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.     

Establishing consistency across all regions in a multi-regional clinical trial

In recent years, global collaboration has become a conventional strategy for new drug development. To accelerate the development process and shorten approval time, the design of multi-regional 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 a global trial, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each region. However, most of the recent approaches developed for the design and evaluation of MRCTs focus on establishing criteria to examine whether the overall results from the MRCT can be applied to a specific region. In this paper, we use the consistency criterion of Method 1 from the Japanese Ministry of Health, Labour and Welfare (MHLW) guidance to assess whether the overall results from the MRCT can be applied to all regions. Sample size determination for the MRCT is also provided to take all the consistency criteria from each individual region into account. Numerical examples are given to illustrate applications of the proposed approach.     

Sample size allocation in multiregional equivalence studies

With the increasing globalization of drug development, the multiregional clinical trial (MRCT) has gained extensive use. The data from MRCTs could be accepted by regulatory authorities across regions and countries as the primary sources of evidence to support global marketing drug approval simultaneously. The MRCT can speed up patient enrollment and drug approval, and it makes the effective therapies available to patients all over the world simultaneously. However, there are many challenges both operationally and scientifically in conducting a drug development globally. One of many important questions to answer for the design of a multiregional study is how to partition sample size into each individual region. In this paper, two systematic approaches are proposed for the sample size allocation in a multiregional equivalence trial. A numerical evaluation and a biosimilar trial are used to illustrate the characteristics of the proposed approaches.     

Test for the equality of several correlation coefficients

We derive two C(α) statistics and the likelihood-ratio statistic for testing the equality of several correlation coefficients, from k ≥ 2 independent random samples from bivariate normal populations. The asymptotic relationship of the C(α) tests, the likelihood-ratio test, and a statistic based on the normality assumption of Fisher's Z-transform of the sample correlation coefficient is established. A comparative performance study, in terms of size and power, is then conducted by Monte Carlo simulations. The likelihood-ratio statistic is often too liberal, and the statistic based on Fisher's Z-transform is conservative. The performance of the two C(α) statistics is identical. They maintain significance level well and have almost the same power as the other statistics when empirically calculated critical values of the same size are used. The C(α) statistic based on a noniterative estimate of the common correlation coefficient (based on Fisher's Z-transform) is recommended.     

Detecting Outliers in Gamma Distribution

Zerbet and Nikulin presented the new statistic Z _k for detecting outliers in exponential distribution. They also compared this statistic with Dixon's statistic D _k . In this article, we extend this approach to gamma distribution and compare the result with Dixon's statistic. The results show that the test based on statistic Z _k is more powerful than the test based on the Dixon's statistic.     

Group-sequential logrank methods for trial designs using bivariate non-competing event-time outcomes

We discuss the multivariate (2L-variate) correlation structure and the asymptotic distribution for the group-sequential weighted logrank statistics formulated when monitoring two correlated event-time outcomes in clinical trials. The asymptotic distribution and the variance–covariance for the 2L-variate weighted logrank statistic are derived as available in various group-sequential trial designs. These methods are used to determine a group-sequential testing procedure based on calendar times or information fractions. We apply the theoretical results to a group-sequential method for monitoring a clinical trial with early stopping for efficacy when the trial is designed to evaluate the joint effect on two correlated event-time outcomes. We illustrate the method with application to a clinical trial and describe how to calculate the required sample sizes and numbers of events.

     

A comparative study on a permutation statistic

We studied asymptotic distribution and finite sample properties of a randomly weighted permutation statistic. The asymptotic normality and the finite sample simulations derived from our studies provided theoretical and numerical justifications for distributional assumption of many useful test statistics used in identifying spatial autocorrelations of mapped data. We compared a new method in computing the mean and the approximated variance of the randomly weighted D statistic, a special permutation statistic, with the Walter’s conditional method. In the numerical illustration of the method, we calculated the standardized values of the D statistic by subtracting the mean from the D statistic and dividing the difference by the standard deviation for the standardized mortality ratios (SMRs) and the life expectancies among the 48 states of the continental USA. Spatial autocorrelations of the SMRs and the life expectancies were found to be statistically significant.     

