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Summary The classical integrated conditional moment test is a promising method for model checking and its basic idea has been applied to develop several variants. However, in diverging-dimension scenarios, the integrated conditional moment test may break down and has completely different limiting properties from the fixed-dimension case. Furthermore, the related wild bootstrap approximation can also be invalid. To extend this classical test to diverging dimension settings, we propose a projected adaptive-to-model version of the integrated conditional moment test. We study the asymptotic properties of the new test under both the null and alternative hypotheses to examine if it maintains significance level, and its sensitivity to the global and local alternatives that are distinct from the null at the rate $n^{-1/2}$. The corresponding wild bootstrap approximation can still work for the new test in diverging-dimension scenarios. We also derive the consistency and asymptotically linear representation of the least squares estimator when the parameter diverges at the fastest possible known rate in the literature. Numerical studies show that the new test can greatly enhance the performance of the integrated conditional moment test in high-dimensional cases. We also apply the test to a real dataset for illustration.

Summary Quantitative comparison of microbial composition from different populations is a fundamental task in various microbiome studies. We consider two-sample testing for microbial compositional data by leveraging phylogenetic information. Motivated by existing phylogenetic distances, we take a minimum-cost flow perspective to study such testing problems. We first show that multivariate analysis of variance with permutation using phylogenetic distances, one of the most commonly used methods in practice, is essentially a sum-of-squares type of test and has better power for dense alternatives. However, empirical evidence from real datasets suggests that the phylogenetic microbial composition difference between two populations is usually sparse. Motivated by this observation, we propose a new maximum type test, detector of active flow on a tree, and investigate its properties. We show that the proposed method is particularly powerful against sparse phylogenetic composition difference and enjoys certain optimality. The practical merit of the proposed method is demonstrated by simulation studies and an application to a human intestinal biopsy microbiome dataset on patients with ulcerative colitis.

Summary Composite likelihood functions are often used for inference in applications where the data have a complex structure. While inference based on the composite likelihood can be more robust than inference based on the full likelihood, the inference is not valid if the associated conditional or marginal models are misspecified. In this paper, we propose a general class of specification tests for composite likelihood inference. The test statistics are motivated by the fact that the second Bartlett identity holds for each component of the composite likelihood function when these components are correctly specified. We construct the test statistics based on the discrepancy between the so-called composite information matrix and the sensitivity matrix. As an illustration, we study three important cases of the proposed tests and establish their limiting distributions under both null and local alternative hypotheses. Finally, we evaluate the finite-sample performance of the proposed tests in several examples.

Summary Multiple hypothesis testing problems arise naturally in science. This note introduces a new fast closed testing method for multiple testing which controls the familywise error rate. Controlling the familywise error rate is state-of-the-art in many important application areas and is preferred over false discovery rate control for many reasons, including that it leads to stronger reproducibility. The closure principle rejects an individual hypothesis if all global nulls of subsets containing it are rejected using some test statistics. It takes exponential time in the worst case. When the tests are symmetric and monotone, the proposed method is an exact algorithm for computing the closure, is quadratic in the number of tests, and is linear in the number of discoveries. Our framework generalizes most examples of closed testing, such as Holm’s method and the Bonferroni method. As a special case of the method, we propose the Simes and higher criticism fusion test, which is powerful both for detecting a few strong signals and for detecting many moderate signals.

Summary Models for analysing multivariate datasets with missing values require strong, often unassessable, assumptions. The most common of these is that the mechanism that created the missing data is ignorable, which is a two-fold assumption dependent on the mode of inference. The first part, which is the focus here, under the Bayesian and direct-likelihood paradigms requires that the missing data be missing at random; in contrast, the frequentist-likelihood paradigm demands that the missing data mechanism always produce missing at random data, a condition known as missing always at random. Under certain regularity conditions, assuming missing always at random leads to a condition that can be tested using the observed data alone, namely that the missing data indicators depend only on fully observed variables. In this note we propose three different diagnostic tests that not only indicate when this assumption is incorrect but also suggest which variables are the most likely culprits. Although missing always at random is not a necessary condition to ensure validity under the Bayesian and direct-likelihood paradigms, it is sufficient, and evidence of its violation should encourage the careful statistician to conduct targeted sensitivity analyses.

