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

Abstract

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

Research design and methods: Type 1 Diabetes Intelligence (T1DI) is a combined prospective data set of children from Finland, Germany, Sweden, and the U.S. who have an 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%) children with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from the most stringent definition (mIA/Persistent/2: two or more islet autoantibodies positive at the same visit with two or more antibodies persistent at next visit; 88% [95% CI 85-92%]) to the 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 than mIA/Any (P < 0.05); however, differences waned over the 2-year follow-up among those who did not subsequently reach higher stringency. Among mIA/Persistent/2 individuals with three autoantibodies, loss of one autoantibody by the 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 to 88% based on the 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.

Graphical abstract

Figure 1

Ontologic analysis of islet autoantibody patterns. A: Diagram shows the ontology of islet autoantibody patterns as determined by persistence and number of co-occurring autoantibodies. Examples of serial autoantibody measurements with outcome for each islet autoantibody: +for positive, −for negative. Each visit is labeled with age in years, depicted as annual visit for illustration purposes. Definition chart is in order of increasing stringency. For each example participant, a checkmark indicates whether a definition was met and the age at which criteria were met. B: Cumulative incidence of type 1 diabetes by highest stringency of mIA definition. P < 0.005 by multivariate log-rank test for B. Shaded areas show the 95% CI. Pairwise comparisons are in Supplementary Table 2.

Figure 2

Impact of age on progression. A: Cumulative incidence of mIA/Persistent/2 stratified by age quartile (Q) at sIA/Persistent status (n = 1,047). B: Cumulative incidence of stage 3 type 1 diabetes stratified by age quartile at mIA/Persistent/2 status (n = 819). Age quartile intervals for both A and B are as follows: Q1 (0.0, 2.0), Q2 (2.0, 3.5), Q3 (3.5, 7.1), Q4 (7.1, 18.7); (parentheses indicate participant are older than lower age boundary, bracket indicates age quartile is inclusive of upper boundary age). P < 0.005 by multivariate log-rank test for both A and B. The shaded areas show the 95% CI. Pairwise comparisons are in Supplementary Tables 3 and 4, respectively.

Figure 3

Impact of 2 ± 0.5 years of follow-up on cumulative incidence of stage 3 type 1 diabetes. A: Individuals who were mIA by any definition at baseline, stratified at follow-up by highest stringency of mIA definition achieved. B: Individuals who were mIA/Persistent/2 at baseline stratified at 2-year follow-up by persistence (or loss) of autoantibodies. Shaded areas show the 95% CI. P < 0.005 by multivariate log-rank test for A and B. Pairwise comparisons are in Supplementary Table 5 and Supplementary Table 6, respectively.