrence and acute lymphoblastic leukaemia (ALL). impact of gastrointestinal problems and

ANNUAL REPORT 2014 | 147 The following papers using data from occupational pesticide exposure and this study were published in 2014: the risk of childhood in the offspring: Findings from the Childhood Evans T-J, Milne E, Anderson D, Leukemia International Consortium. de Klerk NH, Jamieson SE, et al. International Journal of Cancer 2014 Confirmation of Childhood Acute 135, 9, 2157-72. Lymphoblastic Leukemia Variants, ARID5B and IKZF1, and Interaction with Peters S, Glass DC, Milne E, Fritschi Parental Environmental Exposures. L. Rule-based exposure assessment PLoS ONE 2014; 9(10): e110255 versus case-by-case expert assessment doi:10.1371/journal.pone.0110255 using the same information in a community-based study. Occupational Bailey HD, Miller M, Greenop KR, and Environmental Medicine. 2014;71: Bower C, Attia J, Marshall G, Armstrong 215–219. BK, Milne E. Paternal intake of folate and vitamins B6 and B12 before Funders of the project: NHMRC Grant conception and risk of childhood acute #254539, and Cancer Council WA. lymphoblastic leukemia. Cancer, Causes National Case-Control Study of the and Control 2014 Dec;25(12):1615-25. Causes of Childhood Brain Tumours Bailey HD, Fritschi L, Metayer C, Infante- Rivard C, Magnani C, Petridou E, Roman Investigators: Elizabeth Milne, Carol E, Spector LG, Kaatsch P, Clavel J, Bower, Nick de Klerk, Peter Dallas, in Milne E, et al. Parental occupational collaboration with Bruce Armstrong, paint exposure and risk of childhood Frank van Bockxmeer, Rodney Scott, leukemia in the offspring: findings from John Attia, Lin Fritschi, David Ashley, the Childhood Leukemia International Lesley Ashton, Judith Thompson, Consortium. Cancer Causes and Control Murray Norris , Richard Cohn, 2014; 25:1351-1367 Margaret Miller, Luce dalla Pozza, John Daubenton, Timothy Hassall, Maria Metayer C, Milne E et al. Maternal Kirby, Stewart Kellie, Ross Pinkerton, Supplementation with Folic Acid and Frank Alvaro, Angela Alessandri. Other Vitamins and Risk of Leukemia in the Offspring: a Childhood Leukemia The Australian Study of Childhood Brain International Consortium Study Tumours (AUS-CBT) was a national Epidemiology 2014. 25:811-822. case-control study into the causes of childhood brain tumours (CBT). It Bailey HD, Fritschi L, Infante-Rivard aimed to investigate genetic, dietary C, Glass DC, Miligi L, Dockerty JD, and environmental risk factors for CBT, Lightfoot T, Clavel J, Roman E, Spector and is the sister study to the Australian LG, Kaatsch P, Metayer C, Magnani C, Study of Causes of Acute Lymphoblastic Milne E, Polychronopoulou S, Simpson Leukaemia in Children (AUS-ALL). J, Rudant J, Sidi V, Rondelli R, Orsi L, The study recruited case and control Kang A, Petridou E, Schüz J. Parental families between 2006 and 2010; data

148 | TELETHON KIDS INSTITUTE collection was completed in 2011. case-control study. Cancer Causes and Control, 2014; 25, 1321-1327. The study involved children aged 0-14 years. Case children and their parents Greenop KR, Miller M, de Klerk NH, were recruited from the nine paediatric Scott RJ, Attia J, Ashton LJ, Dalla-Pozza oncology units nationwide. In total, L, Bower C, Armstrong BK, Milne E. we were notified of 734 eligible cases, Maternal dietary intake of folate, and of whom 568 were invited (77%) to vitamins B6 and B12 during pregnancy participate and 374 consented, with and risk of childhood brain tumors. 335 providing either self-administered Nutrition and Cancer: An International questionnaires or doing short telephone Journal 2014: 66, 800-809. interviews to provide demographic Peters S, Glass DC, Greenop, KR, and basic exposure data. 302 Armstrong, BK, Kirby M, Milne E, Fritschi case families returned full exposure L. Childhood brain tumors: Associations questionnaires, and 295 did a food with parental occupational exposure to frequency questionnaire. We received solvents British Journal of Cancer. 2014; DNA samples from 355 families for 111(5) p 998-1003 genotyping, which is complete. A total of 194 families declined to participate or Greenop KR, Hinwood A, Fritschi L, could not be re-contacted, and a further Scott RJ, Attia J, Ashton LJ, Heath 162 were not invited due to medical or J, Armstrong BK, Milne E. Vehicle psychosocial reasons. refuelling, use of domestic wood heaters and the risk of childhood brain Control children (that is, children without tumors: results from an Australian a brain tumour) and their families were case-control study. Pediatric Blood & recruited through national random digit Cancer (online 4 Oct 2014) DOI: 10.1002/ dialing and frequency matched to the pbc.25268. case children by age, sex and State of residence. A total of 1363 controls Milne E, Greenop KR, Fritschi L, Attia were recruited. We received exposure J, Bailey H D, Scott RJ, Ashton LJ, questionnaires from 941 control families, Smibert E, Armstrong BK Childhood food frequency questionnaires from 726 and Parental Diagnostic Radiological control families and DNA samples from Procedures and risk of Childhood Brain 974 control families for genotyping, Tumors. Cancer Causes and Control. which is complete. 2014;25:375–383. The following papers were published in Greenop KG, Peters S, Fritschi L, Glass 2014: DC, Ashton LJ, Bailey HD, Scott RJ, Daubenton J, de Klerk NH, Armstrong Greenop KR, Miller M, Attia J, Ashton BK, Milne E. Exposure to household LJ, Cohn R, Armstrong BK, Milne E. painting and floor treatments, and Maternal consumption of coffee and tea parental occupational painting and during pregnancy and risk of childhood the risk of childhood brain tumors: brain tumors: Results from an Australian

ANNUAL REPORT 2014 | 149 results from an Australian case-control letters distributed to a wide range of study. Cancer Causes and Control. organizations. These include crèches, 2014;25:283–291. day care centres, playgroups, sports centres and libraries. Greenop K, Blair EM, Bower C, Armstrong BK, Milne E. Factors relating The child’s diet and macro- and micro- to pregnancy and birth and the risk of nutrient intake was assessed using childhood brain tumors: Results from an parent-completed Food Frequency Australian case-control study. Paediatric Questionnaires (FFQs). A sample of Blood and Cancer. 2014;61:493–498. the child’s blood was taken and used to assess micronutrient levels and Funders of the project: NHMRC Grant specific biomarkers of DNA damage. #404089. The blood sample was also used to Nutrition and Genome Health in identify genetic polymorphisms related Children to nutrient metabolism and DNA repair. Saliva samples collected from the Investigators: Elizabeth Milne, Michael child were used to measure cortisol Fenech, Bruce Armstrong, Nick de and cotinine levels, as indicators of Klerk, Margaret Miller. psychological stress and exposure The Nutrition and Genome Health to environmental tobacco smoke, in Children Study aimed to identify respectively. Parents were given key nutritional and genetic factors feedback on their child’s diet, and associated with DNA damage in dietary advice was provided by a children. It aimed to describe the nature dietitian where needed. of the interaction between nutritional In all, 464 participants provided data. and genetic factors in determining level The following papers were published in of DNA damage in children, and also 2014: the associations between body mass index, DNA damage and micronutrient Ramankutty P, Klerk NH, Miller M, levels in children. Fenech M, O’Callaghan N, Armstrong BK, Milne E. Ultra-violet radiation This study was a cross-sectional study exposure and serum vitamin D levels in of 450 Western Australian children, young children. Journal of Pediatric and conducted between 2009 and 2011. Child Health 2014. 50, 9 713-720. Participants were children aged 3, 6 or 9 years at recruitment who had Funders of the project: NHMRC never been diagnosed with asthma, Grant#572623. diabetes, cancer, arthritis or epilepsy. Childhood Cancer Epidemiology: Participants and their parents were other work recruited via primary schools, posters displays and flyers, advertisements Sadetzki S, Langer CE, Bruchim R, in local newspapers and information Kundi M, Merletti F, Vermeulen R,

150 | TELETHON KIDS INSTITUTE Kromhout H, Lee AK, Maslanyj M, and capabilities to conduct research Sim M, Taki M, Wiart J, Armstrong BK, and provide relevant analysis and Milne E, et al. The MOBI-Kids study interpretation of research information protocol: Challenges in assessing to facilitate evidence based planning, childhood and adolescent exposure policy and practice to optimise to electromagnetic fields from wireless maternal, child and youth health telecommunication technologies and outcomes in Western Australia. The possible association with brain tumour role of the Collaboration is to provide risk. Frontiers in Public Health 2014; services for health related policy 2:124. research and development, and program development and evaluation. The strategic approach of the Collaboration for Applied Collaboration in relation to securing Research and Evaluation research funding over the next 3 to 5 years includes the following: The Collaboration was established by 1. To tender successfully for the Telethon Kids Institute in 2000 to quality improvement, research, and progress the translation of research evaluation work on the behalf of into policy and practice and to conduct agencies such Department of Health high quality policy and practice relevant and Department of Education and research based on the priorities of the commonwealth equivalents. Health System. 2. To diversify the financial reach In line with the mission of Telethon of the Collaboration by responding to Kids, the focus of the Collaboration is to opportunities from the Department of contribute to the health and wellbeing Child Protection and Family Support; of Western Australian children and their Department of Education; Disability families. This role in seeking to promote Services, Department of Justice, the health and wellbeing and to reduce the Commissioner for Children and Young burden of illness among children clearly People and Commonwealth Agencies aligns with the goals of the State’s as well as the non-government sector. public health system. 3. To actively investigate other The Strategy of the Collaboration means of research funding based on Research driven by the priorities of the priorities of the Institute and the the WA Department of Health, other expertise of the team. government agencies, non-government The Collaboration’s strategic approach agencies and industry is the focus of over the next 3-5 years will be achieved the Collaboration. through a program of work that focuses, The mission of the Collaboration is through the Collaboration, the Institute’s utilize our unique research expertise skills on:

ANNUAL REPORT 2014 | 151 1. Local priorities of government preventive measures that will assist and non government agencies. agencies to achieve its resource management goals. 2. Our unique ability to function as a “research framing consultancy” 10. Working collaboratively with other internal Telethon Kids research 3. Partnerships with government groups (such as the Human Capabilities agencies, non government agencies Team) and other stakeholders that facilitate the setting of priorities in child and youth 11. Supporting translation across health and wellbeing. all research at the Institute including offering strategic support to the 4. Our research expertise and Knowledge Translation Manager. capabilities (“technologies”) including: a. Qualitative research Program of Research b. Conduct of comprehensive The Collaboration’s program of work research programs involving a number currently spans four domain areas: of research modalities • Services for Healthy Children c. Program and Project Evaluation • Services for Healthy Early Years d. Program/Intervention • Services for Healthy Adolescents Development • Services for Healthy Pregnancy and 5. Translating research Birth evidence into practical strategies and interventions (design and evaluation) to reduce avoidable cost burdens on the The following provides a summary of health system. research projects completed in the 6. Profiling evidence based calendar year 2014; as well as ongoing service delivery to assist health research projects. organisations in ensuring their services Completed research (2014) are cost effective and of the highest quality. Services for Healthy Early Years 7. Evaluating program and service A Pathway from Early Childhood studies that offer guidance in optimising Disadvantage delivery in different settings and for different populations. Investigators: Dr Kim Clark and Tanyana Jackiewicz (Telethon Kids) 8. Analysing data to identify trends in areas of interest to our Why was this research conducted? stakeholders. This project was initiated by the 9. Identifying cost effective Minderoo Foundation and entailed

152 | TELETHON KIDS INSTITUTE detailed review of the Challis model leadership, early childhood education, (located in Armadale, WA) and the and service integration. evidence supporting it with the Funders of the project: Minderoo view to advocating its relevance for Foundation implementation in other vulnerable areas of Australia. This project follows Services for Healthy Pregnancy and extensive work and collaboration in Birth both developing and implementing the Challis model by a range of Evaluation: Alcohol in Pregnancy government and non-government Campaign agencies and groups over more than Investigators: Dr Tracy Reibel and 5 years. In carrying out the project, the Tanyana Jackiewicz (Telethon Kids), Institute reviewed documentation on Drug and Alcohol Office (DAO) the Challis community model, critically analysed relevant academic literature, Why was this research conducted? and examined trend data from the Strong Spirit Strong Future (SSSF) is community. the state-wide Aboriginal fetal alcohol How has the research been used? spectrum disorder (FASD) Prevention Program, coordinated by the Drug and The rapid and significant signs of the Alcohol Office (DAO). The DAO sought Challis model’s success in altering an independent evaluation of the SSSF the life course of local children have Project to ensure they had implemented encouraged stakeholders, including the SSSF according to best practice. the Minderoo Foundation, to seek to Further, they wanted to use the results share the findings and to suggest the of the evaluation to inform future policy relevance of the Challis model prevention programs in the alcohol and as a low-cost, evidence supported other drugs area for Aboriginal people. Australian strategy for reducing long- term disadvantage and its associated How has the research been used? social and economic costs. They did This retrospective ‘process’ evaluation this by launching the report at the utilising a purpose built evaluation tool October 2014. has provided independent evidence Synopsis that the SSSF Program has incorporated all the elements in the literature The paper attempts to situate itself suggesting effectiveness in reducing as reflecting a next generation of alcohol consumption in pregnancy. knowledge about ways in which The DAO have indicated that they will Australian governments can effectively be using the Telethon Kids report to reduce entrenched disadvantage request additional funding to support across the Nation, bringing together the program’s activities in the coming evidence from a spectrum of disciplines years. The evaluation will also be used spanning brain science, organisational

ANNUAL REPORT 2014 | 153 as a pre-cursor to an impact evaluation was developed as part of the research to determine whether the SSSF has outputs. resulted in behavioural changes among Funders of the project: WA Department the target group. Finally, an output of of Health the evaluation included a set of best practice indicators that has redefined Informing Pregnancy Care for Young health promotion programs for Aboriginal Women Aboriginal audiences. This combined with the complete documentation Investigators: Dr Tracy Reibel, Lisa of the SSSF Program from inception Morrison (Telethon Kids), Aboriginal to implementation means the SSSF Maternity Services Support Unit, Program can be replicated elsewhere. Women and Newborn Health Service Synopsis Why was this research conducted? The SSSF Project comprised three This project was conducted as part components: [1] a mass reach media of the Aboriginal Maternity Services campaign; [2] community resources Support Unit’s strategic development to promoting the NHMRC guidelines form a comprehensive understanding regarding alcohol use in pregnancy; of what is likely to encourage young and, [3] workforce development. The pregnant Aboriginal women to access process evaluation sought to determine antenatal services. Specific consultation whether SSSF met its stated aims with young (<20 years) pregnant and objectives, and whether it was Aboriginal women had not previously implemented in accordance with a been conducted on a wide scale in a framework of evidence-based and range of locations in Western Australia culturally informed consultation and to explore what their views of antenatal development. Having considered all the care services are. This project aimed evidence, the evaluators were able to to inform the delivery of culturally confidently state that DAO through the and age appropriate services that SSSF has achieved a robust, acceptable improve access to and sustained use and appropriate health promotion of antenatal services by adolescent campaign. The Project meets the Aboriginal women (<20 years). criteria for best practice in Aboriginal How has the research been used? health promotion practice and is an This research has informed the exemplar of process, from conception continuing work of the AMSSU and design through to application. towards improving service and health Drawing on the evaluation outcomes provider knowledge of Aboriginal and building on the purpose specific perspectives of maternity care. The evaluation tool, a set of best practice recommendations have been combined principles in Aboriginal alcohol and with another report as the basis of a other drugs health promotion programs service provider workshop to identify

154 | TELETHON KIDS INSTITUTE which of the recommendations can be to leave their home communities implemented within existing service would improve the cultural security of frameworks and resources. The final antenatal service delivery. project report was also submitted to Funders of the project: WA Department the State Parliamentary Enquiry into the of Health Patient Assisted Transport Scheme. A journal article has been submitted and Improving Journey Planning for accepted for publication. Pregnant Aboriginal Women

Synopsis Investigators: Dr Paula Wyndow, The main research question was: Tanyana Jackiewicz (Telethon Kids), What are the essential elements of Aboriginal Maternity Services Support antenatal services that encourage Unit, Women and Newborn Health young (<20 years) pregnant Aboriginal Service women to access antenatal care early Why was this research done? in pregnancy as well as continue to access this care. This project was Despite making substantial undertaken to improve understanding improvements in the health of of young Aboriginal women’s over the last knowledge of pregnancy and identify ten years, significant gaps between factors that may encourage them to Aboriginal and non-Aboriginal people seek early pregnancy care. The study in maternal and infant health outcomes sample was recruited from metropolitan, remain. This project responded to regional and remote parts of Western concerns regarding Aboriginal women, Australia including those in the main and their babies, and the impact of the target group (pregnant Aboriginal lack of documented patient transfer women or birth mothers 16-21 years); models for journey planning (through elder women and other Aboriginal antenatal, birth, postnatal, and primary community members; and, health care). The Aboriginal Maternity Services and other professionals working in Support Unit (AMSSU) engaged with relevant settings. The primary area the Telethon Kids Institute to undertake of concern noted in the study relates research with the view to improving the to young Aboriginal women living in patient journey for pregnant Aboriginal locations without birth services and women and their families. being required to leave their home How has the research been used? communities to attend another location This report has been submitted to the for childbirth up to six weeks prior to Parliamentary Inquiry into the Patient their due date. Young women require Assisted Transport Scheme (PATS) familial support during a vulnerable time currently taking place in Western in their lives. A documented patient Australia and is currently being used as relocation pathway for those required a basis for planning for the priorities and

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focus of the work of the AMSSU. for the long term. This is seen as successfully engendering respectful Synopsis and trusting relationships between The overall aim of this project was service providers and the Aboriginal to determine the feasibility of an people they support. integrated model of care for Aboriginal Funders of the project: WA Department women in Western Australia during of Health pregnancy. To do this it was important to understand the current system of Services for Healthy Adolescents identification, referral, and support available and to identify barriers that A 15 year Follow-up of Children prevent important information related of Participants in a Parenting to these women and their babies being Intervention transferred between these services. This research, with the support and Investigators: Grant Smith (Telethon involvement of appropriate governance Kids), Child Adolescent Community structures involved the conduct Health, Child Adolescent Health Service of focus groups and one on one Why was this research done? interviews across Western Australia. The Triple P Positive Parenting Program Overall, health professionals agreed is a behavioural family intervention that the development of an integrated that aims to promote optimal child journey plan needed to occur at the development and prevention of level of the health region, rather than childhood behavioural disorders State-wide. There was an optimism through enhancing ‘positive parenting that each region, supported by an practices’. Despite a substantial amount inclusive consultation process could of research evidence being available develop their own pathway model on the short term outcomes associated of care that would help facilitate a with this Program, high quality long- culturally secure supported journey for term research into the effectiveness of Aboriginal women and their families Triple P is sparse. Given the widespread throughout the pregnancy journey use of Triple P, particularly in Western and beyond. The consultation did Australia, the need for evidence however, identify significant political, examining the long-term effects is organisational, structural and cultural required. barriers to developing these journey plans. Overcoming these barriers was How has the research been used? not considered to be insurmountable This research provides promising as the consultation revealed that there evidence of a long term effect of Triple was a need to adopt a region-specific P in regard to educational achievement collaborative approach to investing as well as emergency department in maternal and child health services presentations that can be used to

156 | TELETHON KIDS INSTITUTE inform future support of the Triple P behavioural parenting intervention program in Western Australia. was associated with higher reading achievement over the ages of seven to Synopsis 12 years, consistently higher numeracy This study followed up a cohort of achievement up to the age of 12 years, children whose parents took part in and 22.9% fewer days absent from a quasi-experimental trial of Triple P upper secondary school is, whilst conducted by Telethon Kids in 1996. not unexpected, very encouraging. Up to 15 years’ worth of administrative Furthermore if future research indicates records from Western Australian a causal role of Triple P in reducing Departments of Education, Health, and ED visits, a 15.9% fewer ED admissions Corrective Services were linked to between the ages of eight and 20 years the trial records to determine whether also represents a significant impact. the intervention was associated with Where the picture is less clear, however, long-term differences in: emergency is with regard to the effect of Triple P on department (ED) admissions, utilisation of community mental health hospitalisations, community mental services. health contacts, academic achievement, school attendance, teenage births, and court appearances. Triple P was Ongoing Research (2014) associated with a 15.9% reduction Services for Healthy Children in the rate of ED admissions across childhood/adolescence. Further, the Child Development Information pattern of results strongly suggest System Project that the Triple P resulted in a lasting, long-term positive effect on literacy Investigators: Grant Smith (Telethon and numeracy achievement. Evidence Kids), John Wray (Child Development of the impact of the Triple P was Service, Child Adolescent Community observed when examining outcomes Health) measured over primary school (reading The aim of this project is to provide and numeracy) and upper secondary analytical support to the Child school (school attendance). Given the Development Service (CDS) by relatively minimal time burden posed by analyzing the Child Development the intervention, the magnitudes of the Information System (CDIS) according observed effects are not insubstantial; to policy-relevant research questions based on the results Triple P appears of interest to the CDS. CDIS contains to provide a minimal-investment information on all clients of Child solution for parents to provide a Development Services across the meaningful long-term benefit to their metropolitan area. CDIS is used child’s developmental trajectory. The by pediatricians and allied health fact that this eight-week group-based professionals in the CDS to manage

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cases. Clinically relevant information examined to identify risk factors is entered in the database; allowing for anaemia and identify significant quick retrieval for future visits and differences across Western Australian effective sharing of information across communities (particularly remote/ CDS professionals. This system has rural Aboriginal communities). Where an impressive number of records possible, incidence rates of various (over 20,000 clients with over 100,000 subtypes of anaemia will be also be occasions of service) with a wide range examined. This project is expected to of clinical information stored within be completed by the middle of 2015. the database; making it a potentially Funders of the project: WA Department invaluable tool for research. The system of Health has been running for approximately four years. However, universal uptake of Services for Healthy Early Years the system occurred approximately two years ago: this allows analysis of the Evaluation of the integrated service previous two years of collected clinical initiatives targeting the early years in information. Western Australia This research partnership has allowed Investigators: Dr Kim Clark, Rhonda a Telethon Kids researcher to be co- Breen (Telethon Kids), Sue Kiely (Child located with the CDIS Team to allow Adolescent Community Health, Child for greater degree of collaboration and Adolescent Health Service) working relationships to be developed This project explores the provision with the view of producing more of children’s services in communities, relevant outcomes from the analyses. assess how these services work Funders of the Project: WA Department together and evaluate their resulting of Health impact on children’s social, emotional and academic functioning across the Anaemia in Western Australia: early years through to early primary incidence in Aboriginal and non- (0-8 years). The study will provide Aboriginal populations across the insights into how integrated networks state can be evaluated and the impact of Investigators: Grant Smith (Telethon an integrated approach to service on Kids), Professor Karen Edmond families’ and children’s functioning. The (Princess Margaret Hospital) study hypothesis is that higher levels of local education, health, and community The major aim of this study is to service integration lead to higher levels use existing full blood count data to of parent and teacher and other service identify diagnoses of moderate to provider role satisfaction and lower severe anaemia in children across levels of developmental vulnerability Western Australia. Differences across among children in their first year of subpopulations of the state will be

158 | TELETHON KIDS INSTITUTE full-time schooling living in the lowest Investigators: Tanyana Jackiewicz SES quintile of school areas in WA. This (Telethon Kids), Kirsten James, Michael project is expected to be completed by Moltoni (Mental Health Commission), the beginning of 2015. Gary Cooper (State Coroner’s Office) Funders of the project: WA Department This project builds on more than 20 of Health years’ experience by Telethon Kids collecting and analysing information Services for Healthy Adolescents on suicides in Western Australia. With Evaluation of the choice and previous approval by the State Coroner, partnership approach (CAPA) within Telethon Kids has already collected Child and Adolescent Mental Health comprehensive information on all suicides between 1986 and 2008. The Services new information system will include Investigators: Dr Kim Clark. Tess all this information as well as more Fletcher and Dr Rachel Skoss (Telethon recent information (contingent on formal Kids) approval from the Coroner) including information on suspected suicides The aim of this project is to conduct to produce the most comprehensive a comprehensive evaluation of CAPA information system on suicide in across the two trial sites in the Perth Australia. The Western Australian Metropolitan Area. The evaluation will Coronial Suicide Information System is consist of both process and outcome/ anticipated to: impact components. The results of the process evaluation will provide • Provide easily accessible valuable information that other CAMHS information on circumstances sites across WA and Australia, and surrounding persons who die by internationally, can use to inform the suicide that will inform strategies to successful implementation of CAPA prevent suicide. whilst reducing disruption to the service. • Enable early detection of It may also indicate those aspects of systematic trends such as the model that are ‘successful’ and hotspots and clusters to enable a those that are problematic; potentially comprehensive response aimed to allowing the development of a more prevent further suicides. refined model of service delivery for WA CAMHS. This project will be completed • Provide researchers with a by the end of 2015. database to investigate, among other things, relationships between Funders of the project: WA Department risk factors to better understand the of Health circumstances surrounding suicide Western Australian Coronial Suicide in Western Australia to inform Information System suicide prevention efforts.

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Funders of the project: Mental Health of Health Commission until 2017. Western Australian Health and Services for Healthy Pregnancy and Pregnancy Surveillance System: Birth Development of a statewide surveillance system A study examining post natal follow- up of women receiving pregnancy Investigators: Dr Paula Wyndow, care with the Women and Newborn Tanyana Jackiewicz (Telethon Kids), Drug and Alcohol Service (WANDAS) Professor Carol Bower (KEMH)

Investigators: Anna Fletcher (Telethon This project attempts to establish a Kids), Angela O’Connor (WANDAS), state-wide capacity for the monitoring Renate McLaurin (WANDAS) and surveillance of behavioural and other risk factors in pregnancy that This study aims to inform further lead to adverse outcomes such as development of WANDAS to better birth defects. It requires the design facilitate the transition of patient care and establishment of a database to from the tertiary environment into the store the data; as well as provide community post-birth. To inform this a data collection interface for development the study endeavours participants to use when filling in their to describe the experiences of those online questionnaires. The research who attended WANDAS during their infrastructure will be designed to ensure pregnancy, and to identify possible as far as possible the cost effectiveness barriers and enablers to accessing of collecting the information on a long care during the postnatal period. term basis. This project tis due to be Consultation with health and support completed in 2016. services will provide information on the barriers and enablers to engaging Funders of the project: WA Department with WANDAS patients which, together of Health with the patient perspective, will help to Trial of a Novel Pregnancy Care inform the recommendations for service Model for Women with Obesity improvement. This project is currently underway with more than half of the Investigators: Anna Fletcher, Lisa case note review completed; brief Gibson, Tanyana Jackiewicz (Telethon interviews are in the field and in-depth Kids), Professor Yvonne Hauck (KEMH) interviews are being conducted where This project builds on a previous appropriate. A GP survey has been research project that was conducted conducted. An interim report has been by Telethon Kids Institute. The outcome prepared. This project is due to be of that research project was an completed early 2015. evidence-based, acceptable model of Funders of the project: WA Department care designed to support women with

160 | TELETHON KIDS INSTITUTE obesity to achieve a healthy gestational perspectives of public maternity weight gain and reduce obstetric services in WA. The requirement for this and neonatal complications called follow-on project was signalled in the ‘Blooming Together’. Blooming Together initial proposal (Maternal Satisfaction provides, among other things, early with Public Maternity Services in WA) intervention (at 12-14 weeks gestation); which pointed to further work being comprehensive, clear, consistent and required to establish a model for field supportive lifestyle education and work in assessing women’s satisfaction antenatal care; continuity of care (and with public maternity services in each of peers) providing accountability for the State’s health regions. patients; as well as social support. The goals of the new research are to: This new research looks at piloting • Develop a step-by-step site guide the Blooming Together Program in for undertaking and using the its entirety to determine whether the results of maternity care experience Program can be delivered effectively in surveys for WA maternity care both a community and tertiary setting providers; and to quantify the Program costs in the context of operational efficiency • Provide a standard approach and and Activity-based Funding. The first a valid tool for evaluating mothers pilot commenced in December 2014 perspectives of public maternity at the Woodbridge Women’s Clinic, care services in WA; Rockingham. The second pilot will • Develop SOSU’s capacity to be at Hospital and will evaluate Statewide implementation commence in April 2015. This project is of the National Maternity Services expected to be completed in 2016. Plan. Funders of the project: WA Department Funders of the project: Jointly funded of Health by SOSU; Nursing and Midwifery Office Maternal Satisfaction with Public and Research and Development at Maternity Services in WA – Follow-on DOH project

Investigators: Dr Kim Clark, Dr Tracy Publications and Reports Reibel (Telethon Kids), Linda Sinclair Kim Clark and Tanyana Jackiewicz (SOSU) A Pathway from Early Childhood This research follows on from a Disadvantage for Australian Children. previously funded project undertaken Telethon Kids Institute, The University of with the Department of Health’s Western Australia, under contract with Statewide Obstetric Support Unit Minderoo Foundation, October 2014 (SOSU) to develop and pilot a survey Paula Wyndow and Tanyana Jackiewicz tool for use in monitoring women’s

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Health Providers’ perspectives continuum. Midwifery. In Press on journey planning for pregnant Oddy, W, Smith, G, Jacoby, P. (2014) Aboriginal women: A feasibility study. A possible strategy for developing a Telethon Kids Institute, The University model to account for attrition bias in of Western Australia under contract a longitudinal cohort to investigate with the Department of Health, Western associations between exclusive Australia; 2014 breastfeeding and overweight and Tracy Reibel and Tanyana Jackiewicz obesity at 20 years. Annals of Nutrition Strong Spirit Strong Future Health and Metabolism. 65(3): 234-235 Promotion Program: Process Evaluation Wyndow, P, Jackiewicz T, Griffin D, Telethon Kids Institute, The University Chapman L and Woods H What is the of Western Australia under contract feasibility of an integrated pathway with the Department of Health, Western model of care for pregnant Aboriginal Australia; 2014 women in Western Australia? Women Grant Smith 15 Year follow-up of WA and Birth SUBMITTED September 2014. Positive Parenting Trial, Telethon Kids Institute, The University of Western Australia under contract with the Disability Department of Health, Western Australia; 2014 Down Syndrome Clinical Trial- BTD- Reibel, T and Morrison L. Young 001 Aboriginal Women’s Voices on Investigators and Associated Personnel: Pregnancy Care. Telethon Kids Institute, Helen Leonard, Jenny Downs, Jenny The University of Western Australia Bourke, Peter Richmond, Jasminka under contract with the Department of Murdzoska, Kingsley Wong, Tanya Health, Western Australia; 2014 Stoney, Gabi Willis, Camille Gibson, Reibel T, Morrison L, Griffin D, Chapman Eloise Wilson, Kirsten Stirling, Barbara L, Woods H Young Aboriginal Women’s Anderson, Ushma Wadia Voices on Pregnancy Care: factors The purpose of the study is to encouraging antenatal engagement determine if a new formulation of the Women and Birth, 2014 28 (1): 47-53 drug called BTD-001, which behaves Clark, K., Beatty, S., & Reibel, T. (2015). as a GABA antagonist, can improve ‘What Women Want’: Using Image function and cognition in people with Theory to develop an expectations of Down syndrome. This randomized, Maternity Care Framework. Midwifery. double blind, placebo-controlled trial In Press is assessing the safety and preliminary efficacy of the drug. The study involves Clark, K., Beatty, S., & Reibel, T. (2015). taking an oral formulation of BTD-001 Maternity care: A narrative overview of for 12 weeks and undergoing cognitive what women expect across their care

162 | TELETHON KIDS INSTITUTE tests over 7 clinic visits. Participants are and maternal diabetes), increases monitored for adverse events for the in multiple births, social factors such duration of the study. as higher fertility rates in socially disadvantaged high risk mothers and changes in obstetric practice The study is being conducted in relating to reproductive technologies, eight sites across Australia. For our early induction of labour and use site study participants have generally of caesarean section. Our group been contacted through the Down undertakes complex statistical analyses Syndrome NOW database developed principally using linked deidentified at the Institute through previous survey Western Australian population data studies involving families with a child relating to pregnancies, births and with Down syndrome. Participants hospitalisations to investigate the must be aged 13-35 years, be able to determinants and outcomes of preterm complete the required cognitive tests birth and the pathways leading to and be screened for current medical developmental disorders. We have conditions such as epilepsy and already shown how the determinants hypothyroidism, which may indicate of both spontaneous and medically exclusion from the study. Currently indicated pre-term births are changing thirteen individuals have been screened over calendar time. We have also and eight have been randomized. By compared neonatal outcomes for year end 2014, 22 individuals had been babies born pre-term in the public and screened and 14 had completed full private systems. Interestingly following participation. Further screening was the Australian Private Health Insurance anticipated into 2015. Incentive policy reforms, which were Determinants and Outcomes of implemented in 1997–2000, births in privately insured patients and also Preterm Birth & Pathways into caesarean deliveries increased. We Developmental Disorders also showed that from 1996 to 2005, Investigators: Fiona Stanley, Helen the rising caesarean delivery rate in Leonard, Claudia Slimings, Kristjana nulliparous women could mostly be Einarsdottir, Jenny Bourke, Nick De attributed to an increase in prelabour Klerk, Peter Jacoby, Steve Ball, Gavin caesarean deliveries for private patients Pereira, Ravisha Srinivasjois, David delivering in private hospitals. Burgner, Jessica Miller, Emma Glasson, Current work published in 2014 Jenny Fairthorne included investigation of the Increases in preterm birth and survival relationship between various over time of those born pre-term are environmental factors and pregnancy occurring due to a range of factors. complications and birth outcomes. These include increasing maternal age Also published, and in the British and co-morbidity (particularly obesity Medical Journal, was an innovative

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study investigating the effect of inter- R. and Leonard, H. (2014), Hospital pregnancy on adverse birth outcomes Admissions and Gestational Age at such as pre-term birth, low birthweight Birth: 18 Years of Follow Up in Western and intrauterine growth retardation. Australia. Paediatric and Perinatal Using novel methodology this study Epidemiology, 28: 536–544. doi: 10.1111/ questioned some previous research ppe.12155 findings on this topic. Further to these Pereira G, Bell M, Belanger K, de Klerk studies of the determinants of adverse N. Fine particulate matter and risk of birth outcomes we have started to preterm birth and pre-labor rupture of investigate the later hospitalisation membranes in Perth, Western Australia experience of children born at different 1997–2007: A longitudinal study. gestational ages. Some of this work Environment International. 2014; 73: was published in 2014 while further 143-149 studies are ongoing. Ball S J, Pereira G, Jacoby P, de Klerk Another sequel to our examination N, Stanley F J. Re-evaluation of link of the causes of pre-term birth, will between interpregnancy interval and be to follow these vulnerable infants adverse birth outcomes: retrospective born at different gestational ages and cohort study matching two intervals per determine what factors increase or mother BMJ 2014; 349 :g4333 decrease their likelihood of survival with or without a major developmental Multi-Registry Analyses of Risk disability (e.g. intellectual disability, Factors for Autism: iCARE and cerebral palsy and autism). This will MINERvA allow us to explore the impact of changes in antenatal and perinatal care Investigators: Diana Schendel, on these important pathways. Michaeline Bresnahan, Kim Carter, Jakob Christensen, Lyn Colvin, Richard Funders of the project: NHMRC Francis, Mika Gissler, Emma Glasson, Program Grant (572742), NHMRC Senior Nan Hu, Kingsley Wong, Therese Research Fellowship-Helen Leonard Grønborg, Raz Gross, Nina Gunnes, (572568). Mady Hornig, Christina Hultman, Publications 2014 Marlene Lauritsen, Helen Leonard, Erik Parner, Abraham Reichenberg, Sven Fairthorne J, Hammond G, Bourke J, Sandin, Andre Sourander, Camilla Jacoby P, Leonard H. Early mortality Stoltenberg, Auli Suominen, Pal Sure´n, and primary causes of death in Ezra Susser mothers of children with intellectual Although it is well known that genetics disability or autism spectrum disorder: a are important in the aetiology of retrospective cohort study. PLOS ONE. autism, the recent increase in the 2014 Dec 23;9(12):e113430. prevalence of autism as well as reports Slimings, C., Einarsdóttir, K., Srinivasjois, from some studies of a lower familial

164 | TELETHON KIDS INSTITUTE contribution suggest that non-genetic the harmonization process is repeated and environmental factors may also following registry data updates (new be important. For other diseases with ‘‘snapshots’’), the addition of new complex causes, like diabetes or variables, or variable modifications. cancer, it has been necessary to pool Analyses are performed using database data across many different study groups federation techniques developed and populations to achieve large and maintained by our Institute’s enough sample sizes. The International bioinformatics group. These techniques Collaboration for Autism Registry permit transparent access to iCARE Epidemiology (iCARE) was established datasets located and managed at each as a multinational consortium for site without the need for data export sharing and pooling of data for research for pooling or permanent archiving on autism spectrum disorders (ASDs). at a single location. Thus iCARE has iCARE partners from seven different created a computational infrastructure countries (Australia, Denmark, Finland, with a secure, web-based, interface Israel, Norway, Sweden, and the USA) to facilitate analysis of the federated, contribute data for analyses. The data harmonized, research datasets. that are used in iCARE come from data Investigators give careful consideration sets that already exist in each country to the consequences of site differences for public health purposes. These public in case ascertainment (e.g., registry- health data sets have information on specific variation in ascertainment of everyone in the country or the state, different ASD diagnostic or phenotypic such as data sets that record every subtypes), differences in registry birth or death. The data in iCARE from reporting, and changes in diagnostic all seven partners are best used for criteria across sites and over time, and studies that require very large sample their impact on case characteristics sizes or for making comparison across and associations with risk factors. the different countries. The purpose of Pre-analytical, descriptive steps to the original project funded by Autism assess between site heterogeneity Speaks was to establish the iCARE include exploration, variable by partnership and build the necessary variable, of autism and risk factor tools and ways to carry out research on differences over time, by site, and data from different countries. Another diagnostic system. Overall, the benefits purpose was to undertake studies on of establishing iCARE include: (1) cost risk factors and trends in autism using efficiency through use of existing data the pooled data. resources; (2) flexible infrastructure accommodating current research needs Data from each site undergo rigorous and future network growth and data harmonization and quality control upgrades; (3) flexibility in study designs processes prior to analyses; local to suit particular analyses (e.g., cohort, datasets are fixed snapshots of registry case-cohort, multigenerational or data at a particular point of time and