SUMMARY An important and often discussed research problem in statistics is how to compare several populations; examples arise in medical science, engineering, finance and other fields. Often population means or medians are compared. However, one population may have a higher mean income, for example, because of a small number of super-rich individuals; the mean therefore may not reflect the wealth of the general population. Instead, an index of the degree of stochastic dominance of one population over another would better reflect their relative wealth. Currently, we can estimate such an index under restrictive conditions, but there is no generic estimator with a known asymptotic distribution. In this paper, we suggest linking the populations via the density ratio model. Under this model, we develop an empirical likelihood estimator and establish its asymptotic normality. In addition, we improve the estimation efficiency by examining the similarities between the populations. Furthermore, we provide a valid bootstrap method for hypothesis testing and the construction of confidence intervals. Simulation experiments show that the proposed estimator substantially improves the estimation efficiency and power of the test, and leads to confidence intervals with satisfactorily precise coverage probabilities. It is also robust with respect to mild model misspecification. Two examples are given to demonstrate the usefulness of both the method and the concept.

We consider the testing of mutual independence among all entries in a $d$-dimensional random vector based on $n$ independent observations. We study two families of distribution-free test statistics, which include Kendall's tau and Spearman's rho as important examples. We show that under the null hypothesis the test statistics of these two families converge weakly to Gumbel distributions, and propose tests that control the type I error in the high-dimensional setting where $d>n$. We further show that the two tests are rate-optimal in terms of power against sparse alternatives, and outperform competitors in simulations, especially when $d$ is large., Comment: to appear in Biometrika

We consider inference on a scalar parameter of interest in the presence of a nuisance parameter, using a likelihood-based statistic which is asymptotically normally distributed under the null hypothesis. Higher-order expansions are used to compare the repeated sampling distribution, under a general contiguous alternative hypothesis, of $p$-values calculated from the asymptotic normal approximation to the null sampling distribution of the statistic with the distribution of $p$-values calculated by bootstrap approximations. The results of comparisons in terms of power of different testing procedures under an alternative hypothesis are closely related to differences under the null hypothesis, specifically the extent to which testing procedures are conservative or liberal under the null. Empirical examples are given which demonstrate that higher-order asymptotic effects may be seen clearly in small-sample contexts.

SUMMARY Seneta & Chen (2005) tightened the familywise error rate control of Holm’s procedure by sharpening its critical values using pairwise dependencies of the p-values. In this paper we further sharpen these critical values in the case where the distribution functions of the pairwise maxima of null p-values are convex, a property shown to hold in some applications of Holm’s procedure. The newer critical values are uniformly larger, providing tighter familywise error rate control than the approach of Seneta & Chen (2005), significantly so under high pairwise positive dependencies. The critical values can be further improved under exchangeable null p-values. Control of the familywise error rate, the probability of falsely rejecting at least one true null hypothesis, is commonly undertaken when testing multiple hypotheses. Among procedures for controlling this error rate, that of Holm (1979) is one of the most popular. Seneta & Chen (2005) attempted to improve upon Holm’s procedure in situations where pairwise dependencies among the p-values can be quantified. They applied an inequality of Kounias (1968) to obtain an upper bound for the distribution function of the minimum of a set of null p-values which is tighter than that provided by Bonferroni’s inequality, while modifying Holm’s critical values. The modification tightens the familywise error rate control of Holm’s procedure, and can be more powerful than the original step-up procedure of Hochberg (1988), as Seneta & Chen (2005) showed for some multiple testing problems associated with normally distributed test statistics with known correlations. We propose two improved versions of Holm’s step-down procedure for p-values such that the pairwise maxima of the null p-values have known convex distribution functions. The different versions depend on whether the null p-values are exchangeable, and each provides uniformly larger critical values than the method of Seneta & Chen (2005). The convexity of p-values is shown for some commonly used multivariate distributions. Numerical and simulation studies reveal that each of our proposed procedures is a better choice than the method of Seneta & Chen (2005), especially for small-scale multiple testing with high pairwise dependencies among the test statistics.

We consider the detection and identification of recurrent departures from stationary behaviour in genomic or similarly arranged data containing measurements at an ordered set of variables. Our primary focus is on departures that occur only at a single variable, or within a small window of contiguous variables, but involve more than one sample. This encompasses the identification of aberrant markers in genome-wide measurements of DNA copy number and DNA methylation, as well as meta-analyses of genome-wide association studies. We propose and analyse a cyclic shift-based procedure for testing recurrent departures from stationarity. Our analysis establishes the consistency of cyclic shift [Formula: see text]-values for datasets with a fixed set of samples as the number of observed variables tends to infinity, under the assumption that each sample is an independent realization of a stationary Markov chain. Our results apply to any test statistic satisfying a simple invariance condition.

