In this paper, we revisit the notion of partial copula, originally introduced to test conditional independence, highlighting its capability to represent the dependence between two random variables after removing their dependence with a covariate. Building upon results previously presented in the literature, we show that partial copulas can be seen as a nonlinear analogue of partial correlation. Then, we prove several results showing how dependence properties of the conditional copulas constrain the form of the partial copula. Finally, a simulation study is conducted to illustrate the results and to show the potential of the partial copula as a way to describe covariate-adjusted statistical dependence. This highlights the potential of the method to be used in causal inference problems and to recover the true sign of a causal effect.
To maximize clinical benefit, clinicians routinely tailor treatment to the individual characteristics of each patient, where individualized treatment rules are needed and are of significant research interest to statisticians. In the covariate-adjusted randomization clinical trial with many covariates, we model the treatment effect with an unspecified function of a single index of the covariates and leave the baseline response completely arbitrary. We devise a class of estimators to consistently estimate the treatment effect function and its associated index while bypassing the estimation of th…
We consider the problem of identifying sub-groups of participants in a clinical trial that have enhanced treatment effect. Recursive partitioning methods that recursively partition the covariate space based on some measure of between groups treatment effect difference are popular for such sub-group identification. The most commonly used recursive partitioning method, the classification and regression tree algorithm, first creates a large tree by recursively partitioning the covariate space using some splitting criteria and then selects the final tree from all subtrees of the large tree. In the…
We often seek to estimate the causal effect of an exposure on a particular outcome in both randomized and observational settings. One such estimation method is the covariate-adjusted residuals estimator, which was designed for individually or cluster randomized trials. In this manuscript, we study the properties of this estimator and develop a new estimator that utilizes both covariate adjustment and inverse probability weighting We support our theoretical results with a simulation study and an application in an infectious disease setting. The covariate-adjusted residuals estimator is an effic…
In this article, we propose the outcome-adjusted balance measure to perform model selection for the generalized propensity score (GPS), which serves as an essential component in estimation of the pairwise average treatment effects (ATEs) in observational studies with more than two treatment levels. The primary goal of the balance measure is to identify the GPS model specification such that the resulting ATE estimator is consistent and efficient. Following recent empirical and theoretical evidence, we establish that the optimal GPS model should only include covariates related to the outcomes. G…
Two-stage least squares (TSLS) estimators and variants thereof are widely used to infer the effect of an exposure on an outcome using instrumental variables (IVs). They belong to a wider class of two-stage IV estimators, which are based on fitting a conditional mean model for the exposure, and then using the fitted exposure values along with the covariates as predictors in a linear model for the outcome. We show that standard TSLS estimators enjoy greater robustness to model misspecification than more general two-stage estimators. However, by potentially using a wrong exposure model, e.g. when…
Datasets from field experiments with covariate-adaptive randomizations (CARs) usually contain extra covariates in addition to the strata indicators. We propose to incorporate these additional covariates via auxiliary regressions in the estimation and inference of unconditional quantile treatment effects (QTEs) under CARs. We establish the consistency and limit distribution of the regression-adjusted QTE estimator and prove that the use of multiplier bootstrap inference is non-conservative under CARs. The auxiliary regression may be estimated parametrically, nonparametrically, or via regulariza…
To improve precision of estimation and power of testing hypothesis for an unconditional treatment effect in randomized clinical trials with binary outcomes, researchers and regulatory agencies recommend using g-computation as a reliable method of covariate adjustment. However, the practical application of g-computation is hindered by the lack of an explicit robust variance formula that can be used for different unconditional treatment effects of interest. To fill this gap, we provide explicit and robust variance estimators for g-computation estimators and demonstrate through simulations that t…
We develop finite-population asymptotic theory for covariate adjustment in randomization-based causal inference for 2K factorial designs. In particular, we confirm that both the unadjusted and covariate-adjusted estimators of the factorial effects are asymptotically normal, and the latter is more precise than the former.
