Developing a predictive risk score for pre-diabetes in youth.

PROJECT SUMMARY The prevalence of impaired glucose tolerance (IGT) and youth onset type 2 diabetes (YT2D) is increasing. IGT in adolescence is an indicator of increased risk for YT2D. Compared to adults, YT2D is associated with high therapeutic failure rates, decreased response to insulin sensitizers, and rapid progression to diabetes-related complications which suggests a more severe disease process in children. Therefore, identifying children at risk for developing IGT/YT2D and intervening prior to disease onset is critical. Offspring of mothers with hyperglycemia in pregnancy have a greater risk of developing obesity, insulin resistance, and type 2 diabetes. Therefore, utilizing family history, maternal clinical factors, and newborn labs could be helpful in developing a predictive risk score for childhood IGT/YT2D. Epigenetic changes in offspring cord blood may be associated with metabolic changes in early childhood. In this innovative study we hypothesize that using offspring cord blood methylation (cbDNAm) will improve the precision of a predictive risk score. To explore this hypothesis, I will use the well-characterized cohort of mother-offspring pairs from the large, multiethnic Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO) and its Follow-Up Study (HAPO FUS). Our aims are to 1) develop an early predictive risk score utilizing clinical factors known at birth, 2) refine the early life predictive risk score using cord blood biomarkers (c-peptide and methylation) and 3) recruit youth with IGT to phenotype and follow longitudinally to characterize those that progress to YT2D. Analyses will use the following statistical approaches: multiple logistic regression, least absolute shrinkage and selection operator (LASSO) regression. Conducting this study will directly address my career development goals to 1) Gain expertise in YT2D risk factors and epigenetic associations; 2) Develop skills in innovative statistical methods and approaches to disease prediction modeling; 3) Develop clinical research skills and a cohort of children with IGT to study longitudinally that will aid me in succeeding as an independent investigator. This study is the first step in identifying early markers of youth at risk for T2D with the goal of evaluating other biomarkers, such as hormones and genetics, to ultimately propose an R01 to refine and validate the predictive risk score. I will thus achieve my career goal to identify those at risk for developing YT2D and will then be able to focus on preventive interventions to decrease morbidity and mortality.