A recommended analysis for 2 × 2 crossover trials with baseline measurements

In many two‐period, two‐treatment (2 × 2) crossover trials, for each subject, a continuous response of interest is measured before and after administration of the assigned treatment within each period. The resulting data are typically used to test a null hypothesis involving the true difference in treatment response means. We show that the power achieved by different statistical approaches is greatly influenced by (i) the ‘structure’ of the variance–covariance matrix of the vector of within‐subject responses and (ii) how the baseline (i.e., pre‐treatment) responses are accounted for in the analysis. For (ii), we compare different approaches including ignoring one or both period baselines, using a common change from baseline analysis (which we advise against), using functions of one or both baselines as period‐specific or period‐invariant covariates, and doing joint modeling of the post‐baseline and baseline responses with corresponding mean constraints for the latter. Based on theoretical arguments and simulation‐based type I error rate and power properties, we recommend an analysis of covariance approach that uses the within‐subject difference in treatment responses as the dependent variable and the corresponding difference in baseline responses as a covariate. Data from three clinical trials are used to illustrate the main points. Copyright © 2014 John Wiley & Sons, Ltd.     

Post hoc false positive control for structured hypotheses

In a high-dimensional multiple testing framework, we present new confidence bounds on the false positives contained in subsets S of selected null hypotheses. These bounds are post hoc in the sense that the coverage probability holds simultaneously over all S, possibly chosen depending on the data. This article focuses on the common case of structured null hypotheses, for example, along a tree, a hierarchy, or geometrically (spatially or temporally). Following recent advances in post hoc inference, we build confidence bounds for some prespecified forest-structured subsets and deduce a bound for any subset S by interpolation. The proposed bounds are shown to improve substantially previous ones when the signal is locally structured. Our findings are supported both by theoretical results and numerical experiments. Moreover, our bounds can be obtained by an algorithm (with complexity bilinear in the sizes of the reference hierarchy and of the selected subset) that is implemented in the open-source R package sansSouci available from https://github.com/pneuvial/sanssouci , making our approach operational.     

Reference‐based sensitivity analysis for time‐to‐event data

The analysis of time‐to‐event data typically makes the censoring at random assumption, ie, that—conditional on covariates in the model—the distribution of event times is the same, whether they are observed or unobserved (ie, right censored). When patients who remain in follow‐up stay on their assigned treatment, then analysis under this assumption broadly addresses the de jure, or “while on treatment strategy” estimand. In such cases, we may well wish to explore the robustness of our inference to more pragmatic, de facto or “treatment policy strategy,” assumptions about the behaviour of patients post‐censoring. This is particularly the case when censoring occurs because patients change, or revert, to the usual (ie, reference) standard of care. Recent work has shown how such questions can be addressed for trials with continuous outcome data and longitudinal follow‐up, using reference‐based multiple imputation. For example, patients in the active arm may have their missing data imputed assuming they reverted to the control (ie, reference) intervention on withdrawal. Reference‐based imputation has two advantages: (a) it avoids the user specifying numerous parameters describing the distribution of patients' postwithdrawal data and (b) it is, to a good approximation, information anchored, so that the proportion of information lost due to missing data under the primary analysis is held constant across the sensitivity analyses. In this article, we build on recent work in the survival context, proposing a class of reference‐based assumptions appropriate for time‐to‐event data. We report a simulation study exploring the extent to which the multiple imputation estimator (using Rubin's variance formula) is information anchored in this setting and then illustrate the approach by reanalysing data from a randomized trial, which compared medical therapy with angioplasty for patients presenting with angina.     

A general class of test statistics for Van Valen's Red Queen hypothesis

Van Valen's Red Queen hypothesis states that within a homogeneous taxonomic group the age is statistically independent of the rate of extinction. The case of the Red Queen hypothesis being addressed here is when the homogeneous taxonomic group is a group of similar species. Since Van Valen's work, various statistical approaches have been used to address the relationship between taxon age and the rate of extinction. We propose a general class of test statistics that can be used to test for the effect of age on the rate of extinction. These test statistics allow for a varying background rate of extinction and attempt to remove the effects of other covariates when assessing the effect of age on extinction. No model is assumed for the covariate effects. Instead we control for covariate effects by pairing or grouping together similar species. Simulations are used to compare the power of the statistics. We apply the test statistics to data on Foram extinctions and find that age has a positive effect on the rate of extinction. A derivation of the null distribution of one of the test statistics is provided in the supplementary material.     

