There is growing interest in exploring causal effects in target populations via data combination. However, most approaches are tailored to specific settings and lack comprehensive comparative analyses. In this article, we focus on a typical scenario involving a source dataset and a target dataset. We first design six settings under covariate shift and conduct a comparative analysis by deriving the semiparametric efficiency bounds for the ATE in the target population. We then extend this analysis to six new settings that incorporate both covariate shift and posterior drift. Our study uncovers the key factors that influence efficiency gains and the ``effective sample size" when combining two datasets, with a particular emphasis on the roles of the variance ratio of potential outcomes between datasets and the derivatives of the posterior drift function. To the best of our knowledge, this is the first paper that explicitly explores the role of the posterior drift functions in causal inference. Additionally, we also propose novel methods for conducting sensitivity analysis to address violations of transportability between the two datasets. We empirically validate our findings by constructing locally efficient estimators and conducting extensive simulations. We demonstrate the proposed methods in two real-world applications.
This article develops new closed-form variance expressions for power analyses for commonly used difference-in-differences (DID) and comparative interrupted time series (CITS) panel data estimators. The main contribution is to incorporate variation in treatment timing into the analysis. The power formulas also account for other key design features that arise in practice: autocorrelated errors, unequal measurement intervals, and clustering due to the unit of treatment assignment. We consider power formulas for both cross-sectional and longitudinal models and allow for covariates. An illustrative…
Comparative binary outcome data are of fundamental interest in statistics and are often pooled in meta-analyses. Here we examine the simplest case where for each study there are two patient groups and a binary event of interest, giving rise to a series of $2 \times 2$ tables. A variety of measures of treatment effect are then available and are conventionally used in meta-analyses, such as the odds ratio, the risk ratio and the risk difference. Here we propose a new type of measure of treatment effect for this type of data that is very easily interpretable by lay audiences. We give the rational…
Standard tests of the "no-treatment-effect" hypothesis for a comparative experiment include permutation tests, the Wilcoxon rank sum test, two-sample $t$ tests, and Fisher-type randomization tests. Practitioners are aware that these procedures test different no-effect hypotheses and are based on different modeling assumptions. However, this awareness is not always, or even usually, accompanied by a clear understanding or appreciation of these differences. Borrowing from the rich literatures on causality and finite-population sampling theory, this paper develops a modeling framework that afford…
Observational studies can play a useful role in assessing the comparative effectiveness of competing treatments. In a clinical trial the randomization of participants to treatment and control groups generally results in well-balanced groups with respect to possible confounders, which makes the analysis straightforward. However, when analysing observational data, the potential for unmeasured confounding makes comparing treatment effects much more challenging. Causal inference methods such as Instrumental Variable and Prior Even Rate Ratio approaches make it possible to circumvent the need to ad…
Just what the doctor ordered: An evaluation of provider preference-based Instrumental Variable methods in observational studies, with application for comparative effectiveness of type 2 diabetes therapy
Experiments often include multiple treatments, with the primary goal to compare the causal effects of those treatments. This study focuses on comparing the causal anatomies of multiple treatments through the use of causal mediation analysis. It proposes a novel set of comparative causal mediation (CCM) estimands that compare the mediation effects of different treatments via a common mediator. Further, it derives the properties of a set of estimators for the CCM estimands and shows these estimators to be consistent (or conservative) under assumptions that do not require the absence of unobserve…
Instrumental variable (IV) methods are widely used to adjust for the bias in estimating treatment effects caused by unmeasured confounders in observational studies. In this manuscript, we provide empirical and theoretical evidence that the IV methods may result in biased treatment effects if applied on a data set in which subjects are preselected based on their received treatments. We frame this as a selection bias problem and propose a procedure that identifies the treatment effect of interest as a function of a vector of sensitivity parameters. We also list assumptions under which analyzing …
Assessing treatment effects in observational data with missing confounders: A comparative study of practical doubly-robust and traditional missing data methods
Kaiser Permanente Washington Health Research Institute（凯撒永久华盛顿健康研究所）；University of Washington（华盛顿大学）；TL Revolution, LLC（TL革命有限责任公司）；Vanderbilt University（范德堡大学）；University of California at Berkeley（加州大学伯克利分校）；University of Auckland（奥克兰大学）；US Food and Drug Administration（美国食品药品监督管理局）
There is currently a dearth of appropriate methods to estimate the causal effects of multiple treatments when the outcome is binary. For such settings, we propose the use of nonparametric Bayesian modeling, Bayesian Additive Regression Trees (BART). We conduct an extensive simulation study to compare BART to several existing, propensity score-based methods and to identify its operating characteristics when estimating average treatment effects on the treated. BART consistently demonstrates low bias and mean-squared errors. We illustrate the use of BART through a comparative effectiveness analys…
