PROJECT SUMMARY Background: South Africa is a unique, high-risk environment for the emergence of novel drug-resistant strains of Mycobacterium tuberculosis (Mtb). Novel drug-resistant Mtb strains are often identified only after they have achieved sustained transmission and dispersed into larger geographic areas away from their origin location. Strategies for early detection of drug-resistant Mtb strains, at the critical juncture between outbreak and epidemic, are lacking. Candidate: I am infectious disease physician and epidemiologist, with experience in genomic epidemiology, mathematical modeling, and field-level public health research and health service delivery. My research employs multiple data sources (including geolocated microbial genomic data and mobile phone-associated movement data) to understand how epidemics emerge and spread. The overarching objective of my work is to improve and innovate strategies for surveillance and containment of drug-resistant infections, focused on malaria and tuberculosis. Training: I am seeking career development support to pursue my long- term goal of becoming an independent NIH-funded physician scientist. To achieve my research and career goals, I will pursue additional training in Bayesian statistics, spatial population genetics, network science, and research management skills. Mentors and Environment: Dr. Caroline Buckee, a global leader in infectious disease epidemiology and mobility-informed infectious disease modeling, will oversee my research and training activities as primary mentor. Dr. Barun Mathema, a scientific expert in the tuberculosis genomic epidemiology and tuberculosis transmission, will provide focused scientific support as my co-mentors. Key collaborators on this project include Dr. Shaheed Vally Omar (surveillance for drug-resistant TB in South Africa), Dr. Ted Cohen (mathematical modeling and epidemiology of tuberculosis), Dr. Sheetal Silal (agent-based modeling of infectious disease dynamics), and Dr. Sarita Shah (TB surveillance and control). Dr. Marc Lipsitch, Dr. Yonatan Grad, Dr. Louise Ivers, Dr. Neil Schluger, and Dr. Frank Tanser will form a Scientific Advisory Board, who will provide annual feedback on my research and training activities. I will train and conduct research activities during the K08 award at the Harvard T.H. Chan School of Public Health Center for Communicable Disease Dynamics. Research: I will examine novel strategies for early detection of drug-resistant Mtb in South Africa through research activities under three specific aims: (1) Using geolocated Mtb genomic data to estimate likely origin locations and transmission hubs for multiple drug-resistant Mtb strains currently circulating in South Africa; (2) Developing an individual-based computational model of Mtb transmission in South Africa incorporating human mobility data and Mtb within-host evolution; (3) Evaluating multiple candidate surveillance strategies for early detection and containment of novel drug-r...