Genetic Risk Underlying Pediatric Critical Illness

Project Summary/Abstract Children rarely become critically ill. I hypothesize that genetic risk contributes to unexpected pediatric critical illness. Identifying risk groups allows for clinical stratification and targeted therapies, but these benefits can only be realized if risk is known. This proposal will uncover the monogenic (i.e., single gene), polygenic (i.e., many genes), and pharmacogenomic (i.e., genetic effect on drug response) risks contributing to pediatric critical illness. In Aim 1, I apply innovative gene-network discovery methods to uncover monogenic risk for viral respiratory failure, the most common cause of pediatric intensive care unit admission. In Aim 2, I will assess the contribution of polygenic risk to common pediatric intensive care unit morbidities (viral respiratory failure, venous thromboembolism, acute kidney injury). In Aim 3, I will assess pharmacogenomic risk detected by exome and genome sequencing. This K08 will uncover genetic risk in critically ill children which will inform future multi-center genetic association studies and clinical trials to improve care in the pediatric intensive care unit. Candidate: Scientifically, I have a PhD in neuroscience and completed a post-doctoral fellowship in human genetics. Clinically, I am an attending physician in pediatric critical care medicine. There is a need for physician-scientists who can identify unusual disease presentations and uncover novel genetic risk. There is limited application of precision medicine in the pediatric intensive care unit, and I am well positioned to identify opportunities and investigate applications. My goal is to develop an independent research program focused on “the genomics of pediatric critical illness”. During the K08 training period, I will: (1) Refine expertise in gene network discovery, (2) Develop expertise in the novel application of polygenic risk scores to children with critical illness, (3) Develop expertise in pharmacogenomic analysis of exomes and genomes, (4) Become proficient in the Ethical, Legal, and Social Implications (ELSI) of genomics, and (5) Transition to independence. Environment: To guide and support my research and training goals, I have assembled a strong mentorship team of experts in genetics and medicine (Dr Gharavi, Mentor and Dr. Chung, Advisor), polygenic risk scores (Dr. Kiryluk, Advisor), pharmacogenomics (Dr. Jobanputra, Advisor and Dr. Chung, Advisor), statistical genetics (Dr. Ionita-Laza, Advisor), allergy and inborn errors of immunity (Dr. Orange, Advisor), renal genetics (Dr. Gharavi, Mentor and Dr. Kiryluk, Advisor), and Equity and ELSI research (Dr. Sabatello, Advisor). The research will be conducted at Columbia University Irving Medical Center, which will give me access to extensive resources and training to help me successfully transition to independence.