Capillary Blood Islet Autoantibody Screening for Identifying Pre-Type 1 Diabetes in the General Population: Design and Initial Results of the Fr1da Study
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Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2016-011144 on 18 May 2016. Downloaded from Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study Jennifer Raab,1 Florian Haupt,1 Marlon Scholz,1 Claudia Matzke,1 Katharina Warncke,1,2,3 Karin Lange,4 Robin Assfalg,1 Katharina Weininger,1 Susanne Wittich,1 Stephanie Löbner,1 Andreas Beyerlein,1 Uta Nennstiel-Ratzel,5 Martin Lang,6 Otto Laub,7 Desiree Dunstheimer,8 Ezio Bonifacio,9,10 Peter Achenbach,1,2 Christiane Winkler,1,2 Anette-G Ziegler,1,2 the Fr1da Study Group To cite: Raab J, Haupt F, ABSTRACT Strengths and limitations of this study Scholz M, et al. Capillary Introduction: Type 1 diabetes can be diagnosed at an blood islet autoantibody early presymptomatic stage by the detection of islet ▪ screening for identifying pre- The Fr1da study is population based and con- autoantibodies. The Fr1da study aims to assess type 1 diabetes in the general ducted as public healthcare research. population: design and initial whether early staging of type 1 diabetes (1) is feasible ▪ The study uses a novel approach of early diagno- results of the Fr1da study. at a population-based level, (2) prevents severe sis of type 1 diabetes to prevent diabetic ketoaci- BMJ Open 2016;6:e011144. metabolic decompensation observed at the clinical dosis and improve care. doi:10.1136/bmjopen-2016- manifestation of type 1 diabetes and (3) reduces ▪ The study is performed in children at an age that 011144 psychological distress through preventive teaching and maximises the likelihood of achieving early diag- care. nosis of childhood diabetes. ▸ Prepublication history for Methods and analysis: Children aged 2–5 years in ▪ Measurement of psychological impact of early http://bmjopen.bmj.com/ this paper is available online. Bavaria, Germany, will be tested for the presence of diagnosis will allow impact on family well-being To view these files please multiple islet autoantibodies. Between February 2015 to be evaluated. visit the journal online and December 2016, 100 000 children will be screened ▪ Children positive for a single islet autoantibody (http://dx.doi.org/10.1136/ by primary care paediatricians. Islet autoantibodies are in the screening test are not followed. bmjopen-2016-011144). measured in capillary blood samples using a multiplex three-screen ELISA. Samples with ELISA results Received 14 January 2016 may set new standards for the early diagnosis of type Revised 16 March 2016 >97.5th centile are retested using reference Accepted 14 April 2016 radiobinding assays. A venous blood sample is also 1 diabetes and education. obtained to confirm the autoantibody status of children Ethics dissemination: The study was approved by on October 3, 2021 by guest. Protected copyright. with at least two autoantibodies. Children with the ethics committee of Technische Universität confirmed multiple islet autoantibodies are diagnosed München (Nr. 70/14). with pre-type 1 diabetes. These children and their parents are invited to participate in an education and counselling programme at a local diabetes centre. Depression and anxiety, and burden of early diagnosis are also assessed. INTRODUCTION Results: Of the 1027 Bavarian paediatricians, 39.3% Type 1 diabetes is one of the most common are participating in the study. Overall, 26 760 children chronic diseases of childhood with an inci- have been screened between February 2015 and November 2015. Capillary blood collection was dence that is increasing yearly in European sufficient in volume for islet autoantibody detection in countries. The prevalence of type 1 diabetes For numbered affiliations see – – 1–3 end of article. 99.46% of the children. The remaining 0.54% had in children aged 0 20 years is 0.3 0.6%. insufficient blood volume collected. Of the 26 760 Symptomatic type 1 diabetes is usually diag- capillary samples tested, 0.39% were positive for at nosed by blood glucose measurements at the Correspondence to Professor Anette-G Ziegler; least two islet autoantibodies. acute life-threatening onset of this disease. anette-g.ziegler@helmholtz- Discussion: Staging for early type 1 diabetes within a Acute disease onset requires hospitalisation, muenchen.de public health setting appears to be feasible. The study and is characterised by severe metabolic Raab J, et al. BMJ Open 2016;6:e011144. doi:10.1136/bmjopen-2016-011144 1 Open Access decompensation, a major complication of type 1 dia- screening for autoantibodies to GAD65, IA-2, ZnT8 and BMJ Open: first published as 10.1136/bmjopen-2016-011144 on 18 May 2016. Downloaded from betes.12The management of metabolic decompensation, insulin for the diagnosis of pre-type 1 diabetes.18 and the adaptation of the family to the disease and its Here, we report the design of the Fr1da study “Early treatment are major personal and financial burdens.12 diagnosis and care of type 1 diabetes” which was started in Early diagnosis of type 1 diabetes in the asymptomatic February 2015, and