Conditional estimation using prior information in 2‐stage group sequential designs assuming asymptotic normality when the trial terminated early

Two‐stage designs are widely used to determine whether a clinical trial should be terminated early. In such trials, a maximum likelihood estimate is often adopted to describe the difference in efficacy between the experimental and reference treatments; however, this method is known to display conditional bias. To reduce such bias, a conditional mean‐adjusted estimator (CMAE) has been proposed, although the remaining bias may be nonnegligible when a trial is stopped for efficacy at the interim analysis. We propose a new estimator for adjusting the conditional bias of the treatment effect by extending the idea of the CMAE. This estimator is calculated by weighting the maximum likelihood estimate obtained at the interim analysis and the effect size prespecified when calculating the sample size. We evaluate the performance of the proposed estimator through analytical and simulation studies in various settings in which a trial is stopped for efficacy or futility at the interim analysis. We find that the conditional bias of the proposed estimator is smaller than that of the CMAE when the information time at the interim analysis is small. In addition, the mean‐squared error of the proposed estimator is also smaller than that of the CMAE. In conclusion, we recommend the use of the proposed estimator for trials that are terminated early for efficacy or futility.     

Estimates of subgroup treatment effects in overall nonsignificant trials: To what extent should we believe in them?

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall “failed” trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial of limited value to design the replication trial. An empirical Bayesian shrinkage method is suggested to minimize this overestimation. The proposed estimator appears to offer either a good or a conservative correction to the observed subgroup treatment effect hence provides a more reliable subgroup treatment effect estimate for adequate planning of future studies.     

Comparisons of allocating sample size rationally into individual regions under heterogeneous effect size in a multiregional trial by a fixed effect model and a random effect model

ABSTRACT

Recently, sponsors and regulatory authorities pay much attention on the multiregional trial because it can shorten the drug lag or the time lag for approval, simultaneous drug development, submission, and approval in the world. However, many studies have shown that genetic determinants may mediate variability among persons in response to a drug. Thus, some therapeutics benefit part of treated patients. It means that the assumption of homogeneous effect size is not suitable for multiregional trials. In this paper, we conduct the sample size determination of a multiregional clinical trial calculated by fixed effect and random effect under the assumption of heterogeneous effect size. The performances of fixed effect and random effect on allocating sample size on a specific region are compared by statistical criteria for consistency between the region of interest and overall results.     

An empirical Bayes approach to evaluation of results for a specific region in multiregional clinical trials

To accelerate the drug development process and shorten approval time, the design of multiregional clinical trials (MRCTs) incorporates subjects from many countries/regions around the world under the same protocol. After showing the overall efficacy of a drug in all global regions, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each of them. In this paper, we focus on a specific region and establish a statistical criterion to assess the consistency between the specific region and overall results in an MRCT. More specifically, we treat each region in an MRCT as an independent clinical trial, and each perhaps has different treatment effect. We then construct the empirical prior information for the treatment effect for the specific region on the basis of all of the observed data from other regions. We will conclude similarity between the specific region and all regions if the posterior probability of deriving a positive treatment effect in the specific region is large, say 80%. Numerical examples illustrate applications of the proposed approach in different scenarios. Copyright © 2013 John Wiley & Sons, Ltd.     

On the ridge regression estimator with sub-space restriction

In the linear regression model with elliptical errors, a shrinkage ridge estimator is proposed. In this regard, the restricted ridge regression estimator under sub-space restriction is improved by incorporating a general function which satisfies Taylor’s series expansion. Approximate quadratic risk function of the proposed shrinkage ridge estimator is evaluated in the elliptical regression model. A Monte Carlo simulation study and analysis based on a real data example are considered for performance analysis. It is evident from the numerical results that the shrinkage ridge estimator performs better than both unrestricted and restricted estimators in the multivariate t-regression model, for some specific cases.     

A model selection criterion for discriminant analysis of high-dimensional data with fewer observations

This paper is concerned with the problem of selecting variables in two-group discriminant analysis for high-dimensional data with fewer observations than the dimension. We consider a selection criterion based on approximately unbiased for AIC type of risk. When the dimension is large compared to the sample size, AIC type of risk cannot be defined. We propose AIC by replacing maximum likelihood estimator with ridge-type estimator. This idea follows Srivastava and Kubokawa (2008). It has been further extended by Yamamura et al. (2010). Simulation revealed that the proposed AIC performs well.     

Interval shrinkage estimators

This paper considers estimation of an unknown distribution parameter in situations where we believe that the parameter belongs to a finite interval. We propose for such situations an interval shrinkage approach which combines in a coherent way an unbiased conventional estimator and non-sample information about the range of plausible parameter values. The approach is based on an infeasible interval shrinkage estimator which uniformly dominates the underlying conventional estimator with respect to the mean square error criterion. This infeasible estimator allows us to obtain useful feasible counterparts. The properties of these feasible interval shrinkage estimators are illustrated both in a simulation study and in empirical examples.     