John A. Paulson School of Engineering and Applied Sciences, Harvard University（哈佛大学约翰·A·保尔森工程与应用科学学院）；Max Planck Institute for Intelligent Systems（马克斯·普朗克智能系统研究所）；GlaxoSmithKline（葛兰素史克）
Estimating an individual's potential response to interventions from observational data is of high practical relevance for many domains, such as healthcare, public policy or economics. In this setting, it is often the case that combinations of interventions may be applied simultaneously, for example, multiple prescriptions in healthcare or different fiscal and monetary measures in economics. However, existing methods for counterfactual inference are limited to settings in which actions are not used simultaneously. Here, we present Neural Counterfactual Relation Estimation (NCoRE), a new method …
The preponderance of large-scale healthcare databases provide abundant opportunities for comparative effectiveness research. Evidence necessary to making informed treatment decisions often relies on comparing effectiveness of multiple treatment options on outcomes of interest observed in a small number of individuals. Causal inference with multiple treatments and rare outcomes is a subject that has been treated sparingly in the literature. This paper designs three sets of simulations, representative of the structure of our healthcare database study, and propose causal analysis strategies for s…
Data from both a randomized trial and an observational study are sometimes simultaneously available for evaluating the effect of an intervention. The randomized data typically allows for reliable estimation of average treatment effects but may be limited in sample size and patient heterogeneity for estimating conditional average treatment effects for a broad range of patients. Estimates from the observational study can potentially compensate for these limitations, but there may be concerns about whether confounding and treatment effect heterogeneity have been adequately addressed. We propose a…
Estimating the Complier Average Causal Effect in Randomised Controlled Trials with Non-Compliance: A Comparative Simulation Study of the Instrumental Variables and Per-Protocol Analyses
In randomized experiments, treatment and control groups should be roughly the same--balanced--in their distributions of pretreatment variables. But how nearly so? Can descriptive comparisons meaningfully be paired with significance tests? If so, should there be several such tests, one for each pretreatment variable, or should there be a single, omnibus test? Could such a test be engineered to give easily computed $p$-values that are reliable in samples of moderate size, or would simulation be needed for reliable calibration? What new concerns are introduced by random assignment of clusters? Wh…
Estimating treatment effects conditional on observed covariates can improve the ability to tailor treatments to particular individuals. Doing so effectively requires dealing with potential confounding, and also enough data to adequately estimate effect moderation. A recent influx of work has looked into estimating treatment effect heterogeneity using data from multiple randomized controlled trials and/or observational datasets. With many new methods available for assessing treatment effect heterogeneity using multiple studies, it is important to understand which methods are best used in which …
The general idea of this article is to develop a Bayesian model with a flexible link function connecting an exponential family treatment response to a linear combination of covariates and a treatment indicator and the interaction between the two. Generalized linear models allowing data-driven link functions are often called "single-index models," and among popular semi-parametric modeling methods. In this article, we will focus on modeling heterogeneous treatment effects, with the goal of developing a treatment benefit index (TBI) incorporating prior information from historical data. This trea…
Individualizing treatment assignment can improve outcomes for diseases with patient-to-patient variability in comparative treatment effects. When a clinical trial demonstrates that some patients improve on treatment while others do not, it is tempting to assume that treatment effect heterogeneity exists. However, if variability in response is mainly driven by factors other than treatment, investigating the extent to which covariate data can predict differential treatment response is a potential waste of resources. Motivated by recent meta-analyses assessing the potential of individualizing tre…
Background: Comparative effectiveness research using network meta-analysis can present a hierarchy of competing treatments, from the least to most preferable option. However, the research question associated with the hierarchy of multiple interventions is never clearly defined in published reviews. Methods and Results: We introduce the notion of a treatment hierarchy question that describes the criterion for choosing a specific treatment over one or more competing alternatives. For example, stakeholders might ask which treatment is most likely to improve mean survival by at least 2 years or wh…
An unprecedented number of new cancer targets are in development, and most are being developed in combination therapies. Early oncology development is strategically challenged in choosing the best combinations to move forward to late stage development. The most common early endpoints to be assessed in such decision-making include objective response rate, duration of response and tumor size change. In this paper, using independent-drug-action and Bliss-drug-independence concepts as a foundation, we introduce simple models to predict combination therapy efficacy for duration of response and tumo…
