Optimal cross-over designs for nonlinear mixed models using a first-order expansion

We consider the construction of optimal cross-over designs for nonlinear mixed effect models based on the first-order expansion. We show that for AB/BA designs a balanced subject allocation is optimal when the parameters depend on treatments only. For multiple period, multiple sequence designs, uniform designs are optimal among dual balanced designs under the same conditions. As a by-product, the same results hold for multivariate linear mixed models with variances depending on treatments.     

Multiple comparisons to both a negative and a positive control

This paper addresses multiple comparisons in the presence of both a negative and a positive control. The methodology of the three-arm trial is extended to the case of many experimental treatment arms or different doses of a compound. In contrast to the classic three-arm trial, the focus is on the family-wise error type I. Normally distributed data with either homogeneous or heterogeneous group variances are considered. Explicit criteria for an optimal allocation are proposed. Depending on the pattern of heterogeneity, remarkably unbalanced designs are power-optimal. As an example, the method will be applied to a toxicological experiment.     

A Comparison of Analysis of Covariate-Adjusted Residuals and Analysis of Covariance

Various methods to control the influence of a covariate on a response variable are compared. These methods are ANOVA with or without homogeneity of variances (HOV) of errors and Kruskal–Wallis (K–W) tests on (covariate-adjusted) residuals and analysis of covariance (ANCOVA). Covariate-adjusted residuals are obtained from the overall regression line fit to the entire data set ignoring the treatment levels or factors. It is demonstrated that the methods on covariate-adjusted residuals are only appropriate when the regression lines are parallel and covariate means are equal for all treatments. Empirical size and power performance of the methods are compared by extensive Monte Carlo simulations. We manipulated the conditions such as assumptions of normality and HOV, sample size, and clustering of the covariates. The parametric methods on residuals and ANCOVA exhibited similar size and power when error terms have symmetric distributions with variances having the same functional form for each treatment, and covariates have uniform distributions within the same interval for each treatment. In such cases, parametric tests have higher power compared to the K–W test on residuals. When error terms have asymmetric distributions or have variances that are heterogeneous with different functional forms for each treatment, the tests are liberal with K–W test having higher power than others. The methods on covariate-adjusted residuals are severely affected by the clustering of the covariates relative to the treatment factors when covariate means are very different for treatments. For data clusters, ANCOVA method exhibits the appropriate level. However, such a clustering might suggest dependence between the covariates and the treatment factors, so makes ANCOVA less reliable as well.     

Outcome-adaptive allocation with natural lead-in for three-group trials with binary outcomes

ABSTRACT

Just as Bayes extensions of the frequentist optimal allocation design have been developed for the two-group case, we provide a Bayes extension of optimal allocation in the three-group case. We use the optimal allocations derived by Jeon and Hu [Optimal adaptive designs for binary response trials with three treatments. Statist Biopharm Res. 2010;2(3):310–318] and estimate success probabilities for each treatment arm using a Bayes estimator. We also introduce a natural lead-in design that allows adaptation to begin as early in the trial as possible. Simulation studies show that the Bayesian adaptive designs simultaneously increase the power and expected number of successfully treated patients compared to the balanced design. And compared to the standard adaptive design, the natural lead-in design introduced in this study produces a higher expected number of successes whilst preserving power.     

Effects of correlated covariates on the asymptotic efficiency of matching and inverse probability weighting estimators for causal inference

In observational studies, the overall aim when fitting a model for the propensity score is to reduce bias for an estimator of the causal effect. To make the assumption of an unconfounded treatment plausible researchers might include many, possibly correlated, covariates in the propensity score model. In this paper, we study how the asymptotic efficiency of matching and inverse probability weighting estimators for average causal effects change when the covariates are correlated. We investigate the case with multivariate normal covariates, a logistic model for the propensity score and linear models for the potential outcomes and show results under different model assumptions. We show that the correlation can both increase and decrease the large sample variances of the estimators, and that the correlation affects the asymptotic efficiency of the estimators differently, both with regard to direction and magnitude. Moreover, the strength of the confounding towards the outcome and the treatment plays an important role.     

Longitudinal covariate-adjusted response-adaptive randomized designs

Clinical trials often involve longitudinal data set which has two important characteristics: repeated and correlated measurements and time-varying covariates. In this paper, we propose a general framework of longitudinal covariate-adjusted response-adaptive (LCARA) randomization procedures. We study their properties under widely satisfied conditions. This design skews the allocation probabilities which depend on both patients' first observed covariates and sequentially estimated parameters based on the accrued longitudinal responses and covariates. The asymptotic properties of estimators for the unknown parameters and allocation proportions are established. The special case of binary treatment and continuous responses is studied in detail. Simulation studies and an analysis of the National Cooperative Gallstone Study (NCGS) data are carried out to illustrate the advantages of the proposed LCARA randomization procedure.     

