Refining the Definition of Stage 1 Type 1 Diabetes: An Ontology-Driven Analysis of the Heterogeneity of Multiple Islet Autoimmunity
Brigitte I. Frohnert, Mohamed Ghalwash, Ying Li, Kenney Ng, Jessica L. Dunne, Markus Lundgren, William Hagopian, Olivia Lou, Christiane Winkler, Jorma Toppari, Riitta Veijola, Vibha Anand, T1DI Study Group, Anette G. Ziegler, Ezio Bonifacio, Peter Achenbach, Christiane Winkler, Marian Rewers, Brigitte I. Frohnert, Jill M. Norris, Andrea K. Steck, Kathleen Waugh, Liping Yu, William Hagopian, Michael Killian, Angela Wolf, Jocelyn Meyer, Claire Cowen Crouch, Jared Radtke, Åke Lernmark, Helena Elding Larsson, Markus Lundgren, Marlena Maziarz, Lampros Spiliopoulos, Josefin Jönsson, Riitta Veijola, Jorma Toppari, Jorma Ilonen, Mikael Knip, Vibha Anand, Mohamed Ghalwash, Kenney Ng, Zhiguo Li, Byoung-Mog Kwon, Harry Stravopolous, Eileen Koski, Ashwani Malhotra, Shelley Moore, Jianying Hu, Jessica L. Dunne, Bin Liu, Ying Li, Olivia Lou, Frank Martin
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.