Although the exposure can be randomly assigned in studies of mediation effects, any form of direct intervention on the mediator is often infeasible. As a result, unmeasured mediator-outcome confounding can seldom be ruled out. We propose semiparametric identification of natural direct and indirect effects in the presence of unmeasured mediator-outcome confounding by leveraging heteroskedasticity restrictions on the observed data law. For inference, we develop semiparametric estimators that remain consistent under partial misspecifications of the observed data model. We illustrate the proposed estimators through both simulations and an application to evaluate the effect of self-efficacy on fatigue among health care workers during the COVID-19 outbreak.
Proximal Mediation Analysis with Unmeasured Treatment-Induced Confounding
Center for Applied Statistics and School of Statistics, Renmin University of China（中国人民大学统计学院与应用统计中心）；Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison（威斯康星大学麦迪逊分校生物统计与医学信息学系）
It is often of interest in the health and social sciences to investigate the joint mediation effects of multiple post-exposure mediating variables. Identification of such joint mediation effects generally require no unmeasured confounding of the outcome with respect to the whole set of mediators. As the number of mediators under consideration grows, this key assumption is likely to be violated as it is often infeasible to intervene on any of the mediators. In this paper, we develop a simple two-step method of moments estimation procedure to assess mediation with multiple mediators simultaneous…
Causal mediation analysis concerns the pathways through which a treatment affects an outcome. While most of the mediation literature focuses on settings with a single mediator, a flourishing line of research has examined settings involving multiple mediators, under which path-specific effects (PSEs) are often of interest. We consider estimation of PSEs when the treatment effect operates through K(\geq1) causally ordered, possibly multivariate mediators. In this setting, the PSEs for many causal paths are not nonparametrically identified, and we focus on a set of PSEs that are identified under …
Causal mediation in cluster-randomized trials with multiple mediators: spillover-aware decomposition, identification, and semiparametric efficient inference
Semiparametric Mediation Analysis with Separately Observed Mediator and Outcome under Unmeasured Confounding
Department of Biostatistics, University of California, Los Angeles（加州大学洛杉矶分校生物统计系）；Department of Biostatistics, Harvard T.H. Chan School of Public Health（哈佛大学陈曾熙公共卫生学院生物统计系）
The use of causal mediation analysis to evaluate the pathways by which an exposure affects an outcome is widespread in the social and biomedical sciences. Recent advances in this area have established formal conditions for identification and estimation of natural direct and indirect effects. However, these conditions typically involve stringent no unmeasured confounding assumptions and that the mediator has been measured without error. These assumptions may fail to hold in practice where mediation methods are often applied. The goal of this paper is two-fold. First, we show that the natural in…
Unmeasured confounding is a threat to causal inference in observational studies. In recent years, use of negative controls to mitigate unmeasured confounding has gained increasing recognition and popularity. Negative controls have a longstanding tradition in laboratory sciences and epidemiology to rule out non-causal explanations, although they have been used primarily for bias detection. Recently, Miao et al. (2018) have described sufficient conditions under which a pair of negative control exposure and outcome variables can be used to nonparametrically identify the average treatment effect (…
University of Hong Kong（香港大学）；Shanghai Jiao Tong University（上海交通大学）；Shanghai Artificial Intelligence Laboratory（上海人工智能实验室）；Columbia University（哥伦比亚大学）
Causal mediation analysis can unpack the black box of causality and is therefore a powerful tool for disentangling causal pathways in biomedical and social sciences, and also for evaluating machine learning fairness. To reduce bias for estimating Natural Direct and Indirect Effects in mediation analysis, we propose a new method called DeepMed that uses deep neural networks (DNNs) to cross-fit the infinite-dimensional nuisance functions in the efficient influence functions. We obtain novel theoretical results that our DeepMed method (1) can achieve semiparametric efficiency bound without imposi…
While estimation of the marginal (total) causal effect of a point exposure on an outcome is arguably the most common objective of experimental and observational studies in the health and social sciences, in recent years, investigators have also become increasingly interested in mediation analysis. Specifically, upon evaluating the total effect of the exposure, investigators routinely wish to make inferences about the direct or indirect pathways of the effect of the exposure, through a mediator variable or not, that occurs subsequently to the exposure and prior to the outcome. Although powerful…