Locally Efficient Semiparametric Estimators for Proportional Hazards Models with Measurement Error

We propose a new class of semiparametric estimators for proportional hazards models in the presence of measurement error in the covariates, where the baseline hazard function, the hazard function for the censoring time, and the distribution of the true covariates are considered as unknown infinite dimensional parameters. We estimate the model components by solving estimating equations based on the semiparametric efficient scores under a sequence of restricted models where the logarithm of the hazard functions are approximated by reduced rank regression splines. The proposed estimators are locally efficient in the sense that the estimators are semiparametrically efficient if the distribution of the error‐prone covariates is specified correctly and are still consistent and asymptotically normal if the distribution is misspecified. Our simulation studies show that the proposed estimators have smaller biases and variances than competing methods. We further illustrate the new method with a real application in an HIV clinical trial.     

Randomization with non-uniform allocations: fulfillment time distributions and bias properties

This article compares the properties of two balanced randomization schemes with several treatments under non-uniform allocation probabilities. According to the first procedure, the so-called truncated multinomial randomization design, the process employs a given allocation distribution, until a treatment receives its quota of subjects, after which this distribution switches to the conditional distribution for the remaining treatments, and so on. The second scheme, the random allocation rule, selects at random any legitimate assignment of the given number of subjects per treatment. The behavior of these two schemes is shown to be quite different: the truncated multinomial randomization design's assignment probabilities to a treatment turn out to vary over the recruitment period, and its accidental bias can be large, whereas the random allocation rule's this bias is bounded. The limiting distributions of the instants at which a treatment receives the given number of subjects is shown to be that of weighted spacings for normal order statistics with different variances. Formulas for the selection bias of both procedures are also derived.     

Marginal Regression for Binary Longitudinal Data in Adaptive Clinical Trials

Abstract.  In an adaptive clinical trial research, it is common to use certain data-dependent design weights to assign individuals to treatments so that more study subjects are assigned to the better treatment. These design weights must also be used for consistent estimation of the treatment effects as well as the effects of the other prognostic factors. In practice, there are however situations where it may be necessary to collect binary responses repeatedly from an individual over a period of time and to obtain consistent estimates for the treatment effect as well as the effects of the other covariates in such a binary longitudinal set up. In this paper, we introduce a binary response-based longitudinal adaptive design for the allocation of individuals to a better treatment and propose a weighted generalized quasi-likelihood approach for the consistent and efficient estimation of the regression parameters including the treatment effects.     

Estimating Optimal Dynamic Regimes: Correcting Bias under the Null

Abstract.  A dynamic regime provides a sequence of treatments that are tailored to patient-specific characteristics and outcomes. In 2004, James Robins proposed g –estimation using structural nested mean models (SNMMs) for making inference about the optimal dynamic regime in a multi-interval trial. The method provides clear advantages over traditional parametric approaches. Robins' g –estimation method always yields consistent estimators, but these can be asymptotically biased under a given SNMM for certain longitudinal distributions of the treatments and covariates, termed exceptional laws. In fact, under the null hypothesis of no treatment effect, every distribution constitutes an exceptional law under SNMMs which allow for interaction of current treatment with past treatments or covariates. This paper provides an explanation of exceptional laws and describes a new approach to g –estimation which we call Zeroing Instead of Plugging In (ZIPI). ZIPI provides nearly identical estimators to recursive g -estimators at non-exceptional laws while providing substantial reduction in the bias at an exceptional law when decision rule parameters are not shared across intervals.     

Subset selection in two-factor experiments using randomization restricted designs

This paper studies subset selection procedures for screening in two-factor treatment designs that employ either a split-plot or strip-plot randomization restricted experimental design laid out in blocks. The goal is to select a subset of treatment combinations associated with the largest mean. In the split-plot design, it is assumed that the block effects, the confounding effects (whole-plot error) and the measurement errors are normally distributed. None of the selection procedures developed depend on the block variances. Subset selection procedures are given for both the case of additive and non-additive factors and for a variety of circumstances concerning the confounding effect and measurement error variances. In particular, procedures are given for (1) known confounding effect and measurement error variances (2) unknown measurement error variance but known confounding effect (3) unknown confounding effect and measurement error variances. The constants required to implement the procedures are shown to be obtainable from available FORTRAN programs and tables. Generalization to the case of strip-plot randomization restriction is considered.     

Bayesian phase II adaptive randomization by jointly modeling time-to-event efficacy and binary toxicity

In oncology, toxicity is typically observable shortly after a chemotherapy treatment, whereas efficacy, often characterized by tumor shrinkage, is observable after a relatively long period of time. In a phase II clinical trial design, we propose a Bayesian adaptive randomization procedure that accounts for both efficacy and toxicity outcomes. We model efficacy as a time-to-event endpoint and toxicity as a binary endpoint, sharing common random effects in order to induce dependence between the bivariate outcomes. More generally, we allow the randomization probability to depend on patients’ specific covariates, such as prognostic factors. Early stopping boundaries are constructed for toxicity and futility, and a superior treatment arm is recommended at the end of the trial. Following the setup of a recent renal cancer clinical trial at M. D. Anderson Cancer Center, we conduct extensive simulation studies under various scenarios to investigate the performance of the proposed method, and compare it with available Bayesian adaptive randomization procedures.     

