Subtyping COre for Research on the Etiology of Type 2 Diabetes (SCORE-T2D)

PROJECT SUMMARY Type 2 diabetes (T2D) is one of the fastest growing chronic diseases worldwide and is a leading contributor to comorbidities and early mortality. Current prevention and treatment strategies are not optimal for all individuals due to heterogeneity in the etiology and pathophysiology of T2D. Indeed, substantial variation exists across

individuals in the relative contribution of insulin resistance vs. beta cell function to T2D development and progression, as reflected by differences in glucose regulation among persons with comparable glycemia at diagnosis. Recent research has applied clustering algorithms to identify subgroups of diabetic individuals with

varying clinical profiles, risk of diabetes complications, and responsiveness to treatment therapies based on clinical variables measured at diagnosis (e.g., body mass index, age, fasting glucose and insulin, hemoglobin A1c, diabetes autoantibodies). Most of these studies leveraged large registry-based European cohorts, which

boast large sample sizes but lack diversity and/or data on social determinants of health that are known to drive chronic disease risk in the U.S. Moreover, most subtyping methods that have been applied require subjects to be placed in fixed categories which may not reflect the racial/ethnic and sociodemographic diversity of U.S.

populations and may not be ideally suited to accommodate mixed data types (e.g., clinical, omics, behavioral, environmental, social). Such multimodal data provide an untapped opportunity for subtyping based on realistic multi-level drivers of heterogeneity in the clinical course of T2D, from prediabetes to complications and

comorbidities. In response to RFA-DK-23-020, we seek to establish the Subtyping Core for Research on the Etiology of Type 2 Diabetes (SCORE-T2D) at the University of Colorado Anschutz Medical Campus. Partnering with the Consortium, SCORE-T2D will lead innovative analytic activities and provide crucial resources for the

Consortium Cohort Sites through methodological expertise in subtyping algorithms, data harmonization across large datasets, single and multi-omics analyses, lifecourse epidemiology, and integration of social factors; content expertise in T2D etiology and pathophysiology; and programmatic experience in multi-site study

coordination and analyses. Our overarching objective is to work with the Cohort Sites and NIDDK to employ multi-level, multi-dimensional approaches to characterizing heterogeneity in T2D in the Consortium. We will accomplish this through 1) developing and implementing consensus protocols for data sharing, management,

harmonization, and analysis; 2) characterizing subtypes of T2D and identify underlying social and physiologic drivers of the etiology and clinical course for each subtype; and 3) coordinating Consortium logistics on results sharing, outreach, and dissemination. SCORE-T2D at the University of Colorado Anschutz Medical Campus will

bring a fresh perspective on multi-site coordination and biostatistical expertise by spearheading efforts to quantify and understand heterogeneity in the risk factors, pathophysiological mechanisms, manifestations, and consequences of T2D.