Stepped wedge cluster randomized controlled trials are typically analyzed using models that assume the full effect of the treatment is achieved instantaneously. We provide an analytical framework for scenarios in which the treatment effect varies as a function of exposure time (time since the start of treatment) and define the "effect curve" as the magnitude of the treatment effect on the linear predictor scale as a function of exposure time. The "time-averaged treatment effect", (TATE) and "long-term treatment effect" (LTE) are summaries of this curve. We analytically derive the expectation of the estimator resulting from a model that assumes an immediate treatment effect and show that it can be expressed as a weighted sum of the time-specific treatment effects corresponding to the observed exposure times. Surprisingly, although the weights sum to one, some of the weights can be negative. This implies that the estimator may be severely misleading and can even converge to a value of the opposite sign of the true TATE or LTE. We describe several models that can be used to simultaneously estimate the entire effect curve, the TATE, and the LTE, some of which make assumptions about the shape of the effect curve. We evaluate these models in a simulation study to examine the operating characteristics of the resulting estimators and apply them to two real datasets.
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Randomized controlled trials (RCTs) are considered as the gold standard for testing causal hypotheses in the clinical domain. However, the investigation of prognostic variables of patient outcome in a hypothesized cause-effect route is not feasible using standard statistical methods. Here, we propose a new automated causal inference method (AutoCI) built upon the invariant causal prediction (ICP) framework for the causal re-interpretation of clinical trial data. Compared to existing methods, we show that the proposed AutoCI allows to efficiently determine the causal variables with a clear differentiation on two real-world RCTs of endometrial cancer patients with mature outcome and extensive clinicopathological and molecular data. This is achieved via suppressing the causal probability of non-causal variables by a wide margin. In ablation studies, we further demonstrate that the assignment of causal probabilities by AutoCI remain consistent in the presence of confounders. In conclusion, these results confirm the robustness and feasibility of AutoCI for future applications in real-world clinical analysis.
Across research disciplines, cluster randomized trials (CRTs) are commonly implemented to evaluate interventions delivered to groups of participants, such as communities and clinics. Despite advances in the design and analysis of CRTs, several challenges remain. First, there are many possible ways to specify the intervention effect (e.g., at the individual-level or at the cluster-level). Second, the theoretical and practical performance of common methods for CRT analysis remain poorly understood. Here, we use causal models to formally define an array of causal effects as summary measures of counterfactual outcomes. Next, we provide a comprehensive overview of well-known CRT estimators, including the t-test and generalized estimating equations (GEE), as well as less known methods, including augmented-GEE and targeted maximum likelihood estimation (TMLE). In finite sample simulations, we illustrate the performance of these estimators and the importance of effect specification, especially when cluster size varies. Finally, our application to data from the Preterm Birth Initiative (PTBi) study demonstrates the real-world importance of selecting an analytic approach corresponding to the research question. Given its flexibility to estimate a variety of effects and ability to adaptively adjust for covariates for precision gains while maintaining Type-I error control, we conclude TMLE is a promising tool for CRT analysis.
Estimation and evaluation of individualized treatment rules have been studied extensively, but real-world treatment resource constraints have received limited attention in existing methods. We investigate a setting in which treatment is intervened upon based on covariates to optimize the mean counterfactual outcome under treatment cost constraints when the treatment cost is random. In a particularly interesting special case, an instrumental variable corresponding to encouragement to treatment is intervened upon with constraints on the proportion receiving treatment. For such settings, we first develop a method to estimate optimal individualized treatment rules. We further construct an asymptotically efficient plug-in estimator of the corresponding average treatment effect relative to a given reference rule.
In the presence of heterogeneity between the randomized controlled trial (RCT) participants and the target population, evaluating the treatment effect solely based on the RCT often leads to biased quantification of the real-world treatment effect. To address the problem of lack of generalizability for the treatment effect estimated by the RCT sample, we leverage observational studies with large samples that are representative of the target population. This paper concerns evaluating treatment effects on survival outcomes for a target population and considers a broad class of estimands that are functionals of treatment-specific survival functions, including differences in survival probability and restricted mean survival times. Motivated by two intuitive but distinct approaches, i.e., imputation based on survival outcome regression and weighting based on inverse probability of sampling, censoring, and treatment assignment, we propose a semiparametric estimator through the guidance of the efficient influence function. The proposed estimator is doubly robust in the sense that it is consistent for the target population estimands if either the survival model or the weighting model is correctly specified, and is locally efficient when both are correct.Simulation studies confirm the theoretical properties of the proposed estimator and show it outperforms competitors. We apply the proposed method to estimate the effect of adjuvant chemotherapy on survival in patients with early-stage resected non-small lung cancer.
Understanding treatment effect heterogeneity in observational studies is of great practical importance to many scientific fields. Quantile regression provides a natural framework for modeling such heterogeneity. In this paper, we propose a new method for inference on heterogeneous quantile treatment effects in the presence of high-dimensional covariates. Our estimator combines a $\ell_1$-penalized regression adjustment with a quantile-specific bias correction scheme based on quantile regression rank scores. We present a comprehensive study of the theoretical properties of this estimator, including weak convergence of the heterogeneous quantile treatment effect process to a Gaussian process. We illustrate the finite-sample performance of our approach through Monte Carlo experiments and an empirical example, dealing with the differential effect of statin usage for lowering low-density lipoprotein cholesterol levels for the Alzheimer's disease patients who participated in the UK Biobank study.
