Test-Negative Designs with Multiple Testing Sources

Test-negative designs (TNDs), a form of case-cohort study, are widely used to evaluate infectious disease interventions, notably for influenza and, more recently, COVID-19 vaccines. TNDs rely on recruiting individuals who are tested for the disease of interest and comparing test-positive and test-negative individuals by exposure status (e.g., vaccination). Traditionally, TND studies focused on symptomatic individuals to minimize confounding from healthcare-seeking behavior. However, during outbreaks such as COVID-19 and Ebola, testing also occurred for asymptomatic individuals (e.g., through contact tracing), introducing potential bias when combining symptomatic and asymptomatic cases. Motivated by a trial evaluating an Ebola virus disease (EVD) vaccine, we study a specific version of this ``multiple reasons for testing" problem. In this setting, symptomatic individuals were tested under the standard TND approach, while asymptomatic close contacts of test-positive cases were also tested. We propose a simple method to estimate the common vaccine efficacy across these groups and assess whether efficacy differs by recruitment pathway. Although the EVD trial ended early due to the cessation of the outbreak, the proposed methodology remains relevant for future vaccine trials with similar designs.