Effects Among the Affected

Many interventions are both beneficial to initiate and harmful to stop. Traditionally, to determine whether to deploy that intervention in a timelimited way depends on if, on average, the increase in the benefits of starting it outweigh the increase in the harms of stopping it. We propose a novel causal estimand that provides a more nuanced understanding of the effects of such treatments, particularly, how response to an earlier treatment (e.g., treatment initiation) modifies the effect of a later treatment (e.g., treatment discontinuation), thus learning if there are effects among the (un)affected. Specifically, we consider a marginal structural working model summarizing how the average effect of a later treatment varies as a function of the (estimated) conditional average effect of an earlier treatment. We allow for estimation of this conditional average treatment effect using machine learning, such that the causal estimand is a data-adaptive parameter. We show how a sequentially randomized design can be used to identify this causal estimand, and we describe a targeted maximum likelihood estimator for the resulting statistical estimand, with influence curve-based inference. Throughout, we use the “Adaptive Strategies for Preventing and Treating Lapses of Retention in HIV Care” trial (NCT02338739) as an illustrative example, showing that discontinuation of conditional cash transfers for HIV care adherence was most harmful among those who most had an increase in benefits from them initially.