Bonferroni-type Plug-in Procedure Controlling Generalized Familywise Error Rate

Consider the multiple hypotheses testing problem controlling the generalized familywise error rate k-FWER, the probability of at least k false rejections. We propose a plug-in procedure based on the estimation of the number of true null hypotheses. Under the independence assumption of the p-values corresponding to the true null hypotheses, we first introduce the least favorable configuration (LFC) of k-FWER for Bonferroni-type plug-in procedure, then we construct a plug-in k-FWER-controlled procedure based on LFC. For dependent p-values, we establish the asymptotic k-FWER control under some mild conditions. Simulation studies suggest great improvement over generalized Bonferroni test and generalized Holm test.     

Adaptive procedure for generalized familywise error rate control

This article considers multiple hypotheses testing with the generalized familywise error rate k-FWER control, which is the probability of at least k false rejections. We first assume the p-values corresponding to the true null hypotheses are independent, and propose adaptive generalized Bonferroni procedure with k-FWER control based on the estimation of the number of true null hypotheses. Then, we assume the p-values are dependent, satisfying block dependence, and propose adaptive procedure with k-FWER control. Extensive simulations compare the performance of the adaptive procedures with different estimators.     

Estimating the proportion of true null hypotheses, with application to DNA microarray data

Summary.  We consider the problem of estimating the proportion of true null hypotheses, π ₀, in a multiple-hypothesis set-up. The tests are based on observed p -values. We first review published estimators based on the estimator that was suggested by Schweder and Spjøtvoll. Then we derive new estimators based on nonparametric maximum likelihood estimation of the p -value density, restricting to decreasing and convex decreasing densities. The estimators of π ₀ are all derived under the assumption of independent test statistics. Their performance under dependence is investigated in a simulation study. We find that the estimators are relatively robust with respect to the assumption of independence and work well also for test statistics with moderate dependence.     

Two new estimators for the proportion of true null hypotheses in multiple test

In multiple hypothesis test, an important problem is estimating the proportion of true null hypotheses. Existing methods are mainly based on the p-values of the single tests. In this paper, we propose two new estimations for this proportion. One is a natural extension of the commonly used methods based on p-values and the other is based on a mixed distribution. Simulations show that the first method is comparable with existing methods and performs better under some cases. And the method based on a mixed distribution can get accurate estimators even if the variance of data is large or the difference between the null hypothesis and alternative hypothesis is very small.     

Estimating the proportion of true null hypotheses using the pattern of observed p-values

Estimating the proportion of true null hypotheses, π₀, has attracted much attention in the recent statistical literature. Besides its apparent relevance for a set of specific scientific hypotheses, an accurate estimate of this parameter is key for many multiple testing procedures. Most existing methods for estimating π₀ in the literature are motivated from the independence assumption of test statistics, which is often not true in reality. Simulations indicate that most existing estimators in the presence of the dependence among test statistics can be poor, mainly due to the increase of variation in these estimators. In this paper, we propose several data-driven methods for estimating π₀ by incorporating the distribution pattern of the observed p-values as a practical approach to address potential dependence among test statistics. Specifically, we use a linear fit to give a data-driven estimate for the proportion of true-null p-values in (λ, 1] over the whole range [0, 1] instead of using the expected proportion at 1?λ. We find that the proposed estimators may substantially decrease the variance of the estimated true null proportion and thus improve the overall performance.     

Evaluations of FWER-controlling methods in multiple hypothesis testing

Simultaneously testing a family of n null hypotheses can arise in many applications. A common problem in multiple hypothesis testing is to control Type-I error. The probability of at least one false rejection referred to as the familywise error rate (FWER) is one of the earliest error rate measures. Many FWER-controlling procedures have been proposed. The ability to control the FWER and achieve higher power is often used to evaluate the performance of a controlling procedure. However, when testing multiple hypotheses, FWER and power are not sufficient for evaluating controlling procedure’s performance. Furthermore, the performance of a controlling procedure is also governed by experimental parameters such as the number of hypotheses, sample size, the number of true null hypotheses and data structure. This paper evaluates, under various experimental settings, the performance of some FWER-controlling procedures in terms of five indices, the FWER, the false discovery rate, the false non-discovery rate, the sensitivity and the specificity. The results can provide guidance on how to select an appropriate FWER-controlling procedure to meet a study’s objective.     

