Predicting progression to type 1 diabetes from ages 3 to 6 in islet autoantibody positive TEDDY children

Objective: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high-risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Methods: Logistic regression and 4-fold cross-validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non-statistical predictors, multiple autoantibody status, and presence of insulinoma-associated-2 autoantibodies (IA-2A). Results: A total of 363 subjects had at least one autoantibody at age 3. Twenty-one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors - IA-2A status, hemoglobin A1c, body mass index Z-score, single-nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. Conclusions: This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3-year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches