Deep determinism and the assessment of mechanistic interaction between categorical and continuous variables

Our aim is to detect mechanistic interaction between the effects of two causal factors on a binary response, as an aid to identifying situations where the effects are mediated by a common mechanism. We propose a formalization of mechanistic interaction which acknowledges asymmetries of the kind "factor A interferes with factor B, but not viceversa". A class of tests for mechanistic interaction is proposed, which works on discrete or continuous causal variables, in any combination. Conditions under which these tests can be applied under a generic regime of data collection, be it interventional or observational, are discussed in terms of conditional independence assumptions within the framework of Augmented Directed Graphs. The scientific relevance of the method and the practicality of the graphical framework are illustrated with the aid of two studies in coronary artery disease. Our analysis relies on the "deep determinism" assumption that there exists some relevant set V - possibly unobserved - of "context variables", such that the response Y is a deterministic function of the values of V and of the causal factors of interest. Caveats regarding this assumption in real studies are discussed.Comment: 20 pages including the four figures, plus two tables. Submitted to "Biostatistics" on November 24, 201

Integrated multiple mediation analysis: A robustness–specificity trade-off in causal structure

Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two-way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path-specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when cross-world exchangeability is invalid. Consequently, this study yields a robustness–specificity trade-off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer data set from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality

Natural direct and indirect effects on the exposed : effect decomposition under weaker assumptions

We define natural direct and indirect effects on the exposed. We show that these allow for effect decomposition under weaker identification conditions than population natural direct and indirect effects. When no confounders of the mediator-outcome association are affected by the exposure, identification is possible under essentially the same conditions as for controlled direct effects. Otherwise, identification is still possible with additional knowledge on a nonidentifiable selection-bias function which measures the dependence of the mediator effect on the observed exposure within confounder levels, and which evaluates to zero in a large class of realistic data-generating mechanisms. We argue that natural direct and indirect effects on the exposed are of intrinsic interest in various applications. We moreover show that they coincide with the corresponding population natural direct and indirect effects when the exposure is randomly assigned. In such settings, our results are thus also of relevance for assessing population natural direct and indirect effects in the presence of exposure-induced mediator-outcome confounding, which existing methodology has not been able to address

Sharp sensitivity bounds for mediation under unmeasured mediator-outcome confounding

It is often of interest to decompose a total effect of an exposure into the component that acts on the outcome through some mediator and the component that acts independently through other pathways. Said another way, we are interested in the direct and indirect effects of the exposure on the outcome. Even if the exposure is randomly assigned, it is often infeasible to randomize the mediator, leaving the mediator-outcome confounding not fully controlled. We develop a sensitivity analysis technique that can bound the direct and indirect effects without parametric assumptions about the unmeasured mediator-outcome confounding

Sensitivity Analysis for Unmeasured Confounding in Meta-Analyses

Random-effects meta-analyses of observational studies can produce biased estimates if the synthesized studies are subject to unmeasured confounding. We propose sensitivity analyses quantifying the extent to which unmeasured confounding of specified magnitude could reduce to below a certain threshold the proportion of true effect sizes that are scientifically meaningful. We also develop converse methods to estimate the strength of confounding capable of reducing the proportion of scientifically meaningful true effects to below a chosen threshold. These methods apply when a "bias factor" is assumed to be normally distributed across studies or is assessed across a range of fixed values. Our estimators are derived using recently proposed sharp bounds on confounding bias within a single study that do not make assumptions regarding the unmeasured confounders themselves or the functional form of their relationships to the exposure and outcome of interest. We provide an R package, ConfoundedMeta, and a freely available online graphical user interface that compute point estimates and inference and produce plots for conducting such sensitivity analyses. These methods facilitate principled use of random-effects meta-analyses of observational studies to assess the strength of causal evidence for a hypothesis