Disease progression joint model predicts time to type 1 diabetes onset: Optimizing future type 1 diabetes prevention studies

Abstract

AbstractClinical trials seeking type 1 diabetes prevention are challenging in terms of identifying patient populations likely to progress to type 1 diabetes within limited (i.e., short‐term) trial durations. Hence, we sought to improve such efforts by developing a quantitative disease progression model for type 1 diabetes. Individual‐level data obtained from the TrialNet Pathway to Prevention and The Environmental Determinants of Diabetes in the Young natural history studies were used to develop a joint model that links the longitudinal glycemic measure to the timing of type 1 diabetes diagnosis. Baseline covariates were assessed using a stepwise covariate modeling approach. Our study focused on individuals at risk of developing type 1 diabetes with the presence of two or more diabetes‐related autoantibodies (AAbs). The developed model successfully quantified how patient features measured at baseline, including HbA1c and the presence of different AAbs, alter the timing of type 1 diabetes diagnosis with reasonable accuracy and precision (<30% RSE). In addition, selected covariates were statistically significant (p < 0.0001 Wald test). The Weibull model best captured the timing to type 1 diabetes diagnosis. The 2‐h oral glucose tolerance values assessed at each visit were included as a time‐varying biomarker, which was best quantified using the sigmoid maximum effect function. This model provides a framework to quantitatively predict and simulate the time to type 1 diabetes diagnosis in individuals at risk of developing the disease and thus, aligns with the needs of pharmaceutical companies and scientists seeking to advance therapies aimed at interdicting the disease process.