Bayesian Multivariate Spatial Interpolation with Data Missing by Design

In a network of s _g sites, responses like levels of airborne pollutant concentrations may be monitored over time. The sites need not all measure the same set of response items and unmeasured items are considered as data missing by design . We propose a hierarchical Bayesian approach to interpolate the levels of, say, k responses at s _u other locations called ungauged sites and also the unmeasured levels of the k responses at the gauged sites. Our method involves two steps. First, when all hyperparameters are assumed to be known, a predictive distribution is derived. In turn, an interpolator, its variance and a simultaneous interpolation region are obtained. In step two, we propose the use of an empirical Bayesian approach to estimate the hyperparameters through an EM algorithm. We base our theory on a linear Gaussian model and the relationship between a multivariate normal and matrix T -distribution. Our theory allows us to pool data from several existing networks that measure different subsets of response items for interpolation.     

Testing the Equality of Two Proportions for Combined Unilateral and Bilateral Data

In many medical comparative studies (e.g., comparison of two treatments in an otolaryngological study), subjects may produce either bilateral (e.g., responses from a pair of ears) or unilateral (response from only one ear) data. For bilateral cases, it is meaningful to assume that the information between the two ears from the same subject are generally highly correlated. In this article, we would like to test the equality of the successful cure rates between two treatments with the presence of combined unilateral and bilateral data. Based on the dependence and independence models, we study ten test statistics which utilize both the unilateral and bilateral data. The performance of these statistics will be evaluated with respect to their empirical Type I error rates and powers under different configurations. We find that both Rosner's and Wald-type statistics based on the dependence model and constrained maximum likelihood estimates (under the null hypothesis) perform satisfactorily for small to large samples and are hence recommended. We illustrate our methodologies with a real data set from an otolaryngology study.     

Goodness-of-fit tests for one-shot device accelerated life testing data

In this article, we develop a formal goodness-of-fit testing procedure for one-shot device testing data, in which each observation in the sample is either left censored or right censored. Such data are also called current status data. We provide an algorithm for calculating the nonparametric maximum likelihood estimate (NPMLE) of the unknown lifetime distribution based on such data. Then, we consider four different test statistics that can be used for testing the goodness-of-fit of accelerated failure time (AFT) model by the use of samples of residuals: a chi-square-type statistic based on the difference between the empirical and expected numbers of failures at each inspection time; two other statistics based on the difference between the NPMLE of the lifetime distribution obtained from one-shot device testing data and the distribution specified under the null hypothesis; as a final statistic, we use White's idea of comparing two estimators of the Fisher Information (FI) to propose a test statistic. We then compare these tests in terms of power, and draw some conclusions. Finally, we present an example to illustrate the proposed tests.     

A general theory of hypothesis testing based on rankings

In nonparametric statistics, a hypothesis testing problem based on the ranks of the data gives rise to two separate permutation sets corresponding to the null and to the alternative hypothesis, respectively. A modification of Critchlow's unified approach to hypothesis testing is proposed. By defining the distance between permutation sets to be the average distance between pairs of permutations, one from each set, various test statistics are derived for the multi-sample location problem and the two-way layout. The asymptotic distributions of the test statistics are computed under both the null and alternative hypotheses. Some comparisons are made on the basis of the asymptotic relative efficiency.     

Hayter and Tsui's test with double sampling for the vector mean of multivariate normal population

Abstract

In this paper, we introduce a version of Hayter and Tsui's statistical test with double sampling for the vector mean of a population under multivariate normal assumption. A study showed that this new test was more or as efficient than the well-known Hotelling's T² with double sampling. Some nice features of Hayter and Tsui's test are its simplicity of implementation and its capability of identifying the errant variables when the null hypothesis is rejected. Taking that into consideration, a new control chart called HTDS is also introduced as a tool to monitor multivariate process vector mean when using double sampling.     

A multivariate control median test

In this paper, we extend the univariate control median test to the multivariate case. We apply the permutation principle for the null distribution function of the test statistic and obtain a conditionally nonparametric test procedure. Because of the amount of computational work involved in implementing the test, we consider the normal approximation. We prove the consistency and derive the asymptotic efficiency of our control median test relative to Puri and Sen's median test. Finally, we compare the power of our control median test with those of Hotelling's T² test and Puri and Sen's median test through the simulations.     

