Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children
RESEARCH DESIGN AND METHODS: Prospective cohort studies in Finland, Germany, Sweden and the US 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), glutamic acid decarboxylase (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=1076) or 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 50% or higher 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.