The instrumental variable method is widely used in the health and social sciences for identification and estimation of causal effects in the presence of potentially unmeasured confounding. In order to improve efficiency, multiple instruments are routinely used, leading to concerns about bias due to possible violation of the instrumental variable assumptions. To address this concern, we introduce a new class of g-estimators that are guaranteed to remain consistent and asymptotically normal for the causal effect of interest provided that a set of at least $γ$ out of $K$ candidate instruments are…
Robins (1998) introduced marginal structural models (MSMs), a general class of counterfactual models for the joint effects of time-varying treatment regimes in complex longitudinal studies subject to time-varying confounding. He established identification of MSM parameters under a sequential randomization assumption (SRA), which essentially rules out unmeasured confounding of treatment assignment over time. In this technical report, we consider sufficient conditions for identification of MSM parameters with the aid of a time-varying instrumental variable, when sequential randomization fails to…
Suppose one is interested in estimating causal effects in the presence of potentially unmeasured confounding with the aid of a valid instrumental variable. This paper investigates the problem of making inferences about the average treatment effect when data are fused from two separate sources, one of which contains information on the treatment and the other contains information on the outcome, while values for the instrument and a vector of baseline covariates are recorded in both. We provide a general set of sufficient conditions under which the average treatment effect is nonparametrically i…
There is a fast-growing literature on estimating optimal treatment regimes based on randomized trials or observational studies under a key identifying condition of no unmeasured confounding. Because confounding by unmeasured factors cannot generally be ruled out with certainty in observational studies or randomized trials subject to noncompliance, we propose a general instrumental variable approach to learning optimal treatment regimes under endogeneity. Specifically, we establish identification of both value function $E[Y_{\mathcal{D}(L)}]$ for a given regime $\mathcal{D}$ and optimal regimes…
An essential goal of program evaluation and scientific research is the investigation of causal mechanisms. Over the past several decades, causal mediation analysis has been used in medical and social sciences to decompose the treatment effect into the natural direct and indirect effects. However, all of the existing mediation analysis methods rely on parametric modeling assumptions in one way or another, typically requiring researchers to specify multiple regression models involving the treatment, mediator, outcome, and pre-treatment confounders. To overcome this limitation, we propose a novel…
Causal mediation analysis is an important statistical method in social and medical studies, as it can provide insights about why an intervention works and inform the development of future interventions. Currently, most causal mediation methods focus on mediation effects defined on a mean scale. However, in health-risk studies, such as alcohol or risky sex, outcomes are typically count data and heavily skewed. Thus, mediation effects in these setting would be natural on a rate ratio scale, such as in Poisson and negative binomial regression methods. Existing methods also mainly rely on the assu…
Structural Nested Mean Models (SNMMs) are useful for causal inference of treatment effects in longitudinal observational studies. Most existing works assume that the data are collected at pre-fixed time points for all subjects, which, however, is restrictive in practice. To deal with irregularly spaced observations, we assume a class of continuous-time SNMMs and a martingale condition of no unmeasured confounding (NUC) to identify the causal parameters. We develop the first semiparametric efficiency theory and locally efficient estimators for continuous-time SNMMs. This task is non-trivial due…
Standard methods for inference about direct and indirect effects require stringent no unmeasured confounding assumptions which often fail to hold in practice, particularly in observational studies. The goal of this paper is to introduce a new form of indirect effect, the population intervention indirect effect (PIIE), that can be nonparametrically identified in the presence of an unmeasured common cause of exposure and outcome. This new type of indirect effect captures the extent to which the effect of exposure is mediated by an intermediate variable under an intervention that holds the compon…
Unmeasured confounding is a key threat to reliable causal inference based on observational studies. Motivated from two powerful natural experiment devices, the instrumental variables and difference-in-differences, we propose a new method called instrumented difference-in-differences that explicitly leverages exogenous randomness in an exposure trend to estimate the average and conditional average treatment effect in the presence of unmeasured confounding. We develop the identification assumptions using the potential outcomes framework. We propose a Wald estimator and a class of multiply robust…
