Response-adaptive designs have been extensively studied and used in clinical trials. However, there is a lack of a comprehensive study of response-adaptive designs that include covariates, despite their importance in clinical experiments. Because the allocation scheme and the estimation of parameters are affected by both the responses and the covariates, covariate-adjusted response-adaptive (CARA) designs are very complex to formulate. In this paper, we overcome the technical hurdles and lay out a framework for general CARA designs for the allocation of subjects to $K (\geq 2)$ treatments. The asymptotic properties are studied under certain widely satisfied conditions. The proposed CARA designs can be applied to generalized linear models. Two important special cases, the linear model and the logistic regression model, are considered in detail.
It is often important to incorporating covariate information in the design of clinical trials. In literature, there are many designs of using stratification and covariate-adaptive randomization to balance on certain known covariate. Recently Zhang, Hu, Cheung and Chan (2007) have proposed a family of covariate-adjusted response-adaptive (CARA) designs and studied their asymptotic properties. However, these CARA designs often have high variabilities. In this paper, we propose a new family of covariate-adjusted response-adaptive (CARA) designs. We show that the new designs have smaller variabili…
Nonparametric covariate adjustment is considered for log-rank type tests of treatment effect with right-censored time-to-event data from clinical trials applying covariate-adaptive randomization. Our proposed covariate-adjusted log-rank test has a simple explicit formula and a guaranteed efficiency gain over the unadjusted test. We also show that our proposed test achieves universal applicability in the sense that the same formula of test can be universally applied to simple randomization and all commonly used covariate-adaptive randomization schemes such as the stratified permuted block and P…
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…
Covariate-adjusted win statistics in randomized clinical trials with ordinal outcomes
Shenzhen Technology University（深圳理工大学）；Feinberg School of Medicine, Northwestern University（西北大学费恩伯格医学院）；University of Wisconsin - Madison（威斯康星大学麦迪逊分校）；Yale University School of Public Health（耶鲁大学公共卫生学院）；Yale Center for Analytical Sciences, Yale University School of Public Health（耶鲁大学公共卫生学院分析科学中心）；University of Washington（华盛顿大学）；Clinical Learning, Evidence, and Research (CLEAR) Center, University of Washington（华盛顿大学临床学习、证据与研究（CLEAR）中心）；Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine（耶鲁医学院内科学系心血管医学部）；Cardiovascular Medicine Analytics Center, Yale School of Medicine（耶鲁医学院心血管医学分析中心）；Center for Methods in Implementation and Prevention Science, Yale School of Public Health（耶鲁大学公共卫生学院实施与预防科学方法中心）
Understanding the factors that explain differences in survival times is an important issue for establishing policies to improve national health systems. Motivated by breast cancer data arising from the Surveillance Epidemiology and End Results program, we propose a covariate-adjusted proportional hazards frailty model for the analysis of clustered right-censored data. Rather than incorporating exchangeable frailties in the linear predictor of commonly-used survival models, we allow the frailty distribution to flexibly change with both continuous and categorical cluster-level covariates and mod…
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…
Covariate-adaptive randomization is popular in clinical trials with sequentially arrived patients for balancing treatment assignments across prognostic factors which may have influence on the response. However, existing theory on tests for treatment effect under covariate-adaptive randomization is limited to tests under linear or generalized linear models, although covariate-adaptive randomization has been used in survival analysis for a long time and its main application is in survival analysis. Often times, practitioners would simply adopt a conventional test such as the log-rank test or sco…
In the presence of prognostic covariates, inference about the treatment effect with time-to-event endpoints is mostly conducted via the stratified log-rank test or the score test based on the Cox proportional hazards model. In their ground-breaking work Ye and Shao (2020) have demonstrated theoretically that when the model is misspecified, the robust score test (Wei and Lin, 1989) as well as the unstratified log-rank test are conservative in trials with stratified randomization. This fact, however, was not established for the Pocock and Simon covariate-adaptive allocation other than through si…
The analysis of randomized trials with time-to-event endpoints is nearly always plagued by the problem of censoring. As the censoring mechanism is usually unknown, analyses typically employ the assumption of non-informative censoring. While this assumption usually becomes more plausible as more baseline covariates are being adjusted for, such adjustment also raises concerns. Pre-specification of which covariates will be adjusted for (and how) is difficult, thus prompting the use of data-driven variable selection procedures, which may impede valid inferences to be drawn. The adjustment for cova…
Multilevel network meta-regression for multistate models: Population-adjusted joint synthesis of progression and survival data from individual and aggregate evidence
