Testing non-inferiority and superiority for two endpoints for several treatments with a control

Some multiple comparison procedures are described for multiple armed studies. The procedures are appropriate for testing all hypotheses for comparing two endpoints and multiple test arms to a single control group, for example three different fixed doses compared to a placebo. The procedure assumes that among the two endpoints, one is designated as a primary endpoint such that for a given treatment arm, no hypothesis for the secondary endpoint can be rejected unless the hypothesis for the primary endpoint was rejected. The procedures described control the family-wise error rate in the strong sense at a specified level α.     

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.     

Optimally weighted,fixed sequence and gatekeeper multiple testing procedures

We consider a class of closed multiple test procedures indexed by a fixed weight vector. The class includes the Holm weighted step-down procedure, the closed method using the weighted Fisher combination test, and the closed method using the weighted version of Simes’ test. We show how to choose weights to maximize average power, where “average power” is itself weighted by importance assigned to the various hypotheses.Numerical computations suggest that the optimal weights for the multiple test procedures tend to certain asymptotic configurations. These configurations offer numerical justification for intuitive multiple comparisons methods, such as downweighting variables found insignificant in preliminary studies, giving primary variables more emphasis, gatekeeping test strategies, pre-determined multiple testing sequences, and pre-determined sequences of families of tests. We establish that such methods fall within the envelope of weighted closed testing procedures, thus providing a unified view of fixed sequences, fixed sequences of families, and gatekeepers within the closed testing paradigm. We also establish that the limiting cases control the familywise error rate (or FWE), using well-known results about closed tests, along with the dominated convergence theorem.     

Power and sample size when multiple endpoints are considered

A common approach to analysing clinical trials with multiple outcomes is to control the probability for the trial as a whole of making at least one incorrect positive finding under any configuration of true and false null hypotheses. Popular approaches are to use Bonferroni corrections or structured approaches such as, for example, closed-test procedures. As is well known, such strategies, which control the family-wise error rate, typically reduce the type I error for some or all the tests of the various null hypotheses to below the nominal level. In consequence, there is generally a loss of power for individual tests. What is less well appreciated, perhaps, is that depending on approach and circumstances, the test-wise loss of power does not necessarily lead to a family wise loss of power. In fact, it may be possible to increase the overall power of a trial by carrying out tests on multiple outcomes without increasing the probability of making at least one type I error when all null hypotheses are true. We examine two types of problems to illustrate this. Unstructured testing problems arise typically (but not exclusively) when many outcomes are being measured. We consider the case of more than two hypotheses when a Bonferroni approach is being applied while for illustration we assume compound symmetry to hold for the correlation of all variables. Using the device of a latent variable it is easy to show that power is not reduced as the number of variables tested increases, provided that the common correlation coefficient is not too high (say less than 0.75). Afterwards, we will consider structured testing problems. Here, multiplicity problems arising from the comparison of more than two treatments, as opposed to more than one measurement, are typical. We conduct a numerical study and conclude again that power is not reduced as the number of tested variables increases.     

A Rejection Principle for Sequential Tests of Multiple Hypotheses Controlling Familywise Error Rates

We present a unifying approach to multiple testing procedures for sequential (or streaming) data by giving sufficient conditions for a sequential multiple testing procedure to control the familywise error rate (FWER). Together, we call these conditions a ‘rejection principle for sequential tests’, which we then apply to some existing sequential multiple testing procedures to give simplified understanding of their FWER control. Next, the principle is applied to derive two new sequential multiple testing procedures with provable FWER control, one for testing hypotheses in order and another for closed testing. Examples of these new procedures are given by applying them to a chromosome aberration data set and finding the maximum safe dose of a treatment.     

Relations among three parametric multiple testing methods for correlated tests

Multiple endpoints in clinical trials are usually correlated. To control the family-wise type I error rate, both Huque and Alosh's flexible fixed-sequence (FFS) testing method and Li and Mehrotra's adaptive α allocation approach (4A) have taken into account correlations among endpoints. I suggested a weighted multiple testing correction (WMTC) for correlated tests and compared it with FFS. However, the relationship between the 4A method and the FFS method or the relationship between the 4A method and the WMTC method has not been studied. In this paper, simulations are conducted to investigate these relationships. Tentative guidelines to help choosing an appropriate method are provided.     

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.     

Hypothesis testing for two-group incomplete-data growth curve problems

Using simulation techniques, the null distribution properties of seven hypothesis testing procedures and a comparison of their powers are investigated for incomplete-data small-sample growth curve situations. The testing procedures are a combination of two growth curve models (the Potthoff and Roy model for complete data and Kleinbaum's extention to incomplete data) and three estimation techniques (two involving means of existing observations and the other using the EM algorithm) plus an analysis of a subset of complete data. All of the seven tests use the Kleinbaum Wald statistic, but different tests use different information. The hypotheses of identical and parallel growth curves are tested under the assumptions of multivariate normality and a linear polynomial mean growth curve for each of two groups. Good approximate null distributions are found for all procedures and one procedure is identified as empirically most powerful for the situations investigated.     