This paper concerns the modeling of multi-way functional data where double or multiple indices are involved. We introduce a concept of weak separability. The weakly separable structure supports the use of factorization methods that decompose the signal into its spatial and temporal components. The analysis reveals interesting connections to the usual strongly separable covariance structure, and provides insights into tensor methods for multi-way functional data. We propose a formal test for the weak separability hypothesis, where the asymptotic null distribution of the test statistic is a chi-square type mixture. The method is applied to study brain functional connectivity derived from source localized magnetoencephalography signals during motor tasks.

Micro-organisms such as bacteria form complex ecological community networks that can be greatly influenced by diet and other environmental factors. Differential analysis of microbial community structures aims to elucidate systematic changes during an adaptive response to changes in environment. In this paper, we propose a flexible Markov random field model for microbial network structure and introduce a hypothesis testing framework for detecting differences between networks, also known as differential network analysis. Our global test for differential networks is particularly powerful against sparse alternatives. In addition, we develop a multiple testing procedure with false discovery rate control to identify the structure of the differential network. The proposed method is applied to data from a gut microbiome study on U.K. twins to evaluate how age affects the microbial community network.

The higher criticism test is effective for testing a joint null hypothesis against a sparse alternative, e.g., for testing the effect of a gene or genetic pathway that consists of d genetic markers. Accurate p-value calculations for the higher criticism test based on the asymptotic distribution require a very large d, which is not the case for the number of genetic variants in a gene or a pathway. In this paper we propose an analytical method for accurately computing the p-value of the higher criticism test for finite-d problems. Unlike previous treatments, this method does not rely on asymptotics in d or on simulation, and is exact for arbitrary d when the test statistics are normally distributed. The method is particularly computationally advantageous when d is not large. We illustrate the proposed method with a case-control genome-wide association study of lung cancer and compare its power with competing methods through simulations.

This paper proposes a unified framework to characterize the rate function of a recurrent event process through shape and size parameters. In contrast to the intensity function, which is the event occurrence rate conditional on the event history, the rate function is the occurrence rate unconditional on the event history, and thus it can be interpreted as a population-averaged count of events in unit time. In this paper, shape and size parameters are introduced and used to characterize the association between the rate function λ(⋅) and a random variable X. Measures of association between X and λ(⋅) are defined via shape- and size-based coefficients. Rate-independence of X and λ(⋅) is studied through tests of shape-independence and size-independence, where the shape- and size-based test statistics can be used separately or in combination. These tests can be applied when X is a covariable possibly correlated with the recurrent event process through λ(⋅) or, in the one-sample setting, when X is the censoring time at which the observation of N(⋅) is terminated. The proposed tests are shape- and size-based, so when a null hypothesis is rejected, the test results can serve to distinguish the source of violation.

We describe a class of statistical tests for the comparison of two or more survival curves, typically estimated using the Kaplan–Meier method. The class is based on the construction of O’Quigley (2003), and some special cases are of particular interest. Underlying the inferential development are the arguments of Efron & Hinkley (1978), leading to a theoretical sampling model that is in some sense closer to the observed data. The log-rank and weighted log-rank tests arise as special members of the class. In practice the log-rank test will often be a suboptimal, even poor, test due to the presence of non-proportional hazards. The proposed test maintains good power and, in all the cases considered, has greater power than the log-rank test under non-proportional hazards. The power will depend on the alternatives being considered, and under reasonable assumptions on the alternatives, we conclude that the proposed test is more powerful than the log-rank test. Simulations support these conclusions. An example is given as an illustration.

We develop gatekeeping procedures that focus on comparing multiple treatments with a control when there are multiple endpoints. Our procedures utilize estimated correlations among individual test statistics without parametric assumptions. We make comparisons with other gatekeeping procedures with respect to properties of the trade-off in statistical power between families of hypotheses. We introduce a reward function to facilitate these comparisons. We illustrate our methods by simulation and an analysis of data from a randomized, multi-armed clinical trial. Copyright 2013, Oxford University Press.

