Bayesian Sparse Mediation Analysis with Targeted Penalization of Natural Indirect Effects
Yanyi Song, Xiang Zhou, Jian Kang, Max T. Aung, Min Zhang, Wei Zhao, Belinda L. Needham, Sharon L. R. Kardia, Yongmei Liu, John D. Meeker, Jennifer A. Smith, Bhramar Mukherjee
Causal mediation analysis aims to characterize an exposure's effect on an outcome and quantify the indirect effect that acts through a given mediator or a group of mediators of interest. With the increasing availability of measurements on a large number of potential mediators, like the epigenome or the microbiome, new statistical methods are needed to simultaneously accommodate high-dimensional mediators while directly target penalization of the natural indirect effect (NIE) for active mediator identification. Here, we develop two novel prior models for identification of active mediators in high-dimensional mediation analysis through penalizing NIEs in a Bayesian paradigm. Both methods specify a joint prior distribution on the exposure-mediator effect and mediator-outcome effect with either (a) a four-component Gaussian mixture prior or (b) a product threshold Gaussian prior. By jointly modeling the two parameters that contribute to the NIE, the proposed methods enable penalization on their product in a targeted way. Resultant inference can take into account the four-component composite structure underlying the NIE. We show through simulations that the proposed methods improve both selection and estimation accuracy compared to other competing methods. We applied our methods for an in-depth analysis of two ongoing epidemiologic studies: the Multi-Ethnic Study of Atherosclerosis (MESA) and the LIFECODES birth cohort. The identified active mediators in both studies reveal important biological pathways for understanding disease mechanisms.
Causal mediation analysis is widely utilized to separate the causal effect of treatment into its direct effect on the outcome and its indirect effect through an intermediate variable (the mediator). In this study we introduce a functional mediation analysis framework in which the three key variables, the treatment, mediator, and outcome, are all continuous functions. With functional measures, causal assumptions and interpretations are not immediately well-defined. Motivated by a functional magnetic resonance imaging (fMRI) study, we propose two functional mediation models based on the influenc…
Traditional mediation analysis typically examines the relations among an intervention, a time-invariant mediator, and a time-invariant outcome variable. Although there may be a direct effect of the intervention on the outcome, there is a need to understand the process by which the intervention affects the outcome (i.e. the indirect effect through the mediator). This indirect effect is frequently assumed to be time-invariant. With improvements in data collection technology, it is possible to obtain repeated assessments over time resulting in intensive longitudinal data. This calls for an extens…
Causal mediation analysis is used to evaluate direct and indirect causal effects of a treatment on an outcome of interest through an intermediate variable or a mediator.It is difficult to identify the direct and indirect causal effects because the mediator cannot be randomly assigned in many real applications. In this article, we consider a causal model including latent confounders between the mediator and the outcome. We present sufficient conditions for identifying the direct and indirect effects and propose an approach for estimating them. The performance of the proposed approach is evaluat…
Determining the extent to which a patient is benefiting from cancer therapy is challenging. Criteria for quantifying the extent of "tumor response" observed within a few cycles of treatment have been established for various types of solid as well as hematologic malignancies. These measures comprise the primary endpoints of phase II trials. Regulatory approvals of new cancer therapies, however, are usually contingent upon the demonstration of superior overall survival with randomized evidence acquired with a phase III trial comparing the novel therapy to an appropriate standard of care treatmen…
Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior pr…
Natural direct and indirect effects are mediational estimands that decompose the average treatment effect and describe how outcomes would be affected by contrasting levels of a treatment through changes induced in mediator values (in the case of the indirect effect) or not through induced changes in the mediator values (in the case of the direct effect). Natural direct and indirect effects are not generally point-identifiable in the presence of a treatment-induced confounder, however they may still be identified if one is willing to assume monotonicity between a treatment and the treatment-ind…
Mediation analysis seeks to understand the mechanism by which a treatment affects an outcome. Count or zero-inflated count outcome are common in many studies in which mediation analysis is of interest. For example, in dental studies, outcomes such as decayed, missing and filled teeth are typically zero inflated. Existing mediation analysis approaches for count data assume sequential ignorability of the mediator. This is often not plausible because the mediator is not randomized so that there are unmeasured confounders associated with the mediator and the outcome. In this paper, we develop caus…
The synthetic control method (SCM) allows estimating the causal effect of an intervention in settings where panel data on a small number of treated and control units are available. We show that the existing SCM, as well as its extensions, can be easily modified to estimate how much of the ``total'' effect goes through observed causal channels. Our new mediation analysis synthetic control (MASC) method requires additional assumptions that are arguably mild in many settings. We illustrate the implementation of MASC in an empirical application estimating the direct and indirect effects of an anti…
Causally Interpretable Meta-Mediation Analysis With Missing At Random Mediator and Outcome Data
