Traditional regulations of chemical exposure tend to focus on single exposures, overlooking the potential amplified toxicity due to multiple concurrent exposures. We are interested in understanding the average outcome if exposures were limited to fall under a multivariate threshold. Because threshold levels are often unknown a priori, we provide an algorithm that finds exposure threshold levels where the expected outcome is maximized or minimized. Because both identifying thresholds and estimating policy effects on the same data would lead to overfitting bias, we also provide a data-adaptive estimation framework, which allows for both threshold discovery and policy estimation. Simulation studies show asymptotic convergence to the optimal exposure region and to the true effect of an intervention. We demonstrate how our method identifies true interactions in a public synthetic mixture data set. Finally, we applied our method to NHANES data to discover metal exposures that have the most harmful effects on telomere length. We provide an implementation in the CVtreeMLE R package.
Targeted maximum likelihood estimation is a general methodology combining flexible ensemble learning and semiparametric efficiency theory in a two-step procedure for estimation of causal parameters. Proposed targeted maximum likelihood procedures for survival and competing risks analysis have so far focused on events taken values in discrete time. We here present a targeted maximum likelihood estimation procedure for event times that take values in R+. We focuson the estimation of intervention-specific mean outcomes with stochastic interventions on a time-fixed treatment. For data-adaptive est…
Temporal dependence in exposure and hazard-based infectious disease interventions
University of California, Los Angeles（加州大学洛杉矶分校）；Geisel School of Medicine at Dartmouth（达特茅斯医学院）；The Dartmouth Institute for Health Policy and Clinical Practice（达特茅斯健康政策与临床实践研究所）
Mediation analysis in causal inference has traditionally focused on binary exposures and deterministic interventions, and a decomposition of the average treatment effect in terms of direct and indirect effects. In this paper we present an analogous decomposition of the \textit{population intervention effect}, defined through stochastic interventions on the exposure. Population intervention effects provide a generalized framework in which a variety of interesting causal contrasts can be defined, including effects for continuous and categorical exposures. We show that identification of direct an…
We often seek to estimate the impact of an exposure naturally occurring or randomly assigned at the cluster-level. For example, the literature on neighborhood determinants of health continues to grow. Likewise, community randomized trials are applied to learn about real-world implementation, sustainability, and population effects of interventions with proven individual-level efficacy. In these settings, individual-level outcomes are correlated due to shared cluster-level factors, including the exposure, as well as social or biological interactions between individuals. To flexibly and efficient…
Proxy-Adjusted Causal Discovery from Targeted Interventions
School of Statistics, University of Minnesota（明尼苏达大学统计学院）；Division of Biostatistics and Health Data Science School of Public Health, University of Minnesota（明尼苏达大学公共卫生学院生物统计学与健康数据科学系）
Nonparametric efficient causal estimation of the intervention-specific expected number of recurrent events with continuous-time targeted maximum likelihood and highly adaptive lasso estimation
Mediation analysis is a strategy for understanding the mechanisms by which treatments or interventions affect later outcomes. Mediation analysis is frequently applied in randomized trial settings, but typically assumes: a) that randomized assignment is the exposure of interest as opposed to actual take-up of the intervention, and b) no unobserved confounding of the mediator-outcome relationship. In contrast to the rich literature on instrumental variable (IV) methods to estimate a total effect of a non-randomized exposure, there has been almost no research into using IV as an identification st…
For exposures $X$ like obesity, no precise and unambiguous definition exists for the hypothetical intervention $do(X = x_0)$. This has raised concerns about the relevance of causal effects estimated from observational studies for such exposures. Under the framework of structural causal models, we study how the effect of $do(X = x_0)$ relates to the effect of interventions on causes of $X$. We show that for interventions focusing on causes of $X$ that affect the outcome through $X$ only, the effect of $do(X = x_0)$ equals the effect of the considered intervention. On the other hand, for interve…
Longitudinal targeted maximum likelihood estimation (LTMLE) has very rarely been used to estimate dynamic treatment effects in the context of time-dependent confounding affected by prior treatment when faced with long follow-up times, multiple time-varying confounders, and complex associational relationships simultaneously. Reasons for this include the potential computational burden, technical challenges, restricted modeling options for long follow-up times, and limited practical guidance in the literature. However, LTMLE has desirable asymptotic properties, i.e. it is doubly robust, and can y…
Several recently developed methods have the potential to harness machine learning in the pursuit of target quantities inspired by causal inference, including inverse weighting, doubly robust estimating equations and substitution estimators like targeted maximum likelihood estimation. There are even more recent augmentations of these procedures that can increase robustness, by adding a layer of cross-validation (cross-validated targeted maximum likelihood estimation and double machine learning, as applied to substitution and estimating equation approaches, respectively). While these methods hav…
Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including: 1) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be 2) multivariate, and 3) the existence of multivariate mediators. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no estimator for IDE/I…
When developing new interventions to minimize the harmful effects of an exposure, investigators usually target the mechanisms that mediate the causal effect of the exposure on the outcome. Predicting the causal effect of these new interventions is generally done through identifying either (1) the controlled direct effect, or (2) the pure (natural) direct effect. In this opinion piece, we use the interventionist approach to discuss how these two approaches answer different questions, and the additional underlying assumptions of each compared to the other. We use a specific example for the devel…
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…
We address discrete-marks survival analysis, also known as categorical sieve analysis, for a setting of a randomized placebo-controlled treatment intervention to prevent infection by a pathogen to which multiple exposures are possible, with a finite number of types of "failure". In particular, we address the case of interventions that are partially efficacious due to a combination of failure-type-dependent efficacy and subject-dependent efficacy, for an intervention that is "non-leaky" (where "leaky" interventions are those for which each exposure event has a chance of resulting in a "failure"…