SUMMARY In single hypothesis testing, power is a nondecreasing function of Type I error rate; hence it is desirable to test at the nominal level exactly to achieve optimal power. The optimal power puzzle arises from the fact that for multiple testing under the false discovery rate paradigm, such a monotonic relationship may not hold. In particular, exact false discovery rate control may lead to a less powerful testing procedure if a test statistic fails to fulfil the monotone likelihood ratio condition. In this article, we identify different scenarios wherein the condition fails and give caveats for conducting multiple testing in practical settings. We study an important assumption that has been used implicitly in the multiple testing literature. In the context of false discovery rate analysis (Benjamini & Hochberg, 1995), we show that the assumption can be violated in many important settings. The goal of this article is to explicitly state the assumption to bridge the gap in conventional methodological development, rigorously investigate the legitimacy of the assumption in various settings, and give caveats for conducting multiple testing in practice. To identify this assumption, it is helpful to first examine closely the framework of single hypothesis testing. Suppose we want to test H0 versus H1 based on the observed value of a continuous random variable X. A binary decision rule δ ∈{ 0,1} divides the sample space S into two regions, S = S0 ∪ S1, such that δ =0 when X ∈ S0 and δ =1 when X ∈ S1 .L etT (·) be a function of X, with small values indicating evidence against H0. The critical region S1 can be expressed as S1 ={ x ∈ S : T (x ) t }= 1 − G1(t), respectively. Since α(t) increasesint and β(t)decreasesint,weconcludethat β(t)decreasesin α(t).Thereforetheoptimalchoice

Merging data from multiple studies has been widely adopted in biomedical research. In this paper, we consider two major issues related to merging longitudinal datasets. We first develop a rigorous hypothesis testing procedure to assess the validity of data merging, and then propose a flexible joint estimation procedure that enables us to analyse merged data and to account for different within-subject correlations and follow-up schedules in different studies. We establish large sample properties for the proposed procedures. We compare our method with meta analysis and generalized estimating equations and show that our test provides robust control of Type I error against both misspecification of working correlation structures and heterogeneous dispersion parameters. Our joint estimating procedure leads to an improvement in estimation efficiency on all regression coefficients after data merging is validated. Copyright 2012, Oxford University Press.

When testing geometrically irregular parametric hypotheses, the bootstrap is an intuitively appealing method to circumvent difficult distribution theory. It has been shown, however, that the usual bootstrap is inconsistent in estimating the asymptotic distributions involved in such problems. This paper is concerned with the asymptotic size of likelihood ratio tests when critical values are computed using the inconsistent bootstrap. We clarify how the asymptotic size of such a test can be obtained from the size of the corresponding bootstrap test in the relevant limiting normal experiment. For boundary problems, that is, hypotheses given by convex cones, we show the bootstrap test to always be anticonservative, and we compute the size numerically for different two-dimensional examples. The examples illustrate that the size can be below or above the nominal level, and reveal that the relationship between the size of the test and the geometry of the considered hypotheses is surprisingly subtle. Copyright 2011, Oxford University Press.

Statistical analyses often involve testing multiple hypotheses that are naturally grouped into a fixed sequence of families. An effective approach to control the familywise error rate is to prioritize the importance of prespecification in the testing order. A gatekeeping testing procedure examines the first family with no multiple adjustment and then examines the subsequent family depending on the decision made with respect to the previous one. In this paper, we describe the union closure method that can be used to design gatekeeping procedures. A bipolar disorder trial with three primary and two secondary outcomes is presented as an example. Power comparisons based on the bipolar disorder trial show that the proposed gatekeeping procedures under the union closure framework are more powerful than competing methods. Copyright 2011, Oxford University Press.

Working within the framework of a multi-dimensional scaling approach to shape analysis, we develop bootstrap methods for inference about mean reflection shape and size-and-shape based on labelled landmark data. The approach is developed in general dimensions though we focus on the three-dimensional case. We consider two pivotal statistics which we use to construct bootstrap confidence regions for the mean reflection shape or size-and-shape, and present simulation results which show that these statistics perform well in a variety of examples. We also suggest regularized versions of the test statistics that are suitable for more challenging cases where sample size is not sufficiently large in relation to the number of landmarks and present numerical results confirming that regularization indeed leads to better performance. An algorithm for producing a graphical representation of the confidence region for the mean reflection shape is presented and applied in an example involving molecular dynamics simulation data. Copyright 2011, Oxford University Press.

