Advancing Sepsis Biology and Care Through the Power of Modern Biobanks

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY Sepsis is a leading cause of hospital admission and mortality worldwide, posing a significant economic burden. Despite extensive efforts and numerous clinical trials over the past 30 years, no approved drugs for sepsis exist, largely due to inadequate knowledge of the factors that contribute to sepsis clinical heterogeneity and a limited mechanistic understanding of sepsis biology. Human genomics studies can narrow this gap. However, previous large-scale human genomics studies of sepsis lack reproducibility, possibly due to poor phenotyping and lack of accounting for confounding non-genetic factors. They also failed to bring mechanistic understanding of the role of genetic factors in sepsis biology limiting their utility for advancing sepsis biology and care. The overarching goal of the current research program is to gain a holistic picture of the complex factors contributing to sepsis pathogenesis by determining how genetic factors work with clinical, behavioral, and social determinants of health to shape sepsis risk and outcomes and uncovering the biological mechanisms that connect genetic variants to sepsis risk. Modern biobanks are a powerful tool for achieving this goal by providing simultaneous access to patients’ genetic, clinical history, and sociodemographic data. In the next five years: I) We will leverage large and ancestrally diverse electronic health record (EHR)-linked biobanks to define sepsis case-control status based on rigorous clinical criteria, run genetic association tests, and discover novel sepsis risk variants. II) We will stratify cases and controls to no-, low-, or high-comorbidity strata and will repeat our genetic analyses accounting for clinical comorbidity. We will also leverage extensive behavioral and social determinants of health data in biobanks, to account for the potential confounding effect of these factors on sepsis outcomes. Finally, we will assess the interaction between genetic and clinical, behavioral, and social risk factors of sepsis to understand how they work together to shape disease risk. III) We will combine human genomics data with clinical laboratory measurements and molecular phenotypes data from sepsis patients to determine the effect of genetic variants on the regulation of physiological and molecular functions in sepsis and identify the mechanisms that connect variants to disease. Achieving these goals will lead to a better understanding of sepsis biology and could aid the identification of novel targets in a field in which existing approaches to drug development have yet to succeed. Additionally, my program will provide a much-needed framework for leveraging and combining the wealth of diverse data that is available through modern biobanks to advance human health. This program builds on my deep expertise in statistical and functional genomics and the resources and capabilities of my group. It is further supported through collaborations with experts in sepsis clinical care, phenotyping using EHRs, epidemiology, and functional genomics. Following this proposal, we will extend the clinical utility of our findings by investigating the genetics of drug response in sepsis and performing additional experiments to assess the potential of molecules or immunotherapies that target sepsis risk genes and pathways as novel therapies.