Mediation effects that emulate a target randomised trial: Simulation-based evaluation of ill-defined interventions on multiple mediators

Abstract

Many epidemiological questions concern potential interventions to alter the pathways presumed to mediate an association. For example, we consider a study that investigates the benefit of interventions in young adulthood for ameliorating the poorer mid-life psychosocial outcomes of adolescent self-harmers relative to their healthy peers. Two methodological challenges arise. First, mediation methods have hitherto mostly focused on the elusive task of discovering pathways, rather than on the evaluation of mediator interventions. Second, the complexity of such questions is invariably such that there are no well-defined mediator interventions (i.e. actual treatments, programs, etc.) for which data exist on the relevant populations, outcomes and time-spans of interest. Instead, researchers must rely on exposure (non-intervention) data, that is, on mediator measures such as depression symptoms for which the actual interventions that one might implement to alter them are not well defined. We propose a novel framework that addresses these challenges by defining mediation effects that map to a target trial of hypothetical interventions targeting multiple mediators for which we simulate the effects. Specifically, we specify a target trial addressing three policy-relevant questions, regarding the impacts of hypothetical interventions that would shift the mediators’ distributions (separately under various interdependence assumptions, jointly or sequentially) to user-specified distributions that can be emulated with the observed data. We then define novel interventional effects that map to this trial, simulating shifts by setting mediators to random draws from those distributions. We show that estimation using a g-computation method is possible under an expanded set of causal assumptions relative to inference with well-defined interventions, which reflects the lower level of evidence that is expected with ill-defined interventions. Application to the self-harm example in the Victorian Adolescent Health Cohort Study illustrates the value of our proposal for informing the design and evaluation of actual interventions in the future.

Preventing postnatal depression: a causal mediation analysis of a 20-year preconception cohort

“…Our conceptual model included diverse potential preconception confounders (C), based on prior evidence, to maximize the plausibility of exchangeability assumptions [42,43]. We also considered potential periconceptional and pregnancy confounders (L) of the associations between antenatal factors and PND symptoms.…”

“…We extended a recent method for causal mediation with multiple interdependent mediators that extends previous approaches [44,45] to emulate the effects that would be obtained in a hypothetical randomized trial with interventions both on the exposure and each of a set of interdependent mediators [42].…”

Spry_Preventing postpartum depression_Preprint

“…Our conceptual model included diverse potential preconception confounders (C), based on prior evidence, to maximise plausibility of exchangeability assumptions [40,41]. We also considered potential periconceptional and pregnancy confounders (L) of the associations between antenatal factors and PND symptoms.…”

“…We then estimated the potential reduction in PND symptoms in women with prior mental health problems achievable by intervention on antenatal overall social support versus other putative antenatal mediators, and on friend/family versus partner support. We extended a recent method for causal mediation with multiple interdependent mediators that extends previous approaches [42,43] to emulate the effects that would be obtained in a hypothetical randomized trial with interventions both on the exposure and each of a set of interdependent mediators [40]. For this question, we took two approaches.…”

Adiposity and breast, endometrial, and colorectal cancer risk in postmenopausal women: Quantification of the mediating effects of leptin, C‐reactive protein, fasting insulin, and estradiol

“…More importantly, extensions of this framework allow assessment of mediation in settings with multiple dependent mediators 19 . Here, we performed causal mediation analysis using a simulation‐based, regression‐standardization mediation analysis approach 20–22 that permitted us to take the dependencies between biomarkers into account and to quantify the so‐called “interventional indirect (mediating) effects” of CRP/leptin, fasting insulin, and estradiol in explaining the effect of adiposity on ER‐positive breast, endometrial, and colorectal cancers in postmenopausal women.…”