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sibling designs); (4) largest sample sizes database federation via a computational achieved to date based on federated infrastructure with a secure, web-based, data that enhance statistical precision; interface. (5) ability to characterize population The work undertaken in 2014 has trends in reported diagnoses over time mainly involved the completion of (e.g., by age at reporting, birth cohort or ethics applications and applications time period), as well as changes over for provision of the population the life course of affected individuals; data required at the seven sites and (6) enhanced comparison and in Scandinavia (Norway, Sweden, interpretation of between-site results Denmark and Finland), Israel, the US based on data harmonization and (California) and Western Australia in the application of uniform analytic methods expectation of data delivery early 2015. to multi-site data. Much time has been spent in the form In 2013 a paper describing the iCARE of weekly teleconferences developing a infrastructure and methodology manual for the harmonization processes was published whilst work was which will need to occur at each site concurrently being undertaken on once the data is received. This has a number of analyses including, been developed in conjunction with the for example, investigations of the data analysts and those who are going relationships between parental to lead the individual projects which will age and seasonality of birth with occur. This large multinational research autism. The previous year the iCARE team looks forward with anticipation to researchers under the leadership of Dr the arrival of data in 2015 after which Abraham Reichenberg from the Mount the harmonization work will commence Sinai School of Medicine had been to ensure the compatibility of all the successful in their application to be a local datasets. NIH Autism Center of Excellence. The Funders of the project: Autism Speaks goals of the new program known as (iCARE 6249), National Institute of MINERvA are to examine: fundamental Health (MINERvA (RFA¬ HD-12-196)). controversies concerning familial and environmental contributions to risk WA Cerebral Palsy Studies for ASD; transmission of risk across Investigators: Eve Blair, Linda Watson, generations; pregnancy-related Fiona Stanley, Carol Bower environmental factors in ASD, and the potential role of epigenetic changes in Cerebral palsy (CP) is an umbrella those factors. Building on the existing term covering chronic neurological iCARE network study data will now be conditions affecting movement and based on over 4.5 million births (1998- posture, ranging in severity from barely 2007), over 20,000 cases of ASD, and noticeable to severely disabling. The family linkages over three generations primary pathology lies in the brain, and will be again analysed using but for most the cause is poorly

166 | TELETHON KIDS INSTITUTE understood. CP results in life-long disability, and since there is as yet no cure, prevention and effective management are top priorities. The WA Register of Developmental Anomalies - Cerebral Palsy

Investigators: Linda Watson, Eve Blair, CP Alliance Research Institute in NSW Fiona Stanley, Carol Bower in 2007 by which time CP registers had been established in all States and Statutory notification of CP and birth Territories. The ACPR continues to defects was introduced in WA in flourish: The first report of the ACPR January 2011, with the CP and Birth was published in 2009, and the second Defects Registers combining under published in 2013 considers birth years the name of the WA Register of 1993-2006. Both are available at http:// Developmental Anomalies (WARDA). cpregister.com. The most notable The WA CP Register is now known as feature of the latest statistics, both from WARDA – CP. WA (see Figure) and the ACPR report, WARDA - CP, which has existed is the continued decline in proportion continuously since 1979, is used to of live births subsequently meeting monitor the occurrence of CP in WA, the criteria for CP, due primarily to the carry out research to investigate decrease in the proportion seen in very its causes and evaluate treatment preterm births. strategies, identify CP as a long-term The WA investigators have contributed outcome in other WA studies and assist a number of papers to an ACPR in the planning of services for people supplement of the Developmental with CP. A birth cohort is included in Medicine and Child Neurology analyses after case data are updated journal aimed at show-casing the at age 5 years; the register is now research supported by CP registers considered complete to 2009. across Australia. Contributions to this WARDA - CP is also responsible for supplement are now with reviewers. contributing data to the Australian Funders of the project: WARDA - CP is CP Register (ACPR), a national presently funded by NHMRC Program collaboration initiated by the WA team Grant #572742 Early developmental in 2002 to provide information about pathways linking health, disability, CP throughout Australia and create a education, welfare and justice (2010- larger study population to enable more 2014). The ACPR is supported by the CP effective research, particularly into the Alliance (NSW) who are also funding the less frequently occurring types of this DMCN supplement. very heterogeneous condition. The administrative centre relocated to the

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Developing a reliable system of and the Training and Reference DVD. A describing CP PMH Foundation Special Project Grant 2007 has covered travel to conduct Investigators: Sarah Love, Noula training sessions throughout WA, and Gibson, Eve Blair, Linda Watson an Innovative Research Grant from the The cerebral palsies include a wide CP Institute has funded the extension of range of motor impairments across training across Australia. the spectrum of severities and may Case Control Studies of CP in term be accompanied by a wide variety of and preterm infants in WA, 1980 to other impairments which can greatly 1995 affect both functionality and treatment options. The validity of generalising Investigators: Eve Blair, Sarah McIntyre, the results of CP research depends Linda Watson, Nadia Badawi, Karin heavily on a consensus understanding Nelson of what segment of the CP population Comprehensive maternal, pregnancy, the research refers to. International birth and neonatal information on all attention has been focused on CP cases not postneonatally acquired, the challenge of standardising the matched controls, and a representative classification of CP for several decades, sample of perinatal deaths born 1980- during which time WA has been at the 1995 was collected from birth hospitals forefront of promoting description rather throughout the State. This has provided than classification and developing a a wealth of data from which to identify reliable system of describing the clinical causal pathways to the different features of CP. We are continuing to outcomes. The primary aim of these develop and promote an innovative studies is to prevent the occurrence diagrammatic limb-by-limb CP of brain damage responsible for CP Description Form which incorporates by identifying points on each causal the Australian Spasticity Assessment pathway to CP at which it may most Scale (ASAS) devised by Sarah Love effectively, efficiently and ethically be and Noula Gibson, two Cerebral Palsy interrupted. Data analysis continues Habilitation Physiotherapists. A Training with the intent to explore causal and Reference dvd demonstrating how pathways and report research findings to use the CP Description form and the at local, national and international ASAS that includes examples of the forums. different forms of CP is published and a limited number are available from Noula The current focus of our analyses is Gibson . least 35 completed weeks of gestation (term and late preterm singletons). Funders of the project: PLAN Australia This relatively low risk group has generously funded the development received little research attention, of the ASAS, the CP Description Form

168 | TELETHON KIDS INSTITUTE yet it contributes 30% of all perinatal alphabetically)Nadia Badawi, Eve Blair deaths and 70% of all CP and is very , Christine Cans, Kate Himmelmann, likely to be the most aetiologically Ingeborg Krägeloh-Mann , Sarah heterogeneous. In an effort to create McIntyre, Jennie Slee, Peter Uldall, more aetiologically homogeneous Linda Watson and Meredith Wilson. groups we have identified subjects What constitutes cerebral palsy – in with abnormal neonatal neurological the twenty-first century? doi: 10.1111/ signs and the subset of this group dmcn.12262. Developmental Medicine whose signs were attributed to acute and Child Neurology, 2014. 56(4):323-8. intrapartum hypoxia. We have identified Georgiades M, Elliott C, Wilton J, Blair that 53% of neonatal deaths and 68% E, Blackmore M, Garbellini S. et al. of CP in our term and late preterm The Neurological Hand Deformity singleton sample were considered Classification for children with cerebral neurologically normal in the neonatal palsy. Accepted by Australian period. The antecedent factors of all Occupational Therapy Journal July outcomes are being compared. 2014. doi: 10.1111/1440-1630.12150 The original data collected information Blair EM, Nelson KB. Fetal growth on birth defects identified in the restriction and risk of cerebral palsy neonatal period. Linkage with WARDA- in singletons born after at least 35 birth defects has now provided weeks’ gestation. American Journal data on all birth defects identified of Obstetrics and Gynecology. 2014; up to the age of 6 years, greatly Online:1.e-.e7. http://www.scopus. increasing the proportion of CP com/inward/record.url?eid=2-s2.0- cases with an identified birth defect 84919363280&partnerID=40&md5=71d and demonstrating that it is the most e8a7d6d9a6ee84431082d8a82728b frequently identified risk factor for CP in term and near term births, particularly if Love S, Blair E. The right interventions accompanied by fetal growth restriction. for each child with cerebral palsy (letter). Developmental Medicine and Child Funders of the project: This case- Neurology. 2014;56(4):392. control study was funded by NHMRC Program Grants #353514 (2005- ACOG (The American College of 2009) and #572742 (2010-2014). An Obstetricians and Gynecologists). Innovative Research Grant from the Neonatal Encephalopathy and CP Institute provides additional funds Neurologic outcome. 2nd edition,. for analysis and a career development 2014. (Eve Blair and Sarah McIntyre grant from the CP Alliance provides were consultants with input to Executive additional funds for travel for EB. summary and Chapter 1 ‘Background’). Publications 2014 McIntyre, S., Blair, E., Badawi, N., & Nelson, K. Does aetiology of neonatal Hayley Smithers-Sheedy (authors listed encephalopathy and hypoxic ishcaemic

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encephalopathy influence the outcome in Western Australia, creating a unique of treatment? Developmental Medicine data resource for use by researchers & Child Neurology, in press. and policy makers. Smithers-Sheedy, H., Raynes-Greenow, In collaboration with community C., Badawi, N., McIntyre, S., Jones, C. and consumer groups and the State on behalf of the Australian Cerebral government agencies, the findings Palsy Register Group (2014). Congenital from the DPP aim to inform whole cytomegalovirus is associated with of government intervention and severe forms of cerebral palsy and prevention strategies to improve female gender in an Australian outcomes, influence policy frameworks population cohort study. Developmental as well as evaluate and monitor existing Medicine & Child Neurology, In press initiatives and policies that affect the health and wellbeing of children, youth and their families. Developmental Pathways to The primary aims of this collaboration healthy child development are to: and wellbeing 1. Extend and expand the pioneering population level data linkage across The Developmental Pathways in WA multiple disciplines and government Children Project (DPP) links de-identified sectors in Western Australia; population level data from Western departments 2. Ascertain whether changes in factors and agencies to investigate risk and at the child, family and community protective factors leading to differences level increase or reduce vulnerability in developmental outcomes for children to adverse outcomes in mental and and youth. This project provides new physical health, education, child knowledge to inform and enable future maltreatment, juvenile offending, in all policy and prevention strategies to Western Australian children; improve child health and wellbeing. 3. Identify areas of prevention and The DPP has taken a multidisciplinary intervention across multiple government and holistic approach to research into sectors, particularly in regard to the health, development and wellbeing mental health, disabilities, child of children and youth, by initiating and protection, juvenile justice, educational utilising linked, longitudinal population achievement and school attendance; level data. The data are used to 4. Use these data to evaluate existing determine risk and protective factors government initiatives and determine, at leading to poor and good outcomes a population level, how initiatives have in WA children. The DPP pioneered impacted on educational, social and population level data linkage across health outcomes; multiple government service sectors

170 | TELETHON KIDS INSTITUTE 5. Improve the collection, utilisation and outcomes, educational achievement reliability of Government department and school attendance/suspension; and data in program evaluation and policy identification of required interventions development; and to optimally influence pathways; and 6. Respond to the government 2) Monitoring of outcomes and departments’ agendas and policy evaluation of existing initiatives and frameworks, while enhancing whole of policies. government initiatives. Developmental Pathways in WA This project is internationally Children Project (DPP) innovative in its use of linked statutory and government agency data Fiona Stanley [University of Western sets to measure and monitor child Australia (UWA), Telethon Kids Institute]; development and wellbeing at the Helen Leonard [UWA, Telethon Kids population level. We are one of the few Institute]; Nicholas de Klerk [UWA, places in the world that has the depth Telethon Kids Institute]; Jianghong Li and breadth of information, expertise [Curtin University of Technology, WZB and capacity not only to conduct cutting Social Science Research Center Berlin, edge research, but also to translate the Telethon Kids Institute]; Natasha Nassar findings into policy and practice, thus [UWA, University of Sydney]; Stephen making this project innovative on an Zubrick [UWA, Telethon Kids Institute]; international scale. Catherine Taylor [UWA, Telethon Kids Institute]; Amanda Langridge [UWA, The project encompasses a number Telethon Kids Institute]; Cheryl Gwilliam of important areas of research; mental [WA Department of the Attorney and physical health, child abuse and General]; James McMahon [WA neglect, alcohol and drug use, juvenile Department of Corrective Services]; delinquency, disability, education and Ruth Shean [WA Department of Training housing. We have a large number of and Workforce Development]; Alistair research projects overlapping these Jones [WA Department of Treasury]; areas of focus. This reflects the complex Timothy Marney [Mental Health nature of many of the problems facing Commission WA]; Karl O’Callaghan Australian children and youth, and [WA Police]; Sharyn O’Neill [WA highlights the strengths of this project Department of Education]; Grahame to address these multi-sectoral issues. Searle [WA Department of Housing]; The questions can be grouped into two Ronald Chalmers [Disability Services broad areas: Commission WA]; Jennifer Mathews [WA 1) Improving the understanding of the Department of Local Government and child, family and community factors Communities]; Cliff Weeks [Department involved in the pathways to juvenile of Aboriginal Affairs WA]; Emma White offending, child abuse and neglect, [WA Department for Child Protection poor physical and mental health and Family Support]; Laura Miller [Data

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Linkage Branch (DLB) Department future government agency policies, of Health WA] and Bryant Stokes practice and planning initiatives will [Department of Health WA]. be more preventative, culturally appropriate and cost efficient and The Developmental Pathways we have encouraged cross-agency Project is a landmark project taking a collaboration to ensure improved multidisciplinary and holistic approach health, well-being and development to investigate the pathways to health of children and youth, as well as their and wellbeing, education, disability, families and communities. child abuse and neglect and juvenile delinquency outcomes among Western The DPP was made possible by Australian (WA) children and youth. generous cash and in-kind contributions made by our collaborating organisations To achieve this, researchers from the and government departments, which Telethon Kids Institute and UWA have has been matched by the Australian been working in collaboration with Research Council (ARC) through two 14 state government departments, consecutive ARC Linkage Project including the WA Departments of Grants. Health, Education, Training, School Curriculum and Standards Authority, The DPP supports several postgraduate Child Protection and Family Support, students and postdoctoral fellows, to Corrective Services, Local Government conduct individual research projects and Communities, Aboriginal Affairs, which answer specific research and Treasury, Housing, Attorney General, policy relevant questions within and the Disability Services Commission, across the themes and scope of the the Mental Health Commission and WA overall project. Police. Staff and students The project has established the process of linking together de-identified Head of group longitudinal, population-based data Dr Rebecca Glauert collected and stored by a large number of these WA government departments BPsych (Hons), PhD and the Telethon Kids Institute, to create Program Manager a fantastic cost-effective research and policy planning/evaluation resource. Research staff The linked data are being used Marcela Quintero by researchers and the respective MBBS departments to identify multi-level and early determinants of developmental Data analyst outcomes and the interrelationships Dr Melissa O’Donnell among them. Through the effective BPsych (Hons), MPsych, DipEd, PhD communication of research findings,

172 | TELETHON KIDS INSTITUTE National Health and Medical Research Miriam Maclean Council (NHMRC) Research Fellow BA (Hons Psych), MSc Scott Sims Research assistant BSc, MBiostat Data analyst Theses passed Postgraduate students Dr Anna Ferrante Janice Wong DipEd, BA (Mathematics), PhD BSc (Hons Psych) UWA PhD candidate ‘Dimensions of delinquency: Exploring Glenn Pearson group differences in the prevalence and frequency of offending: A linkage- BA (Education) based study of offending in the Western PhD candidate Australian population’ Jocelyn Jones Dr Desiree Silva BSc, MEpi MBBS, MPH, FRACP, PhD PhD candidate UWA Megan Bell ‘Early risk factors of children diagnosed BA (Hons Psych) with attention deficit hyperactivity disorder and their education and justice PhD candidate outcomes’ Miriam Maclean

BA (Hons Psych), MSc Awards PhD candidate Janice Wong Nan Hu Telethon Kids Institute Travel Award BSc, MSc Megan Bell PhD candidate Winner, Best Early Career Presentation Research support International Health Data Linkage Melanie Hansen Conference 2014 BSc External Committees

Research assistant International

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Melissa O’Donnell Miriam Maclean International Society for the Prevention Marce Society Conference Local of Child Abuse and Neglect Organising Committee 2007 – present January 2011 – present Melissa O’Donnell Desiree Silva International Child Maltreatment Data Head of Department Medical Advisory Working Group Committee (HOD/MAC) 2009 – present Desiree Silva Chair of the Royal Australasian College of Physicians National Desiree Silva Rebecca Glauert State Paediatric Implementation Plan Closing the Gap Clearinghouse Board Janice Wong 2013 – 2014 The Australian Association of Cognitive Behavioural Therapy Local December 2010 – present Rebecca Glauert Ngala Professional Advisory Committee Invited presentations 2011 – present The DPP had its work presented at Rebecca Glauert over 15 international, national and state Western Australia Data Linkage conferences, meetings and forums Infrastructure Project Board in 2014, many of those presentations were invited. A list of the various 2014 – present presentations made at international, Rebecca Glauert national and state conferences, Western Australia Data Linkage meetings and forums is provided below. Infrastructure Project Advisory Desiree Silva Committee ‘Long term educational disadvantage by 2014 – present gender for children with ADHD’ Miriam Maclean Eunethydis Conference Perinatal Mental Health Services Istanbul, Turkey Research Committee May 21-24, 2014 July 2010 – present

174 | TELETHON KIDS INSTITUTE Desiree Silva Louisa Alessandri Memorial Fund Oration Evening ‘Early life course for children and adolescents diagnosed with ADHD’ August 11, 2014 55th Annual Meeting of the Japanese Perth, Australia Society for Child and Adolescent Janice Wong October 2014 ‘Using data linkage to determine the Shizuoka, Japan risk factors associated with children being diagnosed with a mental health Fiona Stanley disorder’ ‘Science with a Soul: data to action for International Health Data Linkage health child development’ Conference 2014 International Health Data Linkage Vancouver, Canada Conference April 28-30, 2014 April 28, 2014 Megan Bell Vancouver, Canada ‘Predictors of vulnerability and risk on Fiona Stanley the Australian Early Development Index’ ‘From data to wisdom: using data for International Health Data Linkage health’ Conference 2014 Measuring Health Outcomes to Inform Vancouver, Canada Policy Conference April 30, 2014 May 27, 2014 Megan Bell Melbourne, Australia ‘How do individual, family and Fiona Stanley neighbourhood characteristics influence ‘Population monitoring as a strategy children’s early development and for improved early child development: academic achievement?’ progress and new challenges’ Aboriginal Health CRE Human and Early Learning Partnership June 2014 (HELP) Megan Bell August 30, 2014 ‘How do individual, family and Vancouver, Canada neighbourhood characteristics influence Fiona Stanley children’s early development and ‘How population monitoring has academic achievement?’ improved child development outcomes’ Community Expo, Telethon Kids

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Institute September 14-17, 2014 July 10, 2014 Nagoya, Japan Perth, Australia Nan Hu Melissa O’Donnell, Marni Brownell, ‘Parental psychiatric disorders and Miriam Maclean, Scott Sims & Ruth children’s deliberate self-harm (DSH) in Gilbert adolescence’ ‘Entering out-of-home care during International Health Data Linkage childhood: Cumulative incidence study Conference 2014 in two developed countries’ Vancouver, Canada 20th International Society for the April 30, 2014 Prevention of Child Abuse and Neglect International Congress Rebecca Glauert September 14-17, 2014 ‘The importance of using data in decision making: The Developmental Nagoya, Japan Pathways Project as an example’ Melissa O’Donnell, Miriam Maclean, National Elder Abuse Conference Scott Sims, Helen Leonard, Vera Morgan & Fiona Stanley September 2014 ‘Linking data for child welfare research Perth, Western Australia - Using linked child protection and Rebecca Glauert mental health to investigate mental health diagnoses and child protection ‘Multi-agency data linkage - You CAN risk’ do it!’ 20th International Society for the International Health Data Linkage Prevention of Child Abuse and Neglect Conference International Congress May 2014 September 14-17, 2014 Vancouver, Canada Nagoya, Japan Rebecca Glauert Miriam Maclean, Cate Taylor & Melissa ‘Linking data to build an evidence base: O‘Donnell The WA Developmental Pathways ‘Educational outcomes of children in Project’ contact with the child protection system’ University of Southern California 20th International Society for the February 2014 Prevention of Child Abuse and Neglect International Congress Los Angeles, California

176 | TELETHON KIDS INSTITUTE Active research collaborations looking at the wellbeing and developmental health outcomes for The DPP facilitates the provision maltreated children who have been of de-identified non-health linked in out-of-home care versus those population level data to a number of who have not. A comparative study of other research projects conducted tends was also conducted in relation within other research institutions and to intentional and unintentional injury WA government departments, including admissions associated with alcohol in those led by Professor Jablensky youth in Western Australia and England. (‘Pathways of risk from conception to disease: A population-based study of In addition, researchers were involved the offspring of women with bipolar in a cross-country comparison on disorder and schizophrenia’); Associate neonatal drug withdrawal syndrome Professor Tony Butler (‘Does traumatic using hospital administrative data in brain injury (TBI) lead to offending England, the USA, Western Australia behaviour?’); and Dr Colleen O’Leary and Ontario, Canada. (‘Investigating the effect of a maternal alcohol-related diagnosis on the educational, juvenile justice, and child Active involvement with the protection outcomes of their children’ community and ‘Examining the effect of the dose, The Telethon Kids Institute recognises pattern, and timing of prenatal alcohol the central role of health consumers exposure on educational outcomes’). and community members in its The DPP is currently assisting the research. Our aim is to develop WA Mental Health Commission in partnerships in which consumers, an evaluation of their Supported community members and researchers Accommodation Services for people work together to make decisions with severe and persistent mental about research priorities, goals, health problems, to try to ascertain if methodologies, questions and supported accommodation results in dissemination of results. improved health and mental health The DPP has a Consumer and for residents. We are also working Community Reference Group (CCRG) with Ngala to investigate where their which comprises of members for the services are being most utilised. community who have an interest in our Investigators from the project also topics of research. This groups meets have an ongoing collaboration with four times a year and provides advice, Professor Ruth Gilbert and her team at interpretation and expertise to our the Institute of Child Health, University research projects. College London. The CCRG was established to provide A systematic review was finalised researchers with ongoing support

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and advice and also has an oversight Health, Education and Disability role for governance, standards and Services Commission through the DPP, practices relating to the project from a to conduct a longitudinal analysis of community perspective. prospective data from a large cohort of children. Child abuse and neglect Currently, WA is the only Australian Dr Melissa O’Donnell state that has a comprehensive data Dr Melissa O’Donnell is an NHMRC linkage system including children’s Early Career Fellow and a psychologist education and child protection data, who completed her PhD in 2009 along with data on an array of child, through the DPP. parental and community characteristics. Using this linked data will assist in Melissa’s research uses longitudinal overcoming the many methodological population data provided through difficulties associated with maltreatment the DPP. This administrative data is research and enable a much greater being used to: investigate emergency understanding of the relationships department presentations and hospital between maltreatment and out of home admissions related to child abuse care with educational outcomes, taking and neglect; determine the mental into account a range of risk factors health and juvenile justice outcomes at the child, parental and community of children who have contact with the levels. child protection system; and investigate the child, family and community Aboriginal health characteristics which increase or Glenn Pearson reduce vulnerability to child abuse and neglect. Glenn Pearson, a Noongar from WA and the Manager of Aboriginal Health Miriam Maclean Research at Telethon Kids Institute, is Miriam McLean is completing her completing his doctorate on the DPP. doctorate on the DPP. His qualitative research project Her project is titled ‘Educational explores how the delivery of health, outcomes of children in contact with the education and child protection services child protection system: A longitudinal provided by the WA State Government population study.’ to Aboriginal clients is mediated by The aim of this study is to examine the the perceptions non-Aboriginal and educational outcomes of children in Aboriginal people hold of themselves contact with the child protection system. and each other in the provision and This project is innovative in that it will receipt of these services. use linked government administrative Juvenile offending data from the WA Departments of Child Protection and Family Support, Dr Anna Ferrante

178 | TELETHON KIDS INSTITUTE Anna Ferrante is an Associate Professor Attention Deficit Hyperactivity at the Centre for Data Linkage (CDL), Disorder Curtin University, formerly a Research Associate Professor at the Crime Dr Desiree Silva Research Centre, UWA. Dr Desiree Silva is a paediatrician, and As part of the DPP, Anna undertook Professor of Paediatric Medicine at a population-based study of the Joondalup Health Campus and UWA. dimensions and development of Desiree commenced a PhD through delinquency in WA children. UWA and the Telethon Kids Institute The aim of the project was to contribute on the risk factors and outcomes of to a better understanding of the children and adolescents diagnosed dimensions of juvenile delinquency and with Attention Deficit Hyperactivity of the impact of various factors on the Disorder (ADHD) in WA. development of delinquency over the Her PhD project uses longitudinal life-course. By exploring the interactions population data provided through the between risk factors and their effect DPP. This administrative data, along on offending, it may be possible to with questionnaire data, is being used map ‘pathways’ from early childhood to to: identify potential antenatal and juvenile delinquency and later criminal early neonatal risk factors associated behaviour. with children requiring treatment with Jocelyn Jones stimulant medication; explore hospital and emergency morbidity, accident Jocelyn Jones is completing her related hospitalisation risk, criminal and doctorate through the DPP. antisocial behaviour and service needs Jocelyn’s project is titled ‘Exploring the associated with children on stimulant pathways to contact with juvenile justice treatment for ADHD; examine education in Aboriginal and Torres Strait Islander outcomes of children diagnosed with children: developing a profile of the ADHD and their level of stimulant risk and protective factors to support a medication treatment; and explore the strategy for change.’ mental health burden of parents and family functioning of children diagnosed Using linked longitudinal population and treated with pharmacotherapy for data provided through the DPP this ADHD in WA. project seeks to develop a profile of the developmental, health, socio- Mental health economic, racial and demographic factors associated with risk, protective Janice Wong and resilience factors that contribute to Janice is completing her combined juvenile delinquency in Aboriginal and Masters and doctorate through the DPP. Torres Strait Islander children. Her project is titled ‘The relationship between educational and mental

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health outcomes for Western Australian influence the developmental pathways children: A longitudinal population to DSH related hospitalisation among study.’ young people. This will be achieved by undertaking five sub-studies focusing Using linked longitudinal population on birth factors, family and community data provided through the DPP, this factors, child maltreatment, educational project seeks to explore the dynamic outcome, psychiatric correlates and relationship between children’s certain types of intellectual and educational outcomes and their mental developmental disabilities. health, whilst taking into account variables that have been shown to Early child development and impact this relationship. Children education who are vulnerable to mental health problems are subsequently at risk Megan Bell of experiencing interference with Megan Bell is completing her combined development, and more specifically, Masters and PhD through the DPP and with schooling, and the development UWA. of their identity. Results of this study will potentially inform the development of Megan’s project is titled ‘How do suitable interventions, ultimately with individual, family and neighbourhood the aim to decrease the prevalence characteristics influence children’s of mental health issues and improve early development and academic educational outcomes. achievement? A linked data population study’ and aims to examine how early Nan Hu childhood development is related to Nan Hu is completing his doctorate educational achievement. through the DPP. His project is titled Using a linked data approach, Megan ‘An investigation of the developmental will combine children’s health, pathways to hospitalised deliberate demographic and achievement self-harm behaviours (DSH) among information with data on their parents young people: a birth cohort study and the neighbourhoods they live in. using cross jurisdictional linked data in This method of investigation will allow Western Australia (WA).’ Megan to examine how child, parent This project has two main aims: 1) and neighbourhood characteristics To examine the epidemiological can positively or negatively influence characteristics and the current development up to school entry. trend of deliberate self-harm related Children’s outcomes will be measured hospitalisations in young people aged using the Australian Early Development 10-30 years in WA and 2) To investigate Census (AEDC), which is a nation-wide how specific biological, psychological assessment which gives an indication of and social factors at the child, family, child development at age 5. school and community level interact to

180 | TELETHON KIDS INSTITUTE Megan will also examine whether Board (2014 – present) children’s scores on the AEDC are Rebecca Glauert. Western Australia related to their achievement on the Data Linkage Infrastructure Project National Assessment Program - Literacy Advisory Committee (2014 – present) and Numeracy (NAPLAN) at age 8. This analysis will provide information on how Miriam Maclean. Perinatal Mental Health developmental level at school entry Services Research Committee (July is associated with achievement levels 2010 – present) in later school. This study will identify Miriam Maclean. Marce Society the population subgroups at highest Conference Local Organising risk of developmental and educational Committee (January 2011 – present) disadvantage in WA, which will enable the development of interventions Desiree Silva. Head of Department targeting the most vulnerable groups. Medical Advisory Committee (HOD/ MAC) Joondalup Health Campus Awards Desiree Silva- Chair of the Royal Megan Bell. Winner best Early Career Australasian College of Physicians Presentation, International Health Data Desiree Silva- State Paediatric Linkage Conference 2014, Vancouver, Implementation Plan Canada, April 30, 2014. Janice Wong. The Australian External Committees Association of Cognitive Behavioural International Therapy (December 2010) Melissa O’Donnell. International Society Other notable achievements for the Prevention of Child Abuse and In 2014, the DPP had a paper published Neglect (2007-present) in the Lancet Psychiatry investigating Melissa O’Donnell. International Child the link between ADHD and juvenile Maltreatment Data Working Group offending, and has over 30 other (2009-present) papers published from the grant, with several more under review or under National commencement. Rebecca Glauert. Closing the Gap A list of all papers published in 2014 is Clearinghouse. Board member- 2013 to provided below. 2014 Cooper, M. N., McNamara, K. A., de Local Klerk, N. H., Davis, E. A., & Jones, T. W. Rebecca Glauert. Ngala Professional (2014). School performance in children Advisory Committee (2011 – present) with type 1 diabetes: a contemporary Rebecca Glauert. Western Australia population-based study. Pediatric Data Linkage Infrastructure Project Diabetes. doi: 10.1111/pedi.12243

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Eitelhuber, T., & Davis, G. (2014). The Health Journal. custodian administered research extract We are also conducting an economic server: “improving the pipeline” in analysis of the cost of pre-term birth, linked data delivery systems. Health which is providing an increased burden Information Science and Systems, 2(6). on the health system. Eitelhuber, T., Davies, G., Rosman, D., We are also in the process of & Glauert, R. (2014). Western Australia developing an online child Atlas using unveils advances in linked data delivery linked data, which will provide an online systems. Australian and New Zealand mapping tool for researchers and Journal of Public Health, 38(4), 397-398. government. Silva, D., Colvin, L., Hageman E., & We now employ three full time staff at Bower C. (2014). Environmental risk the WA Department of Health in the factors by gender associated with DLB. These staff have assisted in the Attention Deficit/Hyperactivity Disorder. linkage of new datasets, developed Pediatrics, 133(1), e14-e22. a new server which will significantly Silva, D., Colvin, L., Hageman, E., reduce the burden of data linkage Stanley, F., & Bower, C. (2014) Children on data custodians and acted as a diagnosed with attention deficit disorder liaison point between researchers and and their hospitalisations: population custodians in the Department of Health. data linkage study. European Child & We have now established a world class Adolescent Psychiatry, 23(11), 1043-1050. data linkage resource, which is the Silva, D., Colvin, L., Glauert, R., & Bower, largest in Australia, and arguably, the C. (2014). Contact with the juvenile world. We are leading the way on how justice system in children treated with to link cross-agency data, and have stimulant medication for attention deficit been invited to present all over the hyperactivity disorder: a population world. study. Lancet Psychiatry, 1(4), 278-285. List of Projects Silva, D., Houghton, S., Hagemann, E., Jacoby, P., Jongeling, B., & Bower, We currently have 26 projects in various C. (2014). Child Attention Deficit stages of completion using DPP data Hyperactive Disorder comorbidities and skills. on family stress: effect of medication. Furthermore, we are being approached Community Mental Health Journal, 51(3), by national and international groups to 347-353. access our resource. Silva, D., Houghton, S., Hageman, E., A list of the various projects being & Bower, C. (2014). Comorbidities of undertaken by the DPP is provided Attention Deficit Hyperactivity Disorder: below. All projects listed are expected Pregnancy risk factors and parent to be completed by 2016 at the latest. mental health. Community Mental

182 | TELETHON KIDS INSTITUTE 1. Project: The relationship 9. Project: Investigating the effect between education and mental health of maternal alcohol use disorder on outcomes for Western Australian the health and use of hospital services children: a longitudinal population of the mothers and their offspring study; and social outcomes of the children including educational, juvenile justice 2. Project: Preterm birth and and child protection outcomes; developmental disorders: trends, outcomes and antecedents including 10. Project: Triple P Parenting hospitalisation patterns and long-term Program evaluation; health and social outcomes; 11. Project: Hot-spotting for 3. Project: Public health approach juvenile offenders, risk factors and to child abuse and neglect: antecedents liquor outlets; and outcomes; 12. Project: Towards prevention – 4. Project: Survival, A population health approach to child hospitalisations and school abuse and neglect: A measurement achievement for children born with cleft model and the identification of lip and palate in Western Australia, from antecedent causal pathways; 1980 to 2010; 13. Project: Social and racial 5. Project: An investigation of the inequalities in birth rates and infant developmental pathways to hospitalised outcomes in Western Australia; deliberate self-harm behaviours (DSH) 14. Project: On the dimensions and among young people: a birth cohort development of juvenile delinquency. study using cross-jurisdictional linked A population-based study of the data in Western Australia (WA); prevalence and frequency of offending 6. Project: Promoting positive and the influence of individual, family perinatal mental health, parenting, and community factors on delinquency cultural and spiritual wellbeing, and in Western Australian children; resilience in young Aboriginal parents 15. Project: Exploring the pathways residing in two locations in Western to contact with juvenile justice in Australia; Aboriginal and Torres Strait Islander 7. Project: The relationship children: developing a profile of the between diet and educational risk and protective factors to support a outcomes in a cohort of Western strategy for change; Australian children; 16. Project: An evaluation of 8. Project: Alcohol and pregnancy: Supported Accommodation Services The impact of low to moderate maternal in Western Australia including impact alcohol consumption on child health over time on mental health outcomes and developmental outcomes; and identification of the most effective/

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efficient service delivery models; 23. Project: Youth offending and traumatic brain injuries; 17. Project: Linking population data sources to better define antenatal, 24. Project: Mapping of Ngala call postnatal and environmental risk centre clients to assist with identifying factors including educational, criminal high risk and high need areas; and antisocial behaviours and health 25. Project: Maternal schizophrenia outcomes of children and young adults and bipolar disorder - an investigation who have been prescribed stimulant of children’s outcomes. medication for Attention Deficit Hyperactivity Disorder in Western 26. Project: Modelling linked Australia; population data to understand and improve long-term outcomes for 18. Project: Investigating mortality children of incarcerated mothers to rates and the incidence and risk factors reduce social and economic impacts of diabetes complications and co- morbidities during early adult life in a population based childhood onset type 1 diabetes cohort; Environmental determinants 19. Project: An exploration into the of health delivery of health, education and child This topic was focussed on the protection services by the WA state environmental determinants of health, government to Aboriginal clients in with a focus on the built environment the Perth metropolitan and Geraldton and ambient air pollution exposures. regions; The following studies led by the 20. Project: Community investigator were published since the characteristics associated with last report. Australian Early Development Index Sources of Fine Particulate Matter outcomes; and Risk of Preterm Birth in 21. Project: Childhood Connecticut developmental pathways to educational achievement in Western Australia: A Gavin Pereira, Michelle L. Bell, Hyung multilevel data linkage study. Examining Joo Lee, Petros Koutrakis, and Kathleen the community, family and child Belanger characteristics and their impact on a Pereira, Gavin, et al. “Sources of fine child’s developmental and educational particulate matter and risk of preterm outcomes; birth in Connecticut, 2000–2006: 22. Project: A prevalence study on a longitudinal study.” Environmental parents with intellectual disability and health perspectives 122.10 (2014): 1117. their children; The aim of this study was to assess whether anthropogenic sources are

