Sample size re‐estimation incorporating prior information on a nuisance parameter

Prior information is often incorporated informally when planning a clinical trial. Here, we present an approach on how to incorporate prior information, such as data from historical clinical trials, into the nuisance parameter–based sample size re‐estimation in a design with an internal pilot study. We focus on trials with continuous endpoints in which the outcome variance is the nuisance parameter. For planning and analyzing the trial, frequentist methods are considered. Moreover, the external information on the variance is summarized by the Bayesian meta‐analytic‐predictive approach. To incorporate external information into the sample size re‐estimation, we propose to update the meta‐analytic‐predictive prior based on the results of the internal pilot study and to re‐estimate the sample size using an estimator from the posterior. By means of a simulation study, we compare the operating characteristics such as power and sample size distribution of the proposed procedure with the traditional sample size re‐estimation approach that uses the pooled variance estimator. The simulation study shows that, if no prior‐data conflict is present, incorporating external information into the sample size re‐estimation improves the operating characteristics compared to the traditional approach. In the case of a prior‐data conflict, that is, when the variance of the ongoing clinical trial is unequal to the prior location, the performance of the traditional sample size re‐estimation procedure is in general superior, even when the prior information is robustified. When considering to include prior information in sample size re‐estimation, the potential gains should be balanced against the risks.     

Likelihood Ratio Type Two‐Sample Tests for Current Status Data

Abstract. We introduce fully non‐parametric two‐sample tests for testing the null hypothesis that the samples come from the same distribution if the values are only indirectly given via current status censoring. The tests are based on the likelihood ratio principle and allow the observation distributions to be different for the two samples, in contrast with earlier proposals for this situation. A bootstrap method is given for determining critical values and asymptotic theory is developed. A simulation study, using Weibull distributions, is presented to compare the power behaviour of the tests with the power of other non‐parametric tests in this situation.     

A Matching Prior for the Shape Parameter of the Skew‐Normal Distribution

Abstract. This paper deals with the issue of performing a default Bayesian analysis on the shape parameter of the skew‐normal distribution. Our approach is based on a suitable pseudo‐likelihood function and a matching prior distribution for this parameter, when location (or regression) and scale parameters are unknown. This approach is important for both theoretical and practical reasons. From a theoretical perspective, it is shown that the proposed matching prior is proper thus inducing a proper posterior distribution for the shape parameter, also when the likelihood is monotone. From the practical perspective, the proposed approach has the advantages of avoiding the elicitation on the nuisance parameters and the computation of multidimensional integrals.     

Likelihood Inference for Multivariate Extreme Value Distributions Whose Spectral Vectors have known Conditional Distributions

Multivariate extreme value statistical analysis is concerned with observations on several variables which are thought to possess some degree of tail dependence. The main approaches to inference for multivariate extremes consist in approximating either the distribution of block component‐wise maxima or the distribution of the exceedances over a high threshold. Although the expressions of the asymptotic density functions of these distributions may be characterized, they cannot be computed in general. In this paper, we study the case where the spectral random vector of the multivariate max‐stable distribution has known conditional distributions. The asymptotic density functions of the multivariate extreme value distributions may then be written through univariate integrals that are easily computed or simulated. The asymptotic properties of two likelihood estimators are presented, and the utility of the method is examined via simulation.     

Bayesian robustness in meta‐analysis for studies with zero responses

Statistical meta‐analysis is mostly carried out with the help of the random effect normal model, including the case of discrete random variables. We argue that the normal approximation is not always able to adequately capture the underlying uncertainty of the original discrete data. Furthermore, when we examine the influence of the prior distributions considered, in the presence of rare events, the results from this approximation can be very poor. In order to assess the robustness of the quantities of interest in meta‐analysis with respect to the choice of priors, this paper proposes an alternative Bayesian model for binomial random variables with several zero responses. Particular attention is paid to the coherence between the prior distributions of the study model parameters and the meta‐parameter. Thus, our method introduces a simple way to examine the sensitivity of these quantities to the structure dependence selected for study. For illustrative purposes, an example with real data is analysed, using the proposed Bayesian meta‐analysis model for binomial sparse data. Copyright © 2016 John Wiley & Sons, Ltd.     