This paper studies the generalization of the targeted minimum loss-based estimation (TMLE) framework to estimation of effects of time-varying interventions in settings where both interventions, covariates, and outcome can happen at subject-specific time-points on an arbitrarily fine time-scale. TMLE is a general template for constructing asymptotically linear substitution estimators for smooth low-dimensional parameters in infinite-dimensional models. Existing longitudinal TMLE methods are developed for data where observations are made on a discrete time-grid. We consider a continuous-time cou…
A Framework for Parametric Time-Varying Treatment Effects in Multiple Intervention Stepped Wedge Design Clinical Trials in the Presence of Non-Uniform Cluster-Period Correlation Structures
The Johns Hopkins University Applied Physics Laboratory（约翰斯·霍普金斯大学应用物理实验室）；UTHealth Houston School of Public Health, The University of Texas Health Science Center at Houston（休斯顿德克萨斯大学健康科学中心休斯顿公共卫生学院）
The generalized propensity score (GPS) is an extension of the propensity score for use with quantitative or continuous exposures (e.g., dose of medication or years of education). Current GPS methods allow estimation of the dose-response relationship between a single continuous exposure and an outcome. However, in many real-world settings, there are multiple exposures occurring simultaneously that could be causally related to the outcome. We propose a multivariate GPS method (mvGPS) that allows estimation of a dose-response surface that relates the joint distribution of multiple continuous expo…
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…
Although review papers on causal inference methods are now available, there is a lack of introductory overviews on what they can render and on the guiding criteria for choosing one particular method. This tutorial gives an overview in situations where an exposure of interest is set at a chosen baseline (`point exposure') and the target outcome arises at a later time point. We first phrase relevant causal questions and make a case for being specific about the possible exposure levels involved and the populations for which the question is relevant. Using the potential outcomes framework, we desc…
The public health impact of a harmful exposure can be quantified by the population-attributable fraction (PAF). The PAF describes the attributable risk due to an exposure and is often interpreted as the proportion of preventable cases if the exposure could be extinct. Difficulties in the definition and interpretation of the PAF arise when the exposure of interest depends on time. Then, the definition of exposed and unexposed individuals is not straightforward. We propose dynamic prediction and landmarking to define and estimate a PAF in this data situation. Two estimands are discussed which ar…
The aim of clinical effectiveness research using repositories of electronic health records is to identify what health interventions 'work best' in real-world settings. Since there are several reasons why the net benefit of intervention may differ across patients, current comparative effectiveness literature focuses on investigating heterogeneous treatment effect and predicting whether an individual might benefit from an intervention. The majority of this literature has concentrated on the estimation of the effect of treatment on binary outcomes. However, many medical interventions are evaluate…
Decomposing an exposure effect on an outcome into separate natural indirect effects through multiple mediators requires strict assumptions, such as correctly postulating the causal structure of the mediators, and no unmeasured confounding among the mediators. In contrast, interventional indirect effects for multiple mediators can be identified even when - as often - the mediators either have an unknown causal structure, or share unmeasured common causes, or both. Existing estimation methods for interventional indirect effects require calculating each distinct indirect effect in turn. This can …
Policy interventions can spill over to units of a population that are not directly exposed to the policy but are geographically close to the units receiving the intervention. In recent work, investigations of spillover effects on neighboring regions have focused on estimating the average treatment effect of a particular policy in an observed setting. Our research question broadens this scope by asking what policy consequences would the treated units have experienced under hypothetical exposure settings. When we only observe treated unit(s) surrounded by controls -- as is common when a policy i…
Determining the causal structure of a set of variables is critical for both scientific inquiry and decision-making. However, this is often challenging in practice due to limited interventional data. Given that randomized experiments are usually expensive to perform, we propose a general framework and theory based on optimal Bayesian experimental design to select experiments for targeted causal discovery. That is, we assume the experimenter is interested in learning some function of the unknown graph (e.g., all descendants of a target node) subject to design constraints such as limits on the nu…
Targeted maximum likelihood estimation (TMLE) is a general method for estimating parameters in semiparametric and nonparametric models. Each iteration of TMLE involves fitting a parametric submodel that targets the parameter of interest. We investigate the use of exponential families to define the parametric submodel. This implementation of TMLE gives a general approach for estimating any smooth parameter in the nonparametric model. A computational advantage of this approach is that each iteration of TMLE involves estimation of a parameter in an exponential family, which is a convex optimizati…
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. Firstly, mediation methods have hitherto mostly focused on the elusive task of discovering pathways, rather than on the evaluation of mediator interventions. Secondly, the complexity of such questions is invariably such that…
Estimate Time-Varying Exposure Effects via Ensemble Learning-based Marginal Structural Model with Application to Adolescent Cognitive Development Study
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…
Population attributable fractions aim to quantify the proportion of the cases of an outcome (for example, a disease) that would have been avoided had no individuals in the population been exposed to a given exposure. This quantity thus plays a crucial role in epidemiology and public health, notably to guide policies, interventions or to assess the burden of a disease due to a particular exposure. Various statistical methods have been proposed to estimate attributable fractions using observational data. When time-to-event data are used, several of these formulas yield invalid results. Alternati…
Meek Separators and Their Applications in Targeted Causal Discovery
Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard（麻省理工学院和哈佛大学布罗德研究所埃里克与温迪·施密特中心）；LIDS, Massachusetts Institute of Technology（麻省理工学院信息与决策系统实验室）
