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 unified sequential test procedure for simultaneous testing the equality of several binomial proportions to a specified standard

In this article, we propose a unified sequentially rejective test procedure for testing simultaneously the equality of several independent binomial proportions to a specified standard. The proposed test procedure is general enough to include some well-known multiple testing procedures such as the Ordinary Bonferroni procedure, Hochberg procedure and Rom procedure. It involves multiple tests of significance based on the simple binomial tests (exact or approximate) which can be easily found in many elementary standard statistics textbooks. Unlike the traditional Chi-square test of the overall hypothesis, the procedure can identify the subset of the binomial proportions, which are different from the prespecified standard with the control of the familywise type I error rate. Moreover, the power computation of the procedure is provided and the procedure is illustrated by two real examples from an ecological study and a carcinogenicity study.     

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.     

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.     

Bayesian Analysis of Multiple Hypothesis Testing with Applications to Microarray Experiments

Recently, the field of multiple hypothesis testing has experienced a great expansion, basically because of the new methods developed in the field of genomics. These new methods allow scientists to simultaneously process thousands of hypothesis tests. The frequentist approach to this problem is made by using different testing error measures that allow to control the Type I error rate at a certain desired level. Alternatively, in this article, a Bayesian hierarchical model based on mixture distributions and an empirical Bayes approach are proposed in order to produce a list of rejected hypotheses that will be declared significant and interesting for a more detailed posterior analysis. In particular, we develop a straightforward implementation of a Gibbs sampling scheme where all the conditional posterior distributions are explicit. The results are compared with the frequentist False Discovery Rate (FDR) methodology. Simulation examples show that our model improves the FDR procedure in the sense that it diminishes the percentage of false negatives keeping an acceptable percentage of false positives.     

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.     

On group sequential tests for data in unequally sized groups and with unknown variance

We present a method to generalise the scope of application of group sequential tests designed for equally sized groups of normal observations with known variance. Preserving the significance levels against which standardised statistics are compared leads to tests for unequally grouped data which maintain Type I error probabilities to a high degree of accuracy. The same approach can be followed when observations have unknown variance by setting critical values for Studentised statistics at percentiles of the appropriate t-distributions. This significance level approach is equally applicable to group sequential one-sided tests and two-sided tests, possibly with early stopping permitted to accept the null hypothesis. In applications to equivalence testing, tests are required to maintain a specified power, rather than Type I error rate: such tests can be constructed by defining the standardised test statistics used in the significance level approach with respect to appropriately chosen hypotheses.     

Weighted Multiple Testing Correction for Correlated Binary Endpoints

Multiple binary endpoints often occur in clinical trials and are usually correlated. Many multiple testing adjustment methods have been proposed to control familywise type I error rates. However, most of them disregard the correlation among the endpoints, for example, the commonly used Bonferroni correction, Bonferroni fixed-sequence (BFS) procedure, and its extension, the alpha-exhaustive fallback (AEF). Extending BFS by taking into account correlations among endpoints, Huque and Alosh proposed a flexible fixed-sequence (FFS) testing method, but this FFS method faces computational difficulty when there are four or more endpoints and the power of the first hypothesis does not depend on the correlations among endpoints. In dealing with these issues, Xie proposed a weighted multiple testing correction (WMTC) for correlated continuous endpoints and showed that the proposed method can easily handle hundreds of endpoints by using the R package and has higher power for testing the first hypothesis compared with the FFS and AEF methods. Since WMTC depends on the joint distribution of the endpoints, it is not clear whether WMTC still keeps those advantages when correlated binary endpoints are used. In this article, we evaluated the statistical power of WMTC method for correlated binary endpoints in comparison with the FFS, the AEF, the prospective alpha allocation scheme (PAAS), and the weighted Holm-Bonferroni methods. Furthermore the WMTC method and others are illustrated on a real dataset examining the circumstance of homicide in New York City.     

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.     

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.     

Interpretation of the four types of analysis of variance tables in sas

Various computational methods exist for generating sums of squares in an analysis of variance table. When the ANOVA design is balanced, most of these computational methods will produce equivalent sums of squares for testing the significance of the ANOVA model parameters. However, when the design is unbalanced, as is frequently the case in practice, these sums of squares depend on the computational method used.- The basic reason for the difference in these sums of squares is that different hypotheses are being tested. The purpose of this paper is to describe these hypotheses in terms of population or cell means. A numerical example is given for the two factor model with interaction. The hypotheses that are tested by the four computational methods of the SAS general linear model procedure are specified.

Although the ultimate choice of hypotheses should be made by the researcher before conducting the experiment, this paper

PENDLETON,VON TRESS,AND BREMER

presents the following guidelines in selecting these hypotheses:

When the design is balanced, all of the SAS procedures will agree.

In unbalanced ANOVA designs when there are no missing cells. SAS Type III should be used. SAS Type III tests an unweighted hypothesis about cell means. SAS Types I and II test hypotheses that are functions of the ceil frequencies. These frequencies are often merely arti¬facts of the experimental process and not reflective of any underlying frequencies in the population.

