We consider evaluating the causal effects of dynamic treatments, i.e. of multiple treatment sequences in various periods, based on double machine learning to control for observed, time-varying covariates in a data-driven way under a selection-on-observables assumption. To this end, we make use of so-called Neyman-orthogonal score functions, which imply the robustness of treatment effect estimation to moderate (local) misspecifications of the dynamic outcome and treatment models. This robustness property permits approximating outcome and treatment models by double machine learning even under high dimensional covariates and is combined with data splitting to prevent overfitting. In addition to effect estimation for the total population, we consider weighted estimation that permits assessing dynamic treatment effects in specific subgroups, e.g. among those treated in the first treatment period. We demonstrate that the estimators are asymptotically normal and $\sqrt{n}$-consistent under specific regularity conditions and investigate their finite sample properties in a simulation study. Finally, we apply the methods to the Job Corps study in order to assess different sequences of training programs under a large set of covariates.
We revisit the problem of estimating the local average treatment effect (LATE) and the local average treatment effect on the treated (LATT) when control variables are available, either to render the instrumental variable (IV) suitably exogenous or to improve precision. Unlike previous approaches, our doubly robust (DR) estimation procedures use quasi-likelihood methods weighted by the inverse of the IV propensity score - so-called inverse probability weighted regression adjustment (IPWRA) estimators. By properly choosing models for the propensity score and outcome models, fitted values are ens…
We develop a Bayesian nonparametric (BNP) approach to evaluate the causal effect of treatment in a randomized trial where a nonterminal event may be censored by a terminal event, but not vice versa (i.e., semi-competing risks). Based on the idea of principal stratification, we define a novel estimand for the causal effect of treatment on the nonterminal event. We introduce identification assumptions, indexed by a sensitivity parameter, and show how to draw inference using our BNP approach. We conduct simulation studies and illustrate our methodology using data from a brain cancer trial.
A Causal Inference Approach for Evaluating Diagnostic Tests and AI-Enabled Medical Devices: From Effect Modification to Information-Augmented Decision-Making
Division of Biostatistics, University of California, Berkeley（加州大学伯克利分校生物统计系）
Non-proportional hazards (NPH) have been observed in confirmatory clinical trials with time to event outcomes. Under NPH, the hazard ratio does not stay constant over time and the log-rank test is no longer the most powerful test. The weighted log-rank test (WLRT) has been introduced to deal with the presence of non-proportionality. We focus our attention on the WLRT and the complementary Cox model based on the time-varying treatment effect proposed by Lin and León (2017) (doi: 10.1016/j.conctc.2017.09.004). We will investigate whether the proposed weighted hazard ratio (WHR) approach is unbia…
We derive a formal, decision-based method for comparing the performance of counterfactual treatment regime predictions using the results of experiments that give relevant information on the distribution of treated outcomes. Our approach allows us to quantify and assess the statistical significance of differential performance for optimal treatment regimes estimated from structural models, extrapolated treatment effects, expert opinion, and other methods. We apply our method to evaluate optimal treatment regimes for conditional cash transfer programs across countries where predictions are genera…
Suppose we have a binary treatment used to influence an outcome. Given data from an observational or controlled study, we wish to determine whether or not there exists some subset of observed covariates in which the treatment is more effective than the standard practice of no treatment. Furthermore, we wish to quantify the improvement in population mean outcome that will be seen if this subgroup receives treatment and the rest of the population remains untreated. We show that this problem is surprisingly challenging given how often it is an (at least implicit) study objective. Blindly applying…
Comparative effectiveness research often involves evaluating the differences in the risks of an event of interest between two or more treatments using observational data. Often, the post-treatment outcome of interest is whether the event happens within a pre-specified time window, which leads to a binary outcome. One source of bias for estimating the causal treatment effect is the presence of confounders, which are usually controlled using propensity score-based methods. An additional source of bias is right-censoring, which occurs when the information on the outcome of interest is not complet…
The weighted average treatment effect (WATE) is a causal measure for the comparison of interventions in a specific target population, which may be different from the population where data are sampled from. For instance, when the goal is to introduce a new treatment to a target population, the question is what efficacy (or effectiveness) can be gained by switching patients from a standard of care (control) to this new treatment, for which the average treatment effect for the control (ATC) estimand can be applied. In this paper, we propose two estimators based on augmented inverse probability we…
A Workflow for Evaluating Regional Treatment Effect Heterogeneity in Multi-Regional Clinical Trials
China Novartis Institutes for BioMedical Research Co.（中国诺华生物医学研究有限公司）；Department of Biostatistics, School of Public Health, Peking University（北京大学公共卫生学院生物统计系）；Peking University Cancer Hospital（北京大学肿瘤医院）；Advanced Methodology and Data Science, Novartis Pharma AG（诺华制药AG高级方法与数据科学部）；Advanced Methodology and Data Science, Novartis Pharmaceuticals Corporation（诺华制药公司高级方法与数据科学部）；Department of Public Health Sciences, University of Chicago（芝加哥大学公共卫生学系）；Biostatistics CRM/NS/IMM, Advanced Quantitative Sciences, Global Drug Development Division, Novartis Pharma K.K.（日本诺华制药K.K.全球药物开发部高级定量科学生物统计CRM/NS/IMM）；Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute（北京大学肿瘤医院及研究所癌变与转化教育部重点实验室）
