Journal
DIABETES CARE
Volume 45, Issue 1, Pages 160-168Publisher
AMER DIABETES ASSOC
DOI: 10.2337/dc21-0878
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Funding
- JDRF [IBM: 1-RSC-2017-368-I-X, 1-IND2019-717-I-X, DAISY: 1-SRA-2019-722-I-X, 1-RSC2017-517-I-X, 5-ECR-2017-388-A-N]
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DAISY: DK032493, DK032083, DK104351, DK116073, DiPiS: DK26190]
- Centers for Disease Control and Prevention [DEW-IT: UR6/CCU017247]
- European Union [BMH4-CT98-3314]
- Novo Nordisk Foundation
- Academy of Finland [292538]
- Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research) [20122017, 250114]
- Special Research Funds for University Hospitals in Finland
- Diabetes Research Foundation, Finland
- Sigrid Juselius Foundation, Finland
- German Federal Ministry of Education and Research
- Swedish Research Council [14064]
- Swedish Childhood Diabetes Foundation
- Swedish Diabetes Association
- Nordisk Insulin Fund
- Skane University Hospital Fund
- Lions Club International
- Royal Physiographic Society
- Lund University Diabetes Centre Industrial Research Centre/EXODIAB funding from the Swedish Foundation for Strategic Research [DNR IRC150067]
- Stiftelsen for Strategisk Forskning [DNR 2009-1039]
- Hussman Foundation
- Washington State Life Science Discovery Fund
- Skane County Council Foundation for Research and Development
- The JDRF [DiPiS: 1-SRA2019-720-I-X, 1-RSC-2017-526-I-X, DIPP: 1-RSC2018-555-I-X, 1-SRA-2016-342-M-R, 1-SRA-2019732-M-B, DEW-IT: 1-SRA-2019-719-I-X, 1-RSC-2017-516-I-X]
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This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.
OBJECTIVE To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. RESEARCH DESIGN AND METHODS Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses. RESULTS Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n = 909), GADA (n = 1,076), and IA-2A (n = 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n = 954) and multiple (n = 527) autoantibodies could be stratified from 6 to 75% (P < 0.0001). The thresholds effectively identified children with a >= 50% 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy. CONCLUSIONS This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.
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