PROJECT SUMMARY Lung function measurements are routinely compared to racial/ethnic norms, biasing interpretation and perpetuating asthma disparities. The race/ethnicity-based lung function reference equations used to calculate these norms do not account for genetic ancestry—the genetic origin of one’s population, which can explain over 15% of lung function variation within a racial/ethnic group. Consequently, race/ethnicity-based equations misestimate lung function, often resulting in delayed disease detection and inadequate treatment, especially among populations disproportionately affected by asthma. Dr. Witonsky (candidate) derived equations that use genetic ancestry instead of race/ethnicity to more accurately predict lung function. While genetic ancestry- informed equations appear to remove racial/ethnic bias from lung function measurement, establishing their clinical utility and equity requires evidence that they better predict asthma-related outcomes. In addition, further research is needed to disentangle the social and genetic determinants of genetic ancestry differences in lung function. The proposed mentored research will address these knowledge gaps using data from existing and new cohorts of Black and Hispanic/Latino individuals with and without asthma via three specific aims: (1) to evaluate genetic ancestry-informed, race/ethnicity-based, and “one size fits all” lung function equations for predicting asthma-related outcomes, (2) to quantify the proportion of genetic ancestry differences in lung function that is explained by social exposures, and (3) to quantify the proportion of genetic ancestry differences in lung function that is explained by known lung function-associated genetic loci. In support of this research and Dr. Witonsky’s goal of becoming an independent clinical investigator, this K23 proposal includes formal training with experts in the areas of asthma translational and clinical research (Dr. Prescott Woodruff, primary mentor); advanced statistical and predictive analytic methods (Dr. Stephen Shiboski, co-mentor); social epidemiology and health disparities research (Dr. Luísa Borrell, co-mentor); genetic epidemiology (Dr. Elad Ziv, co-mentor); and statistical genetics (Dr. Noah Zaitlen, advisor). In addition, professional development planning will involve structured meetings with Dr. Woodruff and a leader within Dr. Witonsky’s Division of Pediatric Allergy, Immunology, and Bone Marrow Transplant (Dr. Morna Dorsey, advisor). As a faculty member in the Department of Pediatrics at the University of California, San Francisco, Dr. Witonsky will have access to world-class biomedical and research facilities, workshops and seminars, and an NCATS-funded K Scholars Program. Completion of the proposed research and career development activities in this application will inform the development of an R01 proposal and enable Dr. Witonsky to develop an innovative research program applying computational precision health methods that int...