Genetic, Metabolic, and Sociodemographic Factors Underpinning Pediatric Cardiac Arrest: Developing Mechanistic Drivers and Integrative Frameworks - PROJECT SUMMARY/ABSTRACT Affecting >20,000 children annually in the United States, pediatric out-of-hospital cardiac arrest is fatal in >90% of cases, often occurring in children who otherwise healthy. While existing research focuses on single gene causes, linking cardiac arrest to cardiac channelopathies, neuro-epileptic, developmental, and metabolic abnormalities, its diagnostic yield remains low, suggesting some causes may be oligogenic. Additionally, sociodemographic, environmental, and clinical (non-genetic) factors may contribute to risk, yet it remains unclear: how 1) how genetics interact with environmental and social factors to increase cardiac arrest risk, 2) whether abnormal metabolism underlies race- or community-based differences in incidence, and 3) the relative contributions of genetic, metabolic, and sociodemographic factors to overall cardiac arrest risk. Expanding on our prior population-based research evaluating >900 children with cardiac arrest, we will first evaluate oligogenic patterns observed in a large cohort of children with cardiac arrest, examining variants in genes associated with metabolic, cardiac, and neurodevelopmental function (Aim 1). To additionally investigate biomarkers detectable in early life, we will then assess the association between newborn metabolic screening results and cardiac arrest risk in early life (Aim 2). Finally, we will generate a comprehensive risk model of pediatric cardiac arrest, simultaneously integrating genetic, metabolic, and community-based data (Aim 3). Using one of the most comprehensive data repositories available, this research aims to clarify the multifactorial drivers of pediatric out-of-hospital cardiac arrest and inform targeted public health interventions to generate more robust pre-arrest screening mechanisms and improve post- arrest outcomes. With this research, my objective is to characterize the multifactorial etiology of pediatric cardiac arrest to better identify effective screening and public health interventions aimed at reducing its incidence and mortality in at-risk children. Using structured mentorship, formal training in bioinformatics and genetic epidemiology, and ongoing collaborations with the proposed multidisciplinary panel of experts, the proposed research will allow me to further cultivate my expertise as a pediatric epidemiologist, positioning me to become an independent investigator with my own unique expertise in pediatric public health, cardiac arrest, and genetic epidemiology.