A note on the adaptive control of false discovery rates

Summary.  The use of a fixed rejection region for multiple hypothesis testing has been shown to outperform standard fixed error rate approaches when applied to control of the false discovery rate. In this work it is demonstrated that, if the original step-up procedure of Benjamini and Hochberg is modified to exercise adaptive control of the false discovery rate, its performance is virtually identical to that of the fixed rejection region approach. In addition, the dependence of both methods on the proportion of true null hypotheses is explored, with a focus on the difficulties that are involved in the estimation of this quantity.     

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.     

A flexible fixed-sequence testing method for hierarchically ordered correlated multiple endpoints in clinical trials

Statistical approaches for addressing multiplicity in clinical trials range from the very conservative (the Bonferroni method) to the least conservative the fixed sequence approach. Recently, several authors proposed methods that combine merits of the two extreme approaches. Wiens [2003. A fixed sequence Bonferroni procedure for testing multiple endpoints. Pharmaceutical Statist. 2003, 2, 211–215], for example, considered an extension of the Bonferroni approach where the type I error rate (α)$(\alpha )$ is allocated among the endpoints, however, testing proceeds in a pre-determined order allowing the type I error rate to be saved for later use as long as the null hypotheses are rejected. This leads to a higher power of the test in testing later null hypotheses. In this paper, we consider an extension of Wiens’ approach by taking into account correlations among endpoints for achieving higher flexibility in testing. We show strong control of the family-wise type I error rate for this extension and provide critical values and significance levels for testing up to three endpoints with equal correlations and show how to calculate them for other correlation structures. We also present results of a simulation experiment for comparing the power of the proposed method with those of Wiens’ and others. The results of this experiment show that the magnitude of the gain in power of the proposed method depends on the prospective ordering of testing of the endpoints, the magnitude of the treatment effects of the endpoints and the magnitude of correlation between endpoints. Finally, we consider applications of the proposed method for clinical trials with multiple time points and multiple doses, where correlations among endpoints frequently arise.     

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.     

Adaptive graph‐based multiple testing procedures

Multiple testing procedures defined by directed, weighted graphs have recently been proposed as an intuitive visual tool for constructing multiple testing strategies that reflect the often complex contextual relations between hypotheses in clinical trials. Many well‐known sequentially rejective tests, such as (parallel) gatekeeping tests or hierarchical testing procedures are special cases of the graph based tests. We generalize these graph‐based multiple testing procedures to adaptive trial designs with an interim analysis. These designs permit mid‐trial design modifications based on unblinded interim data as well as external information, while providing strong family wise error rate control. To maintain the familywise error rate, it is not required to prespecify the adaption rule in detail. Because the adaptive test does not require knowledge of the multivariate distribution of test statistics, it is applicable in a wide range of scenarios including trials with multiple treatment comparisons, endpoints or subgroups, or combinations thereof. Examples of adaptations are dropping of treatment arms, selection of subpopulations, and sample size reassessment. If, in the interim analysis, it is decided to continue the trial as planned, the adaptive test reduces to the originally planned multiple testing procedure. Only if adaptations are actually implemented, an adjusted test needs to be applied. The procedure is illustrated with a case study and its operating characteristics are investigated by simulations. Copyright © 2014 John Wiley & Sons, Ltd.     

Nonparametric multiple comparison procedures for unbalanced one-way factorial designs

In this paper, we present several nonparametric multiple comparison (MC) procedures for unbalanced one-way factorial designs. The nonparametric hypotheses are formulated by using normalized distribution functions and the comparisons are carried out on the basis of the relative treatment effects. The proposed test statistics take the form of linear pseudo rank statistics and the asymptotic joint distribution of the pseudo rank statistics for testing treatments versus control satisfies the multivariate totally positive of order two condition irrespective of the correlations among the rank statistics. Therefore, in the context of MCs of treatments versus control, the nonparametric Simes test is validated for the global testing of the intersection hypothesis. For simultaneous testing of individual hypotheses, the nonparametric Hochberg stepup procedure strongly controls the familywise type I error rate asymptotically. With regard to all pairwise comparisons, we generalize various single-step and stagewise procedures to perform comparisons on the relative treatment effects. To further compare with normal theory counterparts, the asymptotic relative efficiencies of the nonparametric MC procedures with respect to the parametric MC procedures are derived under a sequence of Pitman alternatives in a nonparametric location shift model for unbalanced one-way layouts. Monte Carlo simulations are conducted to demonstrate the validity and power of the proposed nonparametric MC procedures.     