This paper derives the asymptotic null distribution of a quasilikelihood ratio test statistic for an autoregressive moving average model against its threshold extension. The null hypothesis is that of no threshold, and the error term could be dependent. The asymptotic distribution is rather complicated, and all existing methods for approximating a distribution in the related literature fail to work. Hence, a novel bootstrap approximation based on stochastic permutation is proposed in this paper. Besides being robust to the assumptions on the error term, our method enjoys more flexibility and needs less computation when compared with methods currently used in the literature. Monte Carlo experiments give further support to the new approach, and an illustration is reported. Copyright 2011, Oxford University Press.

We introduce an algorithm for estimating the parameters in a finite mixture of completely unspecified multivariate components in at least three dimensions under the assumption of conditionally independent coordinate dimensions. We prove that this algorithm, based on a majorization-minimization idea, possesses a desirable descent property just as any em algorithm does. We discuss the similarities between our algorithm and a related one, the so-called nonlinearly smoothed em algorithm for the non-mixture setting. We also demonstrate via simulation studies that the new algorithm gives very similar results to another algorithm that has been shown empirically to be effective but that does not satisfy any descent property. We provide code for implementing the new algorithm in a publicly available R package.

The inverse probability weighted generalized estimating equations approach (Robins et al. 1994; Robins et al. 1995), effectively removes bias and provides valid statistical inference for regression parameter estimation in marginal models when longitudinal data contain missing values. The validity of the weighted generalized estimating equations regarding consistent estimation depends on whether the underlying missing data process is properly modelled. However, there is little work available to examine whether or not this condition holds. In this paper we propose a test constructed from two sets of estimating equations: one set is known to be unbiased, but the other set is not known. We utilize the quadratic inference function (Qu et al. 2000) method to assess their compatibility, which is equivalent to testing for the validity of the weighted generalized estimating equations approach. We conduct simulation studies to assess the performance of the proposed method. The test procedure is illustrated through a real data example. Copyright 2011, Oxford University Press.

Copy number changes, the gains and losses of chromosome segments, are a common type of genetic variation among healthy individuals as well as an important feature in tumour genomes. Microarray technology enables us to simultaneously measure, with moderate accuracy, copy number variation at more than a million chromosome locations and for hundreds of subjects. This leads to massive data sets and complicated inference problems concerning which locations are more likely to vary. In this paper we consider a relatively simple false discovery rate approach to copy number analysis. More careful parametric change-point methods can then be focused on promising regions of the genome. Copyright 2011, Oxford University Press.

We consider empirical likelihood for the mean similarity shape of objects in two dimensions described by labelled landmarks. The restriction to two dimensions permits the representation of preshapes as complex unit vectors. We focus on the use of empirical likelihood techniques for the construction of confidence regions for the mean shape and for testing the hypothesis of a common mean shape across several populations. Theoretical properties and computational details are discussed and the results of a simulation study are presented. Our results show that bootstrap calibrated empirical likelihood performs well in practice in the planar shape setting. Copyright 2010, Oxford University Press.

In the first stage of a two-stage, drop-the-losers design, a candidate for the best treatment is selected. At the second stage, additional observations are collected to decide whether the candidate is actually better than the control. The design also allows the investigator to stop the trial for ethical reasons at the end of the first stage if there is already strong evidence of futility or superiority. Two types of tests have recently been developed, one based on the combined means and the other based on the combined p-values, but corresponding interval estimators are unavailable except in special cases. The problem is that, in most cases, the interval estimators depend on the mean configuration of all treatments in the first stage, which is unknown. In this paper, we prove a basic stochastic ordering lemma that enables us to bridge the gap between hypothesis testing and interval estimation. The proposed confidence intervals achieve the nominal confidence level in certain special cases. Simulations show that decisions based on our intervals are usually more powerful than those based on existing methods. Copyright 2010, Oxford University Press.

The covariate-adaptive randomization method was proposed for clinical trials long ago but little theoretical work has been done for statistical inference associated with it. Practitioners often apply test procedures available for simple randomization, which is controversial since procedures valid under simple randomization may not be valid under other randomization schemes. In this paper, we provide some theoretical results for testing hypotheses after covariate-adaptive randomization. We show that one way to obtain a valid test procedure is to use a correct model between outcomes and covariates, including those used in randomization. We also show that the simple two sample t-test, without using any covariate, is conservative under covariate-adaptive biased coin randomization in terms of its Type I error, and that a valid bootstrap t-test can be constructed. The powers of several tests are examined theoretically and empirically. Our study provides guidance for applications and sheds light on further research in this area. Copyright 2010, Oxford University Press.