Many scientific questions require estimating the effects of continuous treatments. Outcome modeling and weighted regression based on the generalized propensity score are the most commonly used methods to evaluate continuous effects. However, these techniques may be sensitive to model misspecification, extreme weights or both. In this paper, we propose Kernel Optimal Orthogonality Weighting (KOOW), a convex optimization-based method, for estimating the effects of continuous treatments. KOOW finds weights that minimize the worst-case penalized functional covariance between the continuous treatme…
It is important to estimate the local average treatment effect (LATE) when compliance with a treatment assignment is incomplete. The previously proposed methods for LATE estimation required all relevant variables to be jointly observed in a single dataset; however, it is sometimes difficult or even impossible to collect such data in many real-world problems for technical or privacy reasons. We consider a novel problem setting in which LATE, as a function of covariates, is nonparametrically identified from the combination of separately observed datasets. For estimation, we show that the direct …
University of New South Wales（新南威尔士大学）；Data61, CSIRO（澳大利亚联邦科学与工业研究组织Data61部门）
We regularly consider answering counterfactual questions in practice, such as "Would people with diabetes take a turn for the better had they choose another medication?". Observational studies are growing in significance in answering such questions due to their widespread accumulation and comparatively easier acquisition than Randomized Control Trials (RCTs). Recently, some works have introduced representation learning and domain adaptation into counterfactual inference. However, most current works focus on the setting of binary treatments. None of them considers that different treatments' sam…
Interference arises when an individual's potential outcome depends on the individual treatment level, but also on the treatment level of others. A common assumption in the causal inference literature in the presence of interference is partial interference, implying that the population can be partitioned in clusters of individuals whose potential outcomes only depend on the treatment of units within the same cluster. Previous literature has defined average potential outcomes under counterfactual scenarios where treatments are randomly allocated to units within a cluster. However, within cluster…
When drawing causal inferences about the effects of multiple treatments on clustered survival outcomes using observational data, we need to address implications of the multilevel data structure, multiple treatments, censoring and unmeasured confounding for causal analyses. Few off-the-shelf causal inference tools are available to simultaneously tackle these issues. We develop a flexible random-intercept accelerated failure time model, in which we use Bayesian additive regression trees to capture arbitrarily complex relationships between censored survival times and pre-treatment covariates and …
Multidimensional heterogeneity and endogeneity are important features of models with multiple treatments. We consider a heterogeneous coefficients model where the outcome is a linear combination of dummy treatment variables, with each variable representing a different kind of treatment. We use control variables to give necessary and sufficient conditions for identification of average treatment effects. With mutually exclusive treatments we find that, provided the heterogeneous coefficients are mean independent from treatments given the controls, a simple identification condition is that the ge…
In causal inference, a variety of causal effect estimands have been studied, including the sample, uncensored, target, conditional, optimal subpopulation, and optimal weighted average treatment effects. Ad-hoc methods have been developed for each estimand based on inverse probability weighting (IPW) and on outcome regression modeling, but these may be sensitive to model misspecification, practical violations of positivity, or both. The contribution of this paper is twofold. First, we formulate the generalized average treatment effect (GATE) to unify these causal estimands as well as their IPW …
The research described herewith is to re-visit the classical doubly robust estimation of average treatment effect by conducting a systematic study on the comparisons, in the sense of asymptotic efficiency, among all possible combinations of the estimated propensity score and outcome regression. To this end, we consider all nine combinations under, respectively, parametric, nonparametric and semiparametric structures. The comparisons provide useful information on when and how to efficiently utilize the model structures in practice. Further, when there is model-misspecification, either propensit…
We developed a study design for rare disease clinical trials (RDTs) that efficiently evaluate treatments, promotes access to new treatments during treatment development, and optimizes healthcare resource utilization for future treatment allocation, development, and prioritization. Comprehensive literature review and focus group discussion were conducted. To address the multifaceted challenges facing RDTs, four key issues for RDTs must be addressed, which are 1) the opportunity to access the new treatment; 2) assessment of outcomes where clinically validated outcomes may be lacking; 3) patient …
Platform trials have gained a lot of attention recently as a possible remedy for time-consuming classical two-arm randomized controlled trials, especially in early phase drug development. This short article illustrates how to use the CohortPlat R package to simulate a cohort platform trial, where each cohort consists of a combination treatment and the respective monotherapies and standard-of-care. The endpoint is always assumed to be binary. The package offers extensive flexibility with respect to both platform trial trajectories, as well as treatment effect scenarios and decision rules. As a …