Generalized Empirical Likelihood Inference in Generalized Linear Models for Longitudinal Data

In this article, the generalized linear model for longitudinal data is studied. A generalized empirical likelihood method is proposed by combining generalized estimating equations and quadratic inference functions based on the working correlation matrix. It is proved that the proposed generalized empirical likelihood ratios are asymptotically chi-squared under some suitable conditions, and hence it can be used to construct the confidence regions of the parameters. In addition, the maximum empirical likelihood estimates of parameters are obtained, and their asymptotic normalities are proved. Some simulations are undertaken to compare the generalized empirical likelihood and normal approximation-based method in terms of coverage accuracies and average areas/lengths of confidence regions/intervals. An example of a real data is used for illustrating our methods.     

Meta‐analysis of QTc interval – pooling data from heterogeneous trials

A diverse range of non‐cardiovascular drugs are associated with QT interval prolongation, which may be associated with a potentially fatal ventricular arrhythmia known as torsade de pointes. QT interval has been assessed for two recent submissions at GlaxoSmithKline. Meta‐analyses of ECG data from several clinical pharmacology studies were conducted for the two submissions. A general fixed effects meta‐analysis approach using summaries of the individual studies was used to calculate a pooled estimate and 90% confidence interval for the difference between each active dose and placebo following both single and repeat dosing separately. The meta‐analysis approach described provided a pragmatic solution to pooling complex and varied studies, and is a good way of addressing regulatory questions on QTc prolongation. Copyright © 2002 John Wiley & Sons, Ltd.     

Small area estimation via heteroscedastic nested‐error regression

We show that the maximum likelihood estimators (MLEs) of the fixed effects and within‐cluster correlation are consistent in a heteroscedastic nested‐error regression (HNER) model with completely unknown within‐cluster variances under mild conditions. The result implies that the empirical best linear unbiased prediction (EBLUP) method for small area estimation is valid in such a case. We also show that ignoring the heteroscedasticity can lead to inconsistent estimation of the within‐cluster correlation and inferior predictive performance. A jackknife measure of uncertainty for the EBLUP is developed under the HNER model. Simulation studies are carried out to investigate the finite‐sample performance of the EBLUP and MLE under the HNER model, with comparisons to those under the nested‐error regression model in various situations, as well as that of the jackknife measure of uncertainty. The well‐known Iowa crops data is used for illustration. The Canadian Journal of Statistics 40: 588–603; 2012 © 2012 Statistical Society of Canada     

Inference for Box–Cox Transformed Threshold GARCH Models with Nuisance Parameters

Abstract. Generalized autoregressive conditional heteroscedastic (GARCH) models have been widely used for analyzing financial time series with time‐varying volatilities. To overcome the defect of the Gaussian quasi‐maximum likelihood estimator (QMLE) when the innovations follow either heavy‐tailed or skewed distributions, Berkes & Horváth (Ann. Statist., 32, 633, 2004) and Lee & Lee (Scand. J. Statist. 36, 157, 2009) considered likelihood methods that use two‐sided exponential, Cauchy and normal mixture distributions. In this paper, we extend their methods for Box–Cox transformed threshold GARCH model by allowing distributions used in the construction of likelihood functions to include parameters and employing the estimated quasi‐likelihood estimators (QELE) to handle those parameters. We also demonstrate that the proposed QMLE and QELE are consistent and asymptotically normal under regularity conditions. Simulation results are provided for illustration.     