Shrinkage estimation of reliability in the exponential distribution

In this paper we propose two shrinkage testimators for the reliability of the exponential distribution and study their properties. The optimum shrinkage coefficients for the shrinkage testimators are obtained based on a regret function and the minimax regret criterion. Shrinkage testimators are compared with a preliminary test estimator and with the usual estimator in terms of mean squared error. The proposed shrinkage testimators are shown to be preferable to the preliminary test estimator and the usual estimator when the prior value of mean life is close to the true mean life.     

Stein-type estimation using ranked set sampling

In this study, we consider the application of the James–Stein estimator for population means from a class of arbitrary populations based on ranked set sample (RSS). We consider a basis for optimally combining sample information from several data sources. We succinctly develop the asymptotic theory of simultaneous estimation of several means for differing replications based on the well-defined shrinkage principle. We showcase that a shrinkage-type estimator will have, under quadratic loss, a substantial risk reduction relative to the classical estimator based on simple random sample and RSS. Asymptotic distributional quadratic biases and risks of the shrinkage estimators are derived and compared with those of the classical estimator. A simulation study is used to support the asymptotic result. An over-riding theme of this study is that the shrinkage estimation method provides a powerful extension of its traditional counterpart for non-normal populations. Finally, we will use a real data set to illustrate the computation of the proposed estimators.     

On the estimation of reliabilty function in a Weibull lifetime distribution

The estimation of the reliability function of the Weibull lifetime model is considered in the presence of uncertain prior information (not in the form of prior distribution) on the parameter of interest. This information is assumed to be available in some sort of a realistic conjecture. In this article, we focus on how to combine sample and non-sample information together in order to achieve improved estimation performance. Three classes of point estimatiors, namely, the unrestricted estimator, the shrinkage estimator and shrinkage preliminary test estimator (SPTE) are proposed. Their asymptotic biases and mean-squared errors are derived and compared. The relative dominance picture of the estimators is presented. Interestingly, the proposed SPTE dominates the unrestricted estimator in a range that is wider than that of the usual preliminary test estimator. A small-scale simulation experiment is used to examine the small sample properties of the proposed estimators. Our simulation investigations have provided strong evidence that corroborates with asymptotic theory. The suggested estimation methods are applied to a published data set to illustrate the performance of the estimators in a real-life situation.     

Variance estimation of DEE and regression estimator when a first-phase cluster sample is restratified

We consider a variance estimation when a stratified single stage cluster sample is selected in the first phase and a stratified simple random element sample is selected in the second phase. We propose explicit formulas of (asymptotically), we propose explicit formulas of (asymptotically) unbiased variance estimators for the double expansion estimator and regression estimator. We perform a small simulation study to investigate the performance of the proposed variance estimators. In our simulation study, the proposed variance estimator showed better or comparable performance to the Jackknife variance estimator. We also extend the results to a two-phase sampling design in which a stratified pps with replacement cluster sample is selected in the first phase.     

Nonparametric estimation with left-truncated and right-censored data when the sample size before truncation is known

In this article, we consider nonparametric estimation of the survival function when the data are subject to left-truncation and right-censoring and the sample size before truncation is known. We propose two estimators. The first estimator is derived based on a self-consistent estimating equation. The second estimator is obtained by using the constrained expectation-maximization algorithm. Simulation results indicate that both estimators are more efficient than the product-limit estimator. When there is no censoring, the performance of the proposed estimators is compared with that of the estimator proposed by Li and Qin [Semiparametric likelihood-based inference for biased and truncated data when total sample size is known, J. R. Stat. Soc. B 60 (1998), pp. 243–254] via simulation study.     

A High‐dimensional Focused Information Criterion

The focused information criterion for model selection is constructed to select the model that best estimates a particular quantity of interest, the focus, in terms of mean squared error. We extend this focused selection process to the high‐dimensional regression setting with potentially a larger number of parameters than the size of the sample. We distinguish two cases: (i) the case where the considered submodel is of low dimension and (ii) the case where it is of high dimension. In the former case, we obtain an alternative expression of the low‐dimensional focused information criterion that can directly be applied. In the latter case, we use a desparsified estimator that allows us to derive the mean squared error of the focus estimator. We illustrate the performance of the high‐dimensional focused information criterion with a numerical study and a real dataset.     

