The primary importance of the research question: Implications for understanding natural versus controlled direct effects and the 'cross-world independence assumption'

Abstract: When developing new interventions to minimize the harmful effects of an exposure, investigators usually target the mechanisms that mediate the causal effect of the exposure on the outcome. Predicting the causal effect of these new interventions is generally done through identifying either (1) the controlled direct effect, or (2) the pure (natural) direct effect. In this opinion piece, we use the interventionist approach to discuss how these two approaches answer different questions, and the additional underlying assumptions of each compared to the other. We use a specific example for the development of a new intervention that might reduce the harmful effects of smoking on chronic obstructive pulmonary disease by removing the inhalation of harmful chemicals.