184 | TELETHON KIDS INSTITUTE associated with risk of preterm birth, Investigators: Gavin Pereira, Michelle comparing successive pregnancies to L. Bell, Kathleen Belanger, Nicholas de the same woman. Birth certificates were Klerk used to select women who had vaginal “Fine Particulate Matter and Risk of singleton live births at least twice in Preterm Birth and Pre-Labor Rupture of Connecticut during 2000–2006 (n Membranes in Perth, Western Australia = 23,123 women, n = 48,208 births). 1997–2007: A Longitudinal Study.” We procured 4,085 daily samples of Environment International 73 (2014): fine particulate matter on Teflon filters 143-149. from the Connecticut Department of Environmental Protection for six cities Our recent longitudinal study reported in Connecticut. Filters were analyzed an association between fine particulate for chemical composition, and Positive exposure and preterm birth in a US Matrix Factorization was used to cohort. We applied the same design determine contributions of sources of to an Australian cohort to investigate fine particulate matter. Risk estimates associations with preterm birth and were calculated with conditional logistic pre-labor rupture of membranes. From regression, matching pregnancies 287,680 births, we selected 39,189 to the same women. We identified women who had singleton births at least fine particulate matter attributable twice in Western Australia in 1997–2007 to dust, motor vehicle emissions, oil (n = 86,844 births). Analyses matched combustion, and regional sulphur. pregnancies to the same women with There was insufficient evidence to conditional logistic regression. Risk suggest that sources were statistically of pre-labor rupture of membranes significantly associated with preterm was greater for pregnancies with birth. However, elevated central elevated fine particulate exposure in estimates and previously observed the second trimester than were other associations with mass concentration pregnancies to the same Australian motivate the need for further research. women at lower exposure. There was Future studies would benefit from insufficient evidence for an association high source exposure settings and with preterm birth, indicating that a longitudinal study designs, such as that longer time period might be needed to adopted in this study. observe an association if a causal effect exists in Western Australia. Research Support Research Support Gavin Pereira was supported by an NHMRC Early Career Fellowship Gavin Pereira was supported by an (1052236). NHMRC Program Grant NHMRC Early Career Fellowship (572742). (1052236). NHMRC Program Grant (572742). Fine Particulate Matter and Risk of Preterm Birth in Western Australia

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Fine Particulate Matter and Risk of (1052236). NHMRC Program Grant Preterm Birth in Connecticut (572742). Western Australian Health Promotion Foundation grant (18922) Investigators: Gavin Pereira, Kathleen Belanger, Keita Ebisu and Michelle L. Bell Fraser Mustard Centre “Fine Particulate Matter and Risk of Preterm Birth in Connecticut in 2000– At the Telethon Kids Institute (Adelaide 2006: A Longitudinal Study.” American Team), a key component of our work journal of epidemiology 179.1 (2014): continues to include the Australian Early 67-74. Development Census (AEDC – formerly the Australian Early Development Several studies have examined Index) research program, an Australian associations between fine atmospheric Government backed commitment that particulates and preterm birth, but measures children’s development in it is uncertain whether results were communities across the nation. The affected by individual predispositions AEDC is a population measure of how (e.g., genetic factors, social conditions) our children develop through to their that might vary considerably between early school years. Teachers collect women. We tested the hypothesis that data across core areas of learning, a woman is at greater risk of preterm health and wellbeing and this data is delivery when she has had elevated used to develop a snapshot of child exposure to particulates during a development in communities across the pregnancy than when she has not nation. by comparing pregnancies in the same woman. From 271,204 births, Another primary aspect of the Adelaide we selected 29,175 women who had Team is the “Fraser Mustard Centre”, vaginal singleton live births at least established in September 2012 and twice in Connecticut in 2000–2006. named in recognition of Dr Fraser Analyses matched pregnancies to Mustard’s contribution to South the same woman. Pregnancies with Australia. The Telethon Kids Institute has elevated particulate exposure were joined forces with the SA Department more likely to result in preterm birth for Education and Child Development than were other pregnancies to the to create a research partnership same woman at lower exposure. aimed at improving developmental, Associations were most pronounced in health and educational outcomes for the first trimester and among Hispanic children and young people. The Fraser women. Mustard Centre has been created to bring together leading Australian child Research Support researchers and innovative government Gavin Pereira was supported by an policy makers and planners with a focus NHMRC Early Career Fellowship on enhancing programs and services

186 | TELETHON KIDS INSTITUTE for young people. the results were released in April 2013. The second round of data collection Australian Early Development Census involved 289,973 children (96.5 per (AEDC) cent of all children enrolled to begin Sally Brinkman, Tess Gregory, Angela school in 2012) and provided the first Kinnell, Lydia Braunack-Mayer, Alanna opportunity to explore change in the Sincovich level of developmental vulnerability for children living in different communities, The Australian Early Development states and territories within Australia. Census (formerly the Australian Early The AEDC National Report 2012 shows Development Index or AEDI) is a that there has been a significant drop in population measure of young children’s the level of developmental vulnerability development. Like a census, it involves in Australian children from 23.6% in collecting information to help create a 2009 to 22.0% in 2012. snapshot of children’s development in communities across Australia. Teachers In 2011, the Australian Government complete the checklist for children in Department of Education and Training their first year of full-time schooling. The awarded $1.5 million in funding directly AEDC measures five developmental to the Telethon Kids Institute to explore domains: the 2009 and 2012 AEDC data and deliver on policy focused research. • Physical health and wellbeing The research focuses on a range of • Social competence questions pertinent to early childhood development such as: • Emotional maturity • Are there jurisdictional differences • Language and cognitive skills in the level of developmental (school-based) vulnerability across Australia? • Communication skills and general • Is there a differential impact of knowledge living in mining towns vs. non- In 2009, the AEDC was completed mining towns for Aboriginal child nationwide for the first time with the development? Australian Government providing $21.9 • How does the AEDC predict later million for the implementation of the academic outcomes during the AEDC in recognition of the need for all primary school years? communities to have information about early childhood development. In 2009, • What is the best methodology information was collected on 261,203 to use to determine whether children (97.5 per cent of the estimated communities, LGAs etc have national five-year-old population). In experienced significant change 2012, the second national census of in the childhood development child development was completed, and from 2009 to 2012, and what is

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the best way to communicate this the implementation and utilisation information to various stakeholders? of the AEDC by community, schools, governments and researchers. The • How well do perinatal factors (e.g. team also manages an online learning low birth weight) predict childhood portal and forum for AEDC coordinators, development at 5 years old? delivered a National Conference Funder of the Project: Commonwealth focused on the AEDC, and coordinates of Australia, Department of Education, monthly national teleconference and Canberra. quarterly national meetings. Acknowledgement: The Australian Funder of the Project: Federal Government and State and Territory Government, Department of Education Governments are working in and Training partnership with The Royal Children’s Hospital Centre for Community Child Australian Early Development Census Health in Melbourne, the Murdoch (AEDC) Pilot Communities – Exploring Children’s Research Institute, and the results over time. Telethon Kids Institute, Perth, to deliver Sally Brinkman, Tess Gregory, Angela the AEDC. The Social Research Centre, Kinnell, Lydia Braunack-Mayer Melbourne, is managing the AEDC data. The Australian Early Development Provision of Engagement Services for Census (AEDC - formerly the Australian the AEDC Early Development Index) provides Sally Brinkman, Yasmin Harman-Smith, a snapshot of child development at Tess Gregory, Melanie Sander, Alanna school entry for all of the children living Sincovich in Australia once every three years. In 2015, the third census will be completed In 2014 the Telethon Kids Institute was providing the first opportunity to engaged on a three year contract to explore trends in child development for provide support services in relation Australia. to the Australian Early Development Census (AEDC). Within this scope of Prior to the national census, about works, support services are provided to 60 communities across Australia both the Department of Education and were involved in early pilot research Training (Canberra) and the eight AEDC using the same instrument. The State and Territory Coordinators and current project aims to provide these their support staff across Australia. communities with comparable data from the pilot (2004-2008) and the The Institute’s AEDC support team first two census collections (2009 and provides professional development 2012), so that they can compare the opportunities, strategic advice child development outcomes in their and support, and develops AEDC communities over time. This project engagement resources to support has a strong research translation

188 | TELETHON KIDS INSTITUTE component by exploring a range of family friendly; 4) Aboriginal children different ways to present trend data on are safe, healthy, culturally strong and the AEDC over time, which will inform confident (Department for Education the development of community reports and Child Development, 2011). using 2009, 2012 and 2015 AEDC The Telethon Kids Institute through national census data. the Fraser Mustard Centre has been Funders of the Project: Department engaged to undertake a process and of Education and Training (Australian impact evaluation of South Australian Government) Children’s Centres. The mixed methods evaluation commenced in 2012 and Evaluation of South Australian the first stage of qualitative works Children’s Centres were completed in 2014. An interim Sally Brinkman, Yasmin Harman-Smith report on the qualitative findings has been produced and is available on To reduce the impact of social inequality the Fraser Mustard Centre website. A on children’s outcomes, the South survey of staff working in Children’s Australian Government has established Centres, Service Providers working with a number of Children’s Centres across Children’s Centres, and families using South Australia. There are presently Children’s Centres was undertaken 42 Children’s Centres across South during 2014. The survey results will be Australia. Children’s Centres are reported alongside service usage data, generally located in areas of high need which is being collected systematically to enable the provision of high quality in Centres for the first time in 2015. The services to children and families who evaluation is due to be completed by may not otherwise have access to these July 2016. supports. Children’s Centres are based on a model of integrated practice, Funder of the Project: Government bringing together education, health, of South Australia, Department for care, community development activities, Education and Child Development and family support services in order Conceptual paper on screening and to best meet the needs of vulnerable assessment in early childhood and at children and families. school entry Specifically, Children’s Centres are tasked to provide universal services Sally Brinkman, Simon O’Brien with targeted support in order to South Australia, through the Department effect population outcomes in four for Education and Child Development, areas: 1) Children have optimal health, has been tasked with leading a development and learning; 2) Parents national project that will provide a provide strong foundations for their comprehensive picture of the range of children’s healthy development and data collections and specific screening wellbeing; 3) Communities are child and and assessment tools used across

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health, early childhood and education parents have the primary responsibility sectors to consider ways in which for raising their children; however some these tools can support practice, policy families require more support than development and national research others. The pilot program will initially priorities. The Department has engaged be developed in the northern suburbs the Telethon Kids Institute to undertake of SA and will build on the existing an initial state specific review that will interagency partnerships. The broad provide a foundation for this project. aims of the pilot include: The overall objectives of the • Engage pregnant women and evaluation are to: 1) To consider families in the antenatal period in what developmental domains (and order to maximize opportunities for family factors that influence) should effective intervention. be screened and assessed to best • Improve families’ capacity to parent respond to learning and development their children through building needs, 2) When these measures strength and resilience, and would be best implemented taking reducing vulnerabilities. into consideration sensitive periods in development, 3) Current contact points • Improve families’ awareness of for screening and assessment in South infants and children’s health and Australia. Using the findings from these development needs. reviews, a range of recommendations • Enhance the development and will be formulated for consideration by learning capacity of infants and the Department. children. Funder of the Project: South Australian • Improve the health and wellbeing Department for Education and Child outcomes for infants, children and Development families. Strong Start Program Evaluation • Facilitate access to networks of family support services. Sally Brinkman, Yasmin Harman-Smith • Facilitate services within the Researchers from the Fraser Mustard network to have a prevention Centre have been engaged to support orientation. the Strong Start program which is designed to deliver home based • Strengthen the voice of children services to families identified as and families in the community. experiencing significant and complex The evaluators have worked with vulnerabilities. The project recognises the program providers to establish that all children have the right to health, a database to collect administrative wellbeing and safety in a supportive and outcomes data for clients of the family and community environment. The service. The Strong Start program has Strong Start project also recognises that

190 | TELETHON KIDS INSTITUTE been established for the first time, thus inequalities in children’s language the evaluators have worked closely acquisition. This study used novel with the program providers to design speech recognition technology an evaluation that enables them to (Language Environment Analysis: respond to implementation challenges LENA) to unobtrusively measure the as the program becomes imbedded language environment of the child in as well as to measure what difference the home. This was a pilot aimed to the program is making for clients and trial recruitment, the consent forms and their infants. The evaluation uses a participant families’ level of comfort with mixed-methods design to measure both LENA. In addition, the study enabled us process and impact. to test the LENA software and output. To date the evaluators have conducted The study used predominantly interviews with service providers in the qualitative feedback from caregivers, program catchment area who might with cogency checks achieved refer clients into the service to enable through quantitative analysis where Strong Start to address recruitment applicable. Participation involved infants difficulties. The next stage of works and toddlers wearing a specialised will involve interviews with Strong Start recording device for a 16 hour duration staff and clients to identify elements to collect audio environment and social of the program that are working well data. The recording device was worn and those that require refinement. inside a small front pocket of specially A final stage of works will examine designed children’s clothing for the early client outcomes with utilisation day, except whilst napping or bathing. of administrative and outcomes data. Participating caregivers completed a The evaluation is due for completion in series of questionnaires in addition to February 2016. a complimentary time-use diary for the recording day. Funder of the Project: Government of South Australia, Department for The recording device processed the Education and Child Development audio from each 16 hour recording period into five audio environment Investigating the Home Language categories; (1) Meaningful speech Environment in the Early Years (near and clear to the child), (2) Distant Sally Brinkman, Cate Taylor, Veronica speech, (3) TV and electronic sound, (4) Smyth Noise and (5) Silence and background. For meaningful speech, the LENA Language enables literacy, education, software automatically quantified two and employment and is one of the measures of caregiver input, comprising major pathways that support human of Adult Words and Conversational capability formation. Variation in Turns. The software also measured parental talkativeness has shown to child input through quantifying child be a plausible mechanism for social

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vocalisations. Tallies for each of these a voice, an opportunity to communicate three measures were available to be to adults about what their experiences viewed and/or exported in 5-minute, are inside and outside of school. The hourly or daily increments. MDI has great potential to provide educators, parents, researchers, and As a result of the pilot we are confident policy makers with much needed in LENAs ability to discriminate between information about the psychological and background noises (such as TV and social worlds of children. radio) and between different adults and children. LENA has been able to The MDI project is a collaboration provide accurate assessment of all between researchers from the Telethon three key variables (Parent Talk, Parent- Kids Institute/University of Western Child Talk and Child Talk). Feedback Australia (Sally Brinkman, Tess Gregory, from the families from the pilot was Glenn Pearson), Menzies School of positive, with participants finding it Health Research (Sven Silburn) and the extremely easy and stress free to use. University of British Columbia (Kimberly Children liked the clothing choices, and Schonert-Reichl, Martin Guhn, Anne parents commented on how quickly the Gadermann), and policy makers from children and they themselves forgot the Department for Education and about the recording device. Findings Child Development in South Australia from this study provide the preliminary (David Engelhardt) and the Department data and experience to guide future of Education in Western Australia large-scale use in South Australia. (Rosemary Cahill). Funder of the Project: Government Researchers completed a pilot project of South Australia, Department for in 2013, measuring the wellbeing Education and Child Development of approximately 6,000 children across South Australia and Victoria in Assessing the development, well- the middle years of school in order being and community connectedness to provide summary information of children in the middle years: The back to policy makers, schools and Middle Development Instrument for communities about the health and Australia wellbeing of their children. In 2014, DECD completed a second round of The Middle Years Development data collection involving almost 18,000 Instrument (MDI) is a validated children, including schools and students population-level measure of well- which participated in the 2013 research being and contextual assets in middle trial, allowing the accuracy of data to childhood. The MDI was designed be explored further and to provide in Canada, to provide schools and these schools with two data points. communities with pragmatic data to Participating schools have now received inform policies and practice. The Middle their school report containing data on Development Instrument gives children

192 | TELETHON KIDS INSTITUTE student’s self-reported wellbeing. Plan including a mixed method approach with quantitative and In 2013 the MDI received additional qualitative research methodologies for financial support through an ARC evaluation implementation. Linkage grant of $223,000 for 2013- 2015. The grant provides further funding Key evaluation questions include: to establish the validity of the MDI in • Are there discernible differences in Australia, explore the international outcomes for children and families comparability of the instrument between who receive a reunification service Australian and Canada, and culturally from offices involved in the 2011 adapt the MDI for Australian Aboriginal reunification initiative or other children, by leveraging off the MDI data reunification services in comparison collected. to outcomes for other children and Funders of the Project: Australian families? Research Council Linkage Grant, • What factors have contributed to Government of South Australia, these differences? Department for Education and Child Development The next stage of this project requires linked data to be obtained from Families SA Reunification Initiative SANT DataLink – once approvals are Evaluation obtained, researchers can begin data Sally Brinkman, Angela Kinnell analysis. This evaluation project aims to assess Funder of the Project: Government process and impact of the South of South Australia, Department for Australian reunification program Education and Child Development from 2011 to 2013 and beyond. The Thriving in Adversity staggered implementation of changes to the reunification program from 2011- Sally Brinkman, Tess Gregory, Britney 2013 provide an opportunity to assess Keech, Alanna Sincovich the relationship between the nature of Both NAPLAN and Australian Early service provision, parent experience Development Census (AEDC) data and child outcomes. Additionally, this reveal that although socioeconomic evaluation will provide a framework status is a strong predictor of for ongoing assessment of process, developmental and educational parent experience, and the impact on outcomes - it is not destiny. Despite children’s outcomes as the reunification adversity in some low income program changes in 2013. communities, there are communities In conjunction with Families SA, that are performing higher than would researchers at the Fraser Mustard be predicted by statistical models. Centre have developed an Evaluation This project sought to explore the characteristics of these communities,

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which thrive in adversity, to determine however, differences in health services whether there are lessons to be learnt and playgrounds were not notable. The that may be transferable to other full report can be found on the Fraser places. Mustard Centre website. The Thriving in Adversity project Funder of the Project: Government involved both quantitative and of South Australia, Department for qualitative analysis to better Education and Child Development understand what is driving this success. AEDI Analyses for SA and support for Researchers developed reliable statistically risk adjusted (value added Department of Education and Child modelling) techniques to identify the Development Population Planning genuine high performing statistical Sally Brinkman, Tess Gregory, Simon outliers. As a result, eight South O’Brien Australian communities were selected for investigation – four of which were The Australian Early Development performing as expected in adversity, Census (AEDC, formerly the Australian and four that were thriving in adversity. Early Development Index) is undertaken once every three years by the In addition to the quantitative analyses, Department of Education and Training, researchers carried out desktop Canberra as a progress measure of analysis and community consultation. future human capital for the Council of We explored the programs and Australian Governments. The AEDI has services that were available for young been completed in 2009 and 2012, children and their families in each and results for South Australia reveal of the eight communities and aimed patterns of child development across to identify factors that may have the state. Although simple descriptive promoted resilience and improved statistics are produced and mapped child development and educational data for communities are available via outcomes. Thriving communities had the national AEDC website – the AEDC a tendency to work collaboratively results had not been critically analysed across different agencies and for SA. sectors, with co-location of key early childhood education services. Thriving This project will help to inform the communities tended to provide early state and in particular the Department literacy programs to young children by of Education and Child Development a trained facilitator through their local regarding the AEDC results in SA. libraries, had more playgroups and Specifically, this project aimed to: a much higher proportion of children • Determine if the areas where attending playgroups. Community Children’s Centres and the Learning involvement emerged as an important Together program is operating are feature of thriving communities, showing a different pattern of AEDC

194 | TELETHON KIDS INSTITUTE results compared to areas without. and young children under school age, which generally meet once a week • Determine if there are specific for one or two hour sessions. They population groups that have provide an opportunity for children to improved or not, and if not – why learn through unstructured play and not? Are there other characteristics for parents to develop social networks about these groups where we see and improve parenting skills. Playgroup poor results? attendance is likely to impact child • Investigate the pattern which saw development through several pathways, a 6 percentage point drop in the there is, however, limited national and percentage of Aboriginal children international research quantifying who spoke a language other than the specific impact of playgroups on English in the AEDC between 2009 childhood development and wellbeing. and 2012. The overall objectives of the evaluation • Identify policy and service are to: 1) Analyse and describe the changes which may have impacted Community Playgroup Model – how it differently on South Australian sits in the current policy environment children born in 2003/04 compared looking at its strengths and weaknesses to those born in 2006/07. within Australia and internationally, 2) The final project report was delivered Examine and analyse the factors which to DECD in early 2015, and will soon be have resulted in a significant decline made available on the Fraser Mustard of Community Playgroups since 2006, Centre website. 3) Make recommendations about future policy options for Community Funder of the Project: Government Playgroups. The evaluation employs of South Australia, Department for a mixed-methods research design Education and Child Development utilising both qualitative and quantitative Evaluation of the Community data to address the research aims. Playgroup Program Funder of the Project: Playgroup Australia Sally Brinkman, Yasmin Harman-Smith, Tess Gregory, Alanna Sincovich Fraser Mustard Centre PhD Top-Up At the request of Playgroup Australia, in Scholarships 2014 researchers at the Telethon Kids Supervisors: Sally Brinkman and Tess Institute have been engaged to conduct Gregory an evaluation of the Community Playgroup Program across Australia. In honour of Dr Fraser Mustard, the Community playgroups, substantially Fraser Mustard PhD Scholarship was the most common form of playgroup, established to fund one PhD student, are regular gatherings for parents based in the Fraser Mustard Centre, Adelaide. The scholarship provides

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additional funding support to a PhD to investigate influences on children’s candidate who has been awarded an capability formation, particularly in Australian Postgraduate Award (APA) relation to language development. to undertake a PhD. The intent of Funder of the Project: Government this is to attract outstanding students of South Australia, Department for who are passionate about improving Education and Child Development developmental, health and educational outcomes for children and young people. It is envisaged that with the appropriate support, these researchers Health Promotion and will later contribute to the advancement Education Research and of policy and practice in the area of Translation Group child development. The first Fraser Mustard Centre Top-Up Winthrop Professor Donna Cross and Scholarship was awarded in 2013 to Ms her team relocated to the Telethon Shiau Chong. Shiau is completing a PhD Kids Institute in March 2014 from Edith in the School of Population Health at the Cowan University. Their research University of Adelaide. Her project is focuses on the development and titled: The influence of early childhood evaluation of innovative school and temperament and parenting on community-based interventions to cognitive, social and health outcomes. enhance the emotional and social wellbeing of children and adolescents. The second Fraser Mustard Centre Top- Up Scholarship was awarded in 2014 to Ms Catherine Johnson. Catherine Mental Health Research is completing a PhD in the School of Psychology at Flinders University. Promotion of mental health and Her project is titled: Mindfulness in wellbeing in young people Schools: A transdiagnostic prevention programme. Investigators: Donna Cross, Stephen Zubrick (Telethon Kids), Marilyn Veronica Smyth has been awarded Campbell (QUT), George Patton the third Fraser Mustard Centre (UniMelb), Michael Rosenberg (UWA), Top-Up Scholarship. Veronica will Phillip Slee (Flinders), Barbara Spears commence her PhD in 2015 in the (UniSA) School of Population Health at the University of Adelaide, and will conduct The Collaborative Research a project examining inequalities in Network program is part of a suite communication between children and of initiatives established by the their caregivers. Veronica’s PhD work Australian Government to reform will make use of innovative speech higher education teaching, learning, recognition technology and linked data research and research training. The

196 | TELETHON KIDS INSTITUTE ECU-led Collaborative Research of a collaborative group of researchers Network focuses on growing research across Australia working to enhance excellence at the University through the mental health and wellbeing of partnership and engagement. It aims young people. Activities have included to create world-class research capacity joint research proposals, publication, and outcomes through collaborative supervision of research students, partnership with nine universities across and research training seminars and Australia. workshops for early career researchers. The sub-project led by Professor Donna Funders of the project: Collaborative Cross has resulted in the development Research Networks (CRN) Program, of a national group of researchers Department of Innovation, Industry, working collaboratively to promote Science and Research the mental health and wellbeing of Enhancing adolescent mental health young people. This group collaborates on research publications, research through positive education proposals, supervision of higher degree Investigators: Dianne Vella-Brodrick by research students and the provision (UniMelb), Nikki Rickard (Monash), of research training schools for early Donna Cross (Telethon Kids), John career researchers. The research group Hattie (UniMelb), Justin Robinson includes: (Institute Positive Psych), Christine King • Associate Professor Michael (UniQLD) Rosenberg, University of Western Mental disorders are the single greatest Australia burden of disease for adolescents • Professor George Patton, University with reports of around 1 in 4 people of Melbourne; Paediatrics Royal aged 16-24 years experiencing mental Children’s Hospital illness in Australia. Positive Education in schools may offer feasible solutions • Professor Phillip Slee, Flinders for reducing the escalating incidence of University mental illness and promoting engaged • Dr Barbara Spears, University of learners, flourishing and pro-social South Australia behaviours among young people. • Winthrop Professor Steve Zubrick, This project involves evaluation and University of Western Australia; identification of key features of the Telethon Institute for Child Health Positive Education Program at Geelong Research Grammar, and the adaptation of the program to suit public schools. Program • Professor Marilyn Campbell, evaluation will utilize momentary Queensland University of sampling and physiological indicators, Technology to complement focus groups and self- This project involves the development report measures.

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Positive education is a preventative, Motivational Interviewing is particularly strengths-based approach to address powerful when changing the problem the mental health needs of young behaviour elicits resistance from the people in schools. This project uses person engaging in this behaviour. MI innovative methods to examine the has previously been successfully used contribution of positive education to in counselling and guidance settings to adolescent mental health, and to social help young people change and resolve and learning outcomes. problems with alcohol and substance use, eating disorders, gambling Funders of the project: Australian problems, and, most importantly, to Research Council reduce violent behaviour. Bullying, Cyberbullying and The study examines the efficacy Aggression Research of MI as a targeted intervention in Testing a comprehensive targeted conjunction with the Friendly Schools intervention to reduce student Plus whole-school bullying prevention program, which is an evidence-based bullying (‘Beyond Bullying’) program that helps limit problems with Investigators: Donna Cross (Telethon bullying. The study is being conducted Kids), Marilyn Campbell (Qld Uni Tech), at the Telethon Kids Institute, Western Phillip Slee (Flinders), Ken Resnicow Australia, by the lead investigator (University of Michigan), Christina Winthrop Professor Donna Cross and Salmivalli (University of Turku) project director Dr Kevin Runions. Peer bullying is a stubborn social The Beyond Bullying project is being problem. Despite attention to the trialled in Western Australian schools problem by schools, communities and as a way to reduce the prevalence researchers, bullying continues to be and impact of bullying. The project highly prevalent in Australian schools. involves counselling young people who Researchers have found that working are identified as bullying others with with the whole school to address an approach known as Motivational cultures that support bullying has some Interviewing, which is used to enhance effect, but further work is needed to their motivation to change their develop strategies to prevent these behaviour. In addition, the ‘Friendly behaviours. To date, one of the chief Schools Plus’ program is used to challenges has been stopping bullying provide schools with resources and at the source: the young people who strategies to prevent and address engage in repeated or severe bullying bullying behaviours and attitudes behaviours. among all students. The Beyond Bullying project is trialing Funders of the project: NHMRC an innovative approach known (Targeted Mental Health Call) as Motivational Interviewing (MI).

198 | TELETHON KIDS INSTITUTE PAVe (Preventing Anxiety and PAVe is an exciting new research Victimisation through education) intervention project being conducted in over 100 NSW and Western Investigators: Ron Rapee (Macquarie), Australian primary schools, which aims Donna Cross (Telethon Kids), Kay to support students who have been Bussey (Macquarie), Caroline Hunt frequently bullied. The project will help (UniSyd), Jennifer Hudson (Macquarie), schools reduce all forms of bullying Cathy Mihalopoulos (Deakin), Clare by developing students’ social and Roberts (CurtinUniTech), Nick Titov emotional learning, building positive (Macquarie) peer relationships, and empowering The study is being conducted by students to cope successfully with the Centre for Emotional Health difficult situations. at Macquarie University under the Funders of the project: NHMRC, leadership of Professor Ron Rapee Australian Government Department of and with Professor Donna Cross at the Education and Macquarie University Telethon Kids Institute, University of Western Australia. Building school capacity to reduce This study will evaluate the social aggression among students effectiveness of two evidence-based Investigators: Donna Cross (Telethon approaches to support students who Kids), Anjie Brook (WA Dept Education), have been frequently targeted by Elizabeth Healy (WA Dept Education), bullying in primary schools: Rob Nairn (ECU), David Mander (ECU), • Friendly Schools Plus: a strengths- Lydia Hearn (UWA), Sharyn Burns based, whole-of-school program (Curtin), Natasha Pearce (ECU) designed to enhance students’ The Strong Schools Safe Kids research social and emotional learning and project was funded by Healthway under foster the prevention of bullying a ‘research to practice’ grant that aimed behaviours; to support the translation of current • Cool Kids: Taking Control: a evidence of school-based bullying strengths-based, targeted program prevention interventions into real world designed to build resilience in practice. Whilst schools have access those children who have been to a national Australian framework of targeted by bullying behaviours action for safe schools that supports a whole-school approach, and there These programs will help schools exists a greater understanding of the reduce all forms of bullying by barriers and enablers to whole-school developing students’ social and implementation, schools still report emotional learning, building positive implementation challenges limiting their peer relationships, and empowering capacity to achieve positive outcomes students to cope successfully with in policy and practice. This research difficult situations.

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project aims to understand how schools based practices and implement change in different contexts translate empirically to address pastoral care support and supported policy and practices to bullying behaviours. Key learnings prevent and manage student social show that when schools undertake a aggression and bullying behaviours systematic implementation process, and how their capacity to implement capacity for whole-school change can these practices can be strengthened be strengthened to improve positive to promote sustainability and improve social and emotional outcomes for impact. students. Four phases of ‘Translational Formative Funders of the project: Healthway Evaluation Research’ recommended Cyber-aggression and cyber- by O’Hara and colleagues (2013) were conducted including a synthesis of victimization (CAV): A mixed-methods the research findings, an environment study of structural features and and policy context analysis, individual differences in online social longitudinal mixed methods research information processing with schools and consultation with Investigators: Kevin Runions (Telethon key stakeholders over a five year Kids), Danielle Law (Wilfred Laurier period (2010 – 2014). The research University), Jennifer Shapka (Uni findings were used to develop a British Columbia), Debra Pepler (York systematic approach to whole-school University) implementation and capacity building in preparation for wider dissemination Some experiences that may be and implementation of an Australian interpreted as cyber-aggression and evidence-based, whole-school bullying victimisation (CAV) may not, in fact, prevention intervention called Friendly have been acts intended to harm, but Schools. Key learnings show that are nevertheless interpreted as harmful when schools undertake a systematic and result in psychological harm. implementation process, capacity Interpreting the intent and emotional for whole-school change can be tone behind cyber-communications is strengthened for great student impact. a key digital skill, and one that can be challenging. The Strong Schools Safe Kids research project was funded by Healthway and Our conceptual framework (Runions aimed to develop supports for schools et al., 2012) systematically considers to improve their practices to prevent how the new technologies enabling student bullying behaviours. Seven online social networks might present case study schools were observed over distinct influences (i.e., opportunities four years to see how schools used and constraints) for aggression and a new implementation process and victimization that are different from tools to assess needs, select evidence- those afforded by traditional modes of communication. In this study, we

200 | TELETHON KIDS INSTITUTE seek to analyze how interpretation of communications. semantic content is influenced by the Thus there is a skill in both crafting and opportunities and constraints that arise interpreting digital communications, via communicating over that medium. but it is a skill about which we know A key structural property of the bulk of very little. The present research aims communication online is its text-only to increase our understanding of nature (Runions, Shapka, Dooley, & how youth navigate this ambiguity Modecki, 2012). As such, it provides and their experiences in interpreting few or no semantic information from ambiguous but potentially hostile/ body language (i.e., nonverbal cues) or bullying communications, and to tone of voice (i.e., paralinguistic cues). provide preliminary tests of a new The use of emoticons (e.g., :) )and conceptual model (Runions et al., jargon (e.g., LOL) aims to reduce this 2012). The outcomes of this research ambiguity, but research suggests that would provide important directions these can instead increase ambiguity, for how best to prepare youth and and instil an interpretation of sarcasm their teachers and parents for the and condescension (Derks, Bos, & complexities of their digital lives, so Grumbkow, 2007), which may in fact that misinterpretation does not fuel fuel interpretations of hostility. In all, psychological problems. this paucity of social semantic cues When communicating with one leaves online communication ripe for another online, young people rely misinterpretation, including erroneously on text-messages and other written attributing hostility to benign but communication, without being able to ambiguous communication. see one another or hear one another’s The present study aims to better voices. This reliance on text means that understand how this ambiguity operates misunderstandings can arise that might in young people’s interpretation and be taken to be cyberbullying, even if response to cyber-communication. they aren’t really meant that way. This A second phase addresses, via study provides a first look at how young an experimental design, whether people make sense of their online participants discern between communications, and some key factors intentionally harmful (examplar) that might influence what they see as messages and intended jokes, and hostile or not. whether emoticon usage, the status Funders of the project: Social Sciences of the sender (a popular acquaintance and Humanities Research Council vs. an unpopular acquaintance), (Canada) and the perceived audience for the communication (private or public) ‘Cyber Savvy’ Project influence youth’s interpretation This body of research into sexting and and response to cyber-aggressive electronic-image sharing is funded

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through two research projects: these combined findings informing the development of the online Assessing the public health intervention. Qualitative data exploring implications of higher risk online young people’s understanding of behaviours in young people online behaviour, including sexting, Investigators: Donna Cross, Therese was collected from approximately 80 Shaw (Telethon Kids), Rebecca Guy students through group activities and (UniNSW) focus groups during a two-day student Cyber Leader Summit. Funders of the project: Telethon-New Children’s Hospital Research Fund Findings from these qualitative data are being used to help refine items and Students leading change to reduce scales measuring how and why young sexting-related harm to young people people interact with and respond to images in a cyber environment. Cyber Investigators: Donna Cross (Telethon Leaders and staff with experience Kids), Therese Shaw (Telethon Kids), in online educational materials Rebecca Guy (UniNSW), Shirlee-Ann development will use the qualitative Knight (ECU), Karen Murcia (ECU) and quantitative data to inform the Sexting is increasing in prevalence development of the online resource. and beginning at increasingly younger This resource will be implemented via ages among young people. It is linked schools in 2015. Student and teacher to significant social, psychological and process (use and satisfaction) data will legal consequences for those who be collected using face-to-face teacher produce and who share this material interviews, pre-post student survey, with others. Very few of the cyber web metrics and Audio-CASI interviews safety resources currently available in with students. Australia have been developed with Advisory stakeholder committees a comprehensive understanding of engaging young people, parents, young people’s sexting behaviour. This school staff and policy makers are innovative four-phase mixed methods being recruited to facilitate and study not only addresses this new maximize translation validity of the phenomenon but actively engages resources developed, while also young people to determine and deliver guiding the progress of this research. authentic ways to reduce its prevalence and harms. Recent research suggests approximately a quarter of teenagers This study uses a three-stage have sent nude or semi-nude images or exploratory sequential design in its videos of themselves via an electronic formative stages, with qualitative medium. The consequences of sexting data informing the development of a include leaving an online digital trail quantitative questionnaire, and then that might affect future employment and

202 | TELETHON KIDS INSTITUTE relationships; provide opportunities for Australian National Children’s Nutrition blackmailing; humiliation if the image and Physical Activity to address these is shared further; and the resulting issues. emotional trauma. This study aims We found that SSB consumption was to improve what we know about this high and patterns of consumption behavior and help young people make varied by age. The primary source of safe and healthy decisions about the SSB was from supermarkets with less images they share. Young people’s than 17 per cent of products being perspectives are being actively used sourced from fast-food establishments to develop and test an online resource and school canteens. Further, the that will enable families, schools and majority of SSBs were consumed other adults working with young people at home. We found children whose to respond more effectively to reduce parents had lower levels of education sexting-related harms. consumed more SSB on average, while Funders of the project: Healthway and children whose parents had higher the Department of Education education levels were more likely to favour sweetened juices and flavoured milks. Human Capability This research highlights the need for public health interventions which are Sugar Sweetened Beverage evidence based and target the primary consumption by Australian children: source of SSBs in order to reduce Implications for public health strategy current levels of intake by Australian Investigators: Katherine Hafekost, children. Additionally, education Francis Mitrou, David Lawrence and of parents and children regarding Stephen R. Zubrick the health consequences of high consumption of both carbonated and Consumption of sugar sweetened non-carbonated SSBs is required. beverages (SSB) has been linked to unhealthy weight gain and nutrition Funders of the project: NHMRC related chronic disease. Despite public program grant #572742 health efforts to reduce consumption, The influence of long-term such as limiting sales of these products joblessness and separation of in schools and restrictions on marketing, grandparents on grandchildren Australian children’s intake remains high. In addition, little up-to-date Investigators: Kirsten Hancock and information about the primary purchase Stephen R. Zubrick, with Ben Edwards source of SSB, consumption patterns (Australian Institute of Family Studies) and the dietary and demographic profile We have understood for many of SSB consumption in children was years that family experiences such available. We used data from the 2007

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as separation and/or joblessness patterns of disadvantage are therefore have close intergenerational links. valuable, but the availability of To date, there have been limited Australian data to investigate these opportunities to examine how these patterns has been limited until recent intergenerational relationships work years. With new data now available, across three generations of family this study will examine the experience members. In collaboration with the of multiple disadvantages in two Australian Institute of Family Studies, generations of Australian families, this project uses data from over 8,000 and how these experiences relate to families participating in Growing Up in the trajectories of children, the third Australia and examines the extent to generation. This work expands upon which joblessness and family separation our initial projects that examined transfers across generations, and how particular aspects of intergenerational a continuing family history of these disadvantage such as joblessness and disadvantages relates to a variety family separation. of outcomes for children, including ARC Centre of Excellence for Children their social and emotional wellbeing and Families over the Life Course and performance at school. The #CE140100027 initial findings from the project were published in the Longitudinal Study Playgroup participation and social of Australian Children 2012 Annual support outcomes for mothers of Statistical Report, with further work young children currently underway. Investigators: Kirsten Hancock, Nadia ARC Centre of Excellence for Children Cunningham, David Lawrence, and and Families over the Life Course Stephen R. Zubrick with David Zarb #CE140100027 (Playgroup WA Inc). Multiple disadvantage across The project used data from the generations in Australia Longitudinal Study of Australian children to examine friendship networks and Investigators: Kirsten Hancock, Francis social support outcomes for mothers Mitrou, Stephen R. Zubrick according to patterns of playgroup Families are a critical pathway in the attendance when their child was aged transmission of disadvantage. While 3–19 months and 2–3 years. Compared the literature broadly focuses on mothers who participated at both time parent-child transfers in understanding points, mothers whose child did not intergenerational disadvantage, further participate in playgroup at either age insight can be achieved by examining were significantly more likely to report markers of disadvantage across having no support from friends when multiple generations of the same family. the child was 4–5 years and again at Studies examining multigenerational age 8–9 years. The results provide

204 | TELETHON KIDS INSTITUTE evidence that (persistently) participating Using the WA Department of Education in a playgroup may be a protective database of over 400,000 students, factor against poor social support including longitudinal measures of outcomes, and that socially isolated attitude and behavior, attendance and parents may find playgroups a useful achievement, this project will address resource to build their social networks. significant knowledge gaps and provide education policy makers with useful Funders of the project: NHMRC information relevant to Australian program grant #572742. students in the Australian context. Attitude, attendance and ARC Centre of Excellence for Children achievement: A longitudinal view and Families over the Life Course of student development and #CE140100027 participation in education over time. Causes and consequences of student Investigators: Kirsten Hancock, David mobility in Australia Lawrence, Cate Taylor and Stephen R. Zubrick Investigators: Kirsten Hancock, Stephen R. Zubrick This project is an extension of our earlier work, and will examine the Research shows that students who complex interplay between students’ change schools are at greater risk of attitudes and behavior, patterns of lower educational attainment and early absence and academic achievement. dropout than less mobile students. The first part of the study will examine While it is understood that there are whether school absence in the early many reasons, both positive and years is a precursor for poor attitude negative, that underpin unscheduled and behavior in later years, and if so, school transfers, all types of school how early do problems emerge? The moves are typically considered equal. second part of the study will examine This approach has led to inconsistent the fine level detail that accompanies findings related to student mobility each episode of absence, addressing and how it relates to other student questions of whether short, frequent outcomes. In addition, our knowledge absences are more disruptive for regarding the extent and nature of students that long, infrequent absences, student mobility for Australian students and if absences that occur earlier is limited. The aim of this study is in the semester are more disruptive to provide an overview of student than those which occur later in the mobility in Australia using a nationally semester. The reasons provided for representative longitudinal cohort of these absences are also of interest, and Australian children, and to determine whether absences that occur for family whether the different reasons or social reasons have different impacts underlying mobility are related to to absences that are due to illness. differences in progress over time.