The failure of meta-analytic asymptotics for the seemingly efficient estimator of the common risk difference

We consider the case of a multicenter trial in which the center specific sample sizes are potentially small. Under homogeneity, the conventional procedure is to pool information using a weighted estimator where the weights used are inverse estimated center-specific variances. Whereas this procedure is efficient for conventional asymptotics (e. g. center-specific sample sizes become large, number of center fixed), it is commonly believed that the efficiency of this estimator holds true also for meta-analytic asymptotics (e.g. center-specific sample size bounded, potentially small, and number of centers large). In this contribution we demonstrate that this estimator fails to be efficient. In fact, it shows a persistent bias with increasing number of centers showing that it isnot meta-consistent. In addition, we show that the Cochran and Mantel-Haenszel weighted estimators are meta-consistent and, in more generality, provide conditions on the weights such that the associated weighted estimator is meta-consistent.     

Generalized preliminary test stochastic restricted estimator in the linear regression model

ABSTRACT

In this paper, we propose three generalized estimators, namely, generalized unrestricted estimator (GURE), generalized stochastic restricted estimator (GSRE), and generalized preliminary test stochastic restricted estimator (GPTSRE). The GURE can be used to represent the ridge estimator, almost unbiased ridge estimator (AURE), Liu estimator, and almost unbiased Liu estimator. When stochastic restrictions are available in addition to the sample information, the GSRE can be used to represent stochastic mixed ridge estimator, stochastic restricted Liu estimator, stochastic restricted almost unbiased ridge estimator, and stochastic restricted almost unbiased Liu estimator. The GPTSRE can be used to represent the preliminary test estimators based on mixed estimator. Using the GPTSRE, the properties of three other preliminary test estimators, namely preliminary test stochastic mixed ridge estimator, preliminary test stochastic restricted almost unbiased Liu estimator, and preliminary test stochastic restricted almost unbiased ridge estimator can also be discussed. The mean square error matrix criterion is used to obtain the superiority conditions to compare the estimators based on GPTSRE with some biased estimators for the two cases for which the stochastic restrictions are correct, and are not correct. Finally, a numerical example and a Monte Carlo simulation study are done to illustrate the theoretical findings of the proposed estimators.     

Inference under pivotal sampling: Properties,variance estimation,and application to tesselation for spatial sampling

Unequal probability sampling is commonly used for sample selection. In the context of spatial sampling, the variables of interest often present a positive spatial correlation, so that it is intuitively relevant to select spatially balanced samples. In this article, we study the properties of pivotal sampling and propose an application to tesselation for spatial sampling. We also propose a simple conservative variance estimator. We show that the proposed sampling design is spatially well balanced, with good statistical properties and is computationally very efficient.     

A Note on Estimation of a Distribution Function in a Nonparametric Set-up Using Stein’s Shrinkage Estimation Technique

Based on Stein’s famous shrinkage estimation of a multivariate normal distribution, we propose a new type of estimators of the distribution function of a random variable in a nonparametric setup. The proposed estimators are then compared with the empirical distribution function, which is the best equivariant estimator under a well-known loss function. Our extensive simulation study shows that our proposed estimators can perform better for moderate to large sample sizes.     

Variable selection in heterogeneous panel data models with cross-sectional dependence

This paper studies the Bridge estimator for a high-dimensional panel data model with heterogeneous varying coefficients, where the random errors are assumed to be serially correlated and cross-sectionally dependent. We establish oracle efficiency and the asymptotic distribution of the Bridge estimator, when the number of covariates increases to infinity with the sample size in both dimensions. A BIC-type criterion is also provided for tuning parameter selection. We further generalise the marginal Bridge estimator for our model to asymptotically correctly identify the covariates with zero coefficients even when the number of covariates is greater than the sample size under a partial orthogonality condition. The finite sample performance of the proposed estimator is demonstrated by simulated data examples, and an empirical application with the US stock dataset is also provided.     

Empirical bayes shrinkage estimation of reliability in the exponential distribution

In this paper we propose two empirical Bayes shrinkage estimators for the reliability of the exponential distribution and study their properties. Under the uniform prior distribution and the inverted gamma prior distribution these estimators are developed and compared with a preliminary test estimator and with a shrinkage testimator in terms of mean squared error. The proposed empirical Bayes shrinkage estimator under the inverted gamma prior distribution is shown to be preferable to the preliminary test estimator and the shrinkage testimator when the prior value of mean life is clsoe to the true mean life.     

An improved and efficient biased estimation technique in logistic regression model

Abstract

In this article, we propose a new improved and efficient biased estimation method which is a modified restricted Liu-type estimator satisfying some sub-space linear restrictions in the binary logistic regression model. We study the properties of the new estimator under the mean squared error matrix criterion and our results show that under certain conditions the new estimator is superior to some other estimators. Moreover, a Monte Carlo simulation study is conducted to show the performance of the new estimator in the simulated mean squared error and predictive median squared errors sense. Finally, a real application is considered.