PROJECT SUMMARY This application is for a K01 award for Karen Jacobson, M.D., M.P.H., an Assistant in Medicine in the Division of Infectious Diseases at the Massachusetts General Hospital, who is training to become an independent investigator in the epidemiology of drug resistant tuberculosis (TB). TB continues to be a major cause of mortality globally. The current approach to decreasing TB incidence, early detection and treatment, is being compromised by the emergence of drug resistant strains. In order to improve treatment outcomes, it is first necessary to identify where drug resistant cases occur disproportionately and what factors characterize these spatial clusters. The proposed study will use innovative methods in spatial statistics and molecular epidemiology to identify drug resistant TB "hotspots" to advance understanding of where disease transmission and heath care delivery failure are occurring. The aims of the study are: 1) To estimate the burden of drug resistant TB in the Western Cape Province, South Africa, and assess the heterogeneity of disease burden in different geographic locations; 2) To examine the association of host risk factors and population determinants with regions of high drug resistant TB burden; and 3) To describe the spatial and molecular clustering of strains of drug resistant TB in this province. Dr. Jacobson's mentoring team will consist of two primary mentors, one in the U.S. and one in South Africa: Megan Murray, M.D., Sc.D., Associate Professor of Epidemiology at the Harvard School of Public Health (HSPH), who conducts research on the molecular and social epidemiology of TB, and Robin Warren, Ph.D., Associate Professor in the Division of Molecular Biology and Human Genetics at Stellenbosch University, a molecular biologist who has studied TB genetics and disease dynamics in TB epidemic communities. Dr. Jacobson's three co-mentors will be Marcia Castro, Ph.D., an Assistant Professor of Demography at HSPH, who has used spatial methods to study infectious disease dynamics; Ted Cohen, M.D., Dr.P.H., an Assistant Professor of Epidemiology at HSPH whose research focuses on TB transmission dynamics; and Thomas Victor, Ph.D., an Associate Professor in the Division of Molecular Biology and Human Genetics at Stellenbosch University, who has studied the drug resistant TB molecular biology for the past 20 years. Dr. Jacobson has developed a training plan in three areas that link to her research aims: spatial statistics, survey and census data analysis, and molecular epidemiologic techniques, and she will take courses and receive mentoring in each of these areas. The training and mentoring she will receive during the implementation of this project will provide Dr. Jacobson with the necessary skills and preliminary data to prepare an R01 grant application to study the modifiable factors identified in the proposed study, with the goal of developing interventions aimed at decreasing drug resistant TB burden in the region and globally.

PROJECT NARRATIVE Public Health Relevance: Tuberculosis (TB) continues to be a major cause of global mortality despite available therapies and DOTS (directly observed treatment, short course) strategy implementation, due, in part, to the emergence of drug resistant strains of the disease. The proposed research will use innovative spatial statistical and molecular epidemiologic techniques to identify regions of the Western Cape Province of South Africa with high drug resistant TB burden and will then investigate the social determinants and host risk factors associated with these regions. Improved understanding of the dynamics underlying transmission of this disease and the potentially modifiable sociodemographic factors associated with TB drug resistance will enable the development of improved interventions that can be applied both locally and globally.