SEMIPARAMETRIC COMPARISON OF REGRESSION CURVES VIA NORMAL LIKELIHOODS

Härdle & Marron (1990) treated the problem of semiparametric comparison of nonparametric regression curves by proposing a kernel-based estimator derived by minimizing a version of weighted integrated squared error. The resulting estimators of unknown transformation parameters are n-consistent, which prompts a consideration of issues. of optimality. We show that when the unknown mean function is periodic, an optimal nonparametric estimator may be motivated by an elegantly simple argument based on maximum likelihood estimation in a parametric model with normal errors. Strikingly, the asymptotic variance of an optimal estimator of θ does not depend at all on the manner of estimating error variances, provided they are estimated n-consistently. The optimal kernel-based estimator derived via these considerations is asymptotically equivalent to a periodic version of that suggested by Härdle & Marron, and so the latter technique is in fact optimal in this sense. We discuss the implications of these conclusions for the aperiodic case.     

Optimal allocations in sequential tests involving two populations with covariates

We consider the problem of testing which of two normally distributed treatments has the largest mean, when the tested populations incorporate a covariate. From the class of procedures using the invariant sequential probability ratio test we derive an optimal allocation that minimizes, in a continuous time setting, the expected sampling costs. Simulations show that this procedure reduces the number of observations from the costlier treatment and categories while maintaining an overall sample size closer to the “pairwise” procedure. A randomized trial example is given.     

Optimum treatment allocation for dual-objective clinical trials with binary outcomes

A common problem in randomized controlled clinical trials is the optimal assignment of patients to treatment protocols, The traditional optimal design assumes a single criterion, although in reality, there are usually more than one objective in a clinical trial. In this paper, optimal treatment allocation schemes are found for a dual-objective clinical trial with a binary response. A graphical method for finding the optimal strategy is proposed and illustrative examples are discussed.     

Adaptive Isotonic Estimation of the Minimum Effective and Peak Doses in the Presence of Covariates

We consider a problem of estimating the minimum effective and peak doses in the presence of covariates. We propose a sequential strategy for subject assignment that includes an adaptive randomization component to balance the allocation to placebo and active doses with respect to covariates. We conclude that either adjusting for covariates in the model or balancing allocation with respect to covariates is required to avoid bias in the target dose estimation. We also compute optimal allocation to estimate the minimum effective and peak doses in discrete dose space using isotonic regression.     

Covariate-adjusted cost–effectiveness ratios

We describe a method for estimating the marginal cost–effectiveness ratio (CER) of two competing treatments or intervention strategies after adjusting for covariates that may influence the primary endpoint of survival. A Cox regression model is used for modeling covariates and estimates of both the cost and effectiveness parameters, which depend on the survival curve, are obtained from the estimated survival functions for each treatment at a specified covariate. Confidence intervals for the covariate-adjusted CER are presented.     

Estimating a multivariate treatment effect under a biased allocation rule

In a clinical trial with a biased allocation rule whereby all and only those patients at risk are given the new treatment, Robbins and Zhang (1989) derived an asymptotically normal and efficient estimator of the mean difference between the new and old treatments on those at risk. This paper with the use of a well known identity of Stein (1981) generalizes the result to the multivariate situation.     

Response-adaptive randomization for survival trials: the parametric approach

Summary.  Few references deal with response-adaptive randomization procedures for survival outcomes and those that do either dichotomize the outcomes or use a non-parametric approach. In this paper, the optimal allocation approach and a parametric response-adaptive randomization procedure are used under exponential and Weibull distributions. The optimal allocation proportions are derived for both distributions and the doubly adaptive biased coin design is applied to target the optimal allocations. The asymptotic variance of the procedure is obtained for the exponential distribution. The effect of intrinsic delay of survival outcomes is treated. These findings are based on rigorous theory but are also verified by simulation. It is shown that using a doubly adaptive biased coin design to target the optimal allocation proportion results in more patients being randomized to the better performing treatment without loss of power. We illustrate our procedure by redesigning a clinical trial.     

Bayes a-opttmal and efficient block designs for comparing test treatments with a standard treatment

A sufficient condition for the Bayes A-optimality of block designs when comparing a standard treatment with v test treatments is given by Majumdar. (In:Optimal Design and Analysis of Experiments, Y. Dodge, V. V. Fedorov and H. P. Wynn (Eds.), 15-27, North-Holland, 1988). The priors that he considers depend on a constant α ε [0, ∞), with α - 0 corresponding to no prior information at all. The given sufficient condition, consequently, also depends on a. Large families of optimal and highly efficient designs are only known for the case α - 0. We will show how some of the results for α - 0 can be extended to obtain large families of optimal and highly efficient designs for arbitrary values of α. In addition, these results are useful when considering design robustness against an improper choice of α.