Dyadic data is often encountered when quantities of interest are associated with the edges of a network. As such it plays an important role in statistics, econometrics and many other data science disciplines. We consider the problem of uniformly estimating a dyadic Lebesgue density function, focusing on nonparametric kernel-based estimators which take the form of U-process-like dyadic empirical processes. We provide uniform point estimation and distributional results for the dyadic kernel density estimator, giving valid and feasible procedures for robust uniform inference. Our main contributions include the minimax-optimal uniform convergence rate of the dyadic kernel density estimator, along with strong approximation results for the associated standardized $t$-process. A consistent variance estimator is introduced in order to obtain analogous results for the Studentized $t$-process, enabling the construction of provably valid and feasible uniform confidence bands for the unknown density function. A crucial feature of U-process-like dyadic empirical processes is that they may be "degenerate" at some or possibly all points in the support of the data, a property making our uniform analysis somewhat delicate. Nonetheless we show formally that our proposed methods for uniform inference remain robust to the potential presence of such unknown degenerate points. For the purpose of implementation, we discuss uniform inference procedures based on positive semi-definite covariance estimators, mean squared error optimal bandwidth selectors and robust bias-correction methods. We illustrate the empirical finite-sample performance of our robust inference methods in a simulation study. Our technical results concerning strong approximations and maximal inequalities are of potential independent interest.
Since the average treatment effect (ATE) measures the change in social welfare, even if positive, there is a risk of negative effect on, say, some 10% of the population. Assessing such risk is difficult, however, because any one individual treatment effect (ITE) is never observed so the 10% worst-affected cannot be identified, while distributional treatment effects only compare the first deciles within each treatment group, which does not correspond to any 10%-subpopulation. In this paper we consider how to nonetheless assess this important risk measure, formalized as the conditional value at risk (CVaR) of the ITE distribution. We leverage the availability of pre-treatment covariates and characterize the tightest-possible upper and lower bounds on ITE-CVaR given by the covariate-conditional average treatment effect (CATE) function. Some bounds can also be interpreted as summarizing a complex CATE function into a single metric and are of interest independently of being a bound. We then proceed to study how to estimate these bounds efficiently from data and construct confidence intervals. This is challenging even in randomized experiments as it requires understanding the distribution of the unknown CATE function, which can be very complex if we use rich covariates so as to best control for heterogeneity. We develop a debiasing method that overcomes this and prove it enjoys favorable statistical properties even when CATE and other nuisances are estimated by black-box machine learning or even inconsistently. Studying a hypothetical change to French job-search counseling services, our bounds and inference demonstrate a small social benefit entails a negative impact on a substantial subpopulation.
Recently, there has been great interest in estimating the conditional average treatment effect using flexible machine learning methods. However, in practice, investigators often have working hypotheses about effect heterogeneity across pre-defined subgroups of individuals, which we call the groupwise approach. The paper compares two modern ways to estimate groupwise treatment effects, a nonparametric approach and a semiparametric approach, with the goal of better informing practice. Specifically, we compare (a) the underlying assumptions, (b) efficiency characteristics, and (c) a way to combine the two approaches. We also discuss how to obtain cluster-robust standard errors if the study units in the same subgroups are not independent and identically distributed. We conclude by reanalyzing the National Educational Longitudinal Study of 1988.
When are inferences (whether Direct-Likelihood, Bayesian, or Frequentist) obtained from partial data valid? This paper answers this question by offering a new asymptotic theory about inference with missing data that is more general than existing theories. By using more powerful tools from real analysis and probability theory than those used in previous research, it proves that as the sample size increases and the extent of missingness decreases, the mean-loglikelihood function generated by partial data and that ignores the missingness mechanism will almost surely converge uniformly to that which would have been generated by complete data; and if the data are Missing at Random, this convergence depends only on sample size. Thus, inferences from partial data, such as posterior modes, uncertainty estimates, confidence intervals, likelihood ratios, test statistics, and indeed, all quantities or features derived from the partial-data loglikelihood function, will be consistently estimated. They will approximate their complete-data analogues. This adds to previous research which has only proved the consistency and asymptotic normality of the posterior mode, and developed separate theories for Direct-Likelihood, Bayesian, and Frequentist inference. Practical implications of this result are discussed, and the theory is verified using a previous study of International Human Rights Law.
Discrete random structures are important tools in Bayesian nonparametrics and the resulting models have proven effective in density estimation, clustering, topic modeling and prediction, among others. In this paper, we consider nested processes and study the dependence structures they induce. Dependence ranges between homogeneity, corresponding to full exchangeability, and maximum heterogeneity, corresponding to (unconditional) independence across samples. The popular nested Dirichlet process is shown to degenerate to the fully exchangeable case when there are ties across samples at the observed or latent level. To overcome this drawback, inherent to nesting general discrete random measures, we introduce a novel class of latent nested processes. These are obtained by adding common and group-specific completely random measures and, then, normalising to yield dependent random probability measures. We provide results on the partition distributions induced by latent nested processes, and develop an Markov Chain Monte Carlo sampler for Bayesian inferences. A test for distributional homogeneity across groups is obtained as a by product. The results and their inferential implications are showcased on synthetic and real data.
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