A two-groups mixed-effects model for the comparison of (normalized) microarray data from two treatment groups is considered. Most competing parametric methods that have appeared in the literature are obtained as special cases or by minor modification of the proposed model. Approximate maximum likelihood fitting is accomplished via a fast and scalable algorithm, which we call LEMMA (Laplace approximated EM Microarray Analysis). The posterior odds of treatment $\times$ gene interactions, derived from the model, involve shrinkage estimates of both the interactions and of the gene specific error v…
No unmeasured confounding is often assumed in estimating treatment effects in observational data when using approaches such as propensity scores and inverse probability weighting. However, in many such studies due to the limitation of the databases, collected confounders are not exhaustive, and it is crucial to examine the extent to which the resulting estimate is sensitive to the unmeasured confounders. We consider this problem for survival and competing risks data. Due to the complexity of models for such data, we adapt the simulated potential confounders approach of Carnegie et al. (2016), …
Evidence supporting the current World Health Organization recommendations of early antiretroviral therapy (ART) initiation for adolescents is inconclusive. We leverage a large observational data and compare, in terms of mortality and CD4 cell count, the dynamic treatment initiation rules for HIV-infected adolescents. Our approaches extend the marginal structural model for estimating outcome distributions under dynamic treatment regimes (DTR), developed in Robins et al. (2008), to allow the causal comparisons of both specific regimes and regimes along a continuum. Furthermore, we propose strate…
This paper introduces distributional regression, also known as generalized additive models for location, scale and shape (GAMLSS), as a modeling framework for analyzing treatment effects beyond the mean. By relating each parameter of the response distribution to explanatory variables, GAMLSS model the treatment effect on the whole conditional distribution. Additionally, any nonnormal outcome and nonlinear effects of explanatory variables can be incorporated. We elaborate on the combination of GAMLSS with program evaluation methods in economics and provide practical guidance on the usage of GAM…
Coarse Structural Nested Mean Models (SNMMs) provide useful tools to estimate treatment effects from longitudinal observational data with time-dependent confounders. Coarse SNMMs lead to a large class of estimators,within which an optimal estimator can be derived under the conditions of well-specified models for the treatment effect, for treatment initiation, and for nuisance regression outcomes (Lok & Griner, 2015). The key assumption lies in a well-specified model for the treatment effect; however, there is no existing guidance to specify the treatment effect model, and model misspecificatio…
In the comparative interrupted time series design (also called the method of difference-in-differences), the change in outcome in a group exposed to treatment in the periods before and after the exposure is compared to the change in outcome in a control group not exposed to treatment in either period. The standard difference-in-difference estimator for a comparative interrupted time series design will be biased for estimating the causal effect of the treatment if there is an interaction between history in the after period and the groups; for example, there is a historical event besides the sta…
The present paper deals with the problem of allocating patients to two competing treatments in the presence of covariates or prognostic factors in order to achieve a good trade-off among ethical concerns, inferential precision and randomness in the treatment allocations. In particular we suggest a multipurpose design methodology that combines efficiency and ethical gain when the linear homoscedastic model with both treatment/covariate interactions and interactions among covariates is adopted. The ensuing compound optimal allocations of the treatments depend on the covariates and their distribu…
The use of drug combinations in clinical trials is increasingly common during the last years since a more favorable therapeutic response may be obtained by combining drugs. In phase I clinical trials, most of the existing methodology recommends a one unique dose combination as "optimal", which may result in a subsequent failed phase II clinical trial since other dose combinations may present higher treatment efficacy for the same level of toxicity. We are particularly interested in the setting where it is necessary to wait a few cycles of therapy to observe an efficacy outcome and the phase I …
Although combination antiretroviral therapy (ART) is highly effective in suppressing viral load for people with HIV (PWH), many ART agents may exacerbate central nervous system (CNS)-related adverse effects including depression. Therefore, understanding the effects of ART drugs on the CNS function, especially mental health, can help clinicians personalize medicine with less adverse effects for PWH and prevent them from discontinuing their ART to avoid undesirable health outcomes and increased likelihood of HIV transmission. The emergence of electronic health records offers researchers unpreced…
In precision medicine, Dynamic Treatment Regimes (DTRs) are treatment protocols that adapt over time in response to a patient's observed characteristics. A DTR is a set of decision functions that takes an individual patient's information as arguments and outputs an action to be taken. Building on observed data, the aim is to identify the DTR that optimizes expected patient outcomes. Multiple methods have been proposed for optimal DTR estimation with continuous outcomes. However, optimal DTR estimation with binary outcomes is more complicated and has received comparatively little attention. Sol…