provide the initial results for 26 760 period could help to prevent acute disease onset, and children who had been screened by November 2015. reduce the prevalence of metabolic decompensation and associated hospitalisation.45It may also open the path to population-based disease prevention. METHODS Early diagnosis is possible by the detection of multiple Study population islet autoantibodies.6 Nearly all of the children with The Fr1da study is intended to screen at least 100 000 – these biomarkers, regardless of their family history of children aged 2 5 years living in Bavaria, Germany, for the disease, will develop clinical symptomatic diabetes.6 the presence of multiple islet autoantibodies. Screening Therefore, early diagnostic tools should focus on the started in February 2015 and will continue for about first years of life, the time when multiple islet autoanti- 24 months. Children are screened only once. The bodies usually emerge.7 In fact, 80% of children who screening is offered by primary care paediatricians who develop type 1 diabetes in childhood have multiple islet have volunteered to participate in the Fr1da study. autoantibodies before 5 years of age.6 Thus, if efficient The optimal age for performing one-off islet autoanti- screening is implemented within a public health preven- body screening is a compromise between the sensitivity tion programme, the majority of future cases of child- of detecting a large number of children who have hood clinical diabetes could be identified in infancy. already developed multiple islet autoantibodies (better Preventive teaching, education and monitoring may with later screening) and the loss of sensitivity attributed allow us to prevent severe metabolic decompensation to the progression to clinical diabetes (better with and ketoacidosis, and prepare the children and families earlier screening). Islet autoantibodies frequently fi for later insulin therapy. These possibilities are being develop within the rst years of life, with a peak inci- – 71920 ‘ ’ addressed in the Fr1da study. dence at 1 2 years. Therefore, the U medical The Fr1da study was designed as a model project in checkups in Bavaria scheduled at times after the peak order to introduce public health screening of multiple autoantibody incidence represent the best and most islet autoantibodies (pre-type 1 diabetes)8 in Bavaria, practical opportunities to identify children with presymp- Germany. It is assessing 1) whether early staging (as out- tomatic type 1 diabetes. Therefore, we have recom- lined in ref. 8) of type 1 diabetes in the context of mended that screening is performed in the context of – – regular medical checkups in early childhood is feasible medical checkups at 21 24 (checkup U7), 34 36 (U7a), – – and efficient; (2) whether ketoacidosis and hospitalisa- 46 48 (U8), and 60 64 (U9) months of age, and at any http://bmjopen.bmj.com/ tion of children can be prevented; and (3) whether psy- other paediatric visit within these age ranges (http:// chological distress can be reduced through early de.wikipedia.org/wiki/Kindervorsorgeuntersuchung). diagnosis, teaching and care. The Fr1da study is also By targeting several age-groups, we may facilitate the assessing environmental exposures. Its ultimate goal is to implementation of screening into paediatric practice, introduce a trial platform for the prevention and subse- and provide sensitivity estimates for each screening age fi quent management of type 1 diabetes. in order to de ne the optimal age for population-based Large-scale public health screening programmes islet autoantibody screening. require quick and easy blood collection in capillary tubes In Bavaria, there are around 100 000 live-births per on October 3, 2021 by guest. Protected copyright. or dried blood spots, as well as high throughput assays year and around 1000 primary care paediatricians. Over such as widely accepted newborn screening practices. 99.5% of children attend preventive medical checkups The current assays used to detect islet autoantibodies are corresponding to almost 400 000 checkup visits per year – – sensitive, specific, and standardised.9 14 However, in their of children aged 2 5 years. The checkups comprise phys- current format, these are not applicable for high ical examinations, hearing tests, assessments of develop- throughput population screening as they are too expen- mental disorders, and allergen tests, but do not yet sive and labour intensive. Furthermore, there is limited include blood collection. We anticipate that about half – experience of using these assays with capillary blood.15 17 of the primary care paediatricians in Bavaria will partici- To overcome this problem, we have collaborated with pate in the Fr1da Study, and around half of the chil- RSR Ltd., Cardiff, UK, to develop a screening assay dren/families who are offered screening by their for one-shot detection of autoantibodies to the target paediatricians will participate. Therefore, enrolment of antigens glutamic acid decarboxylase-65 (GAD65), 100 000 children is expected to be possible over 2 years fi insulinoma-associated antigen 2 (IA-2) and zinc trans- ( gure 1).