The purpose of this work is to improve the efficiency in estimating the average causal effect (ACE) on the survival scale where right-censoring exists and high-dimensional covariate information is available. We propose new estimators using regularized survival regression and survival random forests (SRF) to make the adjustment for the high dimensional covariates to improve efficiency. We study the behavior of the adjusted estimator under mild assumptions and show theoretical guarantees that the proposed estimators are more efficient than the unadjusted ones asymptotically when using SRF for ad…
Fisher's randomization test (FRT) delivers exact $p$-values under the strong null hypothesis of no treatment effect on any units whatsoever and allows for flexible covariate adjustment to improve the power. Of interest is whether the procedure could also be valid for testing the weak null hypothesis of zero average treatment effect. Towards this end, we evaluate two general strategies for FRT with covariate-adjusted test statistics: that based on the residuals from an outcome model with only the covariates, and that based on the output from an outcome model with both the treatment and the cova…
The statistical tests that are commonly used for detecting mean or median treatment effects suffer from low power when the two distribution functions differ only in the upper (or lower) tail, as in the assessment of the Total Sharp Score (TSS) under different treatments for rheumatoid arthritis. In this article, we propose a more powerful test that detects treatment effects through the expected shortfalls. We show how the expected shortfall can be adjusted for covariates, and demonstrate that the proposed test can achieve a substantial sample size reduction over the conventional tests on the m…
A benefit of randomized experiments is that covariate distributions of treatment and control groups are balanced on average, resulting in simple unbiased estimators for treatment effects. However, it is possible that a particular randomization yields covariate imbalances that researchers want to address in the analysis stage through adjustment or other methods. Here we present a randomization test that conditions on covariate balance by only considering treatment assignments that are similar to the observed one in terms of covariate balance. Previous conditional randomization tests have only a…
Population adjustment methods such as matching-adjusted indirect comparison (MAIC) are increasingly used to compare marginal treatment effects when there are cross-trial differences in effect modifiers and limited patient-level data. MAIC is sensitive to poor covariate overlap and cannot extrapolate beyond the observed covariate space. Current outcome regression-based alternatives can extrapolate but target a conditional treatment effect that is incompatible in the indirect comparison. When adjusting for covariates, one must integrate or average the conditional estimate over the population of …
In clinical trials, a covariate-adjusted response-adaptive (CARA) design allows a subject newly entering a trial a better chance of being allocated to a superior treatment regimen based on cumulative information from previous subjects, and adjusts the allocation according to individual covariate information. Since this design allocates subjects sequentially, it is natural to apply a sequential method for estimating the treatment effect in order to make the data analysis more efficient. In this paper, we study the sequential estimation of treatment effect for a general CARA design. A stopping c…
We propose a new semi-parametric distributional regression smoother that is based on a copula decomposition of the joint distribution of the vector of response values. The copula is high-dimensional and constructed by inversion of a pseudo regression, where the conditional mean and variance are semi-parametric functions of covariates modeled using regularized basis functions. By integrating out the basis coefficients, an implicit copula process on the covariate space is obtained, which we call a `regression copula'. We combine this with a non-parametric margin to define a copula model, where t…
The difference in restricted mean survival times between two groups is a clinically relevant summary measure. With observational data, there may be imbalances in confounding variables between the two groups. One approach to account for such imbalances is to estimate a covariate-adjusted restricted mean difference by modeling the covariate-adjusted survival distribution and then marginalizing over the covariate distribution. We demonstrate that the mean-squared error of the restricted mean difference is bounded by the mean-squared error of the covariate-adjusted survival distribution estimators…
The primary goal of randomized trials is to compare the effects of different interventions on some outcome of interest. In addition to the treatment assignment and outcome, data on baseline covariates, such as demographic characteristics or biomarker measurements, are typically collected. Incorporating such auxiliary covariates in the analysis of randomized trials can increase power, but questions remain about how to preserve type I error when incorporating such covariates in a flexible way, particularly when the number of randomized units is small. Using the Young Citizens study, a cluster-ra…
We consider the problem of estimating and inferring treatment effects in randomized experiments. In practice, stratified randomization, or more generally, covariate-adaptive randomization, is routinely used in the design stage to balance the treatment allocations with respect to a few variables that are most relevant to the outcomes. Then, regression is performed in the analysis stage to adjust the remaining imbalances to yield more efficient treatment effect estimators. Building upon and unifying the recent results obtained for ordinary least squares adjusted estimators under covariate-adapti…
We study regression discontinuity designs when covariates are included in the estimation. We examine local polynomial estimators that include discrete or continuous covariates in an additive separable way, but without imposing any parametric restrictions on the underlying population regression functions. We recommend a covariate-adjustment approach that retains consistency under intuitive conditions, and characterize the potential for estimation and inference improvements. We also present new covariate-adjusted mean squared error expansions and robust bias-corrected inference procedures, with …
Copulas provide an attractive approach for constructing multivariate distributions with flexible marginal distributions and different forms of dependences. Of particular importance in many areas is the possibility of explicitly forecasting the tail-dependences. Most of the available approaches are only able to estimate tail-dependences and correlations via nuisance parameters, but can neither be used for interpretation, nor for forecasting. Aiming to improve copula forecasting performance, we propose a general Bayesian approach for modeling and forecasting tail-dependences and correlations as …
Regression adjustments are often considered by investigators to improve the estimation efficiency of causal effect in randomized experiments when there exists many pre-experiment covariates. In this paper, we provide conditions that guarantee the penalized regression including the Ridge, Elastic Net and Adapive Lasso adjusted causal effect estimators are asymptotic normal and we show that their asymptotic variances are no greater than that of the simple difference-in-means estimator, as long as the penalized estimators are risk consistent. We also provide conservative estimators for the asympt…
Pair-copula constructions are flexible dependence models that use bivariate copulas as building blocks. In this paper, we use generalized additive models to extend them by allowing covariates effects. Borrowing ideas from a traditionally univariate context, we let each pair-copula parameter depend directly on the covariates in a parametric, semiparametric or nonparametric way. We propose a sequential estimation method that we study by simulation, and apply it to investigate the time-varying dependence structure between the intraday returns on four major foreign exchange rates. An R package, a …
We propose a flexible copula model to describe changes with a covariate in the dependence structure of (conditionally exchangeable) random variables. The starting point is a spline approximation to the generator of an Archimedean copula. Changes in the dependence structure with a covariate $x$ are modelled by flexible regression of the spline coefficients on $x$. The performances and properties of the spline estimate of the reference generator and the abilities of these conditional models to approximate conditional copulas are studied through simulations. Inference is made using Bayesian argum…
Differences between biological networks corresponding to disease conditions can help delineate the underlying disease mechanisms. Existing methods for differential network analysis do not account for dependence of networks on covariates. As a result, these approaches may detect spurious differential connections induced by the effect of the covariates on both the disease condition and the network. To address this issue, we propose a general covariate-adjusted test for differential network analysis. Our method assesses differential network connectivity by testing the null hypothesis that the net…
Conditional copula graphic estimator for semi-competing risks data
Children’s Hospital Research Institute of Manitoba, University of Manitoba（曼尼托巴儿童医院研究所，曼尼托巴大学）；Department of Mathematics and Statistics, University of Guelph（圭尔夫大学数学与统计系）；Hospital for Sick Children（多伦多多伦多儿童医院）；Department of Statistics, University of Manitoba（曼尼托巴大学统计系）
Conditional copulas are flexible statistical tools that couple joint conditional and marginal conditional distributions. In a linear regression setting with more than one covariate and two dependent outcomes, we propose the use of additive models for conditional bivariate copula models and discuss computation and model selection tools for performing Bayesian inference. The method is illustrated using simulations and a real example.
