Islet Autoantibody Levels Differentiate Progression Trajectories in Individuals with Presymptomatic Type 1 Diabetes

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Our previous data-driven analysis of evolving patterns of islet autoantibodies (IAbs) against insulin (IAA), glutamic acid decarboxylase (GADA) and islet antigen 2 (IA-2A) discovered three trajectories characterized by either multiple IAbs (TR1), IAA (TR2), or GADA (TR3) as the first appearing autoantibodies. Here we examined the evolution of IAb levels within these trajectories in 2,145 IAb-positive participants followed from early life and compared those who progressed to type 1 diabetes (n=643) to those remaining undiagnosed (n=1,502). Using thresholds determined by 5-year diabetes risk, four levels were defined for each IAb and overlayed onto each visit. In diagnosed participants, high IAA levels were seen in TR1 and TR2 at ages <3 years, whereas IAA remained at lower levels in the undiagnosed. Proportions of dwell times (total duration of follow-up at a given level) at the four IAb levels differed between the diagnosed and undiagnosed for GADA and IA-2A in all three trajectories (p<0.001), but for IAA dwell times differed only within TR2 (p<0.05). Overall, undiagnosed participants more frequently had low IAb levels and later appearance of IAb than diagnosed participants. In conclusion, while it has been long appreciated that the number of autoantibodies is an important predictor of type 1 diabetes, consideration of autoantibody levels within the three autoimmune trajectories improved differentiation of IAb positive children who progressed to type 1 diabetes from those who did not.