In a sequential clinical trial whose stopping rule depends on the primary endpoint, inference on secondary endpoints is an important long-standing problem. Ignoring the possibility of early stopping based on the primary endpoint may result in substantial bias. To address this problem, a commonly used approach is to develop bias correction by estimating the bias in the case of bivariate normal outcomes and appealing to joint asymptotic normality of the statistics associated with the primary and secondary endpoints. We propose herein a new approach that uses resampling and a novel ordering scheme in the sample space of sequential statistics observed up to a stopping time. This approach is shown to provide accurate inference in complex clinical trials, including time-sequential trials with survival endpoints and covariates. Copyright 2009, Oxford University Press.

This paper presents a default model-selection procedure for Gaussian graphical models that involves two new developments. First, we develop a default version of the hyper-inverse Wishart prior for restricted covariance matrices, called the hyper-inverse Wishart g-prior, and show how it corresponds to the implied fractional prior for selecting a graph using fractional Bayes factors. Second, we apply a class of priors that automatically handles the problem of multiple hypothesis testing. We demonstrate our methods on a variety of simulated examples, concluding with a real example analyzing covariation in mutual-fund returns. These studies reveal that the combined use of a multiplicity-correction prior on graphs and fractional Bayes factors for computing marginal likelihoods yields better performance than existing Bayesian methods. Copyright 2009, Oxford University Press.

Fuzzy multiple comparisons procedures are introduced as a solution to the problem of multiple comparisons for discrete test statistics. The critical function of the randomized p-values is proposed as a measure of evidence against the null hypotheses. The classical concept of randomized tests is extended to multiple comparisons. This approach makes all theory of multiple comparisons developed for continuously distributed statistics automatically applicable to the discrete case. Examples of familywise error rate and false discovery rate procedures are discussed and an application to linkage disequilibrium testing is given. Software for implementing the procedures is available. Copyright 2009, Oxford University Press.

We present a theoretical basis for testing related endpoints. Typically, it is known how to construct tests of the individual hypotheses, but not how to combine them into a multiple test procedure that controls the familywise error rate. Using the closure method, we emphasize the role of consonant procedures, from an interpretive as well as a theoretical viewpoint. Surprisingly, even if each intersection test has an optimality property, the overall procedure obtained by applying closure to these tests may be inadmissible. We introduce a new procedure, which is consonant and has a maximin property under the normal model. The results are then applied to PROactive, a clinical trial designed to investigate the effectiveness of a glucose-lowering drug on macrovascular outcomes among patients with type 2 diabetes. Copyright 2009, Oxford University Press.

Under the assumption of proportional hazards, the log-rank test is optimal for testing the null hypothesis , where denotes the logarithm of the hazard ratio. However, if there are additional covariates that correlate with survival times, making use of their information will increase the efficiency of the log-rank test. We apply the theory of semiparametrics to characterize a class of regular and asymptotically linear estimators for when auxiliary covariates are incorporated into the model, and derive estimators that are more efficient. The Wald tests induced by these estimators are shown to be more powerful than the log-rank test. Simulation studies are used to illustrate the gains in efficiency. Copyright 2008, Oxford University Press.

SUMMARY Benjamini and Hochberg's method for controlling the false discovery rate is applied to the problem of testing infinitely many contrasts in linear models. Exact, easily calculated critical values are derived, defining a new multiple comparisons method for testing contrasts in linear models. The method is adaptive, depending on the data through the F-statistic, like the Waller Duncan Bayesian multiple comparisons method. Comparisons with Scheffes method are given, and the method is extended to the simultaneous confidence intervals of Benjamini and Yekutieli. Testing contrasts of a variety of types is a standard practice in the analysis of variance, leading to the problem of multiple comparisons and multiple tests. This issue is also controversial, with much literature that is not completely reviewed here. Hochberg and Tamhane (1987) is a good general reference for multiple comparisons methods that control the familywise error rate. Benjamini and Hochberg (1995) introduced a method to control the false discovery rate, and an extension of this method to confidence intervals for selected significant parameters is given by Benjamini and Yekutieli (2005). A common modem thread in the literature is the 'small n, large k' case, in which the number of tests k is large and the sample size n is small. We provide an exact characterization of the problem of testing infinitely many contrasts, k = oo, in linear models using the Benjamini Hochberg method, for fixed, possibly small n. The characterization is completely nonparametric, without distributional assumptions concerning the data-generating process; instead we assume that the contrasts tested are a random sample from contrast space. The resulting infinite-contrasts characterization of the Benjamini-Hochberg method is shown, surprisingly, to depend on the data