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ARC Centre of Excellence for Children food source. We will also look at and Families over the Life Course whether this varies according to the #CE140100027 child’s age group, sex or any other demographic characteristic. Sources of processed and refined foods in children’s diets Funders of the project: NHMRC program grant #572742. Investigators: Wavne Rikkers, Katherine Hafekost, David Lawrence and Stephen Young Minds Matter: The Second R. Zubrick Australian Child and Adolescent Survey of Mental Health and Public health agencies have Wellbeing consistently called for regulation of ‘takeaway’ food marketing, and access Investigators: Katrina Boterhoven to these food outlets. The main de Haan, Sarah Johnson, Jennifer reason is that food and beverages Hafekost, David Lawrence, Stephen R. sourced from outside the home, such Zubrick, with Michael Sawyer (University as those from ‘takeaway’ food outlets of Adelaide) and John Ainley (Australian and restaurants, are considered to be Council for Educational Research) contributors to the high prevalence The National Survey of Mental Health of obesity and incidence of chronic and Wellbeing includes three main disease in Australia and other Western components - a population-based countries. However, it is possible that survey of adults, a service-based highly processed and refined foods survey of people with low-prevalence of poor nutritional quality, which are psychotic disorders, and a population sourced from supermarkets, may be survey of children. The first Child consumed in the home in equal or and Adolescent component was greater proportion to that of similar conducted in 1998. The Telethon Kids foods sourced from outside the home. Institute is currently conducting Young The aim of this study is to evaluate the Minds Matter, the second child and proportion of children’s diets that come adolescent component of the National from sources outside the home and to Survey of Mental health and Wellbeing, compare the nutritional value of those in collaboration with Roy Morgan foods with that of highly processed Research. Following pilot testing and a and refined foods purchased from dress rehearsal main fieldwork for the supermarkets and prepared inside the survey commenced on 31 May 2013 home. Using results from the National and was completed in April 2014. A final Children’s Nutrition and Physical Activity publication of survey results is due for Survey 2007, we will determine the release mid-2015. proportional contribution (in terms of The broad aims of the National Survey percentage of energy and number of of Mental Health and Wellbeing meals) to children’s diets from each initiative are to determine how many

206 | TELETHON KIDS INSTITUTE Australians have mental disorders, what from the Longitudinal Study is the impact of these disorders (on of Australian Children and the individuals, families and communities), Longitudinal Study of Indigenous what services are being used by Children people with mental disorders, and what services are needed for people with Investigators: Brad Farrant, Stephen R. mental disorders and their families. Zubrick Funders of the project: Australian Vocabulary knowledge is a critical Government Department of Health. component of school readiness. This project aims to investigate the factors Early life influences on child and that promote vocabulary development adolescent mental health problems: across early childhood for Indigenous A life-course approach to prevention and non-Indigenous children. So and intervention far this research has found that low levels of joint attention in infancy and Investigators: Dr Monique Robinson parent-child book reading across (Supervisor: W/Professor Stephen R. early childhood increased the risk Zubrick) of children having poor vocabulary It has been suggested that the best around the time of school entry (using method for avoiding poor mental data from the Longitudinal Study of health outcomes is to build and Australian Children). Children who had promote positive outcomes right low levels of parent-child book reading from the very start of life. The goal across early childhood were two and then shifts from treating problems a half times more likely to have poor after they have occurred, to a model vocabulary at school entry. These enabling the formation and promotion results converge with the findings of positive mental health outcomes. of training studies and underline the However, we have predominantly importance of educating current and used early childhood as the start point future parents about the pivotal roles for development. This project exists of joint attention and parent-child within this new paradigm, exploring book reading for children’s language the early life influences on behavioural development and hence their readiness development. for school. Funders of the project: Australian Funders of the project: NHMRC Rotary Health Colin Dodds Postdoctoral Program Grant #572742. Research Fellowship (2011-2013) and NHMRC Early Career Fellowship (2013- Learning better together: Connecting 2016). the strengths of Aboriginal people and culture to enhance early Factors that promote child vocabulary childhood development in the early school years: Findings

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Investigators: Brad Farrant, Stephen R. social interactions, shared activities, and Zubrick, Glenn Pearson input from caregivers shape the child’s journey to acquiring the adult language Aboriginal children are twice as likely system. The centrality of language to to be classified as developmentally everything we do in life means that vulnerable when they start school. almost everyone has a theory about Aboriginal people are actively seeking why most children acquire language involvement in the design of policies with remarkable ease, while others do and services to improve outcomes not. Recent discoveries about patterns for their children. They want them and predictors of stability, change, to reflect more of their values and improvement, and decline in children’s circumstances because this will improve language abilities in the first 10 years of their relevance and uptake. This life have led us to re-think some deeply project will consult and collaborate with held beliefs about language and literacy Aboriginal parents, families and elders as well as the policies services and to guide research (using three large supports designed to support children’s existing datasets) into the factors that language and literacy development. prompt, facilitate and constrain the early childhood development of Aboriginal Funders of the project: NHMRC children and to direct the translation Program Grant #572742. of the findings into a suite of culturally Twins and singletons with specific appropriate and empowering policies and practices. language impairment (Looking at Language) Funders of the project: NHMRC Program Grant #572742. Investigators: Catherine Taylor, Stephen Zubrick with Mabel Rice, Shelley Smith, Language and Literacy Development Javier Gayan, and Hugh Catts in the Longitudinal Study of Australian Children Looking at Language places the institute at the forefront of research in Investigators: Cate Taylor, Stephen language and literacy worldwide. Our R. Zubrick, Daniel Christensen, David approach and our research crosses a Lawrence, Francis Mitrou. multitude of disciplines and sits within a number of the institute’s Research Our uniquely human capacity for Focus Areas The study, combines language is one of the most important epidemiological, behaviour genetics developmental accomplishments of and molecular genetics methods childhood and is a tool for life. Young to study language development, children acquire the language(s) spoken language impairment, reading and to them at home through everyday reading impairment from infancy to interactions and experiences with their adolescence. caregivers. Neurobiology (including genetics) and the child’s nurturance, This internationally unique study is

208 | TELETHON KIDS INSTITUTE following the language development recognised by leading public health of more than 2000 WA children from organisations and prestigious peer 2-14 years. It is the world’s only study reviewed journals as the biggest to conduct such detailed assessment global health threat of the 21st century. of language and literacy development Along with the old and disadvantaged, from infancy through the formative children are particularly vulnerable adolescent years. For the institute, the to the negative effects of climate ability to continue following the study change. Children suffer around 90% children through early adolescence is of the disease burden from climate ground-breaking. It is vitally important change. Even if current international that we understand the developmental carbon reduction commitments are course of language and literacy from honoured, the global temperature rise infancy and what different trajectories is predicted to be more than double mean for young people’s opportunities the internationally agreed target of 2°C. at school and beyond. Data collection Humanity continues to pour record for this project is based entirely in WA amounts of CO2 into the atmosphere. It and involves 5000 children and families has been estimated that climate change overall. will mean that Australian children will face a 30% to 100% increase across The study has received 15-years selected health risks by 2050. Indeed, continuous funding from the USA if we fail to act, future generations of National Institutes (National Institute on Australians may face a three- to 15-fold Deafness and Other Communication increase in these health risks by 2100. Disorders). The project is a joint We are only beginning to understand initiative between the Telethon Institute the impacts that climate change will for Child Health Research and UWA have on children’s physical and mental and the USA’s University of Kansas health. More research at the regional and University of Nebraska Medical and local levels is desperately needed Centre. All study participants and data so we can adequately understand, collection is based in Western Australia. prepare for and adapt to the impacts Funders of the project: National of climate change. The existence of Institutes of Health (RO1DC05226, cost effective ways to reduce climate P30DC005803, P30HD002528). change means there is no excuse Future under threat: climate change for inaction. Climate change and the carbon-intensive energy system are and children’s health currently costing 1.7% of global GDP and Investigators: Brad Farrant, with Fiona are expected to reach 3.5% by 2030. Armstrong (Climate and Health Alliance, This is much higher than the cost of Victoria) and Glenn Albrecht (Murdoch shifting to a low carbon economy. Right University) now the science is telling us that we are not doing enough. As children are Climate change has been widely

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innocent and non-consenting victims of (Australia, Canada, and New Zealand) climate change, adults have an ethical from 1981–2006. obligation to do everything possible to Funders of the project: NHMRC prevent further damage to their ability program grant #572742. to thrive in the future. To do otherwise is to ignore the very thing many of us see Methods for engaging with the as the most important reason for living. community in setting priorities for Human development of Indigenous child health research versus non-Indigenous populations in Investigators: Wavne Rikkers, Katrina developed nations Boterhoven De Haan, David Lawrence, Anne McKenzie, Hayley Haines, Kirsten Investigators: Francis Mitrou, David Hancock, Daniel Christensen and Lawrence and Stephen R. Zubrick, with Stephen R. Zubrick Martin Cooke (University of Waterloo, Canada), Eric Guimond (Department The vast majority of public health of Aboriginal Affairs and Northern research in Australia is funded by Development, Canada), and David the community. As there are more Povah and Elena Mobilia (Australian research ideas proposed than there Bureau of Statistics) are funds available, it is necessary to make choices as to which research Understanding the economics of will be provided funding. There is a Indigenous disadvantage is of particular recognised role for consumers and importance if we are to lift Aboriginal community members to participate in children and families out of poverty all phases of research, from choosing and reduce over-representation what to research through to translation in human services agencies in the of results. Many countries, including foreseeable future. We have a long- Australia, have formal policies and standing collaboration between The procedures for the involvement of University of Waterloo (Canada), the consumers in health care planning and Department of Aboriginal Affairs and policy setting, however, models for Northern Development Canada, and consumer and community participation the Australian Bureau of Statistics, outside the health services research to examine indicators of human area are less well developed. development among Aboriginal This study aimed to evaluate and populations in colonised Western compare two different methods for nations. This includes plans for several obtaining community participation in papers over the next 2 years, the first a research field broadly described as of which uses a representative cohorts human capability expansion, which methodology to investigate changes encompasses several health as well in key socio-economic outcomes as other disciplines, such as education of Indigenous and non-Indigenous and language development. As such, persons in three developed nations

210 | TELETHON KIDS INSTITUTE the entire community, not just those there was a much higher proportion of currently with young children would females (78%) who participated in the likely benefit from this research. phone survey than are in the general WA population (49.5%). Therefore, while The Participation Program at the the results showed that the Community Telethon Kids Institute has developed Conversations attracted participants a range of methods for fostering active who are representative of those who involvement of community members are willing to give their views on our in various stages of research. While research via a telephone survey, we their participation levels are good, cannot be sure that the participants for their network represents a relatively either the Community Conversations small proportion of the Western or the telephone survey represent the Australian population. We wanted whole community. to test whether there were ways, other than the Institute’s consumer Funders of the project: NHMRC and community consultation forums, program grant # 572742 called Community Conversations, of Suicidality and social media engaging with a broader cross-section of the community and if there were any Investigators: Francis Mitrou, Grant differences in the views obtained using Smith, Monique Robinson and Kim a different participation method and Carter, with Simon Davies, Caroline a larger sample of the population. We Goossens, Amy Cleator and Siew Lan conducted a telephone survey of 800 Ho (Western Australian Child and randomly selected households across Adolescent Mental Health Services), WA to seek people’s views about our Rosanna Capolingua (Western research program. We also ran two Australian Child and Adolescent Health Community Conversations, one using Service) and Chris Harris (Youth Focus). the Participation Program to recruit Child and Adolescent Mental Health participants, and the other using people Services (CAMHS) have noticed recruited from the telephone survey. increasing admissions for self-harm We found that there was little difference with anecdotal evidence of a role in the views about our research for the internet and social media in expressed by participants from the supporting decisions to take self- Community Conversations compared harming action. This project seeks to with the respondents to the telephone develop a clinic based instrument to survey. All respondents were very assess the influence of the internet supportive of our work and were happy and social media on each individual to allocate priorities to different areas of CAMHS presentation for self-harm. This research. Generally, people were also instrument will be tested and refined in favour of community participation in-service before being rolled out as a in the research process. However, permanent tool for assessment across

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all CAMHS units. Intergenerational welfare dependency is a key component of deep persistent Funders of the project: WA Department disadvantage. Documenting the of Health situation in Australia is important to our Contribution of Indigenous cultural understanding of the leverage points factors to survey response for policy action in the welfare space. This project will build on work started Investigators: Francis Mitrou, with Paco by this group prior to the advent of the Perales Perez and Bernard Baffour (The Life Course Centre to understand the University of Queensland) scale and nature of intergenerational Some surveys are designed welfare dependency in Australia, and specifically to collect information from will provide a basis for future research Indigenous populations, and these directions for The Centre. surveys accommodate Indigenous Funders of the project: ARC Centre of ways of understanding questions and Excellence for Children and Families response categories. When surveys are over the Life Course #CE140100027 developed for the general population their design tends not to be tailored Evaluation of headspace (National to Indigenous perspectives and ways Youth Mental Health Foundation) of understanding. This may have Investigators: Francis Mitrou, Daniel implications for the survey results when Christensen, Katherine Hafekost, David general population surveys also collect Lawrence and Stephen R Zubrick with information from Indigenous families Ilan Katz, Kristy Muir and Fiona Hilferty that happen to fall under the sample (The University of New South Wales), capture. Where sample sizes allow, Rebecca Cassells, Alan Duncan (Curtin researchers often compare Indigenous University) to non-Indigenous outcomes as measured through general population The Social Policy Research Centre surveys. This project asks whether such (SPRC) at UNSW is under contract to results could be misleading. the Australian Government Department of Health to deliver a broad ranging Funders of the project: ARC Centre of program evaluation of headspace. Excellence for Children and Families headspace has been operational since over the Life Course #CE140100027 2006 and is funded by the Department Intergenerational Welfare as part of a broader mental health Dependency in Australia service platform. To give an example of the scale of the program, headspace Investigators: Stephen R Zubrick and received operational funding of $81m Francis Mitrou with Paco Perales Perez, for the 2012/13 financial year and will Angela Higginson, Janeen Baxter have 85 centres running nationally by and Mark Western (The University of mid-2015. Queensland)

212 | TELETHON KIDS INSTITUTE UWA have a sub-contract with SPRC to Centres are a new way of providing deliver the economic component of the services and supports for families of headspace program evaluation. UWA young children. The services comprise are required to address three specific universal services plus services based research questions: on the specific needs of a community. Services and supports work together 1. What are of the costs and to support children and parents. The effects of the headspace program? services and supports for children and 2. What is the overall cost parents are all provided under one effectiveness of expanding headspace roof. The first Child and Family Centres beyond 100 centres? in Tasmania opened in 2011. The key 3. What are the maximum funding criteria for selecting Child and Family requirements for headspace to achieve Centre communities were high need national coverage? for services and support (based on socioeconomic area disadvantage); The project is due to be completed by a high population of preschool age May 2015. children; and high projected population Funders of the project: Australian growth. From the outset, community Government Department of Health members have had a high level of control and responsibility for the design, Tasmanian Child and Family Centres implementation, and governance of Evaluation Project Child and Family Centres. Investigators: Cate Taylor, Sally The Tasmanian Child and Family Brinkman, Jasmin Harman-Smith and Centres are designed to have a Daniel Christensen with Wietse van de whole-of-community impact and the Lageweg, Andrew Oakley (Tasmanian outcomes that Child and Family Centres Department of Education) want to achieve have already been documented in the Tasmanian Child and The Tasmanian Child and Family Centre Family Centres Statewide Outcomes model is a community level early Framework. The Statewide Outcomes childhood integrated service model Framework was developed with input to improve the educational outcomes, from communities so researchers know health, development and wellbeing of that these are the outcomes that the Tasmanian children (birth to 5 years). communities want. The aim of this The Tasmanian Government announced project is to understand the impact the Child and Family Centre model in of Child and Family Centres on three 2009 and 11 Child and Family Centres family outcomes from the Statewide opened 2011-2013. The Tasmanian Outcomes Framework: Department of Education is the lead agency for the Child and Family 1. Families are supported by and Centres. Tasmanian Child and Family connected to their communities.

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2. Parents have skills and National Survey of Medical knowledge to nurture their children. Practitioners and Students Mental 3. Families have opportunities to Health participate in learning pathways. Investigators: Katherine Hafekost, Quantitative and qualitative methods David Lawrence and Stephen R Zubrick and use of linked administrative data with Fei Wu and Michael Ireland (Roy are being used to understand the Morgan Research) impact of Child and Family Centres. The National Mental Health Survey Funders of the project: Tasmanian Early of Doctors and Medical Students was Years Foundation conducted with the aims of determining the current mental health status of Development of the Adolescent Self medical practitioners and students, Esteem Questionnaire gaining an understanding of associated Investigators: Katherine Hafekost, issues within the medical and broader Katrina Boterhoven de Haan, and David community, and informing the Lawrence development of mental health services and supports for this group. The project Self-esteem impacts on many aspects identified high levels of distress in of an individual’s life. The current gold both practitioners and students in standard measure of self-esteem was comparison to the general population. developed in 1965. As a result, the In addition, practitioners and students language and concepts are somewhat reported high levels of depression, out-dated. Therefore, for use in Young anxiety, burnout and thoughts of Minds Matter: The National Survey suicide. However, practitioners of Mental Health and Wellbeing, a appeared to have a greater degree contemporary measure of self-esteem of resilience to some of the negative was developed. The Adolescent Self- impacts of poor mental health with few Esteem Questionnaire was specifically doctors reporting being highly impacted designed for young people and is by their mental health symptoms. intended to allow for more accurate Based on these findings, a number of assessment of self-esteem in research recommendations were provided to and practice. Ongoing work aims to beyondblue with the aim of improving determine the validity and reliability the work experience, mental health of the Adolescent Self Esteem status and coping ability of medical questionnaire in a sample of young practitioners. people to allow for the scale to be used in future research and practice. Funders of the project: beyondblue Funders of the project: Australian Systematic Review of the evidence Government Department of Health. for a relationship between trans-fatty acids and blood cholesterol

214 | TELETHON KIDS INSTITUTE Investigators: Katherine Hafekost, Investigators: Therese A O’Sullivan Therese A O’Sullivan (Edith Cowan (Edith Cowan University), Charlotte University), David Lawrence and Francis Wilson (Edith Cowan University), Mitrou Katherine Hafekost, Francis Mitrou and David Lawrence This review sought to identify literature, published between 2010 and 2014, Existing evidence suggests that relating to the consumption of TFA in dietary intake of trans-fatty acids the diet and associated changes in (TFA) is positively associated with blood lipids, compare the outcomes risk of coronary heart disease and of recent literature to the existing cardiovascular disease. In addition, it body of research, and evaluate the has been linked to increased risk of implications of these findings in an chronic conditions including cancer Australian and New Zealand context. and type 2 diabetes. The narrative When considering the existing body review aimed to build on existing risk of literature, a one percent increase assessment in relation to TFA intake in TFA as a percentage of energy and chronic health outcomes. Relevant intake, was associated with a small existing literature was searched and but significant increase LDL, and assessed for suitability for inclusion in decrease in HDL. However, there was the review. Results were not consistent. no significant relationship between total However, it appeared that the balance cholesterol values and intake of TFA. leant towards a detrimental effect of Possible dose response relationships TFA intake and disease outcomes. The were identified. However, there was direction of relationship did not differ by substantial variability in the reported gender, TFA assessment type, or study blood lipid changes at TFA intakes of design. Future research is required to at and below one percent of energy elucidate the effects of TFA from other intake. The results of the review dietary components on chronic health suggest that current dietary guidelines outcomes. and recommendations relating to Funders of the project: Food Standards intake of TFA in the Australian and Australia New Zealand New Zealand diet are appropriate. Ongoing monitoring of industry Tackling overweight and obesity: action and population intake of TFA Does the public health message is recommended to ensure levels of match the science? consumption remain low. Investigators: Katherine Hafekost, David Funders of the project: Food Standards Lawrence, Francis Mitrou and Stephen Australia New Zealand R Zubrick, with Therese O’Sullivan Narrative review: The relationship (Edith Cowan University) between dietary trans-fatty acids and Despite an increasing understanding adverse health outcomes of the mechanisms which relate to

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weight loss and maintenance, there study has sought to quantify the role of are currently no validated public mental illness in current smoking, and health interventions which successfully the possible benefits of considering achieve significant and sustained the impact of mental illness in ongoing weight loss in the population. This tobacco control activities. project examined the model of energy In 2011-12, 20.4% of Australian males balance which underpinned recent aged over 18, and 16.3% of females public health weight loss interventions were current smokers. Over 80% of and compared this to the model these smokers started smoking before provided by basic sciences. It was age 15, and had become daily smokers identified that most public health by age 18. One-third of Australian interventions were based on an overly smokers also have a mental illness, simplistic model of energy balance. most commonly anxiety or depression, It appeared that there was a lack of and these smokers smoke over 40% translation between advances in basic of cigarettes consumed in Australia. science and public health efforts to People with mental illness are more reduce excess weight. This project likely to start smoking at a younger identified a need for a multidisciplinary age, find it more difficult to quit, smoke approach in the design of future weight for longer, and as a result suffer more loss interventions in order to improve physical harm. their long term success. Mental illness has not been a major Funders of the project: NHMRC consideration in tobacco control in program grant #572742. Australia or overseas. Some of the Smoking and mental illness major tools used in tobacco control, such as advertising the long-term health Investigators: David Lawrence, Francis effects of smoking, and stigmatising Mitrou, Jennifer Hafekost, Cate Taylor smoking behaviours are less motivating and Stephen R. Zubrick, with Philip Hull in people with mental illness. Even so, (Cancer Council New South Wales), people with mental illness want to quit Michael Sawyer (University of Adelaide), smoking, and try to quit smoking, as Sharon Lawn (Flinders University), least as much as other smokers, but Ann Bates (Western Australian Mental have substantially less success with Health Commission), Steve Kisely their smoking cessation attempts. (The University of Queensland) and Julie Considine (Australian Bureau of Funders of the project: No specific Statistics) funding received. Although smoking rates have fallen Statistical methods to minimise significantly since the 1960s, smoking disclosure risk in studies using linked and related-health impacts, remain a administrative data significant public health problem. This Investigators: Katherine Hafekost, David

216 | TELETHON KIDS INSTITUTE Lawrence Investigators: Stephen Zubrick with Nina Lucas, Elizabeth Westrupp and Jan Linked administrative data sets are Nicholson becoming increasingly sought after for research and evaluation purposes. As Project blurb: The LSAC mother- and the Western Australian Data Linkage father-reported parenting measures System has grown in both size and used across Waves 1 to 4 were scope, the number of requests examined to establish: a) the extent for linked data extracts has been to which the items used to measure increasing. In considering requests for particular dimensions of parenting are access to linked administrative data for reliable indicators of that construct; and research purposes, data custodians b) the extent to which measures used have the dual responsibility to maximise at different ages appear to measure the the amount of information available same underlying construct. Initial model for research and analysis to improve fitting revealed room for improvement knowledge, understanding and service across the majority of measures: 30% delivery while minimising the risk of of the models exhibited a ‘good’ fit to the privacy of individual’s whose data the data, 38% were an ‘acceptable’ fit are recorded within the system being and 34% failed to meet the specified violated. This project sought to identify fit criteria. Model fits varied across possible statistical methods which waves and respondents. With only four minimise the risk while maximising data exceptions, across 69 models minor availability and utility. modifications resulted in good (58%) or acceptable (36%) fit. We provide The project aimed to determine recommendations on the optimal whether samples of the full population approach for using the LSAC parenting data could be used to calculate measures in future analyses, including accurate and reliable estimates of the use of item weightings and the population parameters in analyses exclusion of poorly performing items. using data from the Western Australian Linked Data System. It was identified Funders of the project: Australian that this method was appropriate in Government Department of Social some situations and ongoing work aims Security to determine whether this method can Research translated into articles in be used for more complex analyses. popular press – Funders of the project: NHMRC program grant #572742. Farrant, B. M. (2014). Talking to kids about emotions matters more than you Parenting measures in the think. The Conversation. Retrieved from Longitudinal Study of Australian https://theconversation.com/talking- Children: Construct validity and to-kids-about-emotions-matters-more- measurement quality, Waves 1-4 than-you-think-21955

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Getting Our Story Right Department of Education, collaborators on the research, have found the The algorithm from this project has research a valuable resource for their been adopted by the Department of review of attendance policy for West Health for use to assist in addressing Australian students. In further work, Indigenous under-identification in data members of the team, in conjunction linkage projects. with the Department, are considering Student attendance and educational future possibilities for developing an outcomes intervention that helps to improve In 2013, members of the Human attendance for disadvantaged students. Capability team released a research The research was also discussed report that investigated the relationship with members of the community in a between student attendance and Community Conversation held at the performance on the National Program Institute in August. of Literacy and Numeracy (NAPLAN) Playgroups tests for public school students in The Human Capability group, within Western Australia. The research found the division of Population Sciences, that disparities in attendance rates, for undertook research to determine if example between disadvantaged and playgroup participation was associated non-disadvantaged students, were with improved outcomes for children. evident as early as Year 1. The report The work showed that for children from also showed that there was no safe disadvantaged backgrounds, those who level of absence for students, and that had persistently attended playgroup every day of absence had an effect on across the early years had better social- NAPLAN scores, and for disadvantaged emotional and cognitive outcomes at students in particular. Together, the age 4-5 years than children who never results indicated that that the early participated in playgroup. The research years are a critical intervention point for has become a core part of lobbying improved attendance and achievement and an essential reference in any outcomes. explanation or literature of playgroups. The report received great interest Playgroup WA have used our findings by researchers and state education in multiple presentations and funding departments across the country. applications, including a major attempt Members of the research team have at lobbying the Federal Government been invited to present the research and Opposition prior to and after the to educators in Western Australia, election and have been in ongoing Canberra, Victoria and Queensland, discussions with the Department of discussing implications for attendance Social Services (formerly FAHCSIA), and policy and the importance of the early have also successfully lobbied to have years for establishing good attendance playgroup participation included in the patterns. The Western Australia

218 | TELETHON KIDS INSTITUTE next AEDI checklist. needed skills and experiences to assist in the Council’s work. The ACCARE members are: Kulunga Aboriginal • Kate George - Chair Research Development Unit • Rhonda Marriott Aboriginal Consultative Committee • June Oscar Advising Research and Evaluation (ACCARE) • Josie Janz • Ian Trust As part of the Institute’s strategic planning process that was conducted • Darryl Kickett in 2013, a parallel strategic process was • Jon Ford undertaken to ensure that the needs of Aboriginal families were considered. • This parallel process was led by Emerita • Glenn Pearson Professor Rhonda Marriott (Senior Aboriginal Researcher), Dr Michael The goal of ACCARE is: Wright (Senior Aboriginal Researcher) To provide high level advice to the and Glenn Pearson (Manager Aboriginal Director around strategic directions Research Program) and supported and operational elements relating by the Institute’s Aboriginal Research to Aboriginal health research at the Leadership Group. Telethon Institute with the aim of The outcomes of these processes ensuring facilitation, translation and have led to the development of the application of research finding into Institute’s Working Together Strategic policy and practice. Plan (2013 -2017) and the objectives of Aboriginal Health Research Focus the Institute’s Commitment to Aboriginal Area Steering Committee Children and Families (2013-2017) with a recommendation that ACCARE As part of the Institute’s Working would be reconstituted as an advisory Together Strategic Plan a Research committee reporting directly to the Focus Area Strategic Framework was Director Telethon Kids Institute – developed to reflect four key areas of Professor Jonathan Carapetis. research of which Aboriginal Health was one. Under each RFA a Steering With the exception of the Director the Committee was established and membership is now entirely comprised comprised of 10-15 senior researchers of Aboriginal people. These members drawn from across the Institute, PMH have not been engage to represent and SPACH. their regions rather that they bring from across the State a vast range and much The purpose of each RFA Steering

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Committee is to facilitate the that confront families in bringing up their development and implementation of children. The Institute established the high quality collaborative research KARDU to progress the key priorities projects consistent with the Institute outlined in the Commitment. Strategic Plan and RFA research goals Aboriginal Governance and to ensure our research makes a difference. Ensuring a clear Aboriginal voice is heard and influences the Institutions The Aboriginal Health RFA Steering work through an Aboriginal board Committee has acknowledged that it member, the establishment of the plays a dual role across the Institute Aboriginal Collaborative Council in both promoting an increase in the Advising Research (ACCARE) and the numbers of Aboriginal health related appointment of the Head, Aboriginal research projects within the Aboriginal Research to the Institutes Leadership Health area as well as across the other Team. three RFA’s. Setting Research Priorities Over the last year the AHRFA Steering Committee has undertaken two Open A key focus of KARDU is facilitating the Space Forums to create an opportunity involvement of Aboriginal families and for researchers to engage with the communities in deciding what research Aboriginal community. The outcomes best responds to their needs. Through of these forums will contribute to a the Aboriginal Health Research Focus deepening in the relationship between Area two open forums were held with researchers and Aboriginal people to Institute researchers and Aboriginal ensure that our research better reflects community members and service the needs of Aboriginal families as well providers to begin identifying what as translates into positive change in the these research priorities are. A third will health and wellbeing of these families. be held in the coming year. A third and final Open Space forum is Aboriginal Employment and Career planned in 2015 to look at identifying a Development Strategy process to prioritise our research. Through the Centre for Research Kulunga Aboriginal Research Excellence in Aboriginal Health and Development Unit (KARDU) Wellbeing the Institute has been developing the next generation It is now one year since the launch of of Aboriginal health researchers. Working Together, the Telethon Kids In addition, KARDU has been Institute Commitment to Aboriginal developing an employment and career Children and Families (2013-2018), development strategy for the Institute which outlines a blueprint for action for for research, professional and other the Institute to continue its work to use staff. our research to answer the questions

220 | TELETHON KIDS INSTITUTE Research Development and Support institutions and 10 Chief Investigators headed by Professor Fiona Stanley. There are a number of research The CREAHW brings the research programs and projects at the Institute strengths of each CI together in a initiated to make a difference to the cohesive program of community-based health and wellbeing of Aboriginal intervention research, well known children and families and which in the both national and internationally, future will come under the Aboriginal but with local relevance to Western Health Research Focus Area. Some Australia. It is being supported by fall directly under KARDU, while others the outstanding track record of the are managed under separate research Institute working with government to groups and are discussed in more detail inform policy and practice and build on elsewhere and include: past achievements by developing the • Alcohol and Pregnancy and Fetal next generation of Aboriginal health Alcohol Spectrum Disorders researchers and leadership among the Research Group CI team. • Wesfarmers Centre for Vaccine and Highlights: The CREAHW funded 2 Infectious Disease international visits. One by Emeritus • Group A Streptococcus and Professor Michael Chandler from the Rheumatic Heart Disease Research University of British Columbia, Canada Group and the other by A/Prof Angela Bowen from the University of Saskatoon, • Collaboration for Applied Research Canada and Prof Sally Kendall from the and Evaluation (CARE) University of Hertfordshire, UK. Additionally, KARDU has been actively The Australian Government funded working with researchers across the a national Aboriginal and Torres Institute to develop new programs of Strait Islander Suicide Prevention research that involve Aboriginal families Evaluation Project (ATSISPEP) led by and communities and in partnership Chief Investigator Prof Pat Dudgeon. with the Aboriginal Heath Council of A/Prof Roz Walker is responsible for WA and the Rural Clinical School of WA overseeing the project implementation to establish a research hub in Broome and outcomes. as the first site in creating the WA Aboriginal Health Knowledge Network. The Working Together: Aboriginal and Torres Strait Islander Mental Health and Wellbeing Principles and Practice Centre for Research Excellence in was launched in Nedlands, June Aboriginal Health and Wellbeing Investigators: Prof Fiona Stanley, Prof Our grant is a collaborative research Pat Dudgeon, Prof Dawn Bessarab, Prof venture between seven research Sandra Eades, Prof Rhonda Marriott, A/

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Prof Roz Walker, Dr Juli Coffin, Dr Cheryl own service structures and delivery Kickett-Tucker, Dr Michael Wright and processes to better meet the mental Glenn Pearson. health needs and drug and alcohol concerns of Nyoongar families. Funding: NHMRC Centre of Research Excellence grant 2010 – 2015. Since late 2013 and throughout 2014, the Project team has facilitated Looking Forward Project meetings and activities with Nyoongar Dr Michael Wright Elders and service providers to shape a way forward for systems change. The Looking Forward Project aims to During this time, the Project team change the way mental health services collected data that would identify and and drug and alcohol support services describe the conditions necessary for respond to the needs of Nyoongar respectful and authentic engagement families living in the southeast Perth between Nyoongar Elders and service metropolitan region (i.e. Armadale to providers. After some data analysis, an Bentley). Mental illness and drug and engagement process titled Debakarn alcohol concerns can be highly charged Koorliny Wangkiny (‘Steady Walking and and emotive issues for the Nyoongar Talking’) was developed and trialed. community living in this region. There Relationships are the foundation for have been significant challenges for this work and the two stakeholder the Project. In particular, the size and groups have spent much time and scope of serious and complex mental effort building and deepening their health issues impacting the Nyoongar relationships in order to be prepared community who have been involved in for the next phase, that is, to co-design this Project. a culturally safe systems change Since the initial community consultation innovation, shaped by this relationship- process undertaken in 2011 and 2012, based approach. the Project team, in conjunction with The Elders are guiding service Nyoongar Elders, has facilitated a providers, who are engaged in a full number of events and activities to multisensory experience, on a spiritual assist service providers to develop journey of transformation. Service an understanding of and respect for providers are being introduced to many Nyoongar culture and its centrality concepts that, for most, are totally to mental health and wellbeing. unfamiliar to their worldview. For some These activities include damper and it has been very challenging, but most bush medicine making, storytelling, are finding the experience enthralling, community days and walks on country. exciting and rewarding. The experience These have helped prepare services for most has been profound. to work more openly and authentically with Nyoongar Elders, as they seek Project Funding: The project is funded to reflect on and reconfigure their by Lotterywest, Centre for Research

222 | TELETHON KIDS INSTITUTE Excellence in Aboriginal Health and This project involved representatives Wellbeing (Telethon Kids Institute, from Telethon Kids Institute and UWA, UWA), Curtin University, Mental Health the WA Data Linkage Unit at the Commission (WA), in partnership with Department of Health Western Australia, Ruah Community Services (WA). the Kurongkurl Katitjin Centre for Indigenous Australian Education and Getting our Story Right Research at Edith Cowan University, Lead Investigator: Michael Wright, the Australian Primary Health Care PhD, Research Fellow (Curtin Research Institute at the Australian University) and Chief Investigator National University, and the Australian Bureau of Statistics. In this project (CREAHW) we used the Western Australian Data A cross agency data linkage and Linkage system to produce derived analysis project to better understand Indigenous statuses for individuals and improve information about using a range of algorithms. We found Aboriginal and Torres Strait Islander that these algorithms reduced the peoples using administrative data amount of missing data and improved collections within‑individual consistency. Measures of the gap in living standards, In 2014 we published a paper on life expectancy, education, health and this project in the Australian Journal employment between Indigenous of Social Issues, outlining the and non‑Indigenous Australians are findings of the project, and making primarily derived from administrative recommendations for a method data sources. However, Indigenous of combining data in the Western identification in these data sources is Australian Data Linkage System. These affected by administrative practices, recommendations have been applied missing data, inconsistency, and error. by the Western Australian Data Linkage Assessing whether the gap between Unit, and a ‘best practice’ Indigenous Indigenous and non‑Indigenous status has been made available to Australians has changed over time, researchers as a variable which can be based on data unadjusted for these requested as part of any linked data sources of error can potentially lead project. to misguided conclusions. Combining Investigators: Daniel Christensen (TKI), administrative data on the same Geoff Davis (Data Linkage Unit, WA individuals collected from different Department of Health), Glenn Draper sources provides a method by which (WA Department of Health), Francis a more consistent derived Indigenous Mitrou (TKI), Sybille McKeown (ABS), status can be applied across all records David Lawrence (TKI/ UWA), Daniel for an individual within a linked data McAullay (Kurongkurl Katitjin Centre for environment. Indigenous Australian Education and