Expected Power for the False Discovery Rate with Independence

The Benjamini–Hochberg procedure is widely used in multiple comparisons. Previous power results for this procedure have been based on simulations. This article produces theoretical expressions for expected power. To derive them, we make assumptions about the number of hypotheses being tested, which null hypotheses are true, which are false, and the distributions of the test statistics under each null and alternative. We use these assumptions to derive bounds for multiple dimensional rejection regions. With these bounds and a permanent based representation of the joint density function of the largest p-values, we use the law of total probability to derive the distribution of the total number of rejections. We derive the joint distribution of the total number of rejections and the number of rejections when the null hypothesis is true. We give an analytic expression for the expected power for a false discovery rate procedure that assumes the hypotheses are independent.     

On the Critical Value Behaviour of Multiple Decision Procedures

In this paper we investigate the asymptotic critical value behaviour of certain multiple decision procedures as e.g. simultaneous confidence intervals and simultaneous as well as stepwise multiple test procedures. Supposing that n hypotheses or parameters of interest are under consideration we investigate the critical value behaviour when n increases. More specifically, we answer e.g. the question by which amount the lengths of confidence intervals increase when an additional parameter is added to the statistical analysis. Furthermore, critical values of different multiple decision procedures as for instance step-down and step-up procedures will be compared. Some general theoretic results are derived and applied for various distributions.     

Estimating the number of true null hypotheses in multiple hypothesis testing

The overall Type I error computed based on the traditional means may be inflated if many hypotheses are compared simultaneously. The family-wise error rate (FWER) and false discovery rate (FDR) are some of commonly used error rates to measure Type I error under the multiple hypothesis setting. Many controlling FWER and FDR procedures have been proposed and have the ability to control the desired FWER/FDR under certain scenarios. Nevertheless, these controlling procedures become too conservative when only some hypotheses are from the null. Benjamini and Hochberg (J. Educ. Behav. Stat. 25:60–83, 2000) proposed an adaptive FDR-controlling procedure that adapts the information of the number of true null hypotheses (m ₀) to overcome this problem. Since m ₀ is unknown, estimators of m ₀ are needed. Benjamini and Hochberg (J. Educ. Behav. Stat. 25:60–83, 2000) suggested a graphical approach to construct an estimator of m ₀, which is shown to overestimate m ₀ (see Hwang in J. Stat. Comput. Simul. 81:207–220, 2011). Following a similar construction, this paper proposes new estimators of m ₀. Monte Carlo simulations are used to evaluate accuracy and precision of new estimators and the feasibility of these new adaptive procedures is evaluated under various simulation settings.     

Closed testing procedures for all pairwise comparisons in a randomized block design

We consider multiple comparison test procedures among treatment effects in a randomized block design. We propose closed testing procedures based on maximum values of some two-sample t test statistics and based on F test statistics. It is shown that the proposed procedures are more powerful than single-step procedures and the REGW (Ryan/Einot–Gabriel/Welsch)-type tests. Next, we consider the randomized block design under simple ordered restrictions of treatment effects. We propose closed testing procedures based on maximum values of two-sample one-sided t test statistics and based on Batholomew’s statistics for all pairwise comparisons of treatment effects. Although single-step multiple comparison procedures are utilized in general, the power of these procedures is low for a large number of groups. The closed testing procedures stated in the present article are more powerful than the single-step procedures. Simulation studies are performed under the null hypothesis and some alternative hypotheses. In this studies, the proposed procedures show a good performance.     

