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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.

SUBMITTER: Moreno-Betancur M

PROVIDER: S-EPMC8371283 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMapping expression quantitative trait loci (eQTLs) has provided insight into gene regulation. Compared to cis-eQTLs, the regulatory mechanisms of trans-eQTLs are less known. Previous studies suggest that trans-eQTLs may regulate expression of remote genes by altering the expression of nearby genes. Trans-association has been studied in the mediation analysis with a single mediator. However, prior applications with one mediator are prone to model misspecification due to correlations between genes. Motivated from the observation that trans-eQTLs are more likely to associate with more than one cis-gene than randomly selected SNPs in the GTEx dataset, we developed a computational method to identify trans-eQTLs that are mediated by multiple mediators.ResultsWe proposed two hypothesis tests for testing the total mediation effect (TME) and the component-wise mediation effects (CME), respectively. We demonstrated in simulation studies that the type I error rates were controlled in both tests despite model misspecification. The TME test was more powerful than the CME test when the two mediation effects are in the same direction, while the CME test was more powerful than the TME test when the two mediation effects are in opposite direction. Multiple mediator analysis had increased power to detect mediated trans-eQTLs, especially in large samples. In the HapMap3 data, we identified 11 mediated trans-eQTLs that were not detected by the single mediator analysis in the combined samples of African populations. Moreover, the mediated trans-eQTLs in the HapMap3 samples are more likely to be trait-associated SNPs. In terms of computation, although there is no limit in the number of mediators in our model, analysis takes more time when adding additional mediators. In the analysis of the HapMap3 samples, we included at most 5 cis-gene mediators. Majority of the trios we considered have one or two mediators.ConclusionsTrans-eQTLs are more likely to associate with multiple cis-genes than randomly selected SNPs. Mediation analysis with multiple mediators improves power of identification of mediated trans-eQTLs, especially in large samples.

Project description:BACKGROUND:The World Health Organization recommends that nations implement evidence-based nutritional guidelines and policies in settings such as schools and childcare services to improve public health nutrition. Understanding the causal mechanism by which implementation strategies exert their effects could enhance guideline implementation. The aim of this study was to assess the mechanisms by which implementation strategies improved schools and childcare services' adherence to nutrition guidelines. METHODS:We conducted a mechanism evaluation of an aggregated dataset generated from three randomised controlled trials conducted in schools and childcare services in New South Wales, Australia. Each trial examined the impact of implementation strategies that targeted Theoretical Domains Framework constructs including knowledge, skills, professional role and identity, environmental context and resources. We pooled aggregated organisation level data from each trial, including quantitative assessments of the Theoretical Domains Framework constructs, as well as measures of school or childcare nutrition guideline compliance, the primary implementation outcome. We used causal mediation analysis to estimate the average indirect and direct effects of the implementation strategies and assessed the robustness of our findings to varying levels of unmeasured and unknown confounding. RESULTS:We included 121 schools or childcare services in the pooled analysis: 79 allocated to receive guideline and policy implementation strategies and 42 to usual practice. Overall, the interventions improved compliance (odds ratio = 6.64; 95% CI [2.58 to 19.09]); however, the intervention effect was not mediated by any of the four targeted Theoretical Domains Framework constructs (average causal mediation effects through knowledge = - 0.00 [- 0.05 to 0.04], skills = 0.01 [- 0.02 to 0.07], professional role and identity = 0.00 [- 0.03 to 0.03] and environmental context and resources = 0.00 [- 0.02 to 0.06]). The intervention had no significant effect on the four targeted Theoretical Domains Framework constructs, and the constructs were not associated with school or childcare nutrition guideline compliance. Potentially, this lack of effect could be explained by imprecise measurement of the mediators. Alternatively, it is likely that that the interventions were operating via alternative mechanisms that were not captured by the four Theoretical Domains Framework constructs we explored. CONCLUSIONS:Even though public health implementation strategies led to meaningful improvements in school or childcare nutrition guideline compliance, these effects were not mediated by key targeted constructs of the Theoretical Domains Framework. Future research should explore the mechanistic role of other Theoretical Domains Framework constructs and evaluate system-level mechanisms informed by an ecological framework. TRIAL REGISTRATION:All trials were prospectively registered with the Australian New Zealand Clinical Trials Registry ( ACTRN12613000543785 . Registered 15/05/2013; ACTRN12614001148662 . Registered 30/10/2014; ACTRN12615001032549 . Registered 1/10/2015).

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

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