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Research at Edith Cowan University, - Telethon Kids Institute, Geraldton, and Australian Primary Health Care Research Assistant Research Institute at the Australian Stuart Crowe - CREAHW - Curtin National University), Glenn Pearson University, Research Assistant (TKI), Wavne Rikkers (TKI), Stephen R. Zubrick (TKI/ UWA) Joy Neri - CREAHW - University of Western Australia, Research Assistant Funders: As a collaborative, cross- agency project, this project involved Sue Renshaw - CREAHW - Pindi Pindi, contributions from Telethon Kids Research Assistant (NHMRC Program Grant 572742), Margaret O’Connell M.Ed, B.A - Looking the Western Australian Department Forward Team, Telethon Kids Institute, of Health, ABS, UWA, and ECU. The Senior Research Officer project was also part-funded by COAG through the National Indigenous Reform Rosemary Walley – Looking Forward Agreement (Schedule F – Data quality Team, Research Assistant, B.ICD improvements) to provide evidence Tanya Jones B.A (Psych) - Looking supporting ‘National Best Practice Forward Team, Telethon Kids Institute Guidelines for Data Linkage Activities Project Officer Relating to Aboriginal and Torres Strait Islander People’ (AIHW & ABS 2012). Kristen White MPA, MPH, LLB/BA – Program Manager, Aboriginal Health (Kimberley and Pilbara) Head of Group Honorary Appointments

Glenn Pearson Professor John Boulton - Emeritus Staff and Students Professor at the University of Newcastle, NSW; A/ Professor Roz Walker – CREAHW - Maureen Carter – CEO Nindilingarri Telethon Kids Institute, Perth WA Cultural Health Services in Fitzroy Chrissie Easton – CREAHW - Telethon Crossing Kids Institute, Perth WA Research Co- Professor Pat Dudgeon – UWA School ordinator of Indigenous Studies Dr Clair Scrine, PhD, - CREAHW - Dr Sandra Eades - Baker IDI Heart and Telethon Kids Institute, Perth WA Senior Diabetes Institute Research Officer Dr Cheryl Kickett Tucker – Pindi Pindi Dr Carrington Shepherd , PhD - Centre CREAHW - Telethon Kids Institute, Perth WA, Senior Research Officer Dr Daniel McAullay – Independent Research Consultant Charmaine Green – CREAHW

224 | TELETHON KIDS INSTITUTE Dr. Brian McCoy – University of Carrington Shepherd –NHMRC Early Melbourne Career Fellowship, June 2014 Bridgette McNamara - Baker IDI Heart CI Rhonda Marriott – Lifetime and Diabetes Institute Achievement Award for CATSINaM (Congress of Aboriginal and Torres June Oscar – CEO Chief Executive Strait Islander Nurses and Midwives) Officer of Marninwarntikura Women’s Resource Centre in Fitzroy Crossing External Committees

Dr. Michael Wright – Curtin University National Students • Prof Pat Dudgeon and Dr Juli Coffin, Prof Dawn Bessarab - National Centre for Research Excellence in Indigenous Research and Knowledges Aboriginal Health and Wellbeing: Network (NIRAKN) –are members of this Lina Gubhaju - Post-Doctoral Fellow, group. Baker IDI Heart and Diabetes Institute, • Prof Pat Dudgeon is co-chair of Melbourne VIC. Assists Prof Eades. the Aboriginal and Torres Strait Islander Denise Groves - PhD student, Murdoch Mental Health and Suicide Prevention University Advisory Group (ATSIMHSPAG). David Hendrickx - PhD student, UWA • Glenn Pearson - Indigenous Robyn Williams - PhD student, Curtin HealthInfonet Advisory Board University, Perth • Glenn Pearson - Australian Ailsa Munns - PhD student, Curtin Bureau of Statistics (ABS) National University, Perth WA Aboriginal and Torres Strait Islander Round Table Clinton Schultz - PhD student, Griffith University, Qld • Glenn Pearson and Roz Walker - National Aboriginal Disability Jocelyn Kickett - Masters student, Researcher¹s Network. Murdoch University Invited Presentations Awards A/Prof Roz Walker - 2nd National Michael Wright – Curtin Indigenous Conference in CQI in Aboriginal and Research Fellowship at Curtin Torres Strait Islander Primary Health University, February 2014 Care (Lowitja). Melbourne 17 - 18 March Fiona Stanley – Honorary doctorate A/Prof Roz Walker - Congress Lowitja at the Catholic University of Leuven in - Many mobs. One Vision. Creating Belgium, February 2014 a Healthy Future. Melbourne, 19 - 20 David Hendrickx – Stan Perron top up March award

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Glenn Pearson - chaired a session Strait Islander Nurses and Midwives at Congress Lowitja called Working CATSINaM, Scarborough, Perth Together: A different way of doing September business. Melbourne, 19 – 20 March Dr Michael Wright – facilitated a A/Prof Roz Walker and Dr Clair Scrine symposium – Working Together Makes presented on ‘50 years on : creating Us Stronger. Perth August genuine research partnerships to Prof Rhonda Marriott – Cultural Security improve Aboriginal Health’. AIATSIS for Aboriginal women in urban settings - Conference. Melbourne, 26 – 28 March Health Care Forum, Aboriginal Maternity CI A/Prof Roz Walker and CI A/ Services Support Unit. Perth, October Professor Dawn Bessarab - ‘Breaking Prof Dawn Bessarab – Doing palliative the Barriers: Transformative Research care and being culturally safe and and Knowledge Translation to improve responsive in delivering services to Aboriginal Health and Wellbeing. Aboriginal people. WA Palliative Care AIATSIS Conference Conference, Perth October Prof Fiona Stanley - plenary talk - Prof Roz Walker – Community Co- ‘Clyde Herzman Memorial Lecture’. researchers Training Workshop, Vancouver, April National Empowerment Project, Perth Prof Fiona Stanley - Population November Monitoring as a Strategy for Improved Prof Pat Dudgeon – Back to the Early Child Development: progress and Future: Collective Reflexivities new challenges. HELP (Human Early for Transformative Change. Perth Learning Partnership). Vancouver, April November CI Prof Rhonda Marriott- PSANZ 18th Glenn Pearson – Identifying the Social, Annual Congress 2014, Perth April Cultural and Economic obstacles to A/Professor Roz Walker and Prof Change - DoHAD Together Towards Rhonda Marriott presented at the Tomorrow Conference -– Panel member DOHaD conference, Perth, April Perth 9th April Dr Juli Coffin and Dr Cheryl Kickett- Glenn Pearson – Aboriginal Research at Tucker - Learning about Identity: An the Telethon Kids Institute – Aboriginal Australian Aboriginal perspective. Maternity Services Support Unit WIPc:E, Oahu Hawaii, May (AMSSU) Perth 10th June Prof Pat Dudgeon – Convenor Glenn Pearson – Aboriginal Research Roundtable on Suicide Prevention, at the Telethon Kids Institute – SAHMRI Perth, June Aboriginal Showcase Conference Adelaide 3rd August Prof Rhonda Marriott – Keynote speaker - Congress of Aboriginal and Torres Glenn Pearson – Panel member

226 | TELETHON KIDS INSTITUTE Growing up Deadly and Strong Centre for Research Excellence in Workshop Lowitija Institute Melbourne Indigenous Ear Health, Professor 10th November Amanda Leach, Menzies School of Health Research Looking Forward Project Team - AIATSIS Conference, Canberra, 26th March Centre for Research Excellence in Improving Health Services for Looking Forward Project Team - District Aboriginal and Torres Strait Islander Aboriginal Health Advisory Group Children, Professor Karen Edmonds, (Health Department), Fremantle, 2nd School of Paediatrics and Child Health, April University of Western Australia Looking Forward Project Team - Improving access to primary care for National Drug Research Institute, Curtin Aboriginal babies in Western Australia: University, Shenton Park, Perth, 8th May The ‘Stork’ population based cluster Looking Forward Project Team- randomised trial, Professor Karen Presentation to Ombudsmans Office, Edmonds, School of Paediatrics and Albert Facey House, Perth, 22nd July Child Health, University of Western Looking Forward Project Team - Mental Australia Health Commission Co-Production ARC Discovery Indigenous Triple Forum Presentation, Curtin University, PMP PCS Wrap Project, Professor 29th July Rhonda Marriott, Aboriginal Health and Looking Forward Project Team - Dr Wellbeing, Murdoch University Michael Wright, Indigenous Forum, NHMRC Partnership Grant at the The Mental Health Service (TheMHS) Kulbardi Aboriginal Centre, Murdoch Conference, Perth WA, 26th August School of Social Work and Occupational Looking Forward Project Team - Therapy, Curtin University, Indigenising Symposium, The Mental Health the Social Work Curriculum Services (The MHS) Conference, Perth, 28th August ACTIVE collaborations with industry Looking Forward Project Team - Aboriginal Health Council of WA Presentation to USA Eisenhower Fellow, Rural Clinical School of WA Cristal Thomas, Atlas Iron Pty Ltd, Perth, 9th September Ruah Community Services (Project community partner) Looking Forward Project Team - Decolonisation workshop, School of Mental Health Commission WA Social Work, Curtin University, 10th Western Australian Association for November Mental Health Services (WAAMHS) ACTIVE research collaborations Western Australian Drug and Alcohol Network of Agencies (WANADA)

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Richmond Fellowship WA Walking and Talking’), as part of Mental Health Week (October) to develop Palmerston Association greater awareness of the positive role North Metropolitan Health Service, of cultural identity and community and Youth Mental Health Services (Youth family support in the lives of those Axis, YouthReach South) experiencing mental illness and drug Armadale Health Service, Mental Health and alcohol related issues. The event Services was in partnership with Richmond Fellowship WA, Champion Centre Drug and Alcohol Withdrawal Network (City of Armadale), Ruah Community (DAWN), St John of God Hospital Services, Rotary Club, and WAAMH. (Subiaco) http://mhw.waamh.org.au/assets/steady- MercyCare walking-and-talking-together-mental- School of Social Work and Occupational health-week.pdf Therapy, Curtin University The Looking Forward Project has been Puntukurnu Aboriginal Medical Service instrumental in bringing Nyoongar Elders and their families to work with ACTIVE involvement with the the Institute to discuss shared health community priorities relating to the Institute’s Commitment to Working with Aboriginal The Aboriginal Health RFA held two Children and Families through a series open forums with Aboriginal community of open space forums. members to discuss working together and research priorities. In late 2014, the Looking Forward Project team was approached by Curtin The Looking Forward Project have University’s School of Social Work and had ongoing communication with Occupational Therapy to assist them community organisations such as with ways in which to develop their Langford Aboriginal Association and programs of teaching and learning the Champion Centre (Armadale), along to encompass Aboriginal ways of with local Aboriginal health services knowing, doing and being. The project in the locations in which the project is team instigated a series of facilitated being run (e.g. Kwinana). workshops with the Social Work Translation (any example of where the teaching group, using the Debakarn research has been used more broadly) Koorliny Wangkiny engagement The Looking Forward Project team framework to bring teaching staff worked in partnership with the Elders’ together with local Elders to begin a stakeholder group and some of the conversation about the redevelopment participating services to develop a of curriculum and teaching and learning Family and Community Day titled, practices. This work will continue into Debakarn Koorliny Wangkiny (‘Steady, 2015 and occur at subject, program and

228 | TELETHON KIDS INSTITUTE whole-of-School levels. aired in 2015. Health policies and guidelines directly The Institute unveiled and launched influenced its monument commemorating that acknowledges that the Telethon Looking Forward meetings with Kids Institute is located on Nyonngar the WA Mental Health Commission Whadjuk Boodjar in December have informed policy discussions in relation to community based service settings and consumer engagement Looking at Language and participation (as demonstrated at the Mental Health Commission Co- Investigators: Professor Mabel Rice from Production Forum Presentation, Curtin the University of Kansas, Professor Cate University, 29th July) Taylor and Winthrop Professor Stephen The Handbook developed with Zubrick from Telethon Kids Institute Nyoongar Elders titled Open Hearts, and Professor Shelley Smith from the Open Hands: A Spiritual Journey University of Nebraska Medical Center. of Change (2013), is already being Looking at Language places the used in policy settings and is now institute at the forefront of research in available publicly via the HealthInfonet language and literacy worldwide. Our website: http://www.healthinfonet. approach and our research crosses a ecu.edu.au/key-resources/promotion- multitude of disciplines and sits within resources?lid=28370 a number of the institute’s Research Focus Areas The study, combines Other achievements epidemiological, behaviour genetics In February of 2014, Dr Michael Wright and molecular genetics methods took up the inaugural Indigenous to study language development, Research Fellowship at Curtin University language impairment, reading and and presented about the Project to reading impairment from infancy to a staff gathering at the Centre for adolescence. Aboriginal Studies. This internationally unique study is Dr Wright and two Nyoongar Elders following the language development were interviewed by NITV for their of more than 2000 WA children from segment, ‘Noongar Danjoo’, on the 2-14 years. It is the world’s only study impact of suicide on Nyoongar families, to conduct such detailed assessment in which Dr Wright and the Elders of language and literacy development described the Looking Forward project from infancy through the formative and how it is changing the way services adolescent years. For the institute, the respond to the needs of families ability to continue following the study experiencing serious mental illness, children through early adolescence is grief and loss. The segment will be ground-breaking. It is vitally important

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that we understand the developmental Investigator: Lisa Gibson (Telethon Kids) course of language and literacy from The psychosocial burden of overweight infancy and what different trajectories and obesity: There is evidence that mean for young people’s opportunities overweight and obese children tend at school and beyond. Data collection to remain overweight or obese into for this project is based entirely in WA adolescence and adulthood. However, and involves 5000 children and families little is known about the long-term overall. The study has received 15-years psychosocial outcomes of childhood continuous funding from the USA overweight and obesity. This study National Institutes (National Institute on aimed to investigate the course Deafness and Other Communication of psychosocial difficulties over a Disorders). The project is a joint 2-year period for children who were initiative between the Telethon Institute overweight or obese at baseline, and for Child Health Research and UWA a comparison sample of children who and the USA’s University of Kansas were a healthy weight at baseline. and University of Nebraska Medical Overweight and obese children were Centre. All study participants and data found to have greater psychosocial collection is based in Western Australia. distress than healthy weight children, Ask any mum or dad what they and these differences were more consider a key milestone in their pronounced for girls than boys. Weight child’s development and more often and psychosocial functioning both than not they will say it is language tracked over the 2-year study period, development. Looking at Language is meaning that children who were following the language development overweight or obese at baseline tended of more than 2000 WA children from to remain overweight or obese at the 2 – 14 years. It is the world’s only study 2-year follow-up, and children with to conduct such detailed assessment impaired psychosocial functioning at of language and literacy development baseline tended to experience ongoing from infancy through the formative impairments over the next 2 years. This adolescent years. Our findings will research suggests that overweight and help improve services and supports for obese children are at risk of ongoing children with language difficulties. psychosocial distress from middle childhood into early adolescence. The Funder of the project: National management of childhood obesity Institutes of Health (RO1DC05226, needs to attend to psychosocial P30DC005803, P30HD002528) functioning as well as weight and Obesity markers of physical health. The role of family and maternal factors Investigating methods for managing in the development and persistence childhood obesity of childhood obesity: Treatment

230 | TELETHON KIDS INSTITUTE programs for childhood obesity have The Raine Study is one of the largest highlighted the importance of the and most successful prospective family in treatment. Considering this, cohorts of pregnancy, childhood, it is surprising that few studies have adolescence and now early adulthood examined the role of family factors in to be carried out anywhere in the world. the development of childhood obesity. The cohort was established between The objective of this study was to 1989 and 1991 to determine how events examine which family and maternal during pregnancy and childhood factors predict increases in weight influence health in later life with nearly in boys and girls during middle to 3,000 pregnant mothers joining the late childhood. Overweight/obese Raine Study. Follow up assessment of children were recruited from clinical the families and their children were and community settings. A broad conducted at birth and then when the range of maternal and family factors children were 1, 2, 3, 5, 8, 10, 13, 16, were assessed. For children recruited 18, 20 and 22 years of age. There are through a community-based setting, still over 2,000 of these children who maternal Body Mass Index (BMI) and are members of the Raine Study. The single-parent family structure were latest Raine Study assessment at age significant longitudinal predictors 22 was completed in June 2014. Over of child BMI z-scores. For children 1,000 participants came to the Centre recruited through clinical settings, low for Sleep Science on UWA campus family income was the only significant and did an overnight sleep study, multivariate predictor of child BMI asthma and allergy testing and various z-scores. The strong association found other assessments. This represents between child BMI, maternal BMI and the biggest study of sleep in this age family structure confirms the need to group in the world. In 2014 an audit of target prevention and intervention Raine Study Biological samples was efforts for childhood obesity towards completed by Dr Marion Macnish. The families with overweight parents, Raine Study has over 170,000 samples particularly single-parent families. securely stored and catalogued across six sites. Funders of the project: Western Australian Health Promotion Foundation During 2014, Raine Study researchers (Healthway). published 70 papers in peer reviewed journals. The Raine Study website has been improved and updated and information on Raine Study publications, research projects, resources and The Western Australian access to the Raine Study are available Pregnancy Cohort (Raine) on the website www.rainestudy.org.au. Study In 2014 NHMRC project grants

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were awarded to Professor Peter for over 10 years. Professor Yeoh Eastwood to examine the prevalence, has provided an enormous wealth of phenotype and genotype of common scientific knowledge and expertise sleep disorders in the Raine Study to the Raine Study. He retired from parents and to Professor Pat Holt to this position in 2014. The Executive examine the waxing and waning of Committee welcomed Professor Paul asthma during transition from teens to Norman to represent the Foundation adulthood in the Raine Study. An ARC on the Executive Committee. Professor grant was awarded to Professor Sharon Susan Prescott accepted the Raine Parker and Professor Leon Straker to Study Executive Committee’s invitation examine work design and the dynamic to join the Committee. interplay of work and person factors The Seventh Raine Study Annual in the Raine Study. Funding support Scientific Meeting was held on Friday was awarded to Professor Eastwood 2 August 2013 at the UWA Club. The and Professor Leon Straker from the Event was opened by Peter Klinken. Western Australia Department of Health Over 100 Raine Study Researchers (WADH) Future Health Initiative to attended the meeting and participated audit and analyse biological samples in over 20 presentations. in the Raine Study. Dr Gina Trapp and Dr Sarah Foster were awarded After over 20 years of being located funding from the WADH Targeted within the Telethon Kids Institute, the Research Fund to examine alcohol Raine Study moved to new premises outlet proximity and density and the at the University of Western Australia implications for alcohol consumption within the UWA School of Population patterns and mental health in Health in late 2014. The new address adolescents and young adults. is 12-14 Parkway, Nedlands, UWA and these offices provide the Raine Study Professor Ian Puddey retired from his with increased capacity to perform position as Chairman of the Raine Study assessments for future follow up Executive Committee. He served as the studies. inaugural Chairman of the Committee since 2005. Professor Puddey retired Cohort Studies as the Dean of the University of Western of Australia, Faculty of Medicine, Raine Study Anaesthesia Dentistry and Health Sciences at the Investigators: Dr Britta Regli Von Ungern end of 2014. The position of Chairman Sternberg, Dr Mary Hegarty, Professor of the Committee ceded to Professor Andrew Whitehouse John Challis The Raine Cohort offers a unique Professor George Yeoh represented the opportunity to investigate the Raine Medical Research Foundation on relationship between early exposure the Raine Study Executive Committee to surgery and anaesthesia, and

232 | TELETHON KIDS INSTITUTE the possibility of developmental Oddy delay in childhood or adolescence. The cardio-metabolic group has been This research may also lead to the examining the effects of prenatal identification of the safest anaesthetic and postnatal factors, lifestyle and agents for use in infants and children. environmental factors on cardio- The benefits of investigating this metabolic health during childhood, relationship in the Raine Cohort are its adolescence and adulthood. The group prospective and longitudinal design, is examining childhood trajectories for large and representative cohort, adiposity, blood pressure and insulin excellent retention rate and very resistance, and the association between detailed data collection. parental and adolescent adiposity and Raine Study Asthma and Allergy cardio-metabolic risk.

Investigators: Patrick Holt, Graham 2014 WA Telethon, Perth Children’s Hall, Peter Sly, Elysia Hollams, Anthony Hospital Research Fund, RC Huang, Bosco E Davis, L Beilin, C Pennell, TPCHRF - Bedside to bench and back to Extensive research into the paediatric obesity clinic: Enabling a development of asthma and allergy has powerful West Australian epigenetic been conducted within the Raine Study resource, $200,000. and collaborating research groups. Ongoing projects include investigations 2014-2016 NHMRC 1059655 RC Huang, into the molecular basis of asthma, K Lillycrop, G Burdge, J Craig, L Beilin, the epidemiology through to genome T Mori, W Oddy, K Godfrey, J Holbrook, wide association studies to unravel Breaking the intergenerational cycle of the genetic and environmental factors obesity: a multigeneration population contributing to asthma and allergy. The study of obesity epigenetics, $1,086,101. Raine Study cohort participants have 2012-2014, NHMRC 1037966, W Oddy, undergone extensive allergy and lung T Mori, L Adams, S Byrne, Nutritional function testing at 5, 14 and 22 years of determinants of cardiometabolic risk age. and mental health: from infancy to 2012-2014, NHMRC 1021858, G Hall, P adulthood, $481,725. Holt, E Hollams, Z Hantos. Transition 2012-2014, NHMRC 1030148, W from childhood to adult asthma: Oddy, F Stanley, L Beilin, C Pennell, B Predicting persistent and adult‐onset Koletzko, Demmelmair, WG Peissner, asthma in young adults in the Raine Analysis of metabolic profiles in young longitudinal birth cohort, $984,248. adults from the Western Australian Raine Study Cardiometabolic Pregnancy Cohort (Raine) Study by metabolomics: biomarkers for metabolic Investigators: Lawrie Beilin, Trevor Mori, consequences of early programming by Rae-Chi Huang, Sally Burrows, Wendy infant feeding type, $323,250.

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Raine Study Developmental Group 2010 - 2014, NHMRC Early career research fellowship, K Allen, Eating Investigators: Andrew Whitehouse, disorders in Western Australia: Murray Maybery, Jeffrey A Keelan Prevalence, maintaining factors, and Each and every child develops in their prospective risk factors, $288,000. own unique way. The ‘Developmental Raine Study Epigenetics research group’ seeks to understand how and why children vary in the Investigators: Rae-Chi Huang, Craig course of their cognitive, social and Pennell, Lawrie Beilin, Trevor Mori, language development. The research Sally Burrows, Jeffrey Craig (Murdoch group examines the links between Children Research Institute, Melbourne), genetic, biological and behavioural Karen A Lillycrop, Graham C Burdge, data. By understanding why children Keith Godfrey (Southampton University) vary in their development, the research The Raine Study Epigenetic research group aims to be able to identify group is investigating the effects children at risk of delayed development of epigenetic modification on as early as possible, and devise adolescent body mass and markers therapies to help these children reach of cardiometabolic health including their full potential. cholesterol, insulin resistance and 2011-2015 NHMRC 1003424, blood pressure. Obesity is a significant A Whitehouse, M Maybery, C adult health problem, and is becoming Dissanayake, M Hickey, C Pennell, increasingly common in children and , Prenatal and early postnatal risk adolescents. factors for autism spectrum disorders, 2014-2016, NHMRC 1059711, RC Huang, $671,938. K Lillycrop, G Burdge, J Craig, L Beilin, Raine Study Eating Disorders T Mori, W Oddy, K Godfrey, J Holbrook, The cycle of obesity, A two generation Investigators: Karina Allen, Sue Byrne, population study of obesity epigenetics, Wendy Oddy $1,086,102. Eating disorders are highly complex Raine Study Growth and serious mental illnesses that occur most frequently in adolescents and Investigators: Catherine Choong, young adults. Researchers in the Raine Nooshi Rath, Julie Marsh, Helen Study Eating Disorder research group Atkinson, Peter Sly are working towards the identification The Raine Study provides longitudinal of factors that contribute to the measures of length, height and weight development of these conditions. We of individuals from birth to, currently, 22 are also identifying factors that may years of age. The availability of genetic predict persisting eating difficulties information from the Raine Study once an eating disorder has developed. provided the opportunity for the Growth

234 | TELETHON KIDS INSTITUTE Team to identify specific polymorphisms and how this affects mental health in the ghrelin gene that were associated outcomes. with growth. Raine Study height data Raine Study Musculoskeletal was also used to compare the Centres for Disease Control and Prevention Investigators: Leon Straker, Peter (CDC) and World Health Organisation O’Sullivan, Anne Smith, Darren Beales (WHO) reference/standards for height in The musculoskeletal group is children. The Raine Study also provide investigating the complex development contemporary normative growth of back and neck pain from childhood, measures against which the RAINE through adolescence, into early Growth Group can assess growth in adulthood, and the impact of backpain children affected by chronic diseases. on work. Back pain is a leading Raine Study Mental Health contributor to work disability in the form of absenteeism (being away from Investigators: Monique Robinson, work) and presenteeism (reduced Andrew Whitehouse, Anne Smith, Jeff productivity at work).Factors that Cannon, Karina Allen, Vijay Panicker, contribute to the development of Peter Jacoby, Craig Pennell backpain in teenagers and young adults The Raine Study has collected include physical factors (posture, fitness, detailed information on behavioural motor competence, weight), lifestyle and emotional development and this factors (computer and TV use, physical information is used to understand the activity, diet, drug use), psychosocial social and biological pathways that lead factors (depression, anxiety, stress, to mental health disorders. Information coping, fear of movement, back pain collected on mothers during their beliefs), genetics (genes linked to pregnancies has enabled the group stress response and pain thresholds) to examine the relationships between and other factors including sleep and the characteristics of prenatal life chronic diseases such as asthma. The (e.g., exposure to chemicals, maternal group is also examining the effects stress, fetal growth) and mental health of sedentary behaviour (periods of outcomes. Physical assessment and inactivity for example working at a desk biological samples have been used to or watching television) health outcomes. identify biological mechanisms that may During the 22 year follow up the group influence mental health outcomes. The collected information on activity levels group has examined social and lifestyle and work patterns to further research factors that may contribute to mental the links between work, activity and health, including the family environment, health outcomes. schooling, friendships, sport, risk taking 2013-2014, SafeWork Australia, L behaviour and bullying. Research has Straker, D Beales, A Smith, R Moorin, also been undertaken on diet and G Pransky, P O’Sullivan, S Linton, nutrition (including breast feeding)

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Work productivity loss associated with 2012-2016, NHMRC 1037966, WH musculoskeletal pain in young adults, Oddy, F Stanley, L Beilin, C Pennell, B $70,000. Koletzko, H Demmelmair, W Peissner, Analysis of metabolic profiles in young 2012-2014, NHMRC 1044840, L Straker, adults from the Western Australian G Healy, M Tremblay, R Abbot, A Smith, Pregnancy Cohort (Raine) Study by G Mishra, A life course approach to Metabolomics: Biomarkers for metabolic characterising and predicting inactivity consequences of programming by and sedentary behaviour of young infant feeding type, $323,250. adults, $291,473. Raine Study Ophthalmology Raine Study Nutrition Investigators: David Mackey, Alex Investigators: Wendy Oddy, Georgina Hewitt, Seyhan Yazar Trapp, Lucinda Black, Therese O’Sullivan, Gina Ambrosini, Siobhan The twenty year Raine Study follow Hickling, Wendy Chen She Ping-Delfos, up was conducted at the Lions Eye Lawrie Beilin, Trevor Mori, Nick De Institute and Sir Charles Gairdner Klerk, Monique Robinson Hospital by the Raine Study team, ophthalmologists, ophthalmology The Nutrition Group have investigated trainees, medical students, orthoptists, the dietary intake of the Raine Study ophthalmic assistants and volunteers. cohort participants from birth through This is one of the first studies to to 23 years of age. Information has determine the prevalence and risk been collected about breastfeeding, factors for eye disease in young adults, first foods and dietary intake through and to characterize ocular biometric childhood, adolescence and early parameters in a young adult cohort adulthood. Fasting blood samples were with myopia (short sightedness) collected for biochemistry, metabolic being the most common condition. and immunological biomarkers. The Data from the Raine Study combined Group is a member of an international with genetic information allows the collaboration on ‘Early Nutrition’, a 36 group to participate in multinational institution, 12 million euro (AUS$17.3 research consortia investigating eye million) project. This collaboration is development, the basis of colour vision, funded by an NHMRC European Union and numerous eye disorders. collaborative grant and aims to uncover the long term impact of early nutrition 2012-2014, NHMRC 1021105, D Mackey, on later health. C Pennell, A Hewitt, T Young, C Hammond, M Coreneo, S Macgregor. 2012-2014, NHMRC 1022134, WH Oddy, Genome-wide association study T Mori, L Adams, S Byrne, Nutritional (GWAS) for juvenile-onset myopia and determinants of cardiometabolic risk its component measures to identify and mental health: from infancy to molecular pathways to prevent myopia, adulthood, $481,725.

236 | TELETHON KIDS INSTITUTE $482,445. comprehensive overnight laboratory- based sleep study at the UWA Centre Raine Study Reproductive Health for Sleep Science. The Sleep research Investigators: Roger Hart, John group is utilising the unique longitudinal Newnham, Martha Hickey, Craig data collected on participants in the Pennell, Dorota Doherty, Jeffrey Keelan, study to determine, for the first time, the Monique Robinson, Jennifer Marino prevalence, phenotype and risk factors for OSA and other sleep disorders The Raine Study Reproductive Group in early adulthood. This study has is investigating the development and generated an internationally unique reproductive health in the Raine Cohort. dataset of full laboratory-based sleep Reproductive health is influenced studies in a group of young adults by age, lifestyle (smoking, alcohol, and represents the first Australian nutrition), genetics, some medications “longitudinal sleep cohort”. and exposure to chemicals in the environment. The Group’s research 2012-2014 NHMRC1027449, P has focused on the age of puberty, Eastwood, D Hillman, A Smith, N menstruation in teenagers, Polycystic McArdle, R Huang, Childhood obesity Ovarian Syndrome (PCOS), hormone and its relationship to adult sleep exposure before birth, and male fertility. disordered breathing, $843,060. Members of this group are involved in Head of Group the first long term study to analyse the long-term health outcomes of children Professor Peter Eastwood, Scientific born resulting from IVF treatment. Director 2013-2017, NHMRC 1042269, R Hart, Professor Leon Straker, Association C Pennell, D Doherty, M Robinson, Scientific Director The long-term consequences of Jenny Mountain, MBA, MClinEpi, Raine IVF treatment for the offspring - a Study Program Manager prospective cohort study using the Raine Cohort for comparison, Angela Jacques MSc, Raine Study $1,552,096. Biostatistician and Database Manager Raine Study Sleep Research Staff

Investigators: Peter Eastwood, David Jenny Mountain MBA MClinEpi Hillman, Nigel McArdle, Romola Bucks, Angela Jacques MSc Anne Smith, Elizabeth Davis, Rae- Chi Huang, Nicholas de Klerk, Craig Louise McKenzie PhD Pennell, Eric Moses, Phillip Melton, Leon Diane Wood BAppSci, Dip Ed Straker, Stuart King Alex D’Vauz BSc (Hons) The Raine Study participants, at 22 years of age underwent a Natasha Haynes BSc (Hons)

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Monique Priston PgDipPubH Craig Hutchinson, Honours PGcertHlthSc Theses passed Annegret Harries BSc, GradDipPubHlth Nicolle Warrington, PhD, UWA, Rebecca Nguyen BA BCom Modelling of complex longitudinal Sue Green phenotypes over childhood: Growth trajectories in the developmental origins Carolyn Smargiassi of health and disease Denny Craig Chi Le Ha, PhD, UWA, Studies of Postgraduate Students antenatal and postnatal factors predicting cardiovascular phenotypes Scott White, PhD from birth to 17 years Richard Maganga, PhD Lauren Hollier, PhD, UWA, The Janice Wong, PhD relationship between prenatal androgens and early social Tegan Grace, PhD development. Jessica Tearne, PhD Awards Anett Nyaradi, PhD Elisha White – Raine Study PhD top-up Carly Herbison, PhD Scholarship Denise Demmer Seyan Yazar – Raine Study PhD top-up Katerina Chin A Loy, PhD Scholarship Sunil Bhat, PhD Carly Herbison – Raine Study PhD top- up Scholarship Seyan Yazar, PhD Denise Anderson – Raine Study Annual Amelia Stephens, PhD Scientific Meeting Raine Medical Elisha White, PhD Foundation award for best presentation Esha Jamnadass, PhD Seyan Yazar - Raine Study Annual Scientific Meeting Raine Medical Anahita Hamidi, PhD Foundation award for best presentation Robert Waller, PhD Anett Nyaradi, UWA Graduate Research James Slater, Masters School prize for Higher Degree by Naomi Heaps, Masters Publication prize. Davinder Gill, Masters Michelle Trevanan, Honours Rett Syndrome

Nicholas Lilleyman, Honours International Rett syndrome study:

238 | TELETHON KIDS INSTITUTE InterRett guidelines for the management of scoliosis and gastrointestinal issues; Investigators: Helen Leonard, Alison and to read snapshots of the over 20 Anderson, Ami Bebbington, Nada peer-reviewed publications arising Murphy, Jenny Downs, Heidi Meyer, from analyses of the InterRett data. Nan Hu. Our research covers a wide range of Rett syndrome is a rare neurological topics such as: pain sensitivity; the disorder which has an incidence characteristics that influence diagnosis; of diagnosis of 1:9000 by the age diagnostic challenges in China; the of 32 years and is associated with influence of mutation type or DNA mutations in the MECP2 gene. Given variations in the BDNF gene on clinical the low number of cases at a national severity; and ageing and survival in level (~415 in Australia) international Rett syndrome. To allow families to collaboration and data collection are contribute at all levels of the research imperative. The InterRett database process, from study design to the project allows clinicians and families dissemination of findings, a Consumer caring for an individual with Rett Reference Group (CRG) has been syndrome to directly contribute established. In 2014 we were awarded to the global research effort by a further two years ongoing funding completing web or paper-based from Rettsyndrome.org to continue questionnaires. The project, which is the management of the database. Our funded by Rettsyndrome.org (formerly current aims are to: the International Rett Syndrome 1. To give families a strong voice Foundation), was established in 2002 in research about Rett syndrome, and continues to grow and expand with online questionnaires available in 2. To expand data collection to Mandarin and six European languages. facilitate evidence-based management, The database currently contains ~ 3. To focus on families who live 2,500 cases representing over 50 in under-represented majority world different countries. New participants countries, and register using a form on the project website (also available in different 4. To further develop the InterRett languages). International support infrastructure to enable linkage with for the InterRett project continues to other Rett syndrome and international strengthen, particularly in China and rare disease database initiatives. we have a Chinese national, Nan Hu This highly successful framework for who is providing translational expertise the collection of data for a rare disorder and assisting families in submitting on a global scale has been replicated their information. The website also for the rare CDKL5 disorder and is now allows users to: generate graphs based being developed for MECP2 duplication on summary data; download clinical syndrome.