Causal mediation analysis aims to estimate the natural direct and indirect effects under clearly specified assumptions. Traditional mediation analysis based on Ordinary Least Squares (OLS) relies on the absence of unmeasured causes of the putative mediator and outcome. When this assumption cannot be justified, Instrumental Variables (IV) estimators can be used in order to produce an asymptotically unbiased estimator of the mediator-outcome link. However, provided that valid instruments exist, bias removal comes at the cost of variance inflation for standard IV procedures such as Two-Stage Leas…
Addressing the Influence of Unmeasured Confounding in Observational Studies with Time-to-Event Outcomes: A Semiparametric Sensitivity Analysis Approach
Causal mediation analysis is routinely conducted by applied researchers in a variety of disciplines. The goal of such an analysis is to investigate alternative causal mechanisms by examining the roles of intermediate variables that lie in the causal paths between the treatment and outcome variables. In this paper we first prove that under a particular version of sequential ignorability assumption, the average causal mediation effect (ACME) is nonparametrically identified. We compare our identification assumption with those proposed in the literature. Some practical implications of our identifi…
The goal of causal mediation analysis, often described within the potential outcomes framework, is to decompose the effect of an exposure on an outcome of interest along different causal pathways. Using the assumption of sequential ignorability to attain non-parametric identification, Imai et al. (2010) proposed a flexible approach to measuring mediation effects, focusing on parametric and semiparametric normal/Bernoulli models for the outcome and mediator. Less attention has been paid to the case where the outcome and/or mediator model are mixed-scale, ordinal, or otherwise fall outside the n…
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…
In observational studies, treatments are typically not randomized and therefore estimated treatment effects may be subject to confounding bias. The instrumental variable (IV) design plays the role of a quasi-experimental handle since the IV is associated with the treatment and only affects the outcome through the treatment. In this paper, we present a novel framework for identification and inference using an IV for the marginal average treatment effect amongst the treated (ETT) in the presence of unmeasured confounding. For inference, we propose three different semiparametric approaches: (i) i…
Interventional effects have been proposed as a solution to the unidentifiability of natural (in)direct effects under mediator-outcome confounders affected by the exposure. Such confounders are an intrinsic characteristic of studies with time-varying exposures and mediators, yet the generalization of the interventional effect framework to the time-varying case has received little attention in the literature. We present an identification result for interventional effects in a general longitudinal data structure that allows flexibility in the specification of treatment-outcome, treatment-mediator…
It is emphasised that for epidemiological studies where disease incidence is rare, results from conventional proportional hazards models can often correctly estimate causal associations. The well-known "backdoor criteria" from causal-inference is applied to the common epidemiological study of rare diseases with a proportional hazards model, providing an example of when and how estimates from conventional proportional hazards studies can be used. A similar study with the "frontdoor criteria", that allows studies with unmeasured confounders, finds similar results to conventional mediation analys…
Mediation analysis seeks to infer how much of the effect of an exposure on an outcome can be attributed to specific pathways via intermediate variables or mediators. This requires identification of so-called path-specific effects. These express how a change in exposure affects those intermediate variables (along certain pathways), and how the resulting changes in those variables in turn affect the outcome (along subsequent pathways). However, unlike identification of total effects, adjustment for confounding is insufficient for identification of path-specific effects because their magnitude is…
We consider the problem of constructing bounds on the average treatment effect (ATE) when unmeasured confounders exist but have bounded influence. Specifically, we assume that omitted confounders could not change the odds of treatment for any unit by more than a fixed factor. We derive the sharp partial identification bounds implied by this assumption by leveraging distributionally robust optimization, and we propose estimators of these bounds with several novel robustness properties. The first is double sharpness: our estimators consistently estimate the sharp ATE bounds when one of two nuisa…
