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.

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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Response-adaptive randomization has recently attracted a lot of attention in the literature. In this paper, we propose a new and simple family of response-adaptive randomization procedures that attain the Cramer-Rao lower bounds on the allocation variances for any allocation proportions, including optimal allocation proportions. The allocation probability functions of proposed procedures are discontinuous. The existing large sample theory for adaptive designs relies on Taylor expansions of the allocation probability functions, which do not apply to nondifferentiable cases. In the present paper, we study stopping times of stochastic processes to establish the asymptotic efficiency results. Furthermore, we demonstrate our proposal through examples, simulations and a discussion on the relationship with earlier works, including Efron's biased coin design.

Classical Kolmogorov's and Rosenthal's inequalities for the maximum partial sums of random variables are basic tools for studying the strong laws of large numbers. In this paper, motived by the notion of independent and identically distributed random variables under the sub-linear expectation initiated by Peng [12] [14], we introduce the concept of negative dependence of random variables and establish Kolmogorov's and Rosenthal's inequalities for the maximum partial sums of negatively dependent random variables under the sub-linear expectations. As an application, we show that Kolmogorov's strong law of larger numbers holds for independent and identically distributed random variables under a continuous sub-linear expectation if and only if the corresponding Choquet integral is finite. Keywordssub-linear expectation, capacity, Kolmogorov's inequality, Rosenthal's inequality, negative dependence, strong laws of large numbers MSC(2010) 60F15, 60F05

The Generalized P\'{o}lya Urn (GPU) is a popular urn model which is widely used in many disciplines. In particular, it is extensively used in treatment allocation schemes in clinical trials. In this paper, we propose a sequential estimation-adjusted urn model (a nonhomogeneous GPU) which has a wide spectrum of applications. Because the proposed urn model depends on sequential estimations of unknown parameters, the derivation of asymptotic properties is mathematically intricate and the corresponding results are unavailable in the literature. We overcome these hurdles and establish the strong consistency and asymptotic normality for both the patient allocation and the estimators of unknown parameters, under some widely satisfied conditions. These properties are important for statistical inferences and they are also useful for the understanding of the urn limiting process. A superior feature of our proposed model is its capability to yield limiting treatment proportions according to any desired allocation target. The applicability of our model is illustrated with a number of examples.Comment: Published at http://dx.doi.org/10.1214/105051605000000746 in the Annals of Applied Probability (http://www.imstat.org/aap/) by the Institute of Mathematical Statistics (http://www.imstat.org

Stochastic approximation algorithms have been the subject of an enormous body of literature, both theoretical and applied. Recently, Laruelle and Pagès (2013) presented a link between the stochastic approximation and response-adaptive designs in clinical trials based on randomized urn models investigated in Hu (1999, 2005), and derived the asymptotic normality or central limit theorem for the normalized procedure using a central limit theorem for the stochastic approximation algorithm. However, the classical central limit theorem for the stochastic approximation algorithm does not include all cases of its regression function, creating a gap between the results of Laruelle and Pagès (2013) and those of Bai and Hu (2005) for randomized urn models. In this paper, we establish new central limit theorems of the stochastic approximation algorithm under the popular Lindeberg condition to fill this gap. Moreover, we prove that the process of the algorithms can be approximated by a Gaussian process that is a solution of a stochastic differential equation. In our application, we investigate a more involved family of urn models and related adaptive designs in which it is possible to remove the balls from the urn, and the expectation of the total number of balls updated at each stage is not necessary a constant. The asymptotic properties are derived under much less stringent assumptions than those in Hu (1999, 2005) and Laruelle and Pagès (2013).