Vibha Anand1, Ying Li2, Bin Liu2, Mohamed Ghalwash2,3, Eileen Koski2, Kenney Ng2, Jessica L Dunne4, Josefine Jönsson5, Christiane Winkler6,7,8, Mikael Knip9,10,11,12, Jorma Toppari13, Jorma Ilonen14, Michael B Killian15, Brigitte I Frohnert16, Markus Lundgren6, Anette-Gabriele Ziegler6,7,8, William Hagopian15, Riitta Veijola17, Marian Rewers. 1. Center for Computational Health, IBM T.J. Watson Research Center, Cambridge, MA, and Yorktown Heights, NY anand@us.ibm.com. 2. Center for Computational Health, IBM T.J. Watson Research Center, Cambridge, MA, and Yorktown Heights, NY. 3. Ain Shams University, Cairo, Egypt. 4. JDRF, New York, NY. 5. Department of Clinical Sciences Malmö, Lund University/CRC, Skåne University Hospital, Malmö. 6. Institute of Diabetes Research, Helmholtz Zentrum München German Research Center for Environmental Health, Munich-Neuherberg, Germany. 7. Forschergruppe Diabetes e.V. am Helmholtz Zentrum München, Munich, Germany. 8. Forschergruppe Diabetes, Technical University Munich, Germany. 9. Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland. 10. Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 11. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 12. Folkhälsan Research Center, Helsinki, Finland. 13. Institute of Biomedicine and Population Research Centre, University of Turku, and Department of Pediatrics, Turku University Hospital, Turku, Finland. 14. Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, and Clinical Microbiology, Turku University Hospital, Turku, Finland. 15. Pacific Northwest Research Institute, Seattle, WA. 16. Barbara Davis Center for Diabetes, University of Colorado, Denver, CO. 17. PEDEGO Research Unit, Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland.
Abstract
OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.
OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.
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