We study tools for checking the validity of a parametric regression model. When the dimension of the regressors is large, many of the existing tests face the curse of dimensionality or require some ordering of the data. Our tests are based on the residual empirical process marked by proper functions of the regressors. They are able to detect local alternatives converging to the null at parametric rates. Parametric and nonparametric alternatives are considered. In the latter case, through a proper principal component decomposition, we are able to derive smooth directional tests which are asymptotically distribution-free under the null model. The new tests take into account precisely the 'geometry of the model'. A simulation study is carried through and an application to a real dataset is illustrated. Copyright 2008, Oxford University Press.

A frequently encountered challenge in high-dimensional regression is the detection of relevant variables. Variable selection suffers from instability and the power to detect relevant variables is typically low if predictor variables are highly correlated. When taking the multiplicity of the testing problem into account, the power diminishes even further. To gain power and insight, it can be advantageous to look for influence not at the level of individual variables but rather at the level of clusters of highly correlated variables. We propose a hierarchical approach. Variable importance is first tested at the coarsest level, corresponding to the global null hypothesis. The method then tries to attribute any effect to smaller subclusters or even individual variables. The smallest possible clusters, which still exhibit a significant influence on the response variable, are retained. It is shown that the proposed testing procedure controls the familywise error rate at a prespecified level, simultaneously over all resolution levels. The method has power comparable to the Bonferroni--Holm procedure on the level of individual variables and dramatically larger power for coarser resolution levels. The best resolution level is selected adaptively. Copyright 2008, Oxford University Press.

In certain circumstances, one wishes to test one hypothesis only if certain other hypotheses have been rejected. This ordering of hypotheses simplifies the task of controlling the probability of rejecting any true hypothesis. In an example from an observational study, a treated group is shown to be further from both of two control groups than the two control groups are from each other. Copyright 2008, Oxford University Press.

One-sided confidence intervals and overall p-values for group-sequential designs are typically based on a sample space ordering which determines both the overall p-value and the corresponding confidence bound. Accordingly, the strength of evidence against the null hypothesis is consistently measured by both quantities such that the order of the p-values of two distinct sample points is consistent with the order of the respective confidence bounds. An exception is the commonly used repeated p-values and repeated confidence intervals. We show that they are not ordering-consistent in the above sense and propose an alternative repeated p-value which is ordering-consistent and has the monitoring property of the classical repeated p-value in being valid even when deviating from the prefixed stopping rule. Copyright 2008, Oxford University Press.

When some of the records used to estimate the imputation models in multiple imputation are not used or available for analysis, the usual multiple imputation variance estimator has positive bias. We present an alternative approach that enables unbiased estimation of variances and, hence, calibrated inferences in such contexts. First, using all records, the imputer samples m values of the parameters of the imputation model. Second, for each parameter draw, the imputer simulates the missing values for all records n times. From these mn completed datasets, the imputer can analyse or disseminate the appropriate subset of records. We develop methods for interval estimation and significance testing for this approach. Methods are presented in the context of multiple imputation for measurement error. Copyright 2008, Oxford University Press.

We develop diagnostic measures for assessing the influence of individual observations when using empirical likelihood with general estimating equations, and we use these measures to construct goodness-of-fit statistics for testing possible misspecification in the estimating equations. Our diagnostics include case-deletion measures, local influence measures and pseudo-residuals. Our goodness-of-fit statistics include the sum of local influence measures and the processes of pseudo-residuals. Simulation studies are conducted to evaluate our methods, and real datasets are analyzed to illustrate the use of our diagnostic measures and goodness-of-fit statistics. Copyright 2008, Oxford University Press.

Under the model of independent test statistics, we propose a two-parameter family of Bayes multiple testing procedures. The two parameters can be viewed as tuning parameters. Using the Benjamini--Hochberg step-up procedure for controlling false discovery rate as a baseline for conservativeness, we choose the tuning parameters to compromise between the operating characteristics of that procedure and a less conservative procedure that focuses on alternatives that a priori might be considered likely or meaningful. The Bayes procedures do not have the theoretical and practical shortcomings of the popular stepwise procedures. In terms of the number of mistakes, simulations for two examples indicate that over a large segment of the parameter space, the Bayes procedure is preferable to the step-up procedure. Another desirable feature of the procedures is that they are computationally feasible for any number of hypotheses. Copyright 2008, Oxford University Press.

