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Introduction of the TIDE Protocol To Sylvia Stockler-Ipsiroglu, MD, PhD, MBA, FRCPC, Suud Nahdi, BSc, MPH, Clara van Karnebeek, MD, PhD, FCCMG Introduction of the TIDE Protocol to screen children for treatable intellectual disability: First evaluation of protocol use by community pediatricians in British Columbia Findings from a survey of BC pediatricians indicate that expanding the use of a two-tiered evidence-based approach to screening children for treatable genetic conditions could lead to improvements in early diagnosis and treatment. ABSTRACT Background: The TIDE (Treatable In­ cians with the help of a consensus­ Conclusions: The acceptance of the tellectual Disability Endeavor) Pro­ building workshop and download­ TIDE Protocol by community pedia­ tocol is a two­tiered evidence­based able resources (available at http:// tricians surveyed suggests there is approach used to screen children tidebc.org/Ph/physicians.html and a solid basis for implementing the for treatable genetic conditions (in­ www.tidebc.org/Ph/Ph/bcmj.html) protocol throughout BC. Because born errors of metabolism) causing designed to facilitate the use of the performing TIDE first­tier tests cap­ intellectual disability. A systematic protocol in a community setting: de­ tures 65% of currently known treat­ literature review performed in 2012 tailed information about the TIDE able conditions causing intellectual identified 81 treatable intellectual Protocol, stickers to place on labo­ disability, expanding the use of the disabilities. The TIDE first­tier as­ ratory requisitions, and forms for re­ protocol could lead to improvements sessment can be used to identify 52 ferral to the Biochemical Diseases in early diagnosis and treatment of of these 81 conditions using readily Clinic at BC Children’s Hospital. To inborn errors of metabolism, and available biochemical tests of urine evaluate knowledge, acceptance, prevention of brain damage. and blood. The TIDE second­tier as­ and use of the protocol, participating sessment takes a more targeted ap­ pediatricians were asked to respond Dr Stockler-Ipsiroglu is a professor in the proach to identifying the remaining to a web­based survey 18 months Department of Pediatrics, University of 29 conditions, and includes single after the workshop was held. British Columbia, and the head of the Di- metabolite or primary molecular anal­ vision of Biochemical Diseases at BC ysis. Because these analyses can be Results: Of the 19 participating com­ Children’s Hospital. Mr Nahdi is an MPH more expensive and require invasive munity pediatricians, 13 responded graduate in the School of Population and sampling procedures, the second­ to the survey (68.4%). Respondents Public Health at UBC. Dr van Karnebeek is tier diagnostic workup is handled by demonstrated knowledge of the an assistant professor in the Division of Bio- hospital­based specialists. TIDE first­tier tests and recognized chemical Diseases, Department of Pediat- the indications for referral to BC rics, at BCCH, and a scientist and Michael Methods: The TIDE Protocol was Children’s Hospital. All respondents Smith Foundation Scholar at the Centre of introduced to 19 BC­based pediatri­ said that the protocol made a change Molecular Medicine and Therapeutics and in their clinical practice. the Child and Family Research Institute of This article has been peer reviewed. BCCH. BC MEDICAL JOURNAL VOL. 57 NO. 9, NOVEMBER 2015 bcmj.org 387 Introduction of the TIDE Protocol to screen children for treatable intellectual disability Background treatable inborn errors of metabolism tic evaluation of a child with unex- Intellectual disability (ID) is a life- that cause ID.10 Of these, 52 conditions plained ID requires considering cur- long condition with onset before the (65%) are detectable by biochemical rent diagnostic guidelines,7-9 which age of 18 years; it is characterized by testing of blood and urine, while the recommend investigations such as limitations in cognitive functioning rest can be diagnosed by considering vision and hearing tests, chromosome (IQ below 70) and adaptive behav- specific clinical symptoms and order- microarray, and, in selected cases, ior. For children younger than 5 years ing appropriate biochemical or single fragile X testing and neuroimaging. with a delay in two or more develop- gene tests.10 Early diagnosis of a treat- At this stage, the TIDE second- mental domains (e.g., fine/gross mo- able ID is essential because medical tier screening process for identifying tor skills, speech, and interaction), diets, vitamin supplements, substrate the remaining 29 treatable IDs begins. the term global developmental delay inhibitors, stem cell transplantation, The second-tier process involves a tar- (DD) is used. Unless otherwise stated, gene therapy, and other treatments can geted workup, including single metab- however, the term ID is used in this prevent irreversible brain damage and olite or primary molecular analysis. article for both DD and ID. optimize developmental outcomes.10 Because these tests can be expensive ID affects 2% to 3% of