University of California, San Francisco（旧金山加利福尼亚大学）；UCSF Helen Diller Family Comprehensive Cancer Center（UCSF海伦·迪勒家族综合癌症中心）；The Philip R. Lee Institute for Health Policy Studies（菲利普·李健康政策研究所）；Precision AQ
Enhancing Longitudinal Clinical Trial Efficiency with Digital Twins and Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM)
The family-wise error rate (FWER) has been widely used in genome-wide association studies. With the increasing availability of functional genomics data, it is possible to increase the detection power by leveraging these genomic functional annotations. Previous efforts to accommodate covariates in multiple testing focus on the false discovery rate control while covariate-adaptive FWER-controlling procedures remain under-developed. Here we propose a novel covariate-adaptive FWER-controlling procedure that incorporates external covariates which are potentially informative of either the statistica…
Balancing treatment allocation for influential covariates is critical in clinical trials. This has become increasingly important as more and more biomarkers are found to be associated with different diseases in translational research (genomics, proteomics and metabolomics). Stratified permuted block randomization and minimization methods [Pocock and Simon Biometrics 31 (1975) 103-115, etc.] are the two most popular approaches in practice. However, stratified permuted block randomization fails to achieve good overall balance when the number of strata is large, whereas traditional minimization m…
There has been a split in the statistics community about the need for taking covariates into account in the design phase of a clinical trial. There are many advocates of using stratification and covariate-adaptive randomization to promote balance on certain known covariates. However, balance does not always promote efficiency or ensure more patients are assigned to the better treatment. We describe these procedures, including model-based procedures, for incorporating covariates into the design of clinical trials, and give examples where balance, efficiency and ethical considerations may be in …
In clinical trials, there is potential to improve precision and reduce the required sample size by appropriately adjusting for baseline variables in the statistical analysis. This is called covariate adjustment. Despite recommendations by regulatory agencies in favor of covariate adjustment, it remains underutilized leading to inefficient trials. We address two obstacles that make it challenging to use covariate adjustment. A first obstacle is the incompatibility of many covariate adjusted estimators with commonly used boundaries in group sequential designs (GSDs). A second obstacle is the unc…
We propose a novel adaptive design for clinical trials with time-to-event outcomes and covariates (which may consist of or include biomarkers). Our method is based on the expected entropy of the posterior distribution of a proportional hazards model. The expected entropy is evaluated as a function of a patient's covariates, and the information gained due to a patient is defined as the decrease in the corresponding entropy. Candidate patients are only recruited onto the trial if they are likely to provide sufficient information. Patients with covariates that are deemed uninformative are filtere…
A tuning-free procedure is proposed to estimate the covariate-adjusted Gaussian graphical model. For each finite subgraph, this estimator is asymptotically normal and efficient. As a consequence, a confidence interval can be obtained for each edge. The procedure enjoys easy implementation and efficient computation through parallel estimation on subgraphs or edges. We further apply the asymptotic normality result to perform support recovery through edge-wise adaptive thresholding. This support recovery procedure is called ANTAC, standing for Asymptotically Normal estimation with Thresholding af…
This commentary regards a recent simulation study conducted by Aouni, Gaudel-Dedieu and Sebastien, evaluating the performance of different versions of matching-adjusted indirect comparison (MAIC) in an anchored scenario with a common comparator. The simulation study uses survival outcomes and the Cox proportional hazards regression as the outcome model. It concludes that using the LASSO for variable selection is preferable to balancing a maximal set of covariates. However, there are no treatment effect modifiers in imbalance in the study. The LASSO is more efficient because it selects a subset…
We consider nonparametric estimation of a regression curve when the data are observed with multiplicative distortion which depends on an observed confounding variable. We suggest several estimators, ranging from a relatively simple one that relies on restrictive assumptions usually made in the literature, to a sophisticated piecewise approach that involves reconstructing a smooth curve from an estimator of a constant multiple of its absolute value, and which can be applied in much more general scenarios. We show that, although our nonparametric estimators are constructed from predictors of the…
This paper investigates the high-dimensional linear regression with highly correlated covariates. In this setup, the traditional sparsity assumption on the regression coefficients often fails to hold, and consequently many model selection procedures do not work. To address this challenge, we model the variations of covariates by a factor structure. Specifically, strong correlations among covariates are explained by common factors and the remaining variations are interpreted as idiosyncratic components of each covariate. This leads to a factor-adjusted regression model with both common factors …
