“All Generalizations Are Dangerous, Even This One.”—Alexandre Dumas
In public health and medicine, there is a tension between internal and external validity.1–12 Many interventions are known to be efficacious at the individual level, but less is known about (1) their impact once scaled to a population level, (2) effect modification by both measured and unmeasured factors, and (3) which intervention components should be implemented universally and which adapted to local context. The field of human immunodeficiency virus (HIV) prevention and treatment provides an illustrative example. Randomized trials and observational studies have shown that immediate initiation of antiretroviral therapy for an HIV-positive individual improves his or her health and prevents transmission between couples and from mothers to children.13–16 Four community randomized trials aim to examine the impact of “universal test and treat” (population-wide HIV testing with immediate antiretroviral therapy initiation for all HIV-positive persons) on HIV incidence in several countries in Eastern and Southern Africa.17–20 These trials are pragmatic in that they aim to learn about effectiveness and implementation in real-world conditions. Nonetheless, the specific components of their interventions, their implementation, and their impact are expected to vary within and across trials. Given promising interim results,21 open questions remain about nation-wide rollout and the heterogeneity in expected impact.