the pedi- To translate these findings into and can require invasive sampling atric and adult populations world- clinical practice, we established procedures (e.g., spinal tap to collect wide.1,2 Based on BC 2013 popula- TIDE-BC, the Treatable Intellectual cerebrospinal fluid, skin biopsy to tion estimates, this means that 18 000 Disability Endeavour (www.tidebc cultivate fibroblasts), hospital-based to 27 000 children are affected by ID, .ca), in 2011. TIDE-BC is the first specialists are needed to facilitate an and 880 to 1300 newborns present Collaborative Area of Innovation ini- efficient diagnostic workup. with ID in the province each year.3 tiative funded by the BC Children’s The TIDE Protocol is supported Individuals with ID have a high num- Hospital Foundation (www.bcchf by an app (available at https://itunes ber of comorbidities,2 including neu- .ca) to improve outcomes for children .apple.com/us/app/treatable-id/ rological conditions, systemic prob- with rare diseases by way of enhanced id634757831?mt=8) that provides lems, and behavioral abnormalities. diagnosis and treatment. information on symptoms, diagnostic Medical costs associated with ID Based on the evidence summa- approach, and management of each exceed those for cardiovascular dis- rized in our 2012 review,10 we created treatable ID.14 ease and cancer combined.4,5 the two-tiered TIDE Protocol to place In a 2.5-year study conducted at ID causes are extremely hetero- screening for treatable IEMs at the BCCH in the divisions of biochemi- geneous and include environmental forefront of the diagnostic evaluation cal diseases, pediatric neurology, causes (e.g., infection, exposure to process for children with unexplained and medical genetics, more than 500 teratogens), genetic causes, and mul- ID. The TIDE Protocol can be viewed children with unexplained ID were tifactorial causes. In developed coun- at www.tidebc.org/Ph/Ph/bcmj.html. screened with the two-tiered TIDE tries, more than 50% of ID causes are The TIDE first-tier screening pro- Protocol. Of the children screened, deemed genetic, ranging from chro- cess uses readily available biochemi- 5% were diagnosed with a treatable mosomal to single gene abnormalities. cal tests of urine and blood with the IEM. Furthermore, a retrospective Current practice for evaluating potential to identify 52 of 81 treat- analysis showed that the protocol was children with ID prioritizes cytoge- able IDs.10-12 These first-tier tests can cost- and time-effective, and that it netic testing, which has a high diag- be ordered by community pediatri- reduced unnecessary diagnostic test- nostic yield.6-9 However, the condi- cians in BC, even though ordering ing and delay.15 tions identified are not all amenable metabolic/biochemical genetic tests To expand the use of the TIDE to causal treatment—that is, interven- is generally not regarded as a com- Protocol in the community practice tions targeting the pathophysiology of munity pediatrician’s responsibility. setting and to simplify a process that the condition at a cellular level. This Most of the tests are offered by the usually involves hospital-based sub- can lead to neglect of inborn errors Biochemical Genetics Laboratory at specialists, we started a provincial of metabolism (IEMs), genetic con- BC Children’s Hospital (BCCH) and pilot project in collaboration with BC ditions causing ID for which causal are funded by the medical services pediatricians and Child Health BC.16 treatment is available. plan for a total cost of approximately We then conducted a formal qualita- In a systematic literature review $528 per patient.13 tive evaluation 18 months after intro- performed in 2012, we identified 81 The next step in the diagnos- ducing the protocol. 388 BC MEDICAL JOURNAL VOL. 57 NO. 9, NOVEMBER 2015 bcmj.org Introduction of the TIDE Protocol to screen children for treatable intellectual disability Methods To facilitate the use of the TIDE ed to complete it (15 minutes). To Our study was conducted through BC Protocol in a community setting, we obtain an optimal response rate we Children’s Hospital, the only tertiary/ also provided the following materials sent regular reminders to the recipi- quaternary care centre in BC that pro- (all available for download at http:// ents and provided an incentive ($20 vides specialized services for children tidebc.org/Ph/physicians.html): coffee/pastry gift card). with inborn errors of metabolism. • The essentials of the TIDE Proto- We approached 19 community- Children diagnosed with a treatable col to serve as a memory aid for the based pediatricians from all health IEM are seen at the Biochemical Dis- pediatrician during assessment of a authorities in British Columbia. Of eases Clinic within the BCCH Depart- child with unexplained ID. these, 16 had taken part in the consen- ment of Pediatrics, and laboratory • Stickers to place on laboratory req- sus-building workshop and 3 had used samples collected from these chil- uisitions when ordering TIDE first- the TIDE Protocol after they heard dren are analyzed by the Biochemical tier tests.
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