Testing of multiple hypotheses involves statistics that are strongly dependent in some applications, but most work on this subject is based on the assumption of independence. We propose a new method for estimating the false discovery rate of multiple hypothesis tests, in which the density of test scores is estimated parametrically by minimizing the Kullback--Leibler distance between the unknown density and its estimator using the stochastic approximation algorithm, and the false discovery rate is estimated using the ensemble averaging method. Our method is applicable under general dependence between test statistics. Numerical comparisons between our method and several competitors, conducted on simulated and real data examples, show that our method achieves more accurate control of the false discovery rate in almost all scenarios. Copyright 2008, Oxford University Press.

Sufficient-component causes are discussed within the deterministic potential outcomes framework so as to formalize notions of sufficient causes, synergism and sufficient cause interactions. Doing so allows for the derivation of counterfactual and empirical conditions for detecting the presence of sufficient cause interactions. The conditions are novel in that, unlike other conditions in the literature, they make no assumption about monotonicity. The conditions can also be generalized and the conditions for three-way sufficient cause interactions are given explicitly. The statistical tests derived for sufficient cause interactions are compared with and contrasted to interaction terms in standard statistical models. Copyright 2008, Oxford University Press.

Test statistics from the weighted log-rank class are commonly used to compare treatment with control when there is right censoring. This paper uses saddlepoint methods to determine mid-p-values from the null permutation distributions of tests from the weighted log-rank class. Analytical saddlepoint computations replace the permutation simulations and provide mid-p-values that are virtually exact for all practical purposes. The speed of these saddlepoint computations makes it practicable to invert the weighted log-rank tests to determine nominal 95% confidence intervals for the treatment effect with right-censored data. Such analytical inversions lead to permutation confidence intervals that are easily computed and virtually identical to the exact intervals that would normally require massive amounts of simulation. Copyright 2007, Oxford University Press.

Holm's method and Hochberg's method for multiple testing can be viewed as step-down and step-up versions of the Bonferroni test. We show that both are special cases of partition testing. The difference is that, while Holm's method tests each partition hypothesis using the largest order statistic, setting a critical value based on the Bonferroni inequality, Hochberg's method tests each partition hypothesis using all the order statistics, setting a series of critical values based on Simes' inequality. Geometrically, Hochberg's step-up method 'cuts corners' off the acceptance regions of Holm's step-down method by making assumptions on the joint distribution of the test statistics. As can be expected, partition testing making use of the joint distribution of the test statistics is more powerful than partition testing using probabilistic inequalities. Thus, if the joint distribution of the test statistics is available, through modelling for example, we recommend partition step-down testing, setting exact critical values based on the joint distribution. Copyright 2007, Oxford University Press.

We introduce a method based on a pseudolikelihood ratio for estimating the distribution function of the survival time in a mixed-case interval censoring model. In a mixed-case model, an individual is observed a random number of times, and at each time it is recorded whether an event has happened or not. One seeks to estimate the distribution of time to event. We use a Poisson process as the basis of a likelihood function to construct a pseudolikelihood ratio statistic for testing the value of the distribution function at a fixed point, and show that this converges under the null hypothesis to a known limit distribution, that can be expressed as a functional of different convex minorants of a two-sided Brownian motion process with parabolic drift. Construction of confidence sets then proceeds by standard inversion. The computation of the confidence sets is simple, requiring the use of the pool-adjacent-violators algorithm or a standard isotonic regression algorithm. We also illustrate the superiority of the proposed method over competitors based on resampling techniques or on the limit distribution of the maximum pseudolikelihood estimator, through simulation studies, and illustrate the different methods on a dataset involving time to HIV seroconversion in a group of haemophiliacs. Copyright 2007, Oxford University Press.

The aim of this article is to develop optimal sufficient dimension reduction methodology for the conditional mean in multivariate regression. The context is roughly the same as that of a related method by Cook & Setodji (2003), but the new method has several advantages. It is asymptotically optimal in the sense described herein and its test statistic for dimension always has a chi-squared distribution asymptotically under the null hypothesis. Additionally, the optimal method allows tests of predictor effects. A comparison of the two methods is provided. Copyright 2007, Oxford University Press.