Project Summary / Abstract The incidence of Clostridium difficile infections (CDI) has increased substantially since 2000. CDIs result in an estimated 453,000 cases and 29,000 deaths each year in the United States alone and impart an estimated $ 4.8 billion in excess US healthcare expenditures on a potentially preventable healthcare-associated infection. Vulnerable populations of immunosuppressed patients with frequent contact with healthcare environments and high prevalence of antimicrobial use such as solid organ transplant (SOT) patients have extraordinarily high incidence rates of CDI, which results in excess mortality and graft loss post transplantation. Despite widely publicized infection prevention measures that have been successful in controlling hospital epidemics of C. difficile, the goal of zero incident hospital-acquired C. difficile infections has remained elusive, particularly in SOT patients. In my prior research, I have shown that CDI is frequently related to transmission from asymptomatic carriers of C. difficile, who outnumber patients with CDI within hospitals. The prevalence of asymptomatic colonization (AC) in SOT patients, the role of AC in CDI transmission to SOT patients, the long- term outcome of AC, and the origins of AC among SOT patients are all poorly understood. With their extremely high incidence rates of CDI, SOT patients are an ideal patient group to study the hypothesis that CDI results from widespread prevalence of AC related to frequent contact with healthcare environments rather than the alternative hypothesis that host susceptibility mediated by post-transplant immunosuppression and antibiotic exposures plays the greatest role in CDI in SOT patients. In this application, I propose a series of studies in C. difficile and hospital epidemiology that test the hypothesis that AC and CDI in SOT patients results principally from exposure to C. difficile-contaminated outpatient clinics, inpatient environments, and other SOT patients with AC. The present career development proposal seeks to extend my previous training and experience in infectious diseases epidemiology to include advanced cohort and survival analysis techniques as well as facility in analysis of whole genome sequencing data, which is fast becoming the new standard method in for the molecular epidemiology of C. difficile transmission, in order to complete my research aims in a prospective cohort of SOT patients.