Empirical Likelihood Intervals for Conditional Value‐at‐Risk in Heteroscedastic Regression Models

Abstract. Non‐parametric regression models have been studied well including estimating the conditional mean function, the conditional variance function and the distribution function of errors. In addition, empirical likelihood methods have been proposed to construct confidence intervals for the conditional mean and variance. Motivated by applications in risk management, we propose an empirical likelihood method for constructing a confidence interval for the pth conditional value‐at‐risk based on the non‐parametric regression model. A simulation study shows the advantages of the proposed method.     

Location‐invariant Multi‐sample U‐tests for Covariance Matrices with Large Dimension

For two or more multivariate distributions with common covariance matrix, test statistics for certain special structures of the common covariance matrix are presented when the dimension of the multivariate vectors may exceed the number of such vectors. The test statistics are constructed as functions of location‐invariant estimators defined as U‐statistics, and the corresponding asymptotic theory is used to derive the limiting distributions of the proposed tests. The properties of the test statistics are established under mild and practical assumptions, and the same are numerically demonstrated using simulation results with small or moderate sample sizes and large dimensions.     

Estimating the variance for heterogeneity in arm‐based network meta‐analysis

Network meta‐analysis can be implemented by using arm‐based or contrast‐based models. Here we focus on arm‐based models and fit them using generalized linear mixed model procedures. Full maximum likelihood (ML) estimation leads to biased trial‐by‐treatment interaction variance estimates for heterogeneity. Thus, our objective is to investigate alternative approaches to variance estimation that reduce bias compared with full ML. Specifically, we use penalized quasi‐likelihood/pseudo‐likelihood and hierarchical (h) likelihood approaches. In addition, we consider a novel model modification that yields estimators akin to the residual maximum likelihood estimator for linear mixed models. The proposed methods are compared by simulation, and 2 real datasets are used for illustration. Simulations show that penalized quasi‐likelihood/pseudo‐likelihood and h‐likelihood reduce bias and yield satisfactory coverage rates. Sum‐to‐zero restriction and baseline contrasts for random trial‐by‐treatment interaction effects, as well as a residual ML‐like adjustment, also reduce bias compared with an unconstrained model when ML is used, but coverage rates are not quite as good. Penalized quasi‐likelihood/pseudo‐likelihood and h‐likelihood are therefore recommended.     

Empirical Likelihood Inference for the Rao‐Hartley‐Cochran Sampling Design

The Hartley‐Rao‐Cochran sampling design is an unequal probability sampling design which can be used to select samples from finite populations. We propose to adjust the empirical likelihood approach for the Hartley‐Rao‐Cochran sampling design. The approach proposed intrinsically incorporates sampling weights, auxiliary information and allows for large sampling fractions. It can be used to construct confidence intervals. In a simulation study, we show that the coverage may be better for the empirical likelihood confidence interval than for standard confidence intervals based on variance estimates. The approach proposed is simple to implement and less computer intensive than bootstrap. The confidence interval proposed does not rely on re‐sampling, linearization, variance estimation, design‐effects or joint inclusion probabilities.     

Robust Small Sample Inference for Generalised Estimating Equations: An Application of the Anova‐type Test

Asymptotically, the Wald‐type test for generalised estimating equations (GEE) models can control the type I error rate at the nominal level. However in small sample studies, it may lead to inflated type I error rates. Even with currently available small sample corrections for the GEE Wald‐type test, the type I error rate inflation is still serious when the tested contrast is multidimensional. This paper extends the ANOVA‐type test for heteroscedastic factorial designs to GEE and shows that the proposed ANOVA‐type test can also control the type I error rate at the nominal level in small sample studies while still maintaining robustness with respect to mis‐specification of the working correlation matrix. Differences of inference between the Wald‐type test and the proposed test are observed in a two‐way repeated measures ANOVA model for a diet‐induced obesity study and a two‐way repeated measures logistic regression for a collagen‐induced arthritis study. Simulation studies confirm that the proposed test has better control of the type I error rate than the Wald‐type test in small sample repeated measures models. Additional simulation studies further show that the proposed test can even achieve larger power than the Wald‐type test in some cases of the large sample repeated measures ANOVA models that were investigated.     