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…
We consider covariate adjusted regression (CAR), a regression method for situations where predictors and response are observed after being distorted by a multiplicative factor. The distorting factors are unknown functions of an observable covariate, where one specific distorting function is associated with each predictor or response. The dependence of both response and predictors on the same confounding covariate may alter the underlying regression relation between undistorted but unobserved predictors and response. We consider a class of highly flexible adjustment methods for parameter estima…
Classical multivariate principal component analysis has been extended to functional data and termed functional principal component analysis (FPCA). Most existing FPCA approaches do not accommodate covariate information, and it is the goal of this paper to develop two methods that do. In the first approach, both the mean and covariance functions depend on the covariate $Z$ and time scale $t$ while in the second approach only the mean function depends on the covariate $Z$. Both new approaches accommodate additional measurement errors and functional data sampled at regular time grids as well as s…
In this paper, we propose a covariate-adjusted nonlinear regression model. In this model, both the response and predictors can only be observed after being distorted by some multiplicative factors. Because of nonlinearity, existing methods for the linear setting cannot be directly employed. To attack this problem, we propose estimating the distorting functions by nonparametrically regressing the predictors and response on the distorting covariate; then, nonlinear least squares estimators for the parameters are obtained using the estimated response and predictors. Root $n$-consistency and asymp…
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…
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…
Pocock and Simon's marginal procedure (Pocock and Simon, 1975) is often implemented forbalancing treatment allocation over influential covariates in clinical trials. However, the theoretical properties of Pocock and Simion's procedure have remained largely elusive for decades. In this paper, we propose a general framework for covariate-adaptive designs and establish the corresponding theory under widely satisfied conditions. As a special case, we obtain the theoretical properties of Pocock and Simon's marginal procedure: the marginal imbalances and overall imbalance are bounded in probability,…
Concerns have been expressed over the validity of statistical inference under covariate-adaptive randomization despite the extensive use in clinical trials. In the literature, the inferential properties under covariate-adaptive randomization have been mainly studied for continuous responses; in particular, it is well known that the usual two sample t-test for treatment effect is typically conservative, in the sense that the actual test size is smaller than the nominal level. This phenomenon of invalid tests has also been found for generalized linear models without adjusting for the covariates …
This paper deals with estimation with functional covariates. More precisely, we aim at estimating the regression function $m$ of a continuous outcome $Y$ against a standard Wiener coprocess $W$. Following Cadre and Truquet (2015) and Cadre, Klutchnikoff, and Massiot (2017) the Wiener-Itô decomposition of $m(W)$ is used to construct a family of estimators. The minimax rate of convergence over specific smoothness classes is obtained. A data-driven selection procedure is defined following the ideas developed by Goldenshluger and Lepski (2011). An oracle-type inequality is obtained which leads to …
Complete randomization balances covariates on average, but covariate imbalance often exists in finite samples. Rerandomization can ensure covariate balance in the realized experiment by discarding the undesired treatment assignments. Many field experiments in public health and social sciences assign the treatment at the cluster level due to logistical constraints or policy considerations. Moreover, they are frequently combined with rerandomization in the design stage. We refer to cluster rerandomization as a cluster-randomized experiment compounded with rerandomization to balance covariates at…
Covariate-adaptive randomization (CAR) procedures are frequently used in comparative studies to increase the covariate balance across treatment groups. However, because randomization inevitably uses the covariate information when forming balanced treatment groups, the validity of classical statistical methods after such randomization is often unclear. In this article, we derive the theoretical properties of statistical methods based on general CAR under the linear model framework. More importantly, we explicitly unveil the relationship between covariate-adaptive and inference properties by der…
The purpose of this article is to provide an adaptive estimator of the baseline function in the Cox model with high-dimensional covariates. We consider a two-step procedure : first, we estimate the regression parameter of the Cox model via a Lasso procedure based on the partial log-likelihood, secondly, we plug this Lasso estimator into a least-squares type criterion and then perform a model selection procedure to obtain an adaptive penalized contrast estimator of the baseline function. Using non-asymptotic estimation results stated for the Lasso estimator of the regression parameter, we estab…