Unit Root Tests in the Presence of Multi-Variance Break and Level Shifts That Have Power Against the Piecewise Stationary Alternative

Structural breaks in the level as well as in the volatility have often been exhibited in economic time series. In this paper, we propose new unit root tests when a time series has multiple shifts in its level and the corresponding volatility. The proposed tests are Lagrangian multiplier type tests based on the residual's marginal likelihood which is free from the nuisance mean parameters. The limiting null distributions of the proposed tests are the χ²distributions, and are affected not by the size and the location of breaks but only by the number of breaks.

We set the structural breaks under both the null and the alternative hypotheses to relieve a possible vagueness in interpreting test results in empirical work. The null hypothesis implies a unit root process with level shifts and the alternative connotes a stationary process with level shifts. The Monte Carlo simulation shows that our tests are locally more powerful than the OLSE-based tests, and that the powers of our tests, in a fixed time span, remain stable regardless the number of breaks. In our application, we employ the data which are analyzed by Perron (1990), and some results differ from those of Perron's (1990).     

Testing Equality of Order Constrained Inverse Gaussian Means

The inverse Gaussian family of non negative, skewed random variables is analytically simple, and its inference theory is well known to be analogous to the normal theory in numerous ways. Hence, it is widely used for modeling non negative positively skewed data. In this note, we consider the problem of testing homogeneity of order restricted means of several inverse Gaussian populations with a common unknown scale parameter using an approach based on the classical methods, such as Fisher's, for combining independent tests. Unlike the likelihood approach which can only be readily applied to a limited number of restrictions and the settings of equal sample sizes, this approach is applicable to problems involving a broad variety of order restrictions and arbitrary sample size settings, and most importantly, no new null distributions are needed. An empirical power study shows that, in case of the simple order, the test based on Fisher's combination method compares reasonably with the corresponding likelihood ratio procedure.     

The analysis of multicentre clinical trials when there is heterogeneity between centres

Two-treatment multicentre clinical trials are very common in practice. In cases where a non-parametric analysis is appropriate, a rank-sum test for grouped data called the van Elteren test can be applied. As an alternative approach, one may apply a combination test such as Fisher's combination test or the inverse normal combination test (also called Liptak's method) in order to combine centre-specific P-values. If there are no ties and no differences between centres with regard to the groups’ sample sizes, the inverse normal combination test using centre-specific Wilcoxon rank-sum tests is equivalent to the van Elteren test. In this paper, the van Elteren test is compared with Fisher's combination test based on Wilcoxon rank-sum tests. Data from two multicentre trials as well as simulated data indicate that Fisher's combination of P-values is more powerful than the van Elteren test in realistic scenarios, i.e. when there are large differences between the centres’ P-values, some quantitative interaction between treatment and centre, and/or heterogeneity in variability. The combination approach opens the possibility of using statistics other than the rank sum, and it is also a suitable method for more complicated designs, e.g. when covariates such as age or gender are included in the analysis.     

A more powerful unconditional exact test of homogeneity for 2 × c contingency table analysis

The classical unconditional exact p-value test can be used to compare two multinomial distributions with small samples. This general hypothesis requires parameter estimation under the null which makes the test severely conservative. Similar property has been observed for Fisher's exact test with Barnard and Boschloo providing distinct adjustments that produce more powerful testing approaches. In this study, we develop a novel adjustment for the conservativeness of the unconditional multinomial exact p-value test that produces nominal type I error rate and increased power in comparison to all alternative approaches. We used a large simulation study to empirically estimate the 5th percentiles of the distributions of the p-values of the exact test over a range of scenarios and implemented a regression model to predict the values for two-sample multinomial settings. Our results show that the new test is uniformly more powerful than Fisher's, Barnard's, and Boschloo's tests with gains in power as large as several hundred percent in certain scenarios. Lastly, we provide a real-life data example where the unadjusted unconditional exact test wrongly fails to reject the null hypothesis and the corrected unconditional exact test rejects the null appropriately.     