Strong control, conservative point estimation and simultaneous conservative consistency of false discovery rates: a unified approach

Summary.  The false discovery rate (FDR) is a multiple hypothesis testing quantity that describes the expected proportion of false positive results among all rejected null hypotheses. Benjamini and Hochberg introduced this quantity and proved that a particular step-up p -value method controls the FDR. Storey introduced a point estimate of the FDR for fixed significance regions. The former approach conservatively controls the FDR at a fixed predetermined level, and the latter provides a conservatively biased estimate of the FDR for a fixed predetermined significance region. In this work, we show in both finite sample and asymptotic settings that the goals of the two approaches are essentially equivalent. In particular, the FDR point estimates can be used to define valid FDR controlling procedures. In the asymptotic setting, we also show that the point estimates can be used to estimate the FDR conservatively over all significance regions simultaneously, which is equivalent to controlling the FDR at all levels simultaneously. The main tool that we use is to translate existing FDR methods into procedures involving empirical processes. This simplifies finite sample proofs, provides a framework for asymptotic results and proves that these procedures are valid even under certain forms of dependence.     

Estimating the Proportion of True Null Hypotheses in Nonparametric Exponential Mixture Model with Appication to the Leukemia Gene Expression Data

We revisit the problem of estimating the proportion π of true null hypotheses where a large scale of parallel hypothesis tests are performed independently. While the proportion is a quantity of interest in its own right in applications, the problem has arisen in assessing or controlling an overall false discovery rate. On the basis of a Bayes interpretation of the problem, the marginal distribution of the p-value is modeled in a mixture of the uniform distribution (null) and a non-uniform distribution (alternative), so that the parameter π of interest is characterized as the mixing proportion of the uniform component on the mixture. In this article, a nonparametric exponential mixture model is proposed to fit the p-values. As an alternative approach to the convex decreasing mixture model, the exponential mixture model has the advantages of identifiability, flexibility, and regularity. A computation algorithm is developed. The new approach is applied to a leukemia gene expression data set where multiple significance tests over 3,051 genes are performed. The new estimate for π with the leukemia gene expression data appears to be about 10% lower than the other three estimates that are known to be conservative. Simulation results also show that the new estimate is usually lower and has smaller bias than the other three estimates.     

Asymptotic comparison of the critical values of step-down and step-up multiple comparison procedures

We consider the problem of comparing step-down and step-up multiple test procedures for testing n hypotheses when independent p-values or independent test statistics are available. The defining critical values of these procedures for independent test statistics are asymptotically equal, which yields a theoretical argument for the numerical observation that the step-up procedure is mostly more powerful than the step-down procedure. The main aim of this paper is to quantify the differences between the critical values more precisely. As a by-product we also obtain more information about the gain when we consider two subsequent steps of these procedures. Moreover, we investigate how liberal the step-up procedure becomes when the step-up critical values are replaced by their step-down counterparts or by more refined approximate values. The results for independent p-values are the basis for obtaining corresponding results when independent real-valued test statistics are at hand. It turns out that the differences of step-down and step-up critical values as well as the differences between subsequent steps tend to zero for many distributions, except for heavy-tailed distributions. The Cauchy distribution yields an example where the critical values of both procedures are nearly linearly increasing in n.     

A clarifying comparison of methods for controlling the false discovery rate

Traditional multiple hypothesis testing procedures fix an error rate and determine the corresponding rejection region. In 2002 Storey proposed a fixed rejection region procedure and showed numerically that it can gain more power than the fixed error rate procedure of Benjamini and Hochberg while controlling the same false discovery rate (FDR). In this paper it is proved that when the number of alternatives is small compared to the total number of hypotheses, Storey's method can be less powerful than that of Benjamini and Hochberg. Moreover, the two procedures are compared by setting them to produce the same FDR. The difference in power between Storey's procedure and that of Benjamini and Hochberg is near zero when the distance between the null and alternative distributions is large, but Benjamini and Hochberg's procedure becomes more powerful as the distance decreases. It is shown that modifying the Benjamini and Hochberg procedure to incorporate an estimate of the proportion of true null hypotheses as proposed by Black gives a procedure with superior power.     