When there are missing cells, i.e. no observations for some factor level combinations. Type IV should be used with caution. SAS Type IV tests hypotheses which depend     

Parametric bootstrap inferences for unbalanced panel data models

This article presents parametric bootstrap (PB) approaches for hypothesis testing and interval estimation for the regression coefficients of panel data regression models with incomplete panels. Some simulation results are presented to compare the performance of the PB approaches with the approximate inferences. Our studies show that the PB approaches perform satisfactorily for various sample sizes and parameter configurations, and the performance of PB approaches is mostly better than the approximate methods with respect to the coverage probabilities and the Type I error rates. The PB inferences have almost exact coverage probabilities and Type I error rates. Furthermore, the PB procedure can be simply carried out by a few simulation steps, and the derivation is easier to understand and to be extended to the multi-way error component regression models with unbalanced panels. Finally, the proposed approaches are illustrated by using a real data example.     

Step-up and step-down methods for testing multiple hypotheses in sequential experiments

Sequential methods are developed for testing multiple hypotheses, resulting in a statistical decision for each individual test and controlling the familywise error rate and the familywise power in the strong sense. Extending the ideas of step-up and step-down methods for multiple comparisons to sequential designs, the new techniques improve over the Bonferroni and closed testing methods proposed earlier by a substantial reduction of the expected sample size.     

A revision of the tukey multiple comparisons procedure to control the probability of committing at most one type i error

Halperin et al. (1988) suggested an approach which allows for k Type I errors while using Scheffe's method of multiple comparisons for linear combinations of p means. In this paper we apply the same type of error control to Tukey's method of multiple pairwise comparisons. In fact, the variant of the Tukey (1953) approach discussed here defines the error control objective as assuring with a specified probability that at most one out of the p(p-l)/2 comparisons between all pairs of the treatment means is significant in two-sided tests when an overall null hypothesis (all p means are equal) is true or, from a confidence interval point of view, that at most one of a set of simultaneous confidence intervals for all of the pairwise differences of the treatment means is incorrect. The formulae which yield the critical values needed to carry out this new procedure are derived and the critical values are tabulated. A Monte Carlo study was conducted and several tables are presented to demonstrate the experimentwise Type I error rates and the gains in power furnished by the proposed procedure     

A note on the power of Fisher's least significant difference procedure

Fisher's least significant difference (LSD) procedure is a two-step testing procedure for pairwise comparisons of several treatment groups. In the first step of the procedure, a global test is performed for the null hypothesis that the expected means of all treatment groups under study are equal. If this global null hypothesis can be rejected at the pre-specified level of significance, then in the second step of the procedure, one is permitted in principle to perform all pairwise comparisons at the same level of significance (although in practice, not all of them may be of primary interest). Fisher's LSD procedure is known to preserve the experimentwise type I error rate at the nominal level of significance, if (and only if) the number of treatment groups is three. The procedure may therefore be applied to phase III clinical trials comparing two doses of an active treatment against placebo in the confirmatory sense (while in this case, no confirmatory comparison has to be performed between the two active treatment groups). The power properties of this approach are examined in the present paper. It is shown that the power of the first step global test--and therefore the power of the overall procedure--may be relevantly lower than the power of the pairwise comparison between the more-favourable active dose group and placebo. Achieving a certain overall power for this comparison with Fisher's LSD procedure--irrespective of the effect size at the less-favourable dose group--may require slightly larger treatment groups than sizing the study with respect to the simple Bonferroni alpha adjustment. Therefore if Fisher's LSD procedure is used to avoid an alpha adjustment for phase III clinical trials, the potential loss of power due to the first-step global test should be considered at the planning stage.     

Efficient Stratified Testing Procedure for a False Discovery Rate

The false discovery rate (FDR) has become a popular error measure in the large-scale simultaneous testing. When data are collected from heterogenous sources and form grouped hypotheses testing, it may be beneficial to use the distinct feature of groups to conduct the multiple hypotheses testing. We propose a stratified testing procedure that uses different FDR levels according to the stratification features based on p-values. Our proposed method is easy to implement in practice. Simulations studies show that the proposed method produces more efficient testing results. The stratified testing procedure minimizes the overall false negative rate (FNR) level, while controlling the overall FDR. An example from a type II diabetes mice study further illustrates the practical advantages of this new approach.     

An evaluation of methods for testing hypotheses relating to two endpoints in a single clinical trial

The issues and dangers involved in testing multiple hypotheses are well recognised within the pharmaceutical industry. In reporting clinical trials, strenuous efforts are taken to avoid the inflation of type I error, with procedures such as the Bonferroni adjustment and its many elaborations and refinements being widely employed. Typically, such methods are conservative. They tend to be accurate if the multiple test statistics involved are mutually independent and achieve less than the type I error rate specified if these statistics are positively correlated. An alternative approach is to estimate the correlations between the test statistics and to perform a test that is conditional on those estimates being the true correlations. In this paper, we begin by assuming that test statistics are normally distributed and that their correlations are known. Under these circumstances, we explore several approaches to multiple testing, adapt them so that type I error is preserved exactly and then compare their powers over a range of true parameter values. For simplicity, the explorations are confined to the bivariate case. Having described the relative strengths and weaknesses of the approaches under study, we use simulation to assess the accuracy of the approximate theory developed when the correlations are estimated from the study data rather than being known in advance and when data are binary so that test statistics are only approximately normally distributed.     

Testing Linear Regression Models in Non Regular Case

We propose a new statistic for testing linear hypotheses in the non parametric regression model in the case of a homoscedastic error structure and fixed design. In contrast to most models suggested in the literature, our procedure is applicable in the non parametric model case without regularity condition, and also under either the null or the alternative hypotheses. We show the asymptotic normality of the test statistic under the null hypothesis and the alternative one. A simulation study is conducted to investigate the finite sample properties of the test with application to regime switching.     

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.