In this paper we propose a general class of covariate-adjusted response-adaptive (CARA) designs based on a new functional urn model. We prove strong consistency concerning the functional urn proportion and the proportion of subjects assigned to the treatment groups, in the whole study and for each covariate profile, allowing the distribution of the responses conditioned on covariates to be estimated nonparametrically. In addition, we establish joint central limit theorems for the above quantities and the sufficient statistics of features of interest, which allow to construct procedures to make…
Accurate diagnosis of disease is of fundamental importance in clinical practice and medical research. Before a medical diagnostic test is routinely used in practice, its ability to distinguish between diseased and nondiseased states must be rigorously assessed through statistical analysis. The receiver operating characteristic (ROC) curve is the most popular used tool for evaluating the discriminatory ability of continuous-outcome diagnostic tests. It has been acknowledged that several factors (e.g., subject-specific characteristics, such as age and/or gender) can affect the test's accuracy be…
This paper proposes a modelling strategy to infer the impact of a covariate on the dependence structure of right-censored clustered event time data. The joint survival function of the event times is modelled using a parametric conditional copula whose parameter depends on a cluster-level covariate in a functional way. We use a local likelihood approach to estimate the form of the copula parameter and outline a generalized likelihood ratio-type test strategy to formally test its constancy. A bootstrap procedure is employed to obtain an approximate $p$-value for the test. The performance of the …
In this paper, we present three estimators of the ROC curve when missing observations arise among the biomarkers. Two of the procedures assume that we have covariates that allow to estimate the propensity and the estimators are obtained using an inverse probability weighting method or a smoothed version of it. The other one assumes that the covariates are related to the biomarkers through a regression model which enables us to construct convolution--based estimators of the distribution and quantile functions. Consistency results are obtained under mild conditions. Through a numerical study we …
We present an objective Bayes method for covariance selection in Gaussian multivariate regression models whose error term has a covariance structure which is Markov with respect to a Directed Acyclic Graph (DAG). The scope is covariate-adjusted sparse graphical model selection, a topic of growing importance especially in the area of genetical genomics (eQTL analysis). Specifically, we provide a closed-form expression for the marginal likelihood of any DAG (with small parent sets) whose computation virtually requires no subjective elicitation by the user and involves only conjugate matrix norma…
We present a general framework for using existing data to estimate the efficiency gain from using a covariate-adjusted estimator of a marginal treatment effect in a future randomized trial. We describe conditions under which it is possible to define a mapping from the distribution that generated the existing external data to the relative efficiency of a covariate-adjusted estimator compared to an unadjusted estimator. Under conditions, these relative efficiencies approximate the ratio of sample size needed to achieve a desired power. We consider two situations where the outcome is either fully…
In recent years, conditional copulas, that allow dependence between variables to vary according to the values of one or more covariates, have attracted increasing attention. In high dimension, vine copulas offer greater flexibility compared to multivariate copulas, since they are constructed using bivariate copulas as building blocks. In this paper we present a novel inferential approach for multivariate distributions, which combines the flexibility of vine constructions with the advantages of Bayesian nonparametrics, not requiring the specification of parametric families for each pair copula.…
In contemporary scientific research, it is of great interest to predict a categorical response based on a high-dimensional tensor (i.e. multi-dimensional array) and additional covariates. This mixture of different types of data leads to challenges in statistical analysis. Motivated by applications in science and engineering, we propose a comprehensive and interpretable discriminant analysis model, called CATCH model (in short for Covariate-Adjusted Tensor Classification in High-dimensions), which efficiently integrates the covariates and the tensor to predict the categorical outcome. The CATCH…