On Efficient Estimators of the Proportion of True Null Hypotheses in a Multiple Testing Setup

We consider the problem of estimating the proportion θ of true null hypotheses in a multiple testing context. The setup is classically modelled through a semiparametric mixture with two components: a uniform distribution on interval [0,1] with prior probability θ and a non‐parametric density f . We discuss asymptotic efficiency results and establish that two different cases occur whether f vanishes on a non‐empty interval or not. In the first case, we exhibit estimators converging at a parametric rate, compute the optimal asymptotic variance and conjecture that no estimator is asymptotically efficient (i.e. attains the optimal asymptotic variance). In the second case, we prove that the quadratic risk of any estimator does not converge at a parametric rate. We illustrate those results on simulated data.     

On adaptive procedures controlling the familywise error rate

The idea of modifying, and potentially improving, classical multiple testing methods controlling the familywise error rate (FWER) via an estimate of the unknown number of true null hypotheses has been around for a long time without a formal answer to the question whether or not such adaptive methods ultimately maintain the strong control of FWER, until Finner and Gontscharuk (2009) and Guo (2009) have offered some answers. A class of adaptive Bonferroni and S?idàk methods larger than considered in those papers is introduced, with the FWER control now proved under a weaker distributional setup. Numerical results show that there are versions of adaptive Bonferroni and S?idàk methods that can perform better under certain positive dependence situations than those previously considered. A different adaptive Holm method and its stepup analog, referred to as an adaptive Hochberg method, are also introduced, and their FWER control is proved asymptotically, as in those papers. These adaptive Holm and Hochberg methods are numerically seen to often outperform the previously considered adaptive Holm method.     

On the estimation of the proportion of positives in a sequence of screening experiments

A metaanalytic estimator of the proportion of positives in a sequence of screening experiments is proposed. The distribution-free estimator is based on the empirical distribution of P-values from individual experiments, which is uniform under the global null hypotheses of no positives in the sequence of experiments performed. Under certain regularity conditions, the proportion of positives corresponds to the derivative of this distribution under the alternative hypothesis of the existence of some positives. The statistical properties of the estimator are established, including its bias, variance, and rate of convergence to normality. Optimal estimators with minimum mean squared error are also developed under specific alternative hypotheses. The application of the proposed methods is illustrated using data from a sequence of screening experiments with chemicals to determine their carcinogenic potential.     

Sample size determination in step-down and step-up multiple tests for comparing treatments with a control

We address the problem of sample size determination in multiple comparisons of k treatments with a control for step-down and step-up testing, assuming normal data and homogeneous variances. We define power as the probability of correctly rejecting all hypotheses for which the treatment vs. control difference exceeds a specified value. Our paper supplements papers by Hayter and Tamhane (J. Statist. Plann. Inference 27 (1991) 271–290) who solved the problem for one-sided comparisons using the step-down procedure and by Liu (J. Statist. Plann. Inference 62 (1997b) 255–261) who considered the two-sided case using the single-step method. We provide expressions that allow computer evaluation of the power and necessary sample sizes for one- and two-sided tests using either step-down or step-up procedures. Tables are given from which sample sizes to guarantee a specified power can be determined.     

Asymptotic Expansions in Multi-Group Analysis of Moment Structures with an Application to Linearized Estimators

Asymptotic expansions of the joint distributions of functions of sample means and central moments up to an arbitrary order in multiple populations are given by Edgeworth expansions. The asymptotic distributions of the parameter estimators in moment structures under null/fixed alternative hypotheses and the chi-square statistics based on asymptotically distribution-free theory under fixed alternatives are given as applications of the above results. Asymptotic expansions of the null distributions of the chi-square statistics are also derived. For parameter estimators with the chi-square statistic, the linearized estimators are dealt with as well as fully iterated estimators.