Randomized controlled trials are the gold standard for measuring causal effects. However, they are often not always feasible, and causal treatment effects must be estimated from observational data. Observational studies do not allow robust conclusions about causal relationships unless statistical techniques account for the imbalance of pretreatment confounders across groups while key assumptions hold. Propensity score and balance weighting (PSBW) are useful techniques that aim to reduce the imbalances between treatment groups by weighting the groups to look alike on the observed confounders. T…
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 …
Propensity score (PS) methods have been increasingly used in recent years when assessing treatment effects in nonrandomized studies. In terms of statistical methods, a number of new PS weighting methods were developed, and it was shown that they can outperform PS matching in efficiency of treatment effect estimation in different simulation settings. For assessing balance of covariates in treatment groups, PS weighting methods commonly use the weighted standardized difference, despite some deficiencies of this measure like, for example, the distribution of the weighted standardized difference d…
We study identification and estimation in the Regression Discontinuity Design (RDD) with a multivalued treatment variable. We also allow for the inclusion of covariates. We show that without additional information, treatment effects are not identified. We give necessary and sufficient conditions that lead to identification of LATEs as well as of weighted averages of the conditional LATEs. We show that if the first stage discontinuities of the multiple treatments conditional on covariates are linearly independent, then it is possible to identify multivariate weighted averages of the treatment e…
Evaluating Dynamic Conditional Quantile Treatment Effects with Applications in Ridesharing
DiDi Chuxing（滴滴出行）；University of North Carolina at Chapel Hill（北卡罗来纳大学教堂山分校）；Shanghai University of Finance and Economics（上海财经大学）；London School of Economics and Political Science（伦敦政治经济学院）
In this paper, we study the estimation and inference of the quantile treatment effect under covariate-adaptive randomization. We propose two estimation methods: (1) the simple quantile regression and (2) the inverse propensity score weighted quantile regression. For the two estimators, we derive their asymptotic distributions uniformly over a compact set of quantile indexes, and show that, when the treatment assignment rule does not achieve strong balance, the inverse propensity score weighted estimator has a smaller asymptotic variance than the simple quantile regression estimator. For the in…
Estimates of the effects of treatment on cost from observational studies are subject to bias if there are unmeasured confounders. It is therefore advisable in practice to assess the potential magnitude of such biases. We derive a general adjustment formula for loglinear models of mean cost and explore special cases under plausible assumptions about the distribution of the unmeasured confounder. We assess the performance of the adjustment by simulation, in particular, examining robustness to a key assumption of conditional independence between the unmeasured and measured covariates given the tr…
There has been growing attention on how to effectively and objectively use covariate information when the primary goal is to estimate the average treatment effect (ATE) in randomized clinical trials (RCTs). In this paper, we propose an effective weighting approach to extract covariate information based on the empirical likelihood (EL) method. The resulting two-sample empirical likelihood weighted (ELW) estimator includes two classes of weights, which are obtained from a constrained empirical likelihood estimation procedure, where the covariate information is effectively incorporated into the f…
Simulators make unique benchmarks for causal effect estimation since they do not rely on unverifiable assumptions or the ability to intervene on real-world systems, but are often too simple to capture important aspects of real applications. We propose a simulator of Alzheimer's disease aimed at modeling intricacies of healthcare data while enabling benchmarking of causal effect and policy estimators. We fit the system to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and ground hand-crafted components in results from comparative treatment trials and observational treatment patt…
Evaluating the influence of treatment-effect heterogeneity on discrimination
Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS)（巴黎西岱大学与索邦巴黎北大学、法国国家健康与医学研究院、法国国家农业食品与环境研究院、流行病学与统计学研究中心）；Centre d’Épidémiologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôtel-Dieu（临床流行病学中心，巴黎公立援助医院集团，主宫医院）
When evaluating the effectiveness of a treatment, policy, or intervention, the desired measure of effectiveness may be expensive to collect, not routinely available, or may take a long time to occur. In these cases, it is sometimes possible to identify a surrogate outcome that can more easily/quickly/cheaply capture the effect of interest. Theory and methods for evaluating the strength of surrogate markers have been well studied in the context of a single surrogate marker measured in the course of a randomized clinical study. However, methods are lacking for quantifying the utility of surrogat…
This research was motivated by studying anti-drug antibody (ADA) formation and its potential impact on long-term benefit of a biologic treatment in a randomized controlled trial, in which ADA status was not only unobserved in the control arm but also in a subset of patients from the experimental treatment arm. Recent literature considers the principal stratum estimand strategy to estimate treatment effect in groups of patients defined by an intercurrent status, i.e. in groups defined by a post-randomization variable only observed in one arm and potentially associated with the outcome. However,…
We study a continuous treatment effect model in the presence of treatment spillovers through social networks. We assume that one's outcome is affected not only by his/her own treatment but also by a (weighted) average of his/her neighbors' treatments, both of which are treated as endogenous variables. Using a control function approach with appropriate instrumental variables, we show that the conditional mean potential outcome can be nonparametrically identified. We also consider a more empirically tractable semiparametric model and develop a three-step estimation procedure for this model. As a…