Sample size calculation for the one‐sample log‐rank test

In this paper, an exact variance of the one‐sample log‐rank test statistic is derived under the alternative hypothesis, and a sample size formula is proposed based on the derived exact variance. Simulation results showed that the proposed sample size formula provides adequate power to design a study to compare the survival of a single sample with that of a standard population. Copyright © 2014 John Wiley & Sons, Ltd.     

Model Selection Criterion Based on the Multivariate Quasi‐Likelihood for Generalized Estimating Equations

The generalized estimating equations (GEE) approach has attracted considerable interest for the analysis of correlated response data. This paper considers the model selection criterion based on the multivariate quasi‐likelihood (MQL) in the GEE framework. The GEE approach is closely related to the MQL. We derive a necessary and sufficient condition for the uniqueness of the risk function based on the MQL by using properties of differential geometry. Furthermore, we establish a formal derivation of model selection criterion as an asymptotically unbiased estimator of the prediction risk under this condition, and we explicitly take into account the effect of estimating the correlation matrix used in the GEE procedure.     

Inference of Seasonal Long‐memory Time Series with Measurement Error

We consider the Whittle likelihood estimation of seasonal autoregressive fractionally integrated moving‐average models in the presence of an additional measurement error and show that the spectral maximum Whittle likelihood estimator is asymptotically normal. We illustrate by simulation that ignoring measurement errors may result in incorrect inference. Hence, it is pertinent to test for the presence of measurement errors, which we do by developing a likelihood ratio (LR) test within the framework of Whittle likelihood. We derive the non‐standard asymptotic null distribution of this LR test and the limiting distribution of LR test under a sequence of local alternatives. Because in practice, we do not know the order of the seasonal autoregressive fractionally integrated moving‐average model, we consider three modifications of the LR test that takes model uncertainty into account. We study the finite sample properties of the size and the power of the LR test and its modifications. The efficacy of the proposed approach is illustrated by a real‐life example.     

Semiparametric Inference for the Two‐way Layout Under Order Restrictions

There are many situations in which a researcher would like to analyse data from a two‐way layout. Often, the assumptions of linearity and normality may not hold. To address such situations, we introduce a semiparametric model. The model extends the well‐known density ratio model from the one‐way to the two‐way layout and provides a useful framework for semiparametric analysis of variance type problems under order restrictions. In particular, the likelihood ratio order is emphasized. The model enables highly efficient inference without resorting to fully parametric assumptions or the use of transformations. Estimation and testing procedures under order restrictions are developed and investigated in detail. It is shown that the model is robust to misspecification, and several simulations suggest that it performs well in practice. The methodology is illustrated using two data examples; in the first, the response variable is discrete, whereas in the second, it is continuous.     

Characteristic Function‐based Semiparametric Inference for Skew‐symmetric Models

Skew‐symmetric models offer a very flexible class of distributions for modelling data. These distributions can also be viewed as selection models for the symmetric component of the specified skew‐symmetric distribution. The estimation of the location and scale parameters corresponding to the symmetric component is considered here, with the symmetric component known. Emphasis is placed on using the empirical characteristic function to estimate these parameters. This is made possible by an invariance property of the skew‐symmetric family of distributions, namely that even transformations of random variables that are skew‐symmetric have a distribution only depending on the symmetric density. A distance metric between the real components of the empirical and true characteristic functions is minimized to obtain the estimators. The method is semiparametric, in that the symmetric component is specified, but the skewing function is assumed unknown. Furthermore, the methodology is extended to hypothesis testing. Two tests for a null hypothesis of specific parameter values are considered, as well as a test for the hypothesis that the symmetric component has a specific parametric form. A resampling algorithm is described for practical implementation of these tests. The outcomes of various numerical experiments are presented.