A simple procedure for testing linear hypotheses about the parameters of a nonlinear model using weighted least squares

Suppose the same nonlinear function involving k parameters is fit to each of t populations. Suppose further it is of interest to compare a specific parameter of the models across the populations. Such comparisons can be expressed as linear hypotheses about the parameters of the nonlinear models. A weighted linear least squares (WLLS) procedure is proposed to test these linear hypotheses. The advantages and disadvantages of the WLLS procedure are discussed. This procedure is also compared to a nonlinear least squares procedure for testing these hypotheses in nonlinear models.     

A fixed sequence Bonferroni procedure for testing multiple endpoints

A method for controlling the familywise error rate combining the Bonferroni adjustment and fixed testing sequence procedures is proposed. This procedure allots Type I error like the Bonferroni adjustment, but allows the Type I error to accumulate whenever a null hypothesis is rejected. In this manner, power for hypotheses tested later in a prespecified order will be increased. The order of the hypothesis tests needs to be prespecified as in a fixed sequence testing procedure, but unlike the fixed sequence testing procedure all hypotheses can always be tested, allowing for an a priori method of concluding a difference in the various endpoints. An application will be in clinical trials in which mortality is a concern, but it is expected that power to distinguish a difference in mortality will be low. If the effect on mortality is larger than anticipated, this method allows a test with a prespecified method of controlling the Type I error rate. Copyright © 2003 John Wiley & Sons, Ltd.     

An exponentially weighted moving average chart controlling false discovery rate

A new control chart is developed by using the exponentially weighted moving average (EWMA) statistics and a multiple testing procedure for controlling false discovery rate. The multiple testing procedure considers not only the current EWMA statistic, but also a given number of previous statistics at the same time. Numerical simulations are accomplished to evaluate the performance of the proposed control chart in terms of the average run length and the conditional expected delay. The results are compared with those of the existing control charts including the X-bar chart, EWMA, and cumulative sum control charts. Case studies with real data-sets are also presented.     

Closure properties of classes of multiple testing procedures

Statistical discoveries are often obtained through multiple hypothesis testing. A variety of procedures exists to evaluate multiple hypotheses, for instance the ones of Benjamini–Hochberg, Bonferroni, Holm or Sidak. We are particularly interested in multiple testing procedures with two desired properties: (solely) monotonic and well-behaved procedures. This article investigates to which extent the classes of (monotonic or well-behaved) multiple testing procedures, in particular the subclasses of so-called step-up and step-down procedures, are closed under basic set operations, specifically the union, intersection, difference and the complement of sets of rejected or non-rejected hypotheses. The present article proves two main results: First, taking the union or intersection of arbitrary (monotonic or well-behaved) multiple testing procedures results in new procedures which are monotonic but not well-behaved, whereas the complement or difference generally preserves neither property. Second, the two classes of (solely monotonic or well-behaved) step-up and step-down procedures are closed under taking the union or intersection, but not the complement or difference.     

MMCTest—A Safe Algorithm for Implementing Multiple Monte Carlo Tests

Consider testing multiple hypotheses using tests that can only be evaluated by simulation, such as permutation tests or bootstrap tests. This article introduces MMCTest , a sequential algorithm that gives, with arbitrarily high probability, the same classification as a specific multiple testing procedure applied to ideal p‐values. The method can be used with a class of multiple testing procedures that include the Benjamini and Hochberg false discovery rate procedure and the Bonferroni correction controlling the familywise error rate. One of the key features of the algorithm is that it stops sampling for all the hypotheses that can already be decided as being rejected or non‐rejected. MMCTest can be interrupted at any stage and then returns three sets of hypotheses: the rejected, the non‐rejected and the undecided hypotheses. A simulation study motivated by actual biological data shows that MMCTest is usable in practice and that, despite the additional guarantee, it can be computationally more efficient than other methods.     

Comparisons of estimators of the number of true null hypotheses and adaptive FDR procedures in multiplicity testing

Many exploratory studies such as microarray experiments require the simultaneous comparison of hundreds or thousands of genes. It is common to see that most genes in many microarray experiments are not expected to be differentially expressed. Under such a setting, a procedure that is designed to control the false discovery rate (FDR) is aimed at identifying as many potential differentially expressed genes as possible. The usual FDR controlling procedure is constructed based on the number of hypotheses. However, it can become very conservative when some of the alternative hypotheses are expected to be true. The power of a controlling procedure can be improved if the number of true null hypotheses (m ₀) instead of the number of hypotheses is incorporated in the procedure [Y. Benjamini and Y. Hochberg, On the adaptive control of the false discovery rate in multiple testing with independent statistics, J. Edu. Behav. Statist. 25(2000), pp. 60–83]. Nevertheless, m ₀ is unknown, and has to be estimated. The objective of this article is to evaluate some existing estimators of m ₀ and discuss the feasibility of these estimators in incorporating into FDR controlling procedures under various experimental settings. The results of simulations can help the investigator to choose an appropriate procedure to meet the requirement of the study.