EPILOGY, Institut Mondor of Biomedical Research, INSERM U955（INSERM U955 蒙多尔生物医学研究所 EPILOGY）；Université Paris-Est Créteil（巴黎东克雷泰伊大学）；Mines Paris, Université Paris Sciences Lettres（巴黎矿业学院，巴黎文理研究大学）；Department of Mathematics, Université du Québec à Montréal（蒙特利尔大学数学系）
E-commerce companies have a number of online products, such as organic search, sponsored search, and recommendation modules, to fulfill customer needs. Although each of these products provides a unique opportunity for users to interact with a portion of the overall inventory, they are all similar channels for users and compete for limited time and monetary budgets of users. To optimize users' overall experiences on an E-commerce platform, instead of understanding and improving different products separately, it is important to gain insights into the evidence that a change in one product would i…
Physical activity has long been shown to be associated with biological and physiological performance and risk of diseases. It is of great interest to assess whether the effect of an exposure or intervention on an outcome is mediated through physical activity measured by modern wearable devices such as actigraphy. However, existing methods for mediation analysis focus almost exclusively on mediation variable that is in the Euclidean space, which cannot be applied directly to the actigraphy data of physical activity. Such data is best summarized in the form of an histogram or density. In this pa…
Causal mediation analysis can improve understanding of the mechanisms underlying epidemiologic associations. However, the utility of natural direct and indirect effect estimation has been limited by the assumption of no confounder of the mediator-outcome relationship that is affected by prior exposure---an assumption frequently violated in practice. We build on recent work that identified alternative estimands that do not require this assumption and propose a flexible and double robust semiparametric targeted minimum loss-based estimator for data-dependent stochastic direct and indirect effect…
Causal mediation analysis seeks to investigate how the treatment effect of an exposure on outcomes is mediated through intermediate variables. Although many applications involve longitudinal data, the existing methods are not directly applicable to settings where the mediator and outcome are measured on sparse and irregular time grids. We extend the existing causal mediation framework from a functional data analysis perspective, viewing the sparse and irregular longitudinal data as realizations of underlying smooth stochastic processes. We define causal estimands of direct and indirect effects…
We point out an instantiation of Simpson's paradox in Covid-19 case fatality rates (CFRs): comparing a large-scale study from China (17 Feb) with early reports from Italy (9 Mar), we find that CFRs are lower in Italy for every age group, but higher overall. This phenomenon is explained by a stark difference in case demographic between the two countries. Using this as a motivating example, we introduce basic concepts from mediation analysis and show how these can be used to quantify different direct and indirect effects when assuming a coarse-grained causal graph involving country, age, and cas…
The causal inference literature has increasingly recognized that explicitly targeting treatment effect heterogeneity can lead to improved scientific understanding and policy recommendations. Towards the same ends, studying the causal pathway connecting the treatment to the outcome can be also useful. This paper addresses these problems in the context of \emph{causal mediation analysis}. We introduce a varying coefficient model based on Bayesian additive regression trees to identify and regularize heterogeneous causal mediation effects; analogously with linear structural equation models, these …
Inverse Probability Weighting-based Mediation Analysis for Microbiome Data
The University of Texas at San Antonio（德克萨斯大学圣安东尼奥分校）；The University of Texas MD Anderson Cancer Center（德克萨斯大学安德森癌症中心）；BeOne Medicines（博生医药）；Texas A&M University（德克萨斯农工大学）；University of Toronto（多伦多大学）；Columbia University（哥伦比亚大学）
Disentangling Causal Mechanisms in Conjoint Experiments Using Mediation
College of Management, EPFL（EPFL管理学院）；Department of Government, University of Texas at Austin（德克萨斯大学奥斯汀分校政府系）；Department of Statistics, Rutgers University（罗格斯大学统计系）
A Bayesian semi-parametric approach to causal mediation for longitudinal mediators and time-to-event outcomes with application to a cardiovascular disease cohort study
In causal mediation studies that decompose an average treatment effect into a natural indirect effect (NIE) and a natural direct effect (NDE), examples of post-treatment confounding are abundant. Past research has generally considered it infeasible to adjust for a post-treatment confounder of the mediator-outcome relationship due to incomplete information: it is observed under the actual treatment condition while missing under the counterfactual treatment condition. This study proposes a new sensitivity analysis strategy for handling post-treatment confounding and incorporates it into weightin…
In animal behavior studies, a common goal is to investigate the causal pathways between an exposure and outcome, and a mediator that lies in between. Causal mediation analysis provides a principled approach for such studies. Although many applications involve longitudinal data, the existing causal mediation models are not directly applicable to settings where the mediators are measured on irregular time grids. In this paper, we propose a causal mediation model that accommodates longitudinal mediators on arbitrary time grids and survival outcomes simultaneously. We take a functional data analys…
There is a growing literature on finding so-called optimal treatment rules, which are rules by which to assign treatment to individuals based on an individual's characteristics, such that a desired outcome is maximized. A related goal entails identifying individuals who are predicted to have a harmful indirect effect (the effect of treatment on an outcome through mediators) even in the presence of an overall beneficial effect of the treatment on the outcome. In some cases, the likelihood of a harmful indirect effect may outweigh a likely beneficial overall effect, and would be reason to cautio…
