PROJECT SUMMARY Although largely a curable disease, tuberculosis (TB) remains the leading cause of death in South Africa and the leading single-agent infectious cause of death globally. Nevertheless, over one-third of people with TB – an estimated 3.6 million people worldwide – are never notified to health authorities. The demographic group at greatest risk for TB and also responsible for the majority of TB transmission consists of working-age adults (especially men). These individuals are often highly mobile, making it difficult to engage them with traditional TB case-finding activities such as screening at healthcare facilities or household contact investigation during business hours. Their patterns of movement, however, are highly regularized throughout sub-Saharan Africa and the rest of the world: young adults migrate to cities for work and travel home to rural homelands to visit families during the holidays. These predictable patterns of movement create an opportunity for innovative interventions to engage this high-risk, mobile population that bears a tremendous burden of undiagnosed TB and continues to fuel transmission in many communities. Specifically, mobile young adults can be found at their urban homes during non-working hours (on evenings and weekends) and visiting their families in rural settings during holiday times. Although most TB transmission occurs outside of households, household members of individuals diagnosed with TB remain the highest-risk population that can be identified, outside of congregate living settings (e.g., prisons). There is therefore no better place to look for the “missing 3.6 million” TB cases than in these households. We propose a randomized trial of two novel TB case-finding interventions among household members of patients diagnosed with active TB: holiday-based screening in a rural South African province (Limpopo) and off-peak (weekend/evening) screening in an urban settlement into which many residents of Limpopo migrate for work. We will enroll 2400 index cases of TB plus an estimated 4800 household contacts in each setting (7200 participants per setting, 14400 participants overall) and randomize them to novel versus standard contact investigation. In Specific Aim 1, we will use whole genome sequencing of all cases, overlaying transmission trees with data on human movement, to evaluate associations between mobility and TB transmission in this population. In Specific Aim 2, we will employ a multidisciplinary approach to compare novel versus standard contact investigation in each setting along the following dimensions: (a) effectiveness (number of secondary TB cases diagnosed and starting treatment); (b) implementation (reach, fidelity, and maintenance of contact investigation outside of business hours); (c) cost-effectiveness (cost per disability-adjusted life year) and budget impact; and (d) projected population-level impact on TB incidence. Successful completion of these aims will have long-term impac...