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(≥ 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.
A general doubly adaptive biased coin design is proposed for the allocation of subjects to K treatments in a clinical trial. This design follows the same spirit as Efron's biased coin design and applies to the cases where the desired allocation proportions are unknown, but estimated sequentially. Strong consistency, a law of the iterated logarithm and asymptotic normality of this design are obtained under some widely satisfied conditions. For two treatments, a new family of designs is proposed and shown to be less variable than both the randomized play-the-winner rule and the adaptive randomized design. Also the proposed design tends toward a randomization scheme (with a fixed target proportion) as the size of the experiment increases.
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 methods
also suffer from the potential drawback of large within-stratum imbalances.
Moreover, the theoretical bases of minimization methods remain largely elusive.
In this paper, we propose a new covariate-adaptive design that is able to
control various types of imbalances. We show that the joint process of
within-stratum imbalances is a positive recurrent Markov chain under certain
conditions. Therefore, this new procedure yields more balanced allocation. The
advantages of the proposed procedure are also demonstrated by extensive
simulation studies. Our work provides a theoretical tool for future research in
this area.Comment: Published in at http://dx.doi.org/10.1214/12-AOS983 the Annals of
Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical
Statistics (http://www.imstat.org
This paper studies a very general urn model stimulated by designs in clinical trials, where the number of balls of different types added to the urn at trial n depends on a random outcome directed by the composition at trials 1, 2,. .. , n − 1. Patient treatments are allocated according to types of balls. We establish the strong consistency and asymptotic normality for both the urn composition and the patient allocation under general assumptions on random generating matrices which determine how balls are added to the urn. Also we obtain explicit forms of the asymptotic variance-covariance matrices of both the urn composition and the patient allocation. The conditions on the nonhomogeneity of generating matrices are mild and widely satisfied in applications. Several applications are also discussed.
Markov chain marginal bootstrap (MCMB) is a new method for constructing con dence intervals or regions for maximum likelihood estimators of certain parametric models and for a wide class of M estimators of linear regression. The MCMB method distinguishes itself from the usual bootstrap methods in two important aspects: it involves solving only one-dimensional equations for parameters of any dimension and produces a Markov chain rather than a (conditionally) independent sequence. It is designed to alleviate computational burdens often associated with bootstrap in high-dimensional problems. The validity of MCMB is established through asymptotic analyses and illustrated with empirical and simulation studies for linear regression and generalized linear models.
Covariate-adaptive designs are often implemented to balance important covariates in clinical trials. However, the theoretical properties of conventional testing hypotheses are usually unknown under covariate-adaptive randomized clinical trials. In the literature, most studies are based on simulations. In this article, we provide theoretical foundation of hypothesis testing under covariate-adaptive designs based on linear models. We derive the asymptotic distributions of the test statistics of testing both treatment effects and the significance of covariates under null and alternative hypotheses. Under a large class of covariate-adaptive designs, (i) the hypothesis testing to compare treatment effects is usually conservative in terms of small Type I error; (ii) the hypothesis testing to compare treatment effects is usually more powerful than complete randomization; and (iii) the hypothesis testing for significance of covariates is still valid. The class includes most of the covariate-adaptive designs in the literature; for example, Pocock and Simon's marginal procedure, stratified permuted block design, etc. Numerical studies are also performed to assess their corresponding finite sample properties. Supplementary material for this article is available online.
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