Ezio Bonifacio1,2, Andreas Weiß3, Christiane Winkler3,4, Markus Hippich3, Marian J Rewers5, Jorma Toppari6, Åke Lernmark7, Jin-Xiong She8, William A Hagopian9, Jeffrey P Krischer10, Kendra Vehik10, Desmond A Schatz11, Beena Akolkar12, Anette-Gabriele Ziegler. 1. Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany ezio.bonifacio@tu-dresden.de anette-g.ziegler@helmholtz-muenchen.de. 2. Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Dresden, Germany. 3. Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany. 4. Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany. 5. Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO. 6. Department of Pediatrics, Turku University Hospital, and Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland. 7. Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital (SUS), Malmo, Sweden. 8. Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA. 9. Pacific Northwest Research Institute, Seattle, WA. 10. Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL. 11. Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL. 12. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.
Abstract
OBJECTIVE: Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. RESULTS: The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8-4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8-1.3) at a landmark age of 6.25 years (P < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, HLA, and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5-7 years of age. CONCLUSIONS: The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life.
OBJECTIVE: Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. RESULTS: The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8-4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8-1.3) at a landmark age of 6.25 years (P < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, HLA, and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5-7 years of age. CONCLUSIONS: The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life.
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