Goodness-of-fit tests via ϕ-measures of divergence for censored data

Measures of divergence or discrepancy are used extensively in statistics in various fields. In this article, we are focusing on divergence measures that are based on a class of measures known as Csiszar's divergence measures. In particular, we propose a class of goodness-of-fit tests based on Csiszar's class of measures designed for censored survival or reliability data. Further, we derive the asymptotic distribution of the test statistic under simple and composite null hypotheses as well as under contiguous alternative hypotheses. Simulations are furnished and real data are analysed to show the performance of the proposed tests for different ?-divergence measures.     

A New Goodness-of-Fit Test for Censored Data with an Application in Monitoring Processes

In this article, we propose a new goodness-of-fit test for Type I or Type II censored samples from a completely specified distribution. This test is a generalization of Michael's test for censored data, which is based on the empirical distribution and a variance stabilizing transformation. Using Monte Carlo methods, the distributions of the test statistics are analyzed under the null hypothesis. Tables of quantiles of these statistics are also provided. The power of the proposed test is studied and compared to that of other well-known tests also using simulation. The proposed test is more powerful in most of the considered cases. Acceptance regions for the PP, QQ, and Michael's stabilized probability plots are derived, which enable one to visualize which data contribute to the decision of rejecting the null hypothesis. Finally, an application in quality control is presented as illustration.     

Empirical null distribution-based modeling of multi-class differential gene expression detection

In this paper, we study the multi-class differential gene expression detection for microarray data. We propose a likelihood-based approach to estimating an empirical null distribution to incorporate gene interactions and provide a more accurate false-positive control than the commonly used permutation or theoretical null distribution-based approach. We propose to rank important genes by p-values or local false discovery rate based on the estimated empirical null distribution. Through simulations and application to lung transplant microarray data, we illustrate the competitive performance of the proposed method.     

Testing linear hypotheses in high-dimensional regressions

For a multivariate linear model, Wilk's likelihood ratio test (LRT) constitutes one of the cornerstone tools. However, the computation of its quantiles under the null or the alternative hypothesis requires complex analytic approximations, and more importantly, these distributional approximations are feasible only for moderate dimension of the dependent variable, say p≤20. On the other hand, assuming that the data dimension p as well as the number q of regression variables are fixed while the sample size n grows, several asymptotic approximations are proposed in the literature for Wilk's Λ including the widely used chi-square approximation. In this paper, we consider necessary modifications to Wilk's test in a high-dimensional context, specifically assuming a high data dimension p and a large sample size n. Based on recent random matrix theory, the correction we propose to Wilk's test is asymptotically Gaussian under the null hypothesis and simulations demonstrate that the corrected LRT has very satisfactory size and power, surely in the large p and large n context, but also for moderately large data dimensions such as p=30 or p=50. As a byproduct, we give a reason explaining why the standard chi-square approximation fails for high-dimensional data. We also introduce a new procedure for the classical multiple sample significance test in multivariate analysis of variance which is valid for high-dimensional data.     

Adaptive-Cox model averaging for right-censored data

In medical studies, Cox proportional hazards model is a commonly used method to deal with the right-censored survival data accompanied by many explanatory covariates. In practice, the Akaike's information criterion (AIC) or the Bayesian information criterion (BIC) is usually used to select an appropriate subset of covariates. It is well known that neither the AIC criterion nor the BIC criterion dominates for all situations. In this paper, we propose an adaptive-Cox model averaging procedure to get a more robust hazard estimator. First, by applying AIC and BIC criteria to perturbed datasets, we obtain two model averaging (MA) estimated survival curves, called AIC-MA and BIC-MA. Then, based on Kullback–Leibler loss, a better estimate of survival curve between AIC-MA and BIC-MA is chosen, which results in an adaptive-Cox estimate of survival curve. Simulation results show the superiority of our approach and an application of the proposed method is also presented by analyzing the German Breast Cancer Study dataset.     

A Unified Approach to Estimating and Testing Income Distributions With Grouped Data

We propose a unified approach that is flexibly applicable to various types of grouped data for estimating and testing parametric income distributions. To simplify the use of our approach, we also provide a parametric bootstrap method and show its asymptotic validity. We also compare this approach with existing methods for grouped income data, and assess their finite-sample performance by a Monte Carlo simulation. For empirical demonstrations, we apply our approach to recovering China's income/consumption distributions from a sequence of income/consumption share tables and the U.S. income distributions from a combination of income shares and sample quantiles. Supplementary materials for this article are available online.