PROJECT SUMMARY A large and growing number of pediatric diabetes cases cannot be classified at diagnosis with the current criteria, particularly among non-Caucasian children. The longitudinal observation of the clinical course that is often needed to classify diabetes causes harmful delays in the correct treatment. Mistakes in diagnosis and treatment may contribute to the higher frequency of diabetic complications in racial/ethnic minorities. Thus, there is a critical need for robust criteria that can be applied at diagnosis to inform clinical decisions in children of all racial/ethnic backgrounds. The long-term objective is to characterize pediatric diabetes at onset to inform clinical management in a timely fashion and thus, ultimately improve outcomes in racially/ethnically diverse children. As preliminary data, the applicants have developed and validated type 1 diabetes (T1D) Genetic Risk Scores (GRSs) that, in adults with unclear diabetes, identify those with T1D, defined by rapid insulin dependence; and have also demonstrated that a T1D GRS improves the current predictive model for progression to T1D in individuals at risk. The central hypothesis of this application is that T1D GRSs, in combination with islet autoantibodies and other factors at diabetes onset, can be used in racially/ethnically diverse children to identify those who have T1D, defined by rapid loss of C-peptide (measure of beta-cell function), as this is the T1D characteristic with the largest clinical impact. The rationale for this proposal is that timely characterization of diabetes, which is particularly difficult in minority children, will facilitate early establishment of the correct treatment, improve diabetes outcomes and lower the costs of diabetes, which are currently over $327 billion yearly. Guided by strong preliminary data, this hypothesis will be tested in racially/ethnically diverse children with diabetes by assessing the ability of T1D GRSs, in combination with other factors, to identify those who have T1D, defined as insulin deficiency (low C-peptide), in a cross-sectional (Specific Aim 1) and prospective (Specific Aim 2) manner. This project is significant because it is ultimately expected to improve the treatment of pediatric diabetes and thus its clinical outcomes, with particular impact on disadvantaged racial/ethnic groups. This project is innovative because it seeks to shift the current clinical and research practices by proposing to utilize genetics as a novel, affordable, time-independent strategy to diagnose T1D, identified by a clinically relevant characteristic.