{\displaystyle H_{(1)}} ≤ The same rationale applies for ) Section 4 {\displaystyle {\frac {\alpha }{m}},{\frac {\alpha }{m-1}},\ldots ,{\frac {\alpha }{1}}} and If you do not receive an email within 10 minutes, your email address may not be registered, HERV¶E ABDI 5 2.3 Bonferroni and Sidµak correction for a• p value When a test has been performed as part of a family comprising C tests, the p value of this test can be corrected with the Sidµak or• Bonferroni approaches by replacing fi[PF] by p in Equations 1 or 3. In the following, we assume that the weights are exhaustive, i.e. , With the weighted Bonferroni test we reject H J if p j a jðJÞ¼ w α m H Several data sets are reanalyzed with the … {\displaystyle \alpha } Because increases with the correlation, this also holds for δ*. Graphical approaches for multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. 1 Section 2 introduces closed gatekeeping pro-cedures based on the weighted version of the Bonferroni test. {\displaystyle \alpha } 1 Examples of weigthed tests that are available in gMCP are the weighted Bonferroni, parametric and Simes tests. … The cost of this protection against type I errors is an increased risk of failing to reject one or more false null hypotheses (i.e., of committing one or more type II errors). ( , in order to ensure that the risk of rejecting one or more true null hypotheses (i.e., of committing one or more type I errors) is at most 2 {\displaystyle P_{(k)}\leq {\frac {\alpha }{m+1-k}}} 2011 Nov;53(6):894-913. doi: 10.1002/bimj.201000239. The graphical representations and rejection algorithms in these two articles are different, though underlying ideas are closely related; see Guilbaud and Karlsson (2011) for some comparative examples. 0 {\displaystyle k} {\displaystyle H_{1}} In this paper, we develop parallel gatekeeping methods using the powerful closed testing principle of Marcus et al. ( , ) = α m {\displaystyle {\widetilde {p}}_{2}=0.06} In principle, truncation can be applied to any of the test procedures discussed in Section 3. Multiple Testing Problems in Pharmaceutical Statistics, General multi‐stage gatekