Refining the Definition of Stage 1 Type 1 Diabetes: An Ontology-Driven Analysis of the Heterogeneity of Multiple Islet Autoimmunity

OBJECTIVE: To estimate risk of progression to stage 3 type 1 diabetes based on varying definition of multiple islet autoantibody positivity (mIA). 

RESEARCH DESIGN AND METHODS: T1DI is a combined prospective dataset of children from Finland, Germany, Sweden and USA who are at increased genetic risk for type 1 diabetes. Analysis included 16,709 infants-toddlers enrolled by age 2.5 years and comparison between groups using Kaplan-Meier survival analysis. 

RESULTS: Of 865 (5%) with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from most stringent definition (mIA/Persistent/2: ≥2 islet autoantibodies positive at the same visit with ≥2 antibodies persistent at next visit; 88%, [95% CI: 85-92%]) to least stringent (mIA/Any: positivity for two islet autoantibodies without co-occurring positivity or persistence; 18%, [5-40%]). Progression in mIA/Persistent/2 was significantly higher than all other groups (P<0.0001). Intermediate stringency definitions showed intermediate risk and were significantly different from mIA/Any (p<0.05); however, differences waned over 2-year follow-up among those who did not subsequently reach higher stringency. Among mIA/Persistent/2 individuals with 3 autoantibodies, loss of one autoantibody by 2-year follow-up was associated with accelerated progression. Age was significantly associated with time from seroconversion to mIA/Persistent/2 status and mIA to stage 3 type 1 diabetes.

CONCLUSIONS: The 15-year risk of progression to type 1 diabetes risk varies markedly from 18-88% based on stringency of mIA definition. While initial categorization identifies highest risk individuals, short-term follow-up over 2 years may help stratify evolving risk especially for those with less stringent definitions of mIA.