Another Cautionary Note about R 2: Its Use in Weighted Least-Squares Regression Analysis

A recent article in this journal presented a variety of expressions for the coefficient of determination (R ²) and demonstrated that these expressions were generally not equivalent. The article discussed potential pitfalls in interpreting the R ² statistic in ordinary least-squares regression analysis. The current article extends this discussion to the case in which regression models are fit by weighted least squares and points out an additional pitfall that awaits the unwary data analyst. We show that unthinking reliance on the R ² statistic can lead to an overly optimistic interpretation of the proportion of variance accounted for in the regression. We propose a modification of the estimator and demonstrate its utility by example.     

Performance of adaptive estimators in slowly varying parameter models

This paper analyzes the MSE of the exponentially weighted least squares (EWLS) estimator in dynamic regression models with time-varying parameters. Under the assumption of differentiable parameter functions, it is derived an asymptotic expression which is the sum of a stationary and of an evolutionary component. The validity of the analytical expression is illustrated with simulation experiments, and its usefulness in designing the exponential discounting factor is illustrated on a real case-study. The practical finding is similar to the plug-in bandwidth selection in nonparametric smoothers.     

Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation

Children represent a large underserved population of “therapeutic orphans,” as an estimated 80% of children are treated off‐label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or “borrowing”) of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure‐response information for antiepileptic drugs to pediatrics.     

Empirical likelihood inference for a semiparametric hazards regression model

ABSTRACT

We investigated the empirical likelihood inference approach under a general class of semiparametric hazards regression models with survival data subject to right-censoring. An empirical likelihood ratio for the full 2p regression parameters involved in the model is obtained. We showed that it converged weakly to a random variable which could be written as a weighted sum of 2p independent chi-squared variables with one degree of freedom. Using this, we could construct a confidence region for parameters. We also suggested an adjusted version for the preceding statistic, whose limit followed a standard chi-squared distribution with 2p degrees of freedom.     

EMPIRICAL LIKELIHOOD‐BASED INFERENCES FOR PARTIALLY LINEAR MODELS WITH MISSING COVARIATES

This paper considers statistical inference for partially linear models Y = X ^? β +ν(Z) +? when the linear covariate X is missing with missing probability π depending upon (Y, Z). We propose empirical likelihood‐based statistics to construct confidence regions for β and ν(z). The resulting empirical likelihood ratio statistics are shown to be asymptotically chi‐squared‐distributed. The finite‐sample performance of the proposed statistics is assessed by simulation experiments. The proposed methods are applied to a dataset from an AIDS clinical trial.     

William Ramsdell Leonard 1904–1981

In this article, the corrected F statistic in the general linear model is shown to be algebraically equivalent to the corresponding statistic in the weighted least squares procedure, whenever the corrected F statistic exists. Hence, weighted least squares analysis is, in effect, a self-corrected F test procedure.     

Comparison of unweighted and weighted rank based tests for an ordered alternative in randomized complete block designs

In randomized complete block designs, a monotonic relationship among treatment groups may already be established from prior information, e.g., a study with different dose levels of a drug. The test statistic developed by Page and another from Jonckheere and Terpstra are two unweighted rank based tests used to detect ordered alternatives when the assumptions in the traditional two-way analysis of variance are not satisfied. We consider a new weighted rank based test by utilizing a weight for each subject based on the sample variance in computing the new test statistic. The new weighted rank based test is compared with the two commonly used unweighted tests with regard to power under various conditions. The weighted test is generally more powerful than the two unweighted tests when the number of treatment groups is small to moderate.     

Assessing efficacy in important subgroups in confirmatory trials: An example using Bayesian dynamic borrowing

Assessment of efficacy in important subgroups – such as those defined by sex, age, race and region – in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non-informative prior.     

Bootstrapping in a high dimensional but very low-sample size problem

This article is concerned with testing multiple hypotheses, one for each of a large number of small data sets. Such data are sometimes referred to as high-dimensional, low-sample size data. Our model assumes that each observation within a randomly selected small data set follows a mixture of C shifted and rescaled versions of an arbitrary density f. A novel kernel density estimation scheme, in conjunction with clustering methods, is applied to estimate f. Bayes information criterion and a new criterion weighted mean of within-cluster variances are used to estimate C, which is the number of mixture components or clusters. These results are applied to the multiple testing problem. The null sampling distribution of each test statistic is determined by f, and hence a bootstrap procedure that resamples from an estimate of f is used to approximate this null distribution.     