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Funders of the project: diagnosis and management of Rett syndrome. This study aims to: Current: NHMRC Program Grant (572742), Rettsyndrome.org (2575), • develop recommendations for NHMRC Senior Research Fellowship the diagnosis process for Rett Helen Leonard (572568). syndrome; Towards evidence based care for • identify longitudinal changes in Rett syndrome: a research model to gross motor abilities, hand function inform management of rare disorders and development of scoliosis and; • evaluate the clinical effectiveness Investigators: Helen Leonard, John of scoliosis and gastrostomy Christodoulou, Carolyn Ellaway, surgery in children and adults with Helen Woodhead, Jenny Downs, Rett syndrome. Elizabeth Geelhoed, Elizabeth Elliott, Peter Jacoby, Ian Torode, Gordon For the diagnostic study we asked Baikie, Mark Davis, Bruce McPhee, clinicians to complete questionnaires Madhur Ravikumara, Sue Thompson, relating to the characteristics of their Margaret Thomson, Ami Bebbington, patients for whom they requested Amanda Jefferson, Sonya Girdler, Anna MECP2 testing at one of the three Urbanowicz, Kingsley Wong, Catherine Australian accredited laboratories. Bunting, Caitlin Marr, Orla McIlroy, Geoff These are completed prior to the result Askin, Maree Izatt of genetic testing being known. From mid-July 2011 to mid-July 2014 there Rett syndrome is a rare neurological were 276 referrals where a clinician disorder usually affecting females and could be contacted and agreed to caused by a mutation in the MECP2 participate. Questionnaires were gene. AussieRett, as the Australian completed and available for analysis on Rett Syndrome Study is known, is 243/276 (88.0%). Of the 243, 211(86.8%) a population-based study which, were female and pathogenic MECP2 since 1992, has followed a cohort of mutations were identified in 14.7% and Australian Rett syndrome cases born in no males (12.8% positive overall). since 1976. The study aims to describe The goal is to develop tools to support the natural history of Rett syndrome clinical decision making to facilitate and assess the impact of the condition timely diagnostic testing for girls with on resource utilisation as well as to Rett syndrome, thereby assisting examine the economic and social families in the often stressful early stage burden for families and the community. when seeking a diagnosis. We are currently in the final year of an As part of the longitudinal study follow- NHMRC funded study commenced up questionnaires were administered to facilitate best practice in clinical in September 2011 to 269 families decision making, laboratory procedures enrolled in the study and families could and counseling in relation to the

240 | TELETHON KIDS INSTITUTE return data online, on paper or during the questionnaire data. We are also a telephone interview. The response collecting video data and by year end fraction from parents and care- 2014, 175 families had provided video workers has been excellent at over footage of their daughter’s functional 86% and we are also receiving some abilities. additional family data. Information The AussieRett study has continued has been collected on the affected to involve consumers through the individual’s functional ability in daily Consumer Reference Group, biannual living, behaviour, hand function, medical newsletters and online via the new conditions, use of health and education website and Facebook page. The services, and family health and Consumer Reference Group, involving functioning. Questions have also been family members from across Australia included to assess parental satisfaction via regular teleconferences, is an with spinal fusion and gastrostomy opportunity to discuss and give valued procedures for those children and feedback on all facets of the study. adults who have undergone these procedures. The study has a multi-disciplinary investigative team from the fields of Scoliosis is a common complication medicine, physiotherapy, epidemiology, of Rett syndrome, however little is biostatistics, dietetics and occupational known about the natural history of therapy. It has national collaborations curve progression and the relationship with the Children’s Hospital at with the type of genetic mutation, Westmead and the Children’s Hospital age and mobility level. X-ray data on Randwick, Sydney, the Royal Children’s the progression of the spinal curve Hospital, Melbourne, the Mater of children and adults with scoliosis Children’s Hospital, Brisbane and the has now been collected on 188 girls Royal Children’s Hospital, Brisbane and and women with scoliosis. Spinal the Children’s Hospital, Adelaide. fusion (for scoliosis) and gastrostomy insertion (feeding tube into the stomach During 2014 fourteen articles relating due to problems with swallowing or to Rett syndrome were published or poor growth) are surgeries faced by accepted for publication by our group. many children and adults with Rett These articles included investigations of syndrome. The decision to proceed scoliosis, poor growth, gastrointestinal with these surgeries is often difficult dysmotility, gallbladder disease, bone for families, and both clinicians and health and communication in Rett families need accurate information syndrome. We have also investigated about the short and long term risks and participation in activities in the benefits of these procedures. Currently, community and have written a review there are gaps in our knowledge of on hand function in Rett syndrome. outcomes. Collection of data from Funders of the project: the hospital records is supplementing

ANNUAL REPORT 2014 | 241 GROUP NAME

Current: NHMRC Project Grant Kids Institute website, and has been (1004384), NHMRC Program Grant additionally disseminated by family (572742), NHMRC Senior Research associations in the US and UK. Fellowship Helen Leonard (572568). Rett syndrome is also associated with Developing clinical guidelines for osteoporosis and a greater likelihood of the management of gastro-intestinal fracture in comparison with the general disorders and bone health in patients population. We recruited a panel of with Rett syndrome 35 expert clinicians and researchers and again used the Delphi technique Investigators: Jenny Downs, Helen to develop guidelines for optimal Leonard, Gordon Baikie, Madhur bone health in Rett syndrome. A Ravikumara, Nusrat Naseem, Deirdre manuscript describing this research is Croft, Amanda Jefferson, Helen in preparation and we envisage writing Woodhead, Sue Fyfe, Aris Siafarikas a lay booklet and clinician leaflet for dissemination of findings as we did for Rett syndrome is frequently associated the gastrointestinal guidelines. with poor growth, feeding difficulties and problems with gastro-oesophageal Funder of the project: Rett Syndrome dysmotily such as reflux, constipation Association UK, NHMRC Program Grant and abdominal bloating. There is (572742), NHMRC Senior Research limited literature on management Fellowship Helen Leonard (572568). strategies for these common gastro- Publications 2014 intestinal conditions in Rett syndrome and we have previously used the 1. Anderson A, Wong K, Jacoby Delphi technique to develop a P, Downs J, Leonard H. Twenty years consensus for items that describe of surveillance in Rett syndrome: what their assessment and management. does this tell us? Orphanet Journal of Our set of recommendations for the Rare Diseases. 2014;9. assessment and treatment of gastro- 2. Andrews J, Leonard H, intestinal issues has been the subject Hammond GC, Girdler S, Rajapaksa of three publications on the topics R, Bathgate K, Downs J. Community of poor growth, dysmotility and gall participation for girls and women living bladder disease in Rett syndrome. We with Rett syndrome. Disability and have also produced a lay booklet that Rehabilitation. 2014;36(11):894-9. presents the guidelines in a format suitable for families together with two 3. Baikie G, Ravikumara M, Downs leaflets for clinicians on the topics of J, Naseem N, Wong K, Percy A, Lane poor growth and dysmotility. These J, Weiss B, Ellaway C, Bathgate K, have been disseminated to all families Leonard H. Gastrointestinal Dysmotility with a daughter with Rett syndrome in in Rett Syndrome. Journal of Pediatric Australia, is available on our Telethon Gastroenterology and Nutrition. 2014;58(2):237-44.

242 | TELETHON KIDS INSTITUTE 4. Downs J, Parkinson S, Ranelli Emma Glasson, Keely Bebbington, S, Leonard H, Diener P, Lotan M. Kavitha Dorairaj Perspectives on hand function in The aim of the WA Register for Autism girls and women with Rett syndrome. Spectrum Disorders is to monitor Developmental Neurorehabilitation. diagnostic trends of conditions 2014;17(3):210-7. characterized by autism (autism, 5. Downs J, Wong K, Ravikumara Asperger syndrome, Childhood M, Ellaway C, Elliott EJ, Christodoulou Disintegrative Disorder, and Pervasive J, Jacoby P, Leonard H. Experience Developmental Disorder Not Otherwise of Gastrostomy Using a Quality Care Specified (PDD-NOS)). These disorders Framework: The Example of Rett develop in young children and have Syndrome. Medicine. 2014;93(28). long-term impact in areas of social interaction, communication and 6. Freilinger M, Boehm M, Lanator behaviour. The WA Autism Register is I, Vergesslich-Rothschild K, Huber ongoing and since 1999 it has collected W-D, Anderson A, Wong K, Baikie G, data on more than 4,500 individuals. Ravikumara M, Downs J, Leonard H. Prevalence, clinical investigation, and Funders of the project: Government management of gallbladder disease of Western Australia, Department of in Rett syndrome. Developmental Health. Medicine and Child Neurology. 2014;56(8):756-62. 7. Walker EM, Crawford F, Wesfarmers Centre of Leonard H. Community participation: Vaccines and Infectious Conversations with parent-carers of young women with Rett syndrome. Diseases Journal of Intellectual & Developmental The Wesfarmers Centre of Vaccines Disability. 2014;39(3):243-52. and Infectious Diseases was initiated 8. Urbanowicz A, Leonard H, Girdler in 2014 through funding received S, Ciccone N, Downs J. Parental from Wesfarmers Limited. Infectious perspectives on the communication diseases are the number one killer of abilities of their daughters with young children worldwide and the main Rett syndrome. Developmental reason for childhood hospitalisations Neurorehabilitation. 2014. Epub in Australia. The Centre’s mission is to 2014/02/26. reduce the burden of serious childhood infectious diseases by finding better prevention and treatment solutions. WA Register for Autism Reducing the burden of serious infections in Aboriginal children in Spectrum Disorders Western Australia has our particular attention.

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The Centre represents a number of In Australia, Group A Streptococcal independent researchers and research disease now predominantly affects teams working on serious childhood Aboriginal people. Middle ear infections primarily at the Telethon infections occur in non-Aboriginal Kids Institute or elsewhere with clear but more frequently and in a chronic existing links to the Institute. Research form in Aboriginal children often conducted under the umbrella of the leading to lifelong hearing loss. The Centre is focused on finding new epidemiological data-linkage studies solutions to improve the prevention use total population, mostly state and treatment of serious infections wide data and include identifiers for experienced by children or adolescents Aboriginality, which makes it possible in WA and beyond. The breadth of to assess and compare the burden research goes from bench to bed, of disease and risk factors for WA including laboratory-based discovery Aboriginal children and non-Aboriginal and preclinical research, epidemiology children separately. Studies that directly and surveillance, clinical trials and address finding solutions to improve implementation research. the health of Aboriginal children have been marked ($) at the beginning of the The Centre aims is to advance the project title. This does not exclude that research excellence and output of findings of other studies can be applied associated investigators, initiate novel to advance the health of Aboriginal high potential research ideas and attract children. and keep talented researchers through activities stimulating and facilitating Research Theme: Group A new collaborations, connecting the Streptococcal Diseases bench and bed, facilitating community, partnerships and supporting training The focus of the group is to understand activities. and improve disease outcomes caused by the bacteria group A streptococcus In 2014 research associated with the (GAS). GAS causes a wide spectrum Centre’s activities could be grouped of diseases ranging from pharyngitis, into the following themes: Group A skin sores to more severe forms of the Streptococcal Diseases; Ear Health; disease including rheumatic fever (RF), Infectious Disease Epidemiology & rheumatic heart disease (RHD) and Surveillance; Vaccine Clinical Research post-streptococcal glomerulonephritis (the Vaccine Trials Group) ; and (PSGN). Implementation Research. For each theme, related research projects are The group is headed by Prof. Jonathan summarized below. Carapetis under whose leadership the group was awarded a Centre for All themes except that of Vaccine Research Excellence in 2014. The Clinical Research include studies that END RHD CRE aims to develop an directly address Aboriginal child health. endgame for RHD in Australia. In 2014,

244 | TELETHON KIDS INSTITUTE the group was assigned the lead site Council Australia in 2014. The END RHD for CANVAS initiative, a trans-Tasman CRE brings together 20 investigators coalition to advance new vaccines from 16 institutions to develop an for group A streptococcus. This is a endgame for RHD in Australia. At the first of its kind project aimed at fast end of 5 years, the END RHD CRE will tracking the development of anti-GAS provide a stepwise roadmap to ending vaccines. Another key highlight was the RHD in Australia and aim to produce a global partnership between Medtronic clear vision for achieving measurable Philanthropy, RhEACH and the World disease control targets. The END Heart Federation to establish the RHD RHD CRE will undertake a number Action Alliance which will focuses on of projects across several disciplines reducing premature mortality from RHD of research including epidemiology, by 25 percent by 2025 for those under biomedical sciences; implementation 25 years of age, with an emphasis on and translation; and understanding the developing comprehensive projects in RHD community with a special focus on targeted countries. documenting the experiences of those living with the disease. The END RHD CRE: Developing an end game for rheumatic heart disease in Funding: National Health and Medical Australia Research Council (NHMRC)

Investigators: Jonathan Carapetis, RHD Action Alliance Nicholas de Klerk, Tom Snelling, Investigators: RhEACH, World Rosemary Wyber Heart Federation (WHF), Medtronic Rheumatic heart disease (RHD) is Philanthropy caused by an abnormal immune In September 2014 RhEACH was reaction to some bacterial infections. named as a global partner in the Although RHD is rare in developed largest private-sector contribution countries, Indigenous Australians still to date to address rheumatic heart live with the burden of RHD. The END disease (RHD). RHD is the most RHD CRE will explore risk factors commonly acquired heart disease in for RHD, prevention with antibiotics, children in many of the world’s poorest management of RHD and the potential countries. The RHD Action Alliance, for vaccine development. Individuals funded by Medtronic Philanthropy and communities experiencing RHD are is a consortium of global partners integral partners to this work. The CRE including RhEACH (headquartered will establish a strategy for ending RHD at Telethon Kids Institute), Medtronic in Australia. Philanthropy and the World Heart The END RHD CRE is a five year Centre Foundation, and focuses on reducing of Research Excellence funded by the premature mortality from RHD by 25 National Health and Medical Research percent by 2025 for those under 25

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years of age, with an emphasis on Funding: Medtronic Philanthropy developing comprehensive projects Coalition to advance new vaccines in targeted countries. Over the next five years, funding at country levels against group A streptococcus will support efforts to integrate RHD (CANVAS) interventions into primary care facilities, Investigators: Jonathan Carapetis, Meru while leveraging current efforts Sheel focused on maternal and newborn care and HIV, including the training of CANVAS is a Trans-Tasman initiative community healthcare workers who funded by the governments of will be the link between patients and Australia and New Zealand; aimed at the health system. All interventions accelerating the development of a will be implemented with the goal of vaccine for rheumatic fever prevention strengthening the entire health system and reducing the burden of GAS rather than supporting RHD-only associated diseases. The CANVAS projects. This partnership will work program offers the opportunity to to influence policy decisions related leverage public funds to take a to RHD, serve as a technical hub for vaccine through the initial stages of RHD that can provide assistance to clinical development to the point of an all countries where RHD is prevalent, efficacy study for GAS pharyngitis, in advocate for people living with RHD the expectation that this early stage and increase the network of supporters “de-risking” will allow partners in for RHD. industry and significant international organisations to enter the development Announced in September 2014 this program with confidence. CANVAS five-year, $6 million (USD) Medtronic program incorporates an objective Philanthropy commitment will support pre-clinical and clinical evaluation a global movement to end premature of leading GAS vaccine candidates mortality resulting from rheumatic currently in development. GAS is fever and rheumatic heart disease. diverse with over 200 distinct strains The World Heart Federation will serve identified to date. A successful vaccine as the Global Policy Partner, leading must confer protection against the efforts to influence and inform policy vast majority of GAS strains circulating decisions related to RHD. RhEACH in a target population, with different will serve as a Global Technical Partner geographical regions having a and scientific hub leading clinical and different range of predominant strains. public health strategies to control RHD. Furthermore, a GAS vaccine must not Both organizations will provide policy cause autoimmune cross reactivity and technical assistance to all countries with human tissue that is the hallmark where RHD is prevalent. Medtronic of acute RF. In order to collectively Philanthropy will lead the engagement address the hurdles associated with of private sector in the RHD dialogue. GAS vaccine development, three major

246 | TELETHON KIDS INSTITUTE research focuses involve selection of secondary prophylaxis is low and can minimal strain set that will represent a be attributed to a combination of factors wide range of disease manifestations. including, frequency and duration of Lead vaccine candidate will be selected injection, pain at injection site, access on the basis of efficacy against the to health care providers (especially for selected GAS strains. Finally, a health those living in poor remote settings). economic evaluation of interventions This projects aims at developing a to control GAS infections to rationalize longer acting formulation of penicillin the investment in GAS vaccine G, such that frequency of the injection development is also being undertaken. can be increased up to 3-6 months. It is hoped that the total direct and indirect Funding: National Health and Medical cost of the new formulation would be Research Council (NHMRC) and the equal to or lesser than the annual cost Health Research Council (New Zealand) of delivering current forms of secondary Development of a longer acting prophylaxis. The new formulation of formulation of Penicillin G for the penicillin will also aim at targeting the treatment and prevention of acute issues of poor quality of BPG available rheumatic fever and rheumatic heart in developing countries. disease Funding: Telethon - New Children’s Hospital Research Fund Investigators: Jonathan Carapetis, Meru Sheel Genetic associations of rheumatic ARF and RHD are rare in developed heart disease in Aboriginal Australian countries, prevalence and associated and Torres Strait Island communities morbidity and mortality is high within Investigators: Jonathan Carapetis, developing countries. Most recent Jenefer Blackwell, Clancy Read figures show the global prevalence of RHD to be as high as 34 million and Although poorly understood, the number of deaths due to RHD to be pathogenesis of RHD appears to greater than 345,000. In Australia and involve infections with “rheumatogenic” New Zealand, the disease burden strains of Group A Streptococcus in amongst the indigenous communities a host with inherited susceptibility is one of the highest in the world. resulting in an abnormal immune The most effective recommended response and the development of treatment of ARF requires four-weekly autoimmunity. This project aims to intramuscular injections of 1.2 million identify regions of the human genome units of benzathine penicillin G (BPG). that confer susceptibility to rheumatic Secondary prophylaxis for ARF and heart disease (RHD) in Australian RHD with BPG is recommended for Aboriginal and Torres Strait Islander a minimum of 10 years, and in some populations. Results may lead to cases even for a life time. Adherence to improved diagnostics, therapeutics

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and vaccines for RHD. The project intervention designed to optimize will enroll approximately 500 remote health systems improves the delivery Aboriginal people with RHD and 1,000 of SP, using a stepped-wedge trial in 10 community-matched controls across the communities in the Northern Territory Northern Territory. A major component of Australia. A detailed mixed-methods of this study is to explore better ways evaluation will be undertaken to to undertake community consultation ascertain the degree to which adopting and gain informed consent for genetics the systems-based intervention research in Aboriginal people, and to improves processes of RHD care and develop appropriate mechanisms for adherence to SP and which elements governance of the use of data and of the intervention are most effective samples in the long term. The study will in activating change. If successful, be a model for the conduct of genetic this model will provide a practical and studies in Aboriginal populations. transferable model for improving SP delivery. Funding: National Health and Medical Research Council (NHMRC) Funding: National Health and Medical Research Council (NHMRC) Improving delivery of secondary prophylaxis for rheumatic heart Ear Health disease Otitis Media (OM) refers to disease of Investigators: Jonathan Carapetis, the middle ear. It is a common illness Clancy Read in young children, peaking in infancy and again in pre-school years. Otitis Rheumatic heart disease (RHD) is a media is best described as a spectrum major health problem in Indigenous of disease, ranging from Acute OM communities. Continued progress (which may cause pain but in Aboriginal in controlling RHD requires an children is commonly asymptomatic) understanding of how to improve to Acute OM with perforation to delivery of regular injections of penicillin Otitis Media with Effusion (OME, also - secondary prophylaxis (SP). Due to known as ‘glue ear’) in which there proven benefit and demonstrated cost is fluid present in the middle ear and effectiveness, secondary prevention fluctuating hearing loss, through to of RHD remains the focus of most chronic suppurative otitis media (CSOM) RHD control strategies. Secondary when there is recurrent ear discharge prophylaxis involves a four-weekly through a perforated tympanic administration of penicillin for at least membrane associated with hearing loss. 10 years to all people with a history of Otitis media can seriously affect speech, ARF or RHD to control and reduce their ability to learn language, childhood chance of progressing to established, development, school performance and or more severe disease outcomes. subsequent social and economic well- This study will evaluate whether an being.

248 | TELETHON KIDS INSTITUTE In the general population, episodes of associated hearing loss, high carriage OM tend to resolve though a substantial of bacteria in the upper respiratory number of children do require surgery. tract from a very young age in However, in Aboriginal children the Aboriginal children, and an increased disease starts within weeks of birth risk of OM among children exposed and chronic disease with hearing loss to environmental tobacco smoke. is common. The prevalence of CSOM The overall aim is to have Aboriginal is very high, up to 40% in some remote children hearing well by the time they Aboriginal communities, well above start school. the World Health Organization (WHO) The objectives of this project are to: threshold of 4% constituting “a public health emergency” requiring immediate (1) Develop and implement a attention. multifaceted ear health promotion program in collaboration with Aboriginal Preventing Otitis Media to Give organisations in the Goldfields. a Sound Start for School (Pina Palya Pina Kulilku, Good Ears Good (2) Evaluate the impact and effectiveness of an ear health Learning) promotion program that includes (a) Investigators: Deborah Lehmann1, an awareness program, (b) training Ruth Monck1, Wenxing Sun1, Lorraine of health personnel in screening and Sholson1, Fay Sambo1, Kirsten Alpers1, health promotion and (c) a screening Tanyana Jackiewicz1, Anne Mahony2, program for OM. 3 Charles Douglas , Michelle Forrest, (3) Evaluate use at primary health care 4 Daniel McAullay , Bega Garnbirringu level of a simple tool (which measures Health Services, Ngunytju Tjitji Pirni otoacoustic emissions) that can detect 5 6 Inc, Francis Lannigan , Sharon Weeks , fluid in the middle ear at a very young 7 Bradley Gilchrist, Annette Stokes , age and hence identify a target group 7 Christine Jeffries-Stokes of children at subsequent risk of 1. Telethon Kids Institute; 2. WA developing OM. 3. Country Health Services, Goldfields; (4) Evaluate the overall program in Kalgoorlie-Boulder Population Health terms of feasibility and sustainability. Unit; 4. Aboriginal Council of WA; 5. Princess Margaret Hospital for Children; Over a 3-year period, we conducted 6. Professional Hearing Services, South 357 ear examinations in Aboriginal Perth; 7. UWA Rural Clinical School of children under the age of 5 years. WA, Kalgoorlie Of the 250 valid examinations, only half had bilateral normal middle ears; This project follows on from the 15% had perforated ear drums which Kalgoorlie Otitis Media Research is often chronic and can lead to Project, in which we found very long term hearing loss. A total of 14 high rates of otitis media (OM) and soap-making workshops were held

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in different communities. A series Health Promotion Foundation of music workshops, culminating in (Healthway) public performances of a musical, was WA Aboriginal Ear Health Project conducted with school children at 5 locations to promote regular hand Investigators: Peter Richmond1,2, washing, keeping cigarette smoke away Deborah Lehmann1, Victoria Stroud1, from children and regular ear screening. Karen Edmond1,2 Since the launch of the Big Ear (an 1. Telethon Kids Institute; 2. UWA inflatable ear that children and adults School of Pediatrics and Child Health can walk through) in February 2012, it has been used ~30 times at community In collaboration with Karen Edmond, events and schools. who heads the Centre of Research Excellence in Improving Health Services Interviews were conducted with for Aboriginal And Torres Strait Islander members of the community at the start Children (ISAC), and members of her of the project and towards the end of team (Natalie Strobel and Kimberley the study period. At the end of the study McAuley) the Ear Health project has period 56% had heard about the project been conducting a mapping and and half of them had attended an gapping exercise to identify the gaps activity. Twice as many people reported in knowledge in evidence regarding that ear disease can be prevented practices currently used to prevent by not smoking around children and and treat OM in Aboriginal children. washing hands than at the start of the The findings will help identify research project. The project was well received priority areas to inform evidence-based by the community; they acknowledged policy. that it helped to identify children with hearing problems early and they To assist in identifying gaps in evidence commented that the development of and implementation of best practice, the the musical through workshops was Aboriginal Ear Health Project has also culturally appropriate and effective. started to work on building partnerships Collaboration between different to consolidate the various ear health health service providers, education activities across WA and gathering the department and wider community has various players involved in ear health been greatly enhanced through the ear from around the state. To support this health project. A community report was there will be a Stakeholder Forum for launched at a public event in Kalgoorlie people working in ear health across WA in September 2014. Findings were in March 2015. A steering committee to presented at the 3rd OMOz Australian prepare for the Stakeholder Forum met Otitis Media Conference in Melbourne in December 2014. in August 2014. Members of the ear health steering Project funding: Western Australian committee included:

250 | TELETHON KIDS INSTITUTE - Charles Watson, Curtin - Ms Helen Humes, Centre Care University and Health Department of - Ms Victoria Stroud, Telethon WA (Chair) Kids Institute - Melissa Vernon, WA Country The Ear Health project is being done in Health Service (WACHS) the context of a national collaboration - Marianne Wood, Aboriginal around ear health research and Health Council of WA (AHCWA) advocacy that will be coordinated through the recently awarded NHMRC - Kathy Currie, Northern Territory Centre of Research Excellence in Department of Health Indigenous Ear health. - Professor Harvey Coates, ENT Surgeon, Princess Margaret Hospital for Dissolving the glue in glue ear: Children assessment of the use of Dornase alfa as an adjunct therapy to ventilation - Belinda Bailey, Rural Health tube insertion. West 1,2 - Deborah Lehmann, Telethon Investigators: Peter Richmond , Ruth 1,2 Kids Institute Thornton , Stephanie Jeffares (study coordinator) 1, Harvey Coates2, Shyan - Menzies School of Health Vijayasekaran2, Peter Jacoby1, Lea-Ann Research Kirkham1,2, Paul Bumbak3 - Francis Lannigan, ENT 1.Telethon Kids Institute; 2. UWA School Surgeon, Princess Margaret Hospital for of Paediatrics and Child Health; 3. St Children John of God Health Care, Perth - Peter Morris, Menzies School We have demonstrated that the of Health Research and Royal Darwin presence of bacteria in biofilm within Hospital the middle ear contributes to the - Karen Edmond, School of persistence and recurrence of ear Paediatrics and Child Health, University infections. We have also shown that of Western Australia these biofilms can stay in the ears in big nets of DNA that are produced by the - Hasantha Gunasekera, children’s own immune responses. University of Sydney This is a double-blinded phase IIB - Peter Richmond, School of trial studying the safety, tolerability Paediatrics and Child Health, University and efficacy of the off-licence use of of Western Australia Dornase alfa (an agent to cut up the - and Paediatrician & Paediatric extra DNA) in reducing future ventilation Immunologist, Princess Margaret tube insertions in children with chronic Hospital for Children otitis media effusion and recurrent acute otitis media.

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To be eligible for this study the child Approximately 2 million children suffer must be between 6 months and 5 from otitis media (middle ear infection, years of age; undergoing surgery for OM)in Australia each year. The health, ventilation tube insertion for recurrent social and financial costs of OM to acute otitis media and/or otitis media Australia are substantial, with treatment effusion for the first time; and have had alone estimated to cost $100-400 bilateral fluid for 3 months or longer. million/year. In Australia, the bacterium A child will have the investigational nontypeable Haemophilus influenzae treatment (Dornase alfa) administered (NTHi) is the predominant cause of OM. in one ear and the same volume of A pneumococcal conjugate vaccine 0.9% sodium chloride (salty water) (Synflorix ®) that includes an NTHi administered to the alternate ear at the protein D carrier has been licensed time of surgery. in Australia, which has the potential to reduce the burden of OM through The recruitment target of 60 children inducing protein-D specific immune was achieved in April 2014 and a total responses. Accurate surveillance of of 20 participants have completed all the impact of this vaccine is hampered study visits while 40 remain to present by another bacterium, H. haemolyticus for the last two follow-up visits. (Hh), which masquerades as NTHi Funding and cannot be distinguished using State Health Research Advisory Council standard techniques. This has resulted Grant, Princess Margaret Hospital for in inaccurate surveillance. We are Children Translational Research Grant. developing sensitive and specific molecular assays to accurately identify Dynamics of Haemophilus NTHi and Hh. These assays will be haemolyticus and nontypeable important for studies assessing the Haemophilus influenzae colonisation impact of Synflorix vaccination and in otitis-prone children other new OM-targeted vaccines.

Investigators: Lea-Ann Kirkham1,2, Funding: NHMRC (2011-2014) Selma Wiertsema1,2, Peter Richmond1,2, Evaluation of Haemophilus Deborah Lehmann1, Tom Riley3, haemolyticus as a preventative Amanda Leach4, Heidi Smith-Vaughan4 therapy for ear disease and Peter Jacoby1 Chief Investigators: Lea-Ann Kirkham1,2, 1. Telethon Kids Institute; 2. UWA School Ruth Thornton1,2, Peter Richmond1,2, of Paediatrics and Child Health; 3. Peter Hermans3 PathWest/UWA School of Pathology and Laboratory Medicine; 4. Menzies School 1. UWA School of Paediatrics and Child of Health Research, Darwin Health; 2. Telethon Kids Institute; 3. University of Nijmegen, the Netherlands Summary

252 | TELETHON KIDS INSTITUTE Colonisation of the respiratory tract with colonisation of their babies with a nontypeable Haemophilus influenzae harmless commensal rather than NTHi. (NTHi) is essential for development of In older otitis-prone children, a nasal infection. We have found that children probiotic spray following antibiotic use at risk of developing NTHi otitis media could ensure that nasopharyngeal are less likely to be colonised with commensals rather than pathogens a related harmless bacterium called re-colonise the respiratory tract, thereby Haemophilus haemolyticus. We have reducing the likelihood of recurrent also shown in-vitro that pre-treatment infection. of human respiratory epithelial cells Funding: Telethon-Perth Children’s with H. haemolyticus can protect the Hospital Research Fund 2013 cells from being infected with NTHi. We believe that H. haemolyticus could Infectious Diseases Epidemiology & be used as a probiotic to prevent NTHi Surveillance colonisation of the respiratory tract, which in turn may prevent development Using total population data to of otitis media. This study will provide describe the characteristics of in-vivo proof of principle whether respiratory infections in order treatment of the respiratory tract of to predict future epidemics and mice with H. haemolyticus can prevent recommend vaccination strategies for NTHi otitis media. We will also develop Western Australian children fluorescent probes for microscopy to examine how H. haemolyticus interacts Investigators: Hannah Moore1, Nicholas with NTHi and with respiratory cells de Klerk1, Peter Jacoby1, Denise to determine how H. haemolyticus Anderson1, Alexandra Hogan 2, Kathryn prevents NTHi colonisation, and guide Glass 2 its use as a preventative therapy for 1. Telethon Kids Institute; 2. Australian otitis media in children. Successful National University, Canberra completion of this study will allow more significant investment through Acute lower respiratory infections, or research commercialisation or NHMRC chest infections, such as bronchiolitis, development funding. influenza, pneumonia and whooping cough are a major cause of morbidity As NTHi colonisation and otitis media in children. This project follows on occurs so early in life, particularly in from previous work of the infectious Indigenous children, preventative disease epidemiology research group therapies need to provide early to investigate the pathogen-specific protection. This could be in the form burden of respiratory infections, and of a probiotic H. haemolyticus nasal focuses on bronchiolitis caused by spray, either directly administered respiratory syncytial virus (RSV). Using to neonates, infants or even given a linked dataset of RSV detections in to expectant mothers to promote children from 2000 to 2005, the aim of

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the study is to develop a mathematical Investigators: Hannah Moore 1 , model of virus transmission dynamics Christopher Blyth 1,2, Peter Jacoby 1, describing the flow of individuals in Faye Janice Lim 1, Parveen Fathima 1, a population from a pre-infectious Tasnim Abdalla 1, Nicholas de Klerk 1, (susceptible) state, to an infectious state Deborah Lehmann 1, Kim Carter 1, David and then recovered or immune state. Hendrickx1, Alexandra Hogan 3, Kathryn Based on such a model it is possible Glass 3 to characterise and accurately mimic 1. Telethon Kids Institute; 2. UWA School seasonal epidemics of respiratory of Paediatrics and Child Health; 3. syncytial virus to predict the impact Australian National University, Canberra of different intervention strategies on disease burden. This project investigates the epidemiology of acute lower respiratory In collaboration with researchers at infections in young children. The the National Centre for Epidemiology pathogens that most commonly cause and Population Health at the Australian acute lower respiratory infections in National University (Canberra), we have children include respiratory syncytial developed a base model for RSV that viruses, influenza viruses, parainfluenza accurately mimics the viral activity in viruses, rhinoviruses, adenoviruses, children aged < 2 years in metropolitan Streptococcus pneumoniae and Western Australia: this was published in Bordetella pertussis. Often separate 2014. This model can now be extended pathogens can be found simultaneously to other geographical areas of Western in children with respiratory infections Australia. We are also in the process (known as co-infection) and there of understanding the climatic drivers is mixed evidence to suggest that of RSV infections across different co-infection results in worse clinical climate areas of Western Australia by outcomes than single infection. This identifying associations with specific project will use data linkage to identify weather variables such as minimum the contribution of different pathogens and maximum temperature and relative in causing acute lower respiratory humidity. Data analysis has progressed infections resulting in children being in 2014 and we anticipate publishing hospitalised or presenting to the first results in 2015. emergency department between 1996 Project funding: NHMRC Early Career and 2012 in Western Australian. The Fellowship (HM) 1034254 specific aims of this project are: 1) to quantify the pathogen-specific burden Identifying opportunities for of acute lower respiratory infections in preventing respiratory infections Western Australia using individually- in children through integrating linked laboratory, hospitalisation, population-based health and emergency department and disease laboratory data (Triple I project) notification datasets; 2) to assess the

254 | TELETHON KIDS INSTITUTE impact of viral-viral and viral-bacterial Peter Richmond1,2, Parveen Fathima1, co-infections on respiratory infection Tom Snelling1 , Heather Gidding3, Bette outcomes and document the relative Liu3, Peter McIntyre3, Louisa Jorm3 contribution of individual respiratory 1. Telethon Kids Institute; 2. UWA School pathogens to these outcomes; and of Paediatrics and Child Health; 3. 3) to evaluate the direct and indirect University of New South Wales, Sydney population impact of paediatric immunisations on hospitalisations and Infectious diseases are the most emergency department presentations common reason for children to be for acute lower respiratory infections, admitted to hospital. Immunisation their related conditions (such as represents the most important public febrile convulsions) or other vaccine- health intervention to prevent infection. preventable infections by conducting Despite the success of immunisation pre- and post-vaccination introduction programs, outbreaks of vaccine- temporal trend analyses. preventable diseases such as pertussis (whooping cough) continue to occur, The de-identified linked data for this with Aboriginal and Torres Strait Islander project were received in 2014 and data children, children living in remote areas, cleaning and developing analysis plans and children with underlying illnesses were the focus of this year. To inform suffering a disproportionate burden the analysis plan, we established a of preventable disease. Accurate Triple I Scientific Steering Committee information on whether children are consisting of all the named investigators being vaccinated, the timing of their and other key stakeholders with an vaccination and how well the vaccines interest in acute lower respiratory are working to reduce disease in infections. In 2014, we convened two the community overall, are required. meetings of the Scientific Steering Currently, this information is derived Committee. Data cleaning and analyses from stand-alone databases such as will continue in 2015 and we anticipate the Commonwealth funded- Australian that we will present results from first Childhood Immunisation Register and analyses in 2015. compared to separate state-based Project funding: NHMRC New databases of disease notifications or Investigator Project Grant hospitalisations. While studying these datasets in isolation can be informative, Linkage of the Australian Childhood their linkage would allow far more Immunisation Register (ACIR) and accurate analysis on the relationship state-based registers to evaluate between vaccination uptake, timeliness and inform Australia’s immunisation of vaccination, and development of program disease in various population sub- groups. Investigators: Hannah Moore1, Christopher Blyth1,2, Nicholas de Klerk1, Through collaborations with

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researchers in New South Wales, we NHMRC Project Grant APP1082342 developed a cross-jurisdictional project The pathogen-specific burden of linking data on administrative databases for children born in NSW and WA from hospitalisation for enteric and blood 2000 to 2012, including data on births stream infection in children and and deaths, immunisation records, young people in Western Australia hospitalisation admissions, emergency Investigators: Hannah Moore1, department visits, and infectious Tom Snelling1, Claire Waddington1, disease notifications (e.g. whooping Christopher Blyth1,2, Thomas Riley3, cough, pneumococcal disease and Deborah Lehmann1, Parveen Fathima1 influenza). The linked data will allow identifying characteristics of children 1. Telethon Kids Institute; 2. UWA School who are not receiving vaccinations of Paediatrics and Child Health; 3. UWA on time; calculate the effectiveness Microbiology and Immunology of vaccinations in preventing disease; Enteric or gut infections cause and comparing the effectiveness of significant mortality and morbidity in vaccinations between different risk both resource rich and poor settings. In groups, over time, and between NSW Western Australia, enteric infections are and WA. one of the leading causes for infection- In 2014, the Public Interest Certificate related hospitalisations in children authorising the release of ACIR data under the age of 2 years. Aboriginal to the Data linkage unit at AIHW was infants are 8 times more likely to be issued and all other approvals from admitted for enteric infections than non- the relevant data linkage units, ethics Aboriginal infants. committees and data custodians were Although an enteric infection is usually obtained. The linked data was made self-limiting, it can lead to acute available through a remote data access morbidity through dehydration, and laboratory, known as the Secure chronic morbidity in cases of under- Unified Research Environment (SURE) nutrition. Furthermore, certain enteric in February 2015. Data cleaning and pathogens can translocate into the analysis will be the focus of this project normally sterile bloodstream causing over the next few years. bloodstream infection and sepsis. The Project funding: Population Health pathogens causing enteric infection Research Network Proof of Concept are geographically, seasonally and Collaboration #4. The Population Health temporally variable. Rotavirus has been Research Network is a capability of the single most important cause of the Australian Government National enteric disease in Western Australia, Collaborative Research Infrastructure the rest of Australia and globally, Strategy and Education Investment while infections due to the bacteria Fund Super Science Initiative Campylobacter spp., Salmonella spp., Shigella spp. or parasites are

256 | TELETHON KIDS INSTITUTE also frequently reported in infants from all relevant ethics bodies and living in the Northern Territory, and custodians in Western Australia. We children < 5 years in remote Western anticipate that the linked data will be Australia, especially Aboriginal received by the project team in 2015. infants. Routine rotavirus vaccination Project funding: Princess Margaret commenced in mid-2007 and since Hospital Foundation New Investigator then hospitalisations due to rotavirus- Project Grant 2013 specific and all-cause gastroenteritis have declined. We hypothesise that Evaluating the use and effectiveness rotavirus immunisation has not only had of passive immunisation in reducing a direct impact on preventing rotavirus RSV-associated morbidity in high risk gastroenteritis, but also has an indirect infants effect on preventing disease caused by other enteric pathogens by reducing Investigators: Hannah Moore1, Tasnim their transmission. Abdalla1, Tom Snelling1, Tobias Strunk2, Anthony Keil3, Nicholas De Klerk1, Peter Because of our capacity to directly Richmond 2 link hospitalisation records with pathogen-specific pathology data, 1. Telethon Kids Institute; UWA School we are a unique position to address of Paediatrics and Child Health; 3. this hypothesis in Western Australia. PathWest Laboratory Medicine & We will determine the pathogen- Department of Microbiology, Princess specific burden of community-acquired Margaret Hospital enteric and bloodstream infections Respiratory syncytial virus (RSV) is in Aboriginal and non-Aboriginal one of the main causes of acute lower children presenting to the emergency respiratory infections in young children. department or being hospitalised Clinical risk factors such as prematurity, across the state of Western Australia, chronic lung conditions or congenital and will investigate temporal and heart disease increase the susceptibility seasonal trends of enteric pathogens, of infants to RSV infections. In Australia risk factors for hospitalisations and the strategy to prevent serious RSV assess the impact of co-morbidities disease in high-risk infants is through on disease outcome. This study the use of an expensive monoclonal will provide novel understanding of anti-RSV antibody, palivizumab. the overall impact of the rotavirus Palivizumab is given as monthly vaccination program, especially among injections during the RSV peak season, Aboriginal children, and will inform usually from May to October. However, future preventive and management there is no uniform national guideline strategies. or policy on the use of palivizumab In 2014, ethical approvals and data in Australia. Few studies conducted custodian approvals were obtained in other countries have shown that a compliant use of monthly injections of

