More information on RPL project 3: The overall goal of this proposal is to provide Dr. Yilin Yoshida, a project leader of the Tulane COBRE in Sex-Based Precision Medicine (SPM), with indispensable training to develop expertise in precision epidemiology, improve understanding of the sex disparities of diabetic cardiovascular disease (CVD) with a life-course perspective, and optimize diabetic cardiovascular risk prediction. Women’s excessive CVD risk in type 2 diabetes (T2D) relative to men is poorly understood. Potential mechanisms for this “female disadvantage” have been primarily tested in middle-aged cohorts without adequately accounting for the cumulative burden of early-onset T2D. In the past three decades, the greatest relative increases in T2D incidence and prevalence were observed in young adults and adolescents triggered by escalating obesity rates. Notably, early-onset T2D exhibits a female predominance in incidence and a more aggressive prognosis than late-onset T2D. A higher lifetime exposure to risk factor clustering in women compared to men with early-onset T2D, compounded by the aggressive disease course, may accelerate CVD risk in women in midlife. T2D is a heterogeneous disease with variable disease progression, which is illustrated by the sex disparity in the risk of diabetic CVD. Emerging machine learning-based research has sought to classify T2D patients to improve the prediction of complications but has not incorporated sex-specific pathophysiological characteristics. This knowledge gap is concerning, as evidence demonstrates that sex-specific mechanisms, partly driven by sex hormones, are instrumental in atherosclerosis, adiposity, inflammation, and endothelial dysfunction, underscoring sex-based differences in diabetic CVD. Women with T2D also face greater metabolic and reproductive challenges than men across the lifespan, which is implicated in women’s higher CVD risk. The phenotypic heterogeneities in T2D and CVD between men and women warrant the consideration of sex in predicting CVD risk. In this study, the candidate proposes to investigate the role of female sex in the deleterious influence of early-onset T2D on CVD using two intensively phenotyped longitudinal cohorts. The Specific Aims are to 1) quantify the cumulative burden of T2D on CVD risk in women compared to men and 2) identify sex-specific subgroups of individuals with T2D at high CVD risk. The candidate has generated impactful preliminary findings for this proposal through support from her two-year K12 award. The candidate has identified critical next steps in this line of research and training areas to complement her experience, including the pathophysiology of CVD and T2D, machine learning, health disparities research, and sophisticated epidemiological methods for bias reduction. The candidate has successfully leveraged a carefully coordinated set of resources, including a strong mentor team and applied learning activities closely aligned with her training objectives and Specific Aims. This COBRE Research Project and training is essential to advance the candidate’s career objective of becoming an independent, externally-funded investigator specializing in sex-based precision epidemiology in cardiometabolic health.