Linear hypothesis testing for weighted functional data with applications

In socioeconomic areas, functional observations may be collected with weights, called weighted functional data. In this paper, we deal with a general linear hypothesis testing (GLHT) problem in the framework of functional analysis of variance with weighted functional data. With weights taken into account, we obtain unbiased and consistent estimators of the group mean and covariance functions. For the GLHT problem, we obtain a pointwise F-test statistic and build two global tests, respectively, via integrating the pointwise F-test statistic or taking its supremum over an interval of interest. The asymptotic distributions of test statistics under the null and some local alternatives are derived. Methods for approximating their null distributions are discussed. An application of the proposed methods to density function data is also presented. Intensive simulation studies and two real data examples show that the proposed tests outperform the existing competitors substantially in terms of size control and power.     

An LM-type test for idiosyncratic unit roots in the exact factor model with integrated factors

We consider an exact factor model with integrated factors and propose an LM-type test for unit roots in the idiosyncratic component. We show that, for a fixed number of panel individuals (N) and when the number of time points (T) tends to infinity, the limiting distribution of the LM-type statistic is a weighted sum of independent Chi-square variables with one degree of freedom, and when T tends to infinity followed by N tending to infinity, the limiting distribution is standard normal. The results should contribute to the challenging task of deriving likelihood-based unit-root tests in dynamic factor models.     

Testing for normality in linear regression models

The importance of the normal distribution for fitting continuous data is well known. However, in many practical situations data distribution departs from normality. For example, the sample skewness and the sample kurtosis are far away from 0 and 3, respectively, which are nice properties of normal distributions. So, it is important to have formal tests of normality against any alternative. D'Agostino et al. [A suggestion for using powerful and informative tests of normality, Am. Statist. 44 (1990), pp. 316–321] review four procedures Z ²(g ₁), Z ²(g ₂), D and K ² for testing departure from normality. The first two of these procedures are tests of normality against departure due to skewness and kurtosis, respectively. The other two tests are omnibus tests. An alternative to the normal distribution is a class of skew-normal distributions (see [A. Azzalini, A class of distributions which includes the normal ones, Scand. J. Statist. 12 (1985), pp. 171–178]). In this paper, we obtain a score test (W) and a likelihood ratio test (LR) of goodness of fit of the normal regression model against the skew-normal family of regression models. It turns out that the score test is based on the sample skewness and is of very simple form. The performance of these six procedures, in terms of size and power, are compared using simulations. The level properties of the three statistics LR, W and Z ²(g ₁) are similar and close to the nominal level for moderate to large sample sizes. Also, their power properties are similar for small departure from normality due to skewness (γ₁≤0.4). Of these, the score test statistic has a very simple form and computationally much simpler than the other two statistics. The LR statistic, in general, has highest power, although it is computationally much complex as it requires estimates of the parameters under the normal model as well as those under the skew-normal model. So, the score test may be used to test for normality against small departure from normality due to skewness. Otherwise, the likelihood ratio statistic LR should be used as it detects general departure from normality (due to both skewness and kurtosis) with, in general, largest power.     

环境因素对农户借贷行为的影响——来自新疆农村地区的经验证据

基于2013年国家统计局新疆调查总队农村住户调查数据,选取相关7个环境指标,运用Logit模型以及自助法(bootstrap),就环境对农户借贷行为的影响进行了实证分析,并探讨了不同收入条件和不同年龄段下环境对农户借贷行为的差异化影响。结果显示:就社会环境而言,社会不安定因素的增加会导致农户借贷行为减少;在经济环境中,农户家庭恩格尔系数与农户的借贷行为成反比关系,而财政补贴占总收入的比例、通信支出占总收入的比例与农户借贷行为的发生成正比例关系;在自然环境中,本村是否通公路、所处地势以及距离县城距离的远近均会对农户的借贷行为产生影响;在不同收入水平下,低等收入群体的借贷行为对社会环境的依赖程度较高,而中等收入群体的借贷行为受经济环境与自然环境的影响较大,但对于高收入群体来说经济环境更重要;在不同年龄层中,不论社会环境、经济环境还是自然环境对青年的借贷行为都有显著影响,而对于中年农户来说,其借贷行为主要受经济环境影响。