Leveraging within-host M. tuberculosis diversity data to enhance transmission inference

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Project Summary This application to the K01 Career Development Award is to support Dr. Katharine Walter in her training and research into new methods for tuberculosis genomic epidemiology. Dr. Walter’s research focuses on developing and applying tools to harness pathogen variation to characterize infectious disease transmission and evolution in order to interrupt transmission in high-incidence, resource-poor settings. Dr. Walter’s research proposal leverages within-host Mycobacterium tuberculosis genomic variation to reconstruct tuberculosis transmission chains. Genomic epidemiology studies are increasingly used to characterize tuberculosis transmission. However, current approaches have limited resolution because they sequence a single M. tuberculosis genome from each infected individual. Despite the epidemiological and clinical significance of within-host M. tuberculosis diversity, tools to consistently and accurately recover such diversity and to incorporate this information into transmission inferences are lacking. This research proposal aims to (1) systematically assess methods for recovering within-host diversity from sputum samples collected during active screening in a high-incidence setting, (2) measure the M. tuberculosis diversity that is transmitted and persists in a secondary infection, and (3) develop a model to infer transmission linkages using within-host M. tuberculosis diversity data. The proposed project will leverage and expand upon the primary mentor’s NIH- funded R01 studies (AI130058, AI149620; PI: Andrews). In a five-year training plan, Dr. Walter will acquire skills in (1) statistical analysis and visualization of genomic data, (2) mathematical modeling of evolution and transmission, and (3) writing open and reproducible bioinformatic workflows for genomic data. Dr. Walter will be mentored by Dr. Jason Andrews, Associate Professor of Medicine at Stanford School of Medicine, a global expert in the diagnosis, treatment and control of tuberculosis in resource-limited settings. She will be co- mentored by Dr. Theodore Cohen, Associate Professor of Epidemiology of Microbial Diseases at the Yale School of Public Health, whose research pioneered the study of mixed strain infections in M. tuberculosis. In addition, Dr. Walter will collaborate closely with Dr. Julio Croda, an infectious disease physician-scientist and Professor at Federal University of Mato Grosso do Sul, Brazil, who has extensive experiencing leading prospective cohorts, genomic epidemiology studies, and clinical trials on tuberculosis and tropical diseases in Brazil. She will also collaborate with Dr. Caroline Colijn, Professor of Mathematics at Simon Fraser University, who has developed several statistical approaches for transmission inference. The results of this research and training proposal will provide the foundation for a future R01 application, which will develop an automated pipeline for real-time transmission inference and TB incidence estimation harnessing population-level, multi- year genomic surveillance data. This proposal will provide her the research, training, and professional development time to transition to an independent faculty position.