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palivizumab can reduce RSV infections 1. Telethon Kids Institute; 2. UWA School and associated hospitalisations. In of Paediatrics and Child Health Australia there has never been an Acute lower respiratory infections evaluation of the efficacy of palivizumab are a major cause of childhood in preventing RSV disease. This morbidity, with higher rates of data linkage cohort study aims to infection in Aboriginal children. It evaluate the use and compliance is a recommendation that children with palivizumab and its effectiveness hospitalised with respiratory infections in preventing RSV infections. The have a laboratory investigation to cost-effectiveness of palivizumab will determine the causative pathogen. also be analysed. We will link data This is essential to guide patient clinical stored in the Neonatal Clinical Care management and to monitor temporal Unit Database (NeoBase), Midwives trends in specific pathogens which aid Notification System, Princess Margaret in vaccine policy development. Using Hospital and King Edward Memorial population-based data linkage, only Hospital Dispensary Databases, Death 50% of hospitalisations in metropolitan Register, Hospital Morbidity Database Western Australia linked to a laboratory System, Emergency Department Data record from 2000-2005. Linkage was Collection, and the PathWest Laboratory particularly low in non-metropolitan Database. The NeoBase will be used to areas: <5% in some remote areas and identify high risk infants born between <10% in rural areas. Given the low levels 1st January 2002 and 31st December of laboratory data linkage across the 2013 and admitted to Level 3 Neonatal State, we set out to determine whether Intensive Care Unit at KEMH and PMH. hospitalised children are either being Funding for this project was received under-investigated for respiratory mid-2014 and the application for linked pathogens or if there are deficiencies data was submitted at the end of 2014. within our data linkage extraction All project approvals are anticipated to protocols. We developed a medical be obtained in 2015 with receipt of the chart review that was conducted in 7 linked data anticipated to be late 2015. hospitals across Western Australia. The primary purpose was to document the Project funding: Telethon-Perth proportion of ICD10-coded respiratory Children’s Hospital Research Fund infection hospitalisations that had any Grant 2013 microbiological investigations. Validating and enhancing population- Chart reviews were completed for 746 based data linkage for infectious hospital admissions in children aged disease research less than 5 years, who were admitted Investigators: Hannah Moore1, to hospital with a chest infection Christopher Blyth1,2, Janice Lim1 between 2000 and 2011. We reviewed admissions from Princess Margaret

258 | TELETHON KIDS INSTITUTE Hospital for Children, Joondalup pneumoniae among Aboriginal Health Campus, Fremantle Hospital, children and adults in Western Bunbury Regional Hospital, Geraldton Australia Hospital, Broome Hospital and Derby Hospital. These hospitals were chosen Investigators: Anke Hoskins1, Tom because they represented >55% of Snelling1, Deborah Lehmann1, hospital admissions for chest infections Deirdre Collins1, Janice Lim1, Kalpani in children in Western Australia. We Senasinghe1, Peter Richmond1,2, compared the proportion of admission Jacinta Bowman3, Natalie Thomsen3, records with evidence of a laboratory Tom Riley3, Carolien Giele4, Paul test to the proportion of children Effler4, Amanda Leach5 recorded as having laboratory tests 1. Telethon Kids Institute; 2. UWA School through our previous data linkage work. of Paediatrics and Child Health; 3. We also determined the differences in UWA Microbiology and Immunology; 4. requests for laboratory tests in different WA Department of Health; 5. Menzies areas, Aboriginal and non-Aboriginal School of Health Research populations and two time periods (2000-2005 and 2006-2011). Streptococcus pneumoniae is a bacterium that can cause invasive From 746 records, 571 (77%) had a pneumococcal disease (IPD) including laboratory investigation requested or meningitis, pneumonia and septicaemia performed compared to 46% in our (blood poisoning). It is also a cause of population-based data linkage study. middle ear infections. The Australian Laboratory investigations were reported Aboriginal population has among the more frequently in 2006-2011 compared highest reported IPD rates worldwide. to 2000-2005, particularly among The existence of over 90 known infants aged 6-11 months, Aboriginal types (serotypes) of pneumococci children and children admitted to rural increases the challenge of prevention. or remote hospitals, although this A pneumococcal conjugate vaccine increase was not uniformly distributed (Prevenar-7™, PCV7) covering the 7 most among all hospitals. We found that common serotypes causing IPD has very young infants (aged <6 months) been introduced to the immunization and children admitted to metropolitan schedule for Aboriginal children in hospitals were most likely to have a 2001 and was replaced in July 2011 laboratory investigation. A manuscript with Prevenar-13™, which covers six describing these findings is currently additional serotypes. A pneumococcal under review. polysaccharide vaccine (Pneumovax™) Project funding: Telethon Institute for covering 23 serotypes is offered to Child Health Research Small Grant adults. 2012-2013 Pneumococci are carried in the back Monitoring carriage of Streptococcus of the nose of healthy as well as sick

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individuals and the acquisition of conjugate vaccine and predictors of pneumococci is prerequisite to develop pneumococcal carriage in the Western disease. Surveillance of pneumococcal Australian Aboriginal population” is in carriage offers complementary preparation. information to data on IPD on serotypes Funding: Collaboration for Applied circulating in the population. This study Research and Evaluation (CARE), aims to monitor the impact of PCV on Western Australian Department of pneumococcal carriage by collecting Health pernasal swabs opportunistically from Aboriginal adults and children in urban, NHMRC Project Grant #545232 (in rural and remote areas of Western collaboration with the Menzies School Australia. We also collect ear swabs of Health Research) from children with middle ear discharge Investigating the risk factors and co- and data on vaccination status of morbidities associated with invasive children in the study. pneumococcal disease in the Western Due to limited funds, data collection Australian population from remote communities of WA was restricted. Pernasal swabs and ear Investigators: Deborah Lehmann1, swabs were collected from participants Janice Lim1, Hannah Moore1, Catherine attending metropolitan Aboriginal Harrison1, Judith Willis1, Aoiffe clinics and from one rural community McLoughlin1, Carolien Giele2 and (Katanning). To date we have collected Anthony Keil3 2850 pernasal swabs and 53 swabs of 1. Telethon Kids Institute; 2. WA middle ear discharges. Pneumococcal Department of Health; 3. PathWest carriage rates dropped slightly after the Laboratory Medicine & Department introduction of Prevenar-13™ but remain of Microbiology, Princess Margaret high in young children 6 – 23 months Hospital of age (70-80%). More than 60% of children < 6 months of age carried This project involved the analysis of pneumococci. Since 2008, 45 different the Invasive Pneumococcal Disease pneumococcal serotypes have been (IPD) surveillance data collected identified in 1123 pneumococcal positive by the Vaccine Impact Surveillance swabs. Currently, the most common Network (VISN) between 1997 and pneumococcal serotypes in children <5 2007 to investigate the underlying co- years of age are 19F, 6C and 16F, while morbidities and risk factors associated 19F, 10A and 15B are most common with IPD. in older children and adults. Carriage Major findings are: of 19F remains common despite • Approximately 65% of IPD its inclusion in the pneumococcal cases occurred in adults aged ≥15 years vaccines. A manuscript with the title “Effect of 13 valent pneumococcal • Pneumonia was the most

260 | TELETHON KIDS INSTITUTE common diagnosis: 61% of non- 1. UWA School of Paediatrics and Child Aboriginal and 49% of Aboriginal adult Health; 2. Telethon Kids Institute; 3. WA IPD cases Department of Health • Cardiovascular disease and Following introduction of 13-valent chronic respiratory disease were the pneumococcal vaccine, it is expected most common co-morbidities in non- that non-vaccine preventable Aboriginal adults ≥15 years pneumococcal serotypes will emerge. To determine the possible • Smoking and excessive alcohol emerging pneumococcal serotypes, uses were the most common risk pneumococcal strains colonizing the factors in Aboriginal adults ≥15 years nasopharynx of young children will • Smoking was the most be identified from nasopharyngeal common risk factor in Aboriginal and swabs. Swabs are currently taken from non-Aboriginal adults up to 50 years of children presenting for immunization at age the Central Immunisation Clinic, Rheola • 41% of non-Aboriginal and 60% Street. To date, more than 600 children of Aboriginal children were eligible for have been enrolled with pneumococci vaccination but were not vaccinated detected in 20% of those enrolled. Culture and serotyping is currently • Among adults with risk factors, being performed. eligible for vaccination and with known vaccination status, more than 75% were Streptococcus pneumonia is the most not vaccinated common bacterial cause of pneumonia and meningitis in WA. Following The findings of this study have been the introduction of pneumococcal published in 2014 in the Pneumonia vaccines in 2005, a number of strains journal (vol. 4, p 24-34). of the bacteria emerged that were not Funding: Western Australian protected by the vaccine. Following Department of Health through the introduction of a new vaccine in 2011, Collaboration for Applied Research and we expect that further strains will Evaluation and the Meningitis Centre emerge. This project will identify these emerging strains by detecting what Examining Streptococcus strains are present in immunised and pneumoniae colonisation in young non-immunised children children in Western Australia (Urban Funding: WA Department of Health pneumococcal colonisation project) West Australian Influenza Vaccine Investigators: Christopher Blyth1,2, Effectiveness Study (WAIVE) Deborah Lehmann2, Paul Effler3, Peter Richmond1,2, Anke Hoskins2, Kalapani Investigators: Christopher Blyth1,2, Senasinghe2 Peter Richmond1,2, Chris Robbins (study coordinator) 2, Paul Effler3, David

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Smith4, Heath Kelly5, Gabrielle Willis2, 2014), the WAIVE study has been Peter Jacoby2, Hannah Moore2, Avram able to demonstrate that the overall Levy5, Meredith Borland6, Jennifer vaccine effectiveness of TIV is 70% Kent2, Katie Lindsay3 and Anthony Keil7 in preventing medically attended laboratory proven influenza in 1. UWA School of Paediatrics and children. This is comparable to the Child Health; 2. Telethon Kids Institute; effectiveness in young adults. It also 3. WA Department of Health; 3. has demonstrated that TIV is effective PathWest Laboratory Medicine; 4. Royal in children less than 2 years of age. Melbourne Hospital; 5. UWA School of Despite demonstrated vaccine Pathology and Laboratory Medicine; 6. effectiveness, vaccine uptake is still low. Princess Margaret Hospital; 7. PathWest Laboratory Medicine & Department Influenza vaccination is recommended of Microbiology, Princess Margaret for all children in Western Australia age Hospital 6 months to 5 years. To date, there has been little evidence demonstrating This prospective observational that influenza vaccination prevents study is designed to evaluate the influenza in very young children. The effectiveness of trivalent influenza data from this study demonstrate that vaccine (TIV) in young children and the influenza vaccination prevents 2 out to assess the burden of influenza of 3 children from presenting to hospital in young children and their families. with influenza. Children aged between 6 months and 5 years presenting to Princess Margaret Project funding: WA Department of Hospital for Children (PMH) Emergency Health Department or admitted to a hospital FLuCAN - A Rapid Alert System for ward with an influenza-like-illness (ILI) are eligible for enrolment. Severe Respiratory Illness (The FluCAN Surveillance system) In 2014, the 7th consecutive year that the study has run at PMH, we enrolled Investigators: Christopher Blyth1,2, 548 children between early July and Carolyn Finucane (study coordinator) mid-October. 22% of the children 2, Allen Cheng3, Paul Kelly5, Tom enrolled tested positive for influenza. Kotsimbos5, Heath Kelly6, Tony Parents completed two questionnaires Korman5, Deb Friedman6, Louis details about the child’s illness and Irving7, Sanjaya Senanayake8, Grant its impact on the child and the family, Waterer9, Simon Brown10, Mark attitudes to influenza vaccine, and Holmes11, Cameron Hunter12, Simon details about influenza-like illness in Bowler13, John Upham14, Graham other household members at the same Simpson15, Stephen Brady16, Saliya time. Hewagama17, Dominic Dwyer18, Kristine Macartney17,Peter Wark18 With data collected over the previous six influenza seasons (2008, 2010-

262 | TELETHON KIDS INSTITUTE 1. UWA School of Paediatrics and predisposing to severe influenza. Child Health; 2. Telethon Kids Institute; In those with laboratory-confirmed 3. Monash University, Melbourne; 4. influenza, Influenza A was detected in ACT Health Directorate, Canberra; 5. 90% of cases; with influenza A(H1N1) Monash Medical Centre, Melbourne; pdm09 the most frequent subtype 6. Barwon Health, Melbourne; 7. Royal (109/141 who had subtyping performed). Melbourne Hospital, Melbourne; 8. The adjusted vaccine effectiveness of Australian National University, Canberra one or more doses of TIV for preventing 9. UWA School of Medicine and hospitalised influenza was estimated Pharmacology, Royal Perth Hospital at 47.4% (-0.7%, 72.5%). Effectiveness Unit; 10. UWA Centre for Medical against influenza A(H1N1)pdm09 was Research; 11. University of Adelaide, high at 92.2% (40.8%, 99.0%) Adelaide; 12. Royal Hobart Hospital, Project funding: Commonwealth Hobart, Tasmania; 13. Mater Hospitals, Department of Health and Ageing Brisbane; 14. University of Queensland, Brisbane; 15. Cairns Base Hospital, FluMum - a prospective cohort study Cairns; 16. Alice Springs Hospital, of mother-infant pairs assessing the Alice Springs; 17. University of Sydney, effectiveness of maternal influenza Sydney; 18. University of Newcastle, vaccination in prevention of influenza Newcastle in early infancy The Influenza Complications Alert Investigators: Kerry-Ann O’Grady1, Network (FluCAN) has operated Lisa McHugh2, Terry Nolan3, Peter since 2009, initially as a network of 9 Richmond4, Caroline Talbot (study hospitals. The aims are to collect real- coordinator)4, Nicholas Wood5, Helen time surveillance for influenza requiring Marshall6, Stephen Lambert2, Mark hospitalisation and to provide a reliable Chatfield7, Ross Andrews7 and timely source of information to inform public health policy. FluCAN 1. Queensland University of Technology, determines burden of influenza disease 2. Queensland Children’s Medical requiring hospitalisation and estimates Research Institute 3. The University of the effectiveness of influenza vaccine Melbourne; 4. Telethon Kids Institute against hospitalisation. In 2014, we & UWA School of Paediatrics and expanded this surveillance to include Child Health; 5. University of Sydney; two large specialist paediatric hospitals 6. University of Adelaide; 7. Charles including Princess Margaret Hospital. Darwin University, Darwin From 3 April until 31 October 2014, The primary aim of the FluMum Study 402 children were admitted with PCR- is to determine the effectiveness confirmed influenza. Of these, 28% of maternal influenza vaccination in were <1 year, 16% were Aboriginal, pregnancy against laboratory confirmed and 39% had underlying conditions influenza in infants during the first 6-months of life. Also while conducting

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this study we aim to; Peter Jacoby2, Parveen Fathima2, Kristine Macartney4, Nicholas Wood4, • Establish the first national system of Gulam Khandaker4, David Durrheim5, validated annual influenza vaccine Craig Dalton5, Patrick Cashman5, Jody uptake in pregnancy. Stevenson5, Sally Munnoch5, Stephen • Monitor annual changes in vaccine Clarke5, Michelle Butler5, Mark uptake over time within each of the Ferson5, Deborah Thomson5, Keira participating sites. Glasgow5, Lauren Dalton5, Stephen • Assess the factors that influence Corbett5, Salwa Gabriel5, Michael the decision to receive influenza Crampton5, Katherine Veale5, Marina vaccination during pregnancy and Fulcher5, Karen Orr6, Kath Canning6, examine why women are not being Jennifer Murphy6, Brendan McMullan6, vaccinated in pregnancy. Geraldine Dunne6, Jim Buttery7, Nigel Crawford7, Gowri Selvaraj7, • Estimate the effectiveness of Annette Alafaci7, Greg Rowles8, Peter maternal influenza vaccine in Eizenburg8 pregnancy against laboratory confirmed influenza in the 1. UWA School of Paediatrics and Child mother during pregnancy and Health;2. Telethon Kids Institute; 3.WA hospitalization of the infant with Department of Health; 4. University of acute lower respiratory infection Sydney; 5. New South Wales Health, (ALRI) during the first six months of Sydney; 6. The Sydney Children’s life. Hospitals Network; 7. Royal Children’s Hospital and Monash Hospitals, 10,106 mother-infant pairs will be Melbourne; 8. General practitioners, recruited in six study sites (Darwin, Victoria Brisbane, Sydney, Melbourne, Adelaide and Perth) over four consecutive Building upon the FAST study (2011- influenza seasons (2012-2015). 2013), this national collaboration Assuming equivalent recruitment rates, undertook a prospective parental this will equate to 421 mother-infant survey to identify any significant pairs per site per year. Over the past increase in adverse events following three consecutive years Perth has immunization with a seasonal trivalent recruited 1162 mother-infant pairs, with inactivated influenza vaccine (TIV). In the shortfall to be made up in the final 2014, the parents/carers of children year of recruitment next year (2015). aged 6 months to less than 5 years who received influenza vaccine as Funding: NHMRC part of routine clinical care at sentinel AusVaxSafety sites in three States (NSW, Victoria and WA) were offered participation in Investigators: Christopher Blyth1,2, AusVaxSafety surveillance. Information Peter Richmond1,2, Paul Effler2, Annette was requested using an SMS message Regan2, Lauren Tracey2, Tom Snelling2,

264 | TELETHON KIDS INSTITUTE or email at 3 days after vaccination to Paediatric Active Enhanced Diseases parents/carers asking whether the child Surveillance (PAEDS) experienced any adverse event in the time since vaccination. Investigators: Christopher Blyth1, Peter Richmond1, Tom Snelling1, Chris Robbins During the surveillance period (10 (study coordinator) 1 and Carolyn March - 15 July 2014) 879 children Finucane (study coordinator) 1 together were enrolled and 782 surveys were with Kristine McCartney2, Elizabeth completed for 715 (81.3%) children, Elliott2, Yvonne Zurynski2, Peter noting that some parents completed the McIntyre2, Robert Booy2, Nicholas survey for both dose 1 and dose 2. Data Wood2, Jim Buttery3, Nigel Crawford3, on all 4 vaccine brands registered for Helen Marshall4, Michael Gold4, Julia use in children was captured; however, Clark5 and Anne Kynaston5 the majority of children received the two vaccines funded under the National 1. Princess Margaret Hospital/Telethon Immunisation Program, Vaxigrip (86.2%) Kids Institute; 2. The Children’s Hospital and Fluarix (10.7%). at Westmead, Sydney; 3. The Royal Children’s Hospital, Melbourne; 4. Overall 18.4% (95% CI 15.8-21.3%) Women’s and Children’s Hospital, reported any systemic and/or local Adelaide; 5. Royal Children’s Hospital, adverse events within 3 days of Brisbane vaccination. Reactions were generally mild and resolved within 1 to 2 days. Of Children’s hospitals are uniquely all vaccination encounters in children, placed to monitor key conditions or 6.8% (95% CI 5.1-8.8%) had fever and complications in childhood infectious 4.3% (95% CI 3.0-6.0%) had injection diseases. Given the importance of site reactions. There were only three vaccines in preventing childhood reports of severe adverse events infectious diseases, key vaccine (SAEs) during the surveillance period; preventable conditions and severe side all were in children with elevated effects from vaccines are monitored temperatures (≥39.5º C) who also in five paediatric hospitals in Australia. appeared to have concurrent upper These data are used to inform public respiratory tract infections. All children health authorities and the Australian with SAEs recovered completely within Immunisation Program. a week. There were no seizures or PAEDS is coordinated by the Australian hospitalisations within the follow-up Paediatric Surveillance Unit (APSU) and period. the National Centre for Immunisation Project funding: Commonwealth and Surveillance of Vaccine- Department of Health, WA Department Preventable Diseases (NCIRS). There of Health are currently five sites involved across Australia: • Princess Margaret Hospital for

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Children (PMH), Perth Horwood4, Ilomo Hwaihwanje2, Johanna Wapling2, Lea-Ann Kirkham1, • Women’s and Children’s Laurens Manning5, Trevor Duke6, Peter Hospital, Adelaide Richmond1,2 • Royal Children’s Hospital, 1. UWA School of Paediatrics and Child Melbourne Health; 2. Telethon Kids Institute; 3. PNG • Royal Children’s Hospital, Institute of Medical Research, Goroka, Brisbane Papua New Guinea; 3. Federation • The Children’s Hospital at University, Ballarat, Victoria; 4. Institut Westmead, NSW (coordinating centre) Pasteur du Cambodge, Phnom Penh, Cambodia; 5. UWA School of Medicine Using hospital-based active and Pharmacology; 6. University of surveillance, key vaccine preventable Melbourne diseases or vaccine-associated adverse events are monitored. Specific Papua New Guinea (PNG) has the conditions are chosen if they are of highest rates of child deaths in public health importance and difficult the Western Pacific Region, with to adequately capturing data through pneumonia, meningitis and septicaemia other surveillance mechanisms. The being the most common causes of six conditions included as surveillance death. Earlier studies conducted in PNG studies in 2014 were: Acute Childhood have repeatedly demonstrated that Encephalitis, Acute Flaccid Paralysis, most of these infections are caused by Febrile Seizures, Intussusception, the bacteria Streptococcus pneumoniae Hospitalised Pertussis and Severe and Haemophilus influenzae type b, Varicella. but no detailed studies have been conducted since 1993. The aim of this Project funding: Commonwealth study is to re-assess which pathogens Department of Health; WA Department are currently the most important causes of Health of pneumonia and meningitis in children The Aetiology of Acute Lower living in the Highlands of PNG. Respiratory Tract Infection and In the first 24 months of the study, 576 Meningitis in Hospitalised Children cases and 473 controls have been from the Eastern Highlands Province, enrolled. The majority of children had Papua New Guinea no known premorbid conditions. Of all children presenting, 346 (60.4%) Investigators: Christopher Blyth1,2, Willie were admitted to hospital with the Pomat3, Deborah Lehmann2, Rebecca remainder managed as outpatients. Ford3, Celestine Aho3, Geraldine Of those requiring admission, the Masiria3, Joycelyn Sapura3, John median length of stay was 3 days (IQ Kave3, Tonni Kumani3, Yazid Abdad3, range: 2 to 5 days). Nine cased died in Peter Siba3, Andrew Greenhill3, Paul hospital (9/573: 1.6%) including five with

266 | TELETHON KIDS INSTITUTE pneumonia, two with meningitis and two months in Papua New Guinean with both pneumonia and meningitis. children previously primed with Through blood cultures, we identified 7-valent pneumococcal conjugate seven patients with H. influenzae vaccine type b bacteraemia, fourteen with S. pneumoniae bacteraemia and a further Investigators: Peter Richmond1,2, patient with mixed pneumococcal and Deborah Lehmann2, Peter Jacoby2, HiB bacteraemia. One patient had Denise Anderson2, Anita van den Staphylococcus aureus bacteraemia Biggelaar2, Angela Fuery1, Peter Siba3, and a further patient had a non- William Pomat3, Andrew Greenhill4, typhoidal Salmonella bacteraemia. Mition Yoannes3, Christine Opa3, To date, only one cerebrospinal fluid Gerard Saleu3 sample was found positive in culture 1. UWA School of Paediatrics and Child (S. pneumoniae). Serotyping of the Health; 2.Telethon Kids Institute; 3. PNG invasive pneumococcal species has Institute of Medical Research, Goroka, been performed on all 16 isolates: Papua New Guinea; 4. Federation 56.2% of invasive isolates are vaccine University, Ballarat, Victoria preventable. Concerns have been raised Project funding: Investigator Initiated that administering the 23-valent Research Funds: Pfizer Global pneumococcal polysaccharide Internal Competitive Research Award vaccine (PPV) in infants who first have Scheme: Papua New Guinea Institute of been vaccinated with pneumococcal Medical Research conjugate vaccine (PCV) may potentially lead to immunological ‘hypo- Vaccine Clinical Trials (Vaccine Trials responsiveness’. Group) This study aims to determine whether Our mission is to improve the health of PPV given at 9 months of age: the community through immunisation 1) provides enhanced persistence and the prevention of infectious of antibody levels protecting against diseases. Our research teams are invasive disease at 3 to 5 years of age evaluating new vaccines and vaccine compared to unvaccinated controls schedules for a range of infectious diseases through investigator-initiated 2) has an impact on the as well as industry-sponsored trials. development of serotype-specific B-cell memory at 3 to 5 years of age Investigation of serotype-specific antibody persistence and B-cell 3) enhances antibody persistence memory at age 3 - 4 years and B-cell memory for those serotypes following 23-valent pneumococcal included in 7vPCV among children who received 7vPCV in early infancy polysaccharide vaccine at age 9

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4) has an effect on long-term 9th International Symposium on pneumococcal carriage in children Pneumococci and Pneumococcal primed or not primed with 7vPCV Diseases in Hyderabad, India in March 2014. A manuscript reporting these We are assessing immune function by findings is in preparation. measuring pneumococcal serotype- specific antibody concentrations, Project funding: Papua New Guinea opsonophagocytic antibodies and Institute of Medical Research Internal memory B-cell responses, and Competitive Research Award Grant nasopharyngeal carriage at age 3-5 Merck Sharp & Dohme years prior to and one month after a challenge dose (0.1ml) of PPV. A study to determine the safety and Key findings are: immunogenicity of 10-valent and 13-valent pneumococcal conjugate • Pneumococcal carriage rates vaccines in Papua New Guinean remain high to age 5 years (>70%) children and are predominantly serotypes not included in 7vPCV, irrespective of Investigators: Deborah Lehmann1, vaccination history. Andrew Greenhill2, Peter Richmond1,3, Lea-Ann Kirkham1,3, Peter Siba4, • Most children respond to the William Pomat4, Audrey Michael 4†, challenge dose with elevated serotype- Celestine Aho4, Rebecca Ford4, Tilda specific IgG antibody levels Orami4, Vela Solomon4, Geraldine • In both PPV-vaccinated and Masiria4, William Lagani4, Trevor Duke5, unvaccinated children, those who have Megan Passey6 higher IgG concentrations to start off 1. Telethon Kids Institute; 2. Federation with respond with lower IgG responses University, Ballarat, Victoria; 3. UWA to the challenge School of Paediatrics and Child Health; • Children who were immunised 4. PNG Institute of Medical Research, with PPV at 9 months of age did not Goroka, Papua New Guinea; 5. respond with lower IgG response to the ; 5. University of challenge dose Sydney • Memory B-cell responses Approximately 800,000 children die were similar in children given PPV annually from pneumococcal disease at 9 months compared to that in worldwide, the majority in early infancy. unvaccinated children Pneumococcal conjugate vaccines • Hypo-responsiveness after PPV (PCVs) have been introduced into may be less likely in children with high routine immunization programs in carriage rates many industrialised countries and an increasing number of third world Findings were presented at the countries. The Global Alliance for

268 | TELETHON KIDS INSTITUTE Vaccines and Immunisation (GAVI) and A total of 1200 pernasal swabs, 1100 the World Health Organization (WHO) serum samples and 630 PBMC samples have committed to the introduction have been collected to date. of PCV for infants in GAVI-eligible Findings so far are that PCV10 and countries (including PNG). No PCV13 are immunogenic in the early pneumococcal vaccine was available 1-2-3 month schedule in PNG infants, in PNG until 13vPCV was distributed in inducing comparable antibody levels 2014. and achieving high protective antibody The primary aim of this study, which levels at age 4 months. Preliminary began in November 2011, is to results were presented at the determine whether the 10-valent Biomedical and Social Sciences Society (PCV10) or 13-valent (PCV13) meeting in Goroka in September 2014. pneumococcal conjugate vaccines Project funding: (which include 10 or 13 pneumococcal serotypes, respectively) given in a Exxon-Mobil Governance and Public 1-2-3-month schedule are safe and Affairs immunogenic in Papua New Guinean Papua New Guinea Institute of Medical infants. This is an open randomised trial. Research Internal Competitive Research We aim to enrol 260 children at age 1 Award Grant month: half are randomised to receive PCV10 and the other half PCV13 in a CHiRRP – Combating Haemophilus 1-2-3-month schedule. At age 9 months influenza related respiratory half in each group are randomised to pathology receive the 23-valent pneumococcal polysaccharide vaccine (PPV) and Investigators: Kerry-Ann O’Grady1, the other half no PPV. To address the Andrew Wilson1, Peter Richmond2,3, possibility of hyporesponsiveness Ruth Thornton2,3, Tanya Stoney2,3, following PPV, all children will receive Gabriela Willis2,3, Stephanie Jeffares a challenge dose (0.1ml) of PPV at (study coordinator) 3 age 23 months. Enrolment for this 1. Queensland University of Technology, study has been completed, and more Brisbane, 2. UWA School of Paediatrics than 200 children have completed and Child Health; 3. Telethon Kids 9- and 10-month follow-up visits and Institute 140 received a challenge dose at 23 This is a multi-centre, double- months. The last follow-up at 24 months blind, randomised controlled trial is due in March 2016. Assays measuring to evaluate the efficacy of the 10 pneumococcal serotype-specific valent-pneumococcal-Protein D IgG and culture of pernasal swabs conjugate vaccine Synflorix in reducing have been completed on all samples respiratory exacerbations in children collected at ages 1 (pre-PCV) and 4 aged ≥ 18 months and <18 years with months (one month post-dose 3 PCV).

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suppurative lung disease. Non-typeable 1. Telethon Kids Institute; 2. UWA Haemophilus influenzae is the most School of Paediatrics and Child common bacterial pathogen associated Health;3. University of Sydney; 4. with exacerbations (cough and Urdoch Childrens Research Institute; infection) in chronic suppurative lung 5. Women’s and Children’s Hospital, disease (CSLD). The pneumococcal Adelaide, conjugate vaccine Synflorix includes This is an open-labelled follow-up study a NTHi Protein D protein carrier. The of 97 children who received either aim of this study is to establish whether an extra dose of pertussis vaccine at Synflorix through the induction of birth (4 doses of aP by 12 months of Protein-D specific immune responses age) or the normal infant immunisation can reduce NTHi-associated infections. schedule (3 doses of aP by 12 months In this double blinded randomised of age). Children were then randomized controlled trial, children between to receive an extra booster dose of 18 months and 18 years of age are pertussis containing vaccine at 18 randomised to receive either the trial months of age or not. Now at the vaccine Synflorix or the control vaccine age of 4 years, the children are again Menactra (Meningococcal ACWY randomized to receive the scheduled conjugate vaccine). Study sites include normal childhood pertussis containing Perth, Brisbane, Sydney and Melbourne vaccine (Infanrix-IPV) or the lower dose aiming to enrol a total of 206 children pertussis containing vaccine (Boostrix- across Australia. We have enrolled IPV), both together with the schedule 23 children at the Perth site, with Measles, Mumps, Rubella vaccine. recruitment ceasing on August, 2014. Hence there are six different treatment Of these 17 have completed all visits, 2 arms in this study. participants have withdrawn from the study and one participant was a screen The aim of the study is to compare failure. Three remaining participants in the immunogenicity and safety of the study are to complete their follow the normal childhood and low-dose up visits in 2015. pertussis vaccines when administered to these children at 4 years of age. Funders of the project: NHMRC Parents of participants who have Follow up of immunogenicity and already received 4 year vaccinations safety of acellular pertussis vaccine are asked to complete a brief telephone given at birth to 4 years of age questionnaire about reactions that may have occurred after the 4 year old Investigators: Peter Richmond1, 2, Tanya vaccinations. Stoney1, Gabriela Willis1, Camille Gibson (study coordinator)1 , together with So far 11 participants have been enrolled Nicholas Wood3, Peter McIntyre3, Terry in the 4-year follow up study and 32 Nolan4, Helen Marshall5 questionnaires have been completed.

270 | TELETHON KIDS INSTITUTE Funding: NHMRC Project Grant (sponsor) The vaccine response and long- A Phase III, randomised, open, term antibody persistence of GSK controlled, multicentre, primary Biologicals’ MenACWY-TT vaccine vaccination study to evaluate the administered as one dose at 6 years immunogenicity and persistence of post-MenC primary vaccination in 1 and 2 doses of GlaxoSmithKline healthy subjects aged 12-18 months Biologicals’ meningococcal conjugate at primary vaccination vaccine MenACWY-TT in toddlers

Investigators:Peter Richmond, Jennifer Investigators: Peter Richmond, Tanya Kent (study coordinator) Stoney, Gabriela Willis, Stephanie Jeffares (study coordinator) Telethon Kids Institute & UWA School of Paediatrics and Child Health Telethon Kids Institute & UWA School of Paediatrics and Child Health Children who were enrolled in a previous GSK combination vaccine Meningococcus (Neisseria meningitis) HibMenC (Haemophilus influenza is a bacteria that can cause serious type b / Meningococcal type C) trial infections leading to meningitis when they were 12 months of age and septicemia. Different strains of and either received the HibMenC meningococci exist. The vaccine trialed combination or separate Hib and MenC in this study protects against four strains vaccines were asked to participate in of meningococci: types A, C, W and this follow-up study to evaluate the Y, with type C being the only strain safety, immunogenicity and duration that Australian children are currently of antibody persistence of a booster vaccinated against under the National dose of GSK Biologicals’ MenACWY-TT Immunisation Program at 12 months (Meningococcal type A, C, W, Y and of age. This study aims to determine Tetanus Toxoid) vaccine administered at whether toddlers should receive 1 or 2 the age of 7 years. It is expected that doses of the experimental MenACWY the study vaccine will act as a booster vaccine to induce protective antibody for the MenC vaccine and will enlarge titers, and also whether the vaccine the coverage to serogroups A, W135 can be given at the same time as the and Y. The children will be seen at a pneumococcal vaccine Prevenar13 clinic visit 2 and 4 years after receiving without impacting on the safety and the MenACWY-TT booster vaccine, efficacy of that vaccine. In Australia when a blood sample will be taken to Prevenar13 is offered to babies at 2, measure the levels of Hib and MenC 4 and 6 months of age as part of the antibodies. So far 28 children have National Immunisation Program. The been re-enrolled in this trial. study involves attending 5 up to 7 clinic visits, depending on whether the child Funding: GlaxoSmithKline Biologicals is randomized to receive 1 or 2 doses of

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the study vaccine, with follow-up visits with the traditional Hep A vaccination 1, 3 and 5 years after the last dose of guidelines. Subjects are followed up MenACWY. for 6 months after receiving the 3rd injection. So far 7 participants have been enrolled This study has been completed and Funding: GlaxoSmithKline Biologicals we are waiting on the final study report (sponsor) from Pfizer. A Phase 3, Randomized, Active- Funding: Pfizer (sponsor) Controlled, Observer-Blinded Trial to Assess the Safety and Tolerability of a A Randomized, Double-blind, Meningococcal Serogroup B Bivalent Placebo-controlled, 2-Part Study Recombinant Lipoprotein (rLP2086) of Orally Administered ALS- Vaccine Given in Healthy Subjects 008176 to Evaluate the Safety, Aged ≥10 to <26 Years Tolerability, Pharmacokinetics and Pharmacodynamics of Single Investigators: Peter Richmond, Ascending Dosing and Multiple Tanya Stoney, Caroline Talbot (study Ascending Dosing in Infants coordinator) Hospitalized with Respiratory Telethon Kids Institute & UWA School of Syncytial Virus (RSV) Infection Paediatrics and Child Health Investigators: Peter Richmond, Tanya This is a phase 3, randomised, active- Stoney, Gabriela Willis, Stephanie controlled, observer-blinded trial to Jeffares (study coordinator) assess the safety and tolerability of a Meningococcal Serogroup B Bivalent Telethon Kids Institute & UWA School of Recombinant Lipoprotein (rLP2086) Paediatrics and Child Health vaccine given in healthy subjects Respiratory syncytial virus (RSV) is one aged ≥10 to <26 years old. Subjects of the viruses causing the ‘common in the control group not receiving the cold’. Most babies who get RSV experimental vaccine will receive a recover fully after 1-2 weeks, but licensed Hepatitis A vaccine. rLP2086 sometimes RSV infections can lead is given as a 3 dose schedule with the to severe cases of chest infection 2nd and 3rd dose being administered in children. There are currently no 2 and 6 months after the 1st dose RSV vaccines on the market for the respectively (0, 2, 6 month schedule). prevention of RSV infection in healthy The control group will receive two children, and there are no routinely doses of Hep A vaccine (2nd dose 6 used medications available for the months after the 1st, i.e. 0 and 6 months) treatment of RSV. The aim of this two while receiving a normal saline injection part trial is to study the effects of a two months after the first Hep A dose new experimental drug called ALS- (i.e. HepA, Saline, HepA) in keeping 008176, that is under development by

272 | TELETHON KIDS INSTITUTE Alios BioPharma Inc. for use in children 1. University of Sydney; 2 Telethon Kids infected with RSV. ALS-008176 is an Institute antiviral drug that prevents the virus This study is an extension of the HPV- from dividing and making more copies 015 research study with GlaxoSmithKline of itself. The drug is given by mouth (GSK) Biologicals’ human papillomavirus as a liquid. ALS-008176 has been (HPV) vaccine for healthy females over tested in adults infected with RSV and 26 years of age. Currently the HPV- demonstrated to significantly reduce 16/18 vaccine (Cervarix) is licensed in the amount of virus and duration, signs over 100 countries and is offered free and symptoms of RSV infection. to young women in HPV vaccination Up to 144 participants will be enrolled programs in the UK and some other into the first part of the study where European countries. Cervarix was infants will be given a single dose of licensed in Australia in May 2007 for ALS-008176. Blood tests, nose swabs women up to the age of 45 years. This and an ECG are also required. This study allows women over the age of 45 study will take 7 or 8 days to complete. years, who have participated in the HPV Up to 120 participants will be enrolled 015 study, to have access to the vaccine into the second part of the study where if they have not already had it during infants will be given 10 doses of the the course of the study. This study is study drug over 5 days. This study will currently recruiting. take 11 or 12 days to complete. Funding: GSK (sponsor) To date 26 Children have been Evaluation of a Complex Intervention recruited with no safety concerns reported. to Increase Uptake in School HPV Vaccination Program Funding: Alios BioPharma Inc (sponsor) Investigators: Rachel Skinner1, Spring A phase IIIb, open-label, multi-centre Cooper1, Jane Jones (study coordinator) immunization study to evaluate the 1, Helen Marshall2, Tanya Stoney3, safety of GlaxoSmithKline (GSK) Kevin McGeechan1, David Regan4 and Biologicals’ HPV-16/18 L1 VLP ASO4 Patricia Whyte vaccine administered intramuscularly 1. University of Sydney; 2 University of according to a 0, 1, 6-month schedule Adelaide; 3. Telethon Kids Institute; 4. in healthy female subjects who University of New South Wales; received the placebo control in the GSK HPV-015 study The primary aim of this study is to increase the school-based uptake Investigators: Rachel Skinner1, Tanya of the human papillomavirus (HPV) Stoney2, Jane Jones (study coordinator) vaccination. Secondary aims are to 2 improve program logistical outcomes, knowledge and attitudes, decision

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making involvement and reduce fear in It is hoped that the intervention will adolescents receiving the vaccine. have a positive impact on vaccination coverage, adolescent HPV vaccination During 2013 and 2014 forty secondary experience and ease of running the schools across WA and SA participated school-based vaccination program. in this study. Funders of the project: NHMRC and The schools were randomly allocated bioCSL to the study intervention (receive intervention) or wait-list control (receive Efficacy, immunogenicity and safety intervention the following year). The study of Clostridium difficile toxoid intervention consisted of adolescent vaccine in subjects at risk for C. education resources (in-school teaching difficile infection with teacher training, take home information, app and website for use Investigators: Peter Richmond, Tanya in schools and out); and methods for Stoney, Gabriela Willis, Camille Gibson distraction/relaxation on vaccination (study coordinator) day; an information brochure and Telethon Kids Institute & UWA School of decisional support tool for adolescents Paediatrics and Child Health and parents; and logistical strategies targeting consent form return rates, This study aims to assess the efficacy vaccination-room setup and in-school of a Clostridium difficile toxoid vaccine mop-ups. in preventing the onset of Clostridium difficile infection (CDI) in adults aged Students at participating schools were ≥ 50 years who are at risk for CDI and invited to complete a questionnaire have received at least 1 dose of the on three occasions throughout the experimental vaccine. The study is a school year (pre and post-vaccination) randomized, observer blind, placebo to determine changes in adolescent controlled, multicentre, multinational knowledge, confidence with vaccination Phase III trial recruiting 15,000 subjects and decision-making. Information in total. Adults aged ≥ 50 years will be about the school vaccination day enrolled in 1 of 2 risk strata across the was also collected by immunisation treatment groups. nurses and supervising school staff on the day. Another aspect of the study Risk Stratum 1: participant has had at is the qualitative component, which least 2 hospital stays for any condition helps to “put meaning to the data”. The and each lasting at least ≥ 24 hours in gathering of this information has been the 12 months before enrolment and through interviews and focus groups has received systemic (not topical) with interested immunisation nurses, antibiotics in the 12 months before students, parents/guardians and school enrolment. staff who have been involved in the Risk Stratum 2: participant is anticipated Year 8 immunisation program. to have an inpatient hospitalization for

274 | TELETHON KIDS INSTITUTE a planned surgical procedure within 60 VTG enrolled twenty-seven participants days of enrolment. in this study and all participant-related involvement was completed in 2014. Participants will be randomly assigned We are currently awaiting the final study in a 2:1 ratio to receive either the report. experimental vaccine or placebo. Vaccine or placebo will be administered Funding: Novartis Vaccines and in a 3 dose schedule on Days 0, 7, and Diagnostics (sponsor) 30. All subjects will be actively followed Implementation Research for efficacy throughout the follow-up period, which may extend for up to 3 The aim of this team is to ensure that years after the last dose. research is translated into strategies There have been 14 participants that directly improve the wellbeing enrolled in the study by the Vaccine of children. To achieve this, the Trials Group so far, which is below team focuses on understanding and enrolment target. Recruitment and evaluating the real world impact of enrolment have been challenging interventions and contextualizing due to the selection criteria and lack research from other settings to of awareness of CDI within the target our own population. The team population. collaborates widely and uses a range of methodological approaches, including Funding: Sanofi Pasteur (sponsor) pragmatic randomised controlled Elderly Avian Flu Vaccine Study trials, observational comparative effectiveness studies and data linkage Investigators: Peter Richmond (Principal studies. In 2014 the group was awarded Investigator), Fiona McDonald (study over $4M in competitive research coordinator) & Jane Jones (study grants for projects that will commence coordinator) in 2015. Telethon Kids Institute & UWA School of A randomised, placebo-controlled Paediatrics and Child Health trial of oral nitazoxanide for This is a phase II, randomized, observer- the empiric treatment of acute blind, multi-centre study to evaluate the gastroenteritis among Australian safety, tolerability and immunogenicity Indigenous children of two separate doses of an adjuvanted cell culture-derived H5N1 subunit Investigators: Tom Snelling1, Claire influenza virus vaccine (‘bird flu’) at two Waddington1, Asha Bowen2, Ross different formulations in healthy elderly Andrews3; Peter Morris3, Mark subjects. Unlike the conventional Naunton4, Mark Chatfield3 egg-based manufacturing process 1. Telethon Kids Institute; 2. UWA School the aH5N1c vaccine is manufactured of Paediatrics and Child Health; 3 through cell culture technology. Menzies School of Health Research,

ANNUAL REPORT 2014 | 275 GROUP NAME

Darwin; 4. University of Canberra Funding: NHMRC project grant 1069772 Aboriginal children continue to A randomised control trial of novel experience a large burden of disease treatment strategy for the treatment from gastroenteritis. Those living in of bronchiolitis in infants remote settings such as the Northern Territory have a particularly high burden Investigators: Claire Waddington1, Tom of disease, and frequently require Snelling1, Meredith Borland2, Andrew aero-medical retrieval to hospital Martin2, Christopher Blyth1,2 for management of gastroenteritis. 1. Telethon Kids Institute; 2. Princess Despite the obvious need, there are Margaret Hospital for Children/UWA still no effective treatment options for School of Paediatrics and Child Health acute diarrhoeal illness in children. Management is limited to supportive By the time they reach their first care with fluid and electrolyte birthday, 3-5% of all infants have replacement to prevent life-threatening been hospitalised with bronchiolitis, dehydration, correct electrolyte a condition caused by virally induced imbalances and improve nutritional inflammation of the lower respiratory status. tract, resulting in breathing difficulties, cough, poor feeding, irritability and Nitazoxanide (NTZ) is a novel occasionally apnoea. Currently, antimicrobial that has a broad-spectrum there are no effective treatments for activity against many of the pathogens bronchiolitis, and despite considerable implicated in acute gastroenteritis in efforts, vaccines for Respiratory high-burden settings, including in the syncytial virus (RSV) remain elusive. Northern Territory. In other settings, NTZ Expensive prophylactic therapy with treatment has been successfully used RSV monoclonal antibody is of marginal to treat gastroenteritis caused by a wide benefit in extremely high risk infants range of pathogens. but management is otherwise limited to Our team successfully obtained an supportive care with fluids, oxygen and NHMRC project grant in late 2013 ventilatory assistance, with admission to to conduct a pragmatic, placebo intensive care units in severe cases. controlled, randomised clinical trial in Novel approaches that are effective, the Northern Territory to investigate affordable, and well tolerated are the potential benefit of using NTZ desperately needed to reduce the huge as an empiric treatment strategy in morbidity, economic and social burden Indigenous children presenting to of bronchiolitis. The broad-spectrum hospital with acute gastroenteritis. This anti-viral activity of a novel anti-infective study is currently recruiting participants agent has recently been described, and is planned to continue over the including against the principal viral next two years. aetiological agents of bronchiolitis (especially Paramyxoviridae, including

276 | TELETHON KIDS INSTITUTE RSV, Human metapneumovirus Incomplete uptake of vaccination (hMPV), parainfluenza viruses and the remains a problem however, with Orthomyxoviridae, including Influenza vaccine preventable diseases (VPDs) viruses A and B). As such, this anti-viral still occurring in Australia and other treatment may provide a significant countries despite routine provision of and much needed advance in the childhood vaccination. management of infant bronchiolitis. Data from the Australian Childhood This project will examine the effect of Immunisation Register (ACIR) show that this treatment compared to placebo vaccination rates in Western Australia on the duration of significant illness in (WA) are the lowest for any Australian West Australian infants hospitalised with state with approximately one in ten bronchiolitis, to determine if its use as children incompletely vaccinated. empiric treatment for bronchiolitis is beneficial. Following award a successful Determinants of vaccine uptake and funding application in mid-2014, this timeliness in WA are unknown. A wide project is currently in the set-up phase range of social, demographic, maternal and aims to commence recruitment in and infant related factors have been winter 2015. identified as important determinants in other settings but the importance of Funding: Telethon-Perth Children’s these factors as determinants in WA Hospital Research Fund is unclear. Understanding determinant Determinants of incomplete factors in WA is critical to identify vaccination and non-vaccination interventions needed to ensure all among WA children children in WA are protected against vaccine preventable disease. Investigators: Claire Waddington1, Tom Experience from other states has shown Snelling1, Paul Effler 2, Julie Leask 1, Hal that co-ordinated, targeted approaches Willaby3 can successfully increase vaccination 1. Telethon Kids Institute; 2. rates. Potential low cost interventions Communicable Diseases Control to improve uptake, applicable at a Directorate,WA Department of Health; population level, include the use of 3. National Centre for Immunisation text message reminders for routine Research (NCIRS), Sydney vaccination, and phone calls from health Safe and effective vaccination is an professionals for overdue vaccinations. enormously successful public health As well as being effective, the use of intervention. Not only does vaccination modern technologies for vaccination protect the individual against disease, reminder and recall is supported by it provides population level (herd) parents. protection and brings children into This project will identify the contact with the health system during determinants of vaccination in WA their most vulnerable years of life. that will be used design and inform

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a targeted approach to increasing injection site). However, contrary to pre- vaccine coverage in WA using modern licensure data, the real-world use of the technology (such as the use of text acellular vaccine appears to result in message reminders). The impact of inferior immunity compared to the use the approach will be assessed in a of the older whole cell vaccines. randomised control trial. These data The best data available indicate that are an essential step in ensuring that substituting the first infant dose of all children in WA are fully protected for acellular pertussis vaccine with a single vaccine preventable disease. dose of whole cell vaccine could Project funding: WA Department of lead to a significant improvement in Health immune protection against pertussis. Although DTaP has been favoured for The safety and acceptability of mixed its less reactogenic profile, available whole cell/ acellular pertussis vaccine evidence suggests a single DTwP schedules in infants to prevent dose given by 2 months may be only sensitisation to food allergens: a pilot slightly more likely to cause a reaction study than a DTaP dose at this age. This project will assess the acceptability Investigators: Tom Snelling1, Peter and tolerability of this strategy by Richmond1,2, Susan Prescott1,2, Patrick randomising infants to receive the first Holt1 pertussis containing vaccine as either 1. Telethon Kids Institute; 2. UWA School DTaP or DTwP in a pilot phase study. If of Paediatrics and Child Health this study provides proof of principal Prior to the widespread use of effective data supporting the idea that a single pertussis (whooping cough) vaccines, dose of whole cell vaccine at 2 months child mortality from pertussis was of age is acceptable to parents, has an significant, and many more children acceptable reactogenicity profile, and experienced the distressing fits of results in a favourable immune profile, uncontrolled coughing and gasping that a much larger multi-centre study safety, resulted from infection. Despite on- immunogenicity and efficacy study will going vaccine programs there has been be conducted. a concerning resurgence of pertussis Funding: Telethon-Perth Children’s in Europe, the United States and Hospital Research Fund and UWA/WA Australia, resulting in several neonatal Health ‘near-miss’ funding deaths. One factor that may underlie this resurgence is the switch in the late The role of midwifes in tackling 1990s from using whole-cell pertussis vaccine hesitancy vaccines to more refined acellular Investigators: Katie Atwell1, Tom vaccines, a move largely driven by Snelling2, Claire Waddington2 data showing that the later had fewer side effects (such as soreness at the

278 | TELETHON KIDS INSTITUTE 1. Murdoch University (Perth, WA); TESTOV Pneumo- evaluation of 2.Telethon Kids Institute the effectiveness of the 13-valent Parental hesitancy around the decision pneumococcal conjugate vaccine to vaccinate their children (‘vaccine against pneumococcal pneumonia in hesitancy’) represents a major threat children to public health and our ability to Investigators: Adam Jaffe1, Tom prevent unnecessary deaths from Snelling2, Stephen Lambert3, Lyn infection. Midwives have an increasingly Gilbert4 integral role in immunisation advice and provision, but may abstain from 1. University of New South Wales, advocating for immunisation for a Sydney; 2.Telethon Kids Institute; 3. variety of reasons such as limited University of Queensland, Brisbane; 4. understanding of vaccines, lack of University of Sydney access to education resources, or Streptococcus pneumoniae philosophical objections linked to (pneumococcous) causes a range views around bodily autonomy and of infectious diseases, including preference for ‘natural’ processes. pneumonia and invasive pneumococcal There is evidence that expectant disease (IPD), and remains a leading mothers want childhood immunisation cause of childhood morbidity and information early, which midwives mortality globally, and is a significant are ideally placed to give. Health cause of childhood infection in Australia. care providers, including midwives, There are more than 90 different have significant influence on parental serotypes of S. pneumoniae, some of immunisation decisions. To date, which appear to be more pathogenic there has been little research on than others. Paediatric pneumococcal understanding midwives’ perspectives vaccines provide coverage against and practices on immunisation, and a limited number of these serotypes; how they might be better engaged the 10 valent pneumococcal conjugate as advocates of immunisation for vaccine (10vPCV) against 10 serotypes expectant and new parents. This and 13vPCV against 3 additional research aims to explore the evidence serotypes (13 in total). Both vaccines around the role of midwifes in vaccine are used in Australia’s National education and provision, and how Immunisation Program (NIP); however, vaccination may be optimally framed to the real world impact of these vaccines resonate with both midwives and their on IPD and pneumonia has been mixed, audience of birthing mothers. with paradoxical increases in some Funding: Wesfarmers Centre of outcomes, notably for complicated Vaccines and Infectious Diseases seed pneumonia. One explanation for this is funding that vaccination results in a decrease in nasal carriage of vaccine serotypes,

ANNUAL REPORT 2014 | 279 GROUP NAME

opening up a biological niche that Institute members: Glenn Pearson allows non-vaccine serotypes to infect (chair), Anita van den Biggelaar, (‘serotype replacement’). Some of these Deborah Lehmann, Hannah Moore, replacement serotypes may be even Anke Hoskins, Heidi Hutton and Anne more pathogenic than the serotypes McKenzie they replace. The full impact of the use An Infectious Diseases Community of conjugate vaccines and serotype Reference Group (CRG) has been replacement has never been fully meeting at the Institute four times a evaluated. year since it was convened in 2007. This study will assess the contribution The group is comprised of Aboriginal of S. pneumoniae to hospitalisation for and non-Aboriginal community pneumonia in Australian children in the members, Institute researchers and post-vaccine era; determine the factors representatives from the Western that contribute to these infections; and Australian Department of Health, evaluate the real world effectiveness the Vaccine Trials Group (VTG), the of the 13vPCV vaccination program in Meningitis Centre and the Institute’s preventing hospitalisation. Children Consumer and Community Advisory with pneumonia and empyema will be Council. Community members provide recruited from 13 tertiary paediatric input and advice to researchers hospitals. Blood, pleural fluid and presenting their proposed research nasopharyngeal swabs will be tested for studies to the group and identify areas S. pneumoniae (including serotyping), of particular community concern. and other bacteria and respiratory Presentations to the CRG are part of viruses using molecular techniques. informing the wider community about The vaccination status of these cases infectious disease research conducted will be compared with matched both within the Institute and externally. children from the Australian Childhood In 2014, presentations covered research Immunisation Registry to determine projects on rheumatic heart disease, vaccine effectiveness. It is anticipated strategies to improve the rates of that this will be the most comprehensive immunisation in WA, the development evaluation of the impact of a national of a rapid-test to diagnose bacterial pneumococcal vaccine program on invasive disease, RSV infections in hospitalised pneumonia and that the children, and the development of results will directly influence Australian food allergy after whooping cough and international vaccine policy and vaccination. vaccine development. The CRG, provided feedback on Funding: NHMRC project grant documents intended for study Infectious Diseases Community participants and assisted researchers Reference Group by providing letters of support for specific projects.

280 | TELETHON KIDS INSTITUTE Funders of the project:NHMRC Project Ms Samantha Colquhoun, PhD Grant #572590 candidate Theses passed

Research Support Dr Asha Bowen, PhD, Charles Darwin University Dr Anita van den Biggelaar, PhD, MSc Dr Sara Noonan, MSc, Charles Darwin Mrs Marie Abigail Nadal-Sims, BSc University (Hons) External Committees

Research Theme: Group A International Streptococcal Diseases Jonathan Carapetis, Editorial Board Member, Global Heart Journal, Head of Group World Heart Federation and Elsevier, Professor Jonathan Carapetis, PhD, 2011-current FAFPHM, FRACP (Infectious Disease), Jonathan Carapetis, Working Group FRACP (Paediatrics), MBBS, BMedSc on Rheumatic Fever and Rheumatic Research Staff Heart Disease, World Heart Federation, Geneva Dr Rosemary Wyber, MPH, MBChB Jonathan Carapetis, Expert Group Dr Meru Sheel, PhD, BSc Core Member and Head, Expert (Biotechnology) Group on Rheumatic Heart Disease, Cardiovascular Diseases Expert Group, Dr Clancy Read, PhD, GradDip Global Burden of Diseases, Injuries, and (International Health), BBus Risk Factors Study, 2008-current Dr Julie Marsh, PhD National Mr Padraig Oakley, MPH, BSc Jonathan Carapetis, Member, Mr Timothy Johnson, BID Association of Australian Medical Postgraduate Students Research Institutes (AAMRI), 2014 Jonathan Carapetis, Member, Australian Mr Jeffrey Cannon, PhD candidate Indigenous Doctors’ Association (AIDA), Dr Jess De Dassel, PhD candidate 2014 Dr Daniel Engelman, PhD candidate Jonathan Carapetis, Fellow of the Australian Academy of Health and Mr David Hendrickx, PhD candidate Medical Sciences (AAHMS), 2014 Dr Bo Remenyi, PhD candidate Jonathan Carapetis, Member, Australian Dr Kathryn Roberts, PhD candidate Institute of Company Directors,

ANNUAL REPORT 2014 | 281 GROUP NAME

2012-current Jonathan Carapetis, Interscience Conference on Antimicrobial Agents Jonathan Carapetis, Member, Program in Chemotherapy (American Society of Management Committee, RHD Australia, Microbiology), Washington DC, USA. 2012-current Jonathan Carapetis, Public Health Jonathan Carapetis, Board Member, Association of Australia, 43rd Annual One Disease at a Time Foundation, Conference, Perth, WA. 2010-current Jonathan Carapetis, Infection and Jonathan Carapetis, National Immunity in Children International Committee for Medicine, Australian Congress of Paediatric Infectious Academy of Science, 2007-current Disease, Oxford, United Kingdom Local Jonathan Carapetis, The World Jonathan Carapetis, Member, Heart Federation, World Congress Department of Corrective Services WA, of Cardiology Scientific Sessions, Youth Justice Board, 2014 Melbourne, VIC Jonathan Carapetis, Member, Western ACTIVE research collaborations Australian Immunisation Strategy Implementation Steering Committee Prof Bart Currie, Menzies School of (WAISISC), 2013-current Health Research, Darwin, NT Jonathan Carapetis, Chair, Clinical Charles Darwin University, NT Advisory Group, WA RHD Control Prof Ian Wicks, Walter and Eliza Hall Program, 2013-current Institute, Melbourne, VIC Jonathan Carapetis, Member, Western Prof Kim Mulholland, Murdoch Childrens Australian State Health Research Research Institute, Melbourne, VIC Advisory Council (SHRAC), 2012-current Prof Ben Boyd, Monash Institute of Jonathan Carapetis, Executive Director, Pharmaceutical Sciences, Melbourne, Telethon Kids Institute Board of VIC Directors, 2012-current Associate Prof Andrew Steer, Centre of Invited Presentations International Child Health, Melbourne, VIC Jonathan Carapetis, Heart Kids WA Keynote, Perth, WA Dr Leisl Zühlke, University of Cape Town, Cape Town, South Africa Jonathan Carapetis, School of Pathology and Laboratory Medicine Prof John Fraser, University of Auckland, Seminar Series, Faculty of Medicine Auckland, NZ and Dentistry, The University of Western Institute for Health Metrics and Australia, Perth, WA Evaluation, Seattle, USA

282 | TELETHON KIDS INSTITUTE World Heart Federation, Geneva, Dr Ruth Thornton PhD, BSc (Hons) Switzerland Mrs Victoria Stroud, MSc (Speech ACTIVE collaborations with industry Pathology, BSc (Hons)

Mr Mark Sullivan, Medicines Postgraduate Students Development Limited Ms Emma de Jong, PhD candidate ACTIVE involvement with the Ms Stephanie Trend, PhD candidate community Ms Tulia Mateus, PhD candidate Claire Boardman, RHD Australia, Darwin, NT Awards Translation Ms Emma de Jong, Preterm Infants Centre of Research Excellence top-up Tools for implementing rheumatic heart scholarship disease programmes (TIPs) Ms Janessa Pickering, Australian otitis TIPs was launched in May 2014 at media conference (OMOZ) travel award the World Congress of Cardiology 2014 in Melbourne, Australia to define, Ms Tulia Mateus, International Post- describe, and deliver rheumatic Graduate Research Scholarship (IPRS) heart disease control programs. APA The handbook is a compilation of implementation experience from External Committees peer reviewed and grey literature. The resource is intended for program International managers and policy makers to deliver Deborah Lehmann, Papua New priority-based rheumatic heart disease Guinea Institute of Medical Research control programs. Buttressing Coalition, 1998-current Deborah Lehmann, Member of Conference Committee for the 19th Research Theme: Ear Health International Symposium on Recent Advances in Otitis Media (RAOM), Group Leader 2012-current Associate Professor Peter Richmond, National MBBS, MRCP, FRACP Deborah Lehmann: Data safety Research Staff monitoring board of CHiRRP Associate Professor Deborah Lehmann, “Combating H. influenzae related MBBS, MSc respiratory pathology” (2012-current) Dr Lea-Ann Kirkham, PhD, BSc (Hons) Local

ANNUAL REPORT 2014 | 283 GROUP NAME

Deborah Lehmann, Meningitis Centre Country Health Services – Goldfields Management Committee (1998-current) WA Deborah Lehmann, Infectious Diseases Harvey Coates and Francis Lannigan, Community Reference Group (2008- ENT Specialists, Princess Margaret 2014) Hospital for Children, Perth WA Deborah Lehmann, Dissolving the glue Christine Jeffries-Stokes, Annette in glue ear: Assessment of the use of Stokes The Rural Clinical School of WA, Dornase alfa as an adjunct therapy to Kalgoorlie WA ventilation tube insertion, 2013 -current Tom Riley, Microbiology and Invited Presentations Immunology, The University of Western Australia, Perth WA Peter Richmond, Australian Otitis Media Conference (OMOZ), Melbourne, Vic, Amanda Leach, Heidi Smith-Vaughan, Aug 6-8 2014 Menzies School of Health Research, Darwin NT Peter Richmond, The Australian and New Zealand Society of Paediatric Paul Effler, Carolien Giele Otorhinolaryngology, Annual Scientific Communicable Disease Control Meeting. Bunk Bay, WA, Oct 2014 Directorate, Department of Health, Perth WA Deborah Lehmann, Community Ear and Hearing Health Forum, Broome, Ngunytju Tjitji Pirni Inc, Kalgoorlie WA WA, May 14-16 2014 Deborah Lehmann, Bega Garnbirringu Health Services, Australian Otitis Media Conference Kalgoorlie, WA (OMOZ), Melbourne, Vic Aug 6-8 2014 Allan Cripps, Gold Coast Campus, Heidi Hutton, Child and Adolescent Griffith University, Qld Health Research Symposium, Perth, WA, Eileen Dunne, Catherine Satzke, Oct 22-24 2014 Murdoch Children’s Research Institute, Janessa Pickering, Australia Otitis Melbourne Vic Media Conference (OMOZ), Melbourne, Megan Passey, University Centre for Vic, Aug 6-8 2014 Rural Health-North Coast, University of Stephanie Jeffares, Australia Otitis Sydney Media Conference (OMOZ), Vic, Aug Sanjay Jayasinghe, National Centre 6-8 2014 for Immunisation Research and Active research collaborations Surveillance for Vaccine Preventable Diseases, Sydney, NSW David Smith, PathWest Laboratory Medicine, Perth WA Kylie Carville, Victorian Infectious Diseases Reference Laboratory, Anne Mahony, Population Health, WA Melbourne

284 | TELETHON KIDS INSTITUTE ACTIVE collaborations with industry Heats

CSL, Australia – supply of Pneumovax Faye Janice Lim; 1st prize, Telethon for pneumococcal vaccine trials in PNG Kids Institute 8th Annual Student Circle Symposium External Committees Research Theme – Infectious Diseases Epidemiology& Surveillance International

Group Leaders National Chris Blyth, Australian Technical Dr Hannah Moore, BSc (Hons1), Advisory Group on Immunisations GradDipClinEpid, PhD (ATAGI) Australian Government: Associate Professor Christopher Blyth, Department of Health and Aging, MBBS (Hons) DCH FRACP FRCPA Deputy Chair (2014- Current Research Staff Chris Blyth, ATAGI/CNDA Rabies Working Party Australian Government: Ms Faye Janice Lim; BSc, BA, BMedSci Department of Health and Aging, Chair (Hons) (2014 – Current): Ms Parveen Fathima; BDS, M Infect Dis Chris Blyth, ATAGI Varicella / Zoster Ms Tasnim Abdalla; BSc, MPH Working Party Australian Government: Department of Health and Aging, (2013 Postgraduate Students – Current Faye Janice Lim, PhD candidate Chris Blyth, ATAGI Pneumococcal Working Party Australian Government: Alicia Annamalay, BSc Hons Department of Health and Aging, Awards Member (2013 – Current)

Hannah Moore; Telethon Kids Institute Local PhD Supervisor of the Year Award Hannah Moore, Telethon Kids Institute Hannah Moore; Australian Academy Early Environment Research Focus Area of Science/Science and Industry Steering Committee Endowment Fund Fellowship to attend Hannah Moore, Telethon Kids Institute 64th Meeting of the Nobel Laureates in Early-Mid Career Research Council Lindau, Germany Chris Blyth, WA Tuberculosis Advisory Hannah Moore; New Independent Council Health Department of Western Researcher Infrastructure Support Australia (NIRIS) Award Invited Presentations Faye Janice Lim; Finalist, The University of Western Australia 3-Minute-Thesis Hannah Moore, Data Linkage

ANNUAL REPORT 2014 | 285 GROUP NAME

Roundtable, Wollaston College, Perth, Dr Tobias Strunk, Consultant WA, Nov 2014 neonatologist at King Edward Memorial and Princess Margaret Hospitals, Perth Chris Blythe,. Perinatal Society of WA Australia and New Zealand Annual Conference, Perth, WA 2014 Prof Trevor Duke, Centre for International Health, University of Chris Blyth, Influenza Specialist Group Melbourne, Vic Annual Scientific Meeting, Melbourne, Vic, 2014 Prof Peter Siba , Dr William Pomat, Mrs Rebecca Ford, Papua New Guinea Faye Janice Lim, Endeavour College of Institute of Medical Research, Goroka, Natural Health, Perth, WA Aug 26, 2014 Papua New Guinea ACTIVE research collaborations Dr Andrew Greenhill, Federation Dr Kathryn Glass, National Centre for University, Churchill Campus, Vic Epidemiology and Population Health, ACTIVE involvement with the Australian National University, Canberra community ACT Drs Heather Gidding and Bette Liu, Hannah Moore, Infectious Diseases School of Public Health & Community Community Reference Group, Telethon Medicine, University of New South Kids Institute, Perth, WA Wales, Sydney, NSW Dr Pia Hardelid and Professor Ruth Research Theme – Vaccine Clinical Gilbert, Institute for Child Health, Trials (Vaccine Trials Group) University College London, UK Head of Group Prof Peter McIntyre, National Centre for Immunisation Research and Associate Professor Peter Richmond, Surveillance, Sydney NSW Prof David MBBS, MRCP(UK), FRACP Smith, PathWest Laboratory Medicine, Perth WA Research Staff Dr Anthony Keil, PathWest Laboratory Camille Gibson, BSc (Nursing), BSc Medicine and Department of (Environmental Health) Microbiology, Princess Margaret Caroline Talbot, Certificate IV Enrolled Hospital, Perth WA Nursing Prof David Burgner, Infection, Immunity Caroline Wharton, EN Cert IV & Environment, Murdoch Children’s Research Institute, Melbourne Vic Dr Carolyn Finucane, Registered Nurse Paul Effler, Communicable Diseases Christine Robins, Enrolled Nurse Control Directorate, WA Department of Health, Perth WA Fiona McDonald, BSc (Nursing)

286 | TELETHON KIDS INSTITUTE Heidi Hutton, BSc (HMvt), DipEd, MSc Local Committees Jacqueline Connell, Registered Nurse Peter Richmond, New Children’s Hospital Research and Education Jan Jones BSc (Hons) Dip.Ed Reference group (Chair), 2009 Jane Jones, BSc Nursing, BSc Peter Richmond, Child Health Research Environmental Science (Hon) and Education Advisory Committee Jennifer Kent, Registered Nurse (Chair), 2009 Karli Corscadden, BSc (Hons) Peter Richmond, Child and Adolescent Lisa Montgomery Health Service, Activity Based Funding Steering Committee, 2012 Stephanie Jeffares, BSc (Nursing), Immunisation Course Certificate (ECU, Invited Presentations 2004) Peter Richmond, 9th International Susan Patoir, B.Pharm, Registered Nurse Symposium on Pneumococci and Pneumococcal Diseases. Hyderabad, Ushma Wadia, MBBS, FRACP India, Mar 2014 National Committees Peter Richmond, Crucell J&J Bacterial Peter Richmond, Deputy Chairperson, Advisory Board meeting. Antwerp, Australian Technical Advisory Group on Belguim, April 2014 Immunisation (ATAGI), Commonwealth Peter Richmond, Australian Vaccines Department of Health and Ageing, and Immunotherapeutics Development 2010-2014 meeting. Melbourne, Vic, May 2014 Peter Richmond, Chair, ATAGI MMR- Peter Richmond, Papua New Guinea Varicella and Herpes Zoster Vaccine Biomedical and Social Sciences Society Working Party, 2006-current Specialty meeting. Goroka, PNG, Sept Peter Richmond, Member, ATAGI 2014 Pneumococcal Vaccine Working Party, ACTIVE collaborations with industry 2007-current WA Department of Health Peter Richmond, Member, Steering Committee PTNA (Paediatric Trials Commonwealth Department of Health Network of Australia), 2010-current and Ageing Peter Richmond, Member, ATAGI Hib Safe Vic and meningococcal C Vaccine Working Balance Therapeutics Party, 2008-current Pfizer Peter Richmond, Member, ATAGI H1N1 Influenza Vaccine Working Party, Novartis 2009-current GlaxoSmithKline

ANNUAL REPORT 2014 | 287 GROUP NAME

Sanofi Pasteur Research support ACTIVE involvement with the Ms Natalie Eiffler community Ms Ellen Tapsell Heidi Hutton, Infectious Diseases Ms Jessica Edmeades Community Reference Group Awards Peter Richmond, Pregnancy, Babies and Children’s Expo – “The Good Oil on Tom Snelling, Raine Clinical Research Immunisation: what do I need to know?”, Fellowship Perth, WA, Aug 2014 Claire Waddington, Friends of the Peter Richmond, Women’s and Institute travel award Children’s Health Update, Healthed. Claire Waddington, ESPID ADVAC The University of Western Australia, Fellowship Perth, WA, Aug 2014 Claire Waddington, ADVAC prize in Peter Richmond, South Australian vaccinology Vaccinology Update, Robinson Research Institute, Adelaide, SA, Oct Claire Waddington, Telethon Clinical 2014 Research Fellowship Nestle Paediatric Immunisation Seminar Marie Estcourt, Allergy CRE Fellowship - “New options for prevention of External Committees respiratory infections”, South Perth, WA, Nov 2014 National Tom Snelling, Pharmaceutical Benefits Advisory Committee (PBAC), Research Theme – Implementation 2014-current Research Tom Snelling, Economics Sub- Group Leader Committee of the PBAC

Dr Tom Snelling, PhD, FRACP Local Research staff Tom Snelling, Aboriginal Health Research Focus Area steering Dr Claire Waddington, DPhil, MRCP (UK) committee, Telethon Kids Institute, co- chair Dr Julie Marsh, PhD Tom Snelling, Antimicrobial stewardship Mrs Katie Attwell, PhD committee chair, Princess Margret Mrs Yue Wu, PhD (submitted) Hospital Mr Charlie McLeod, BMBS Tom Snelling, WA Committee on Antimicrobials, WA Health

288 | TELETHON KIDS INSTITUTE Tom Snelling and Claire Waddington, Nigel Cunliffe, Murdoch Childrens’ Biological Hazards Committee, Telethon Research Institute, Melbourne, Victoria Kids Institute Margie Danchin, Surveillance of Tom Snelling and Claire Waddington, Adverse Events Following Vaccination WA ACTA in the Community (SAEFVIC), Victoria Invited Presentations Paul Effler, WA Department of Health, Perth, WA Tom Snelling, Methods in vaccine effectiveness and safety workshop, Lyn Gilbert, University of Sydney, Sydney, NSW, Oct 28 2014 Sydney, NSW Tom Snelling, HIV Update, Sydney, Prof Michael Gold, The Women’s and NSW, Oct 23 2014 Children’s Health Network, Adelaide, SA Tom Snelling, Australian Society for Patrick Holt, Telethon Kids Institute, Infectious Diseases Annual Conference, Perth, WA Adelaide, SA, March 26 2014 Adam Jaffe, University of New South Tom Snelling, PHAA Annual Scientific Wales, Sydney, NSW Meeting, Canberra, ACT, Mar 2014 Carl Kirkwood, Murdoch Childrens’ Claire Waddington, Biological Research Institute, Melbourne, Vic challenges to effective vaccines, Royal Julie Leask, University of Sydney, NSW Society, UK, Nov 2014 Andrew Martin, Princess Margaret ACTIVE research collaborations Hospital for Children, Perth, WA

Katie Atwell, Murdoch University, Perth, Peter McIntyre, University of Sydney, WA NSW Ross Andrews, Charles Darwin Peter Morris, Menzies School of Health University, Darwin, NT Research, Darwin, NT Rob Baird, Royal Darwin Hospital, Mark Naunton, University of Canberra, Darwin, NT ACT Meredity Borland, Princess Margaret Andrew Pollard, University of Oxford, Hospital, Perth, WA UK Dianne Campbell, University of Sydney, Susan Prescott, Telethon Kids Institute, Sydney, NSW Perth, WA Mark Chatfield, Menzies School of Tom Riley, University of Western Health Research, Darwin, NT Australia, Perth, WA John Crump, University of Otago, New Roy Robins-Browne, University of Zealand Melbourne, Vic

ANNUAL REPORT 2014 | 289 GROUP NAME

Nick Wood, University of Sydney, NSW ACTIVE involvement with the community

Tom Snelling, ‘Baby Expo’, Claremont Showground, WA Changes to clinical practice

Tom Snelling, PMH antimicrobial stewardship program Tom Snelling and Claire Waddington, literature review to inform the update of the CARPA manual for the management of gastroenteritis Health policies and guidelines directly influenced

Claire Waddington, European Medicines Agency’s review on the role of challenge studies in vaccine licensure (July 2014) Other achievements

The Implementation team was awarded three NHMRC grants in 2014 (as either CI-A or AI), accounting for >$5M of NHMRC research funding starting in 2015

290 | TELETHON KIDS INSTITUTE ANNUAL REPORT 2014 | 291 100 Roberts Road, Subiaco Western Australia 6008 PO Box 855, West Perth Western Australia 6872 T | 08 9489 7777 E | [email protected] W | telethonkids.org.au

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