Project Summary Genomic medicine is a rapidly emerging medical discipline that incorporates the use of genomic information in patient care. Understanding an individual's genetic information holds the potential to improve diagnostic and therapeutic decision-making in clinical care, impact health outcomes and inform policy making. Yet the genomic datasets driving these decisions are often focused on populations of European descent. When these limited discoveries drive genomic medicine, understudied groups are frequently the last to benefit from advances in research, technology and clinical best practices. For true adoption, precision medicine needs to account for genomic diversity inherent to modern health systems. To address the importance of understanding disease risk in fine-scale populations present in modern health systems, and foster opportunities for advancement of genomic medicine in diverse populations, we have assembled a multi-ethnic cohort of over one million genotyped individuals from five international biobanks in health systems linked to electronic medical records. Leveraging this unique research cohort from our institutes, we will engineer fine-scale population detection and monitoring for population health powered by novel statistical and population genetics methods. These in turn can help us understand disease prevalence and refine our understanding of clinical variant pathogenicity. The systems we develop within hospitals will help characterize risk profiles for both rare (via Phenotype Scores) and common (via Polygenic Scores) traits, a necessary step to work in realistic, modern multi-ethnic hospital settings. These goals are implemented through three specific aims: Aim 1: Implement a monitoring system for differences in disease burden between fine-scale populations defined via identity-by-descent (IBD) inferred from genome-wide data across multiple biobanks. In so doing, we will apply a high-throughput, portable method to improve fine-scale ancestry and use it to improve disease and trait monitoring across multiple health systems. Aim 2: Improve our characterization of clinical variant pathogenicity, penetrance and expressivity via improved allele frequency examination through the fine-scale populations determined in Aim 1. Aim 3: Model risk via improved phenotype risk score (PheRS) for rare disease and polygenic risk score (PRS) for common traits across the fine-scale populations determined in Aim 1. We will develop improved trans- ethnic risk models and demonstrate their utility in improving our population-based understanding of disease outcomes. Our long-collaborating interdisciplinary team including clinical, statistical, and population geneticists has already produced preliminary data demonstrating not only a high likelihood of success, but also a desire and capacity to translate results into implemented changes in clinical care. This project will drive a new understanding of human disease, as well as opportunities for new health care interventions, particularly for currently understudied ethnic minority populations, thereby improving precision medicine for all.

Project Narrative This proposed project, entitled “Genomic Approaches to Population Health in Multi-Ethnic Hospital Systems,” is aimed at addressing fundamental roadblocks in delivering genomic medicine across diverse patient populations. We will leverage the unique opportunities provided by our assembly of a >1,000,000 person study with linked electronic health records available at our respective institutes. We will build novel systems to identify and define fine-scale populations, monitor for differences in disease burden, improve our inerpretation of clinical variant pathogenicity, and expand our understanding of risk scoring using both polygenic (PRS) and phenotypic (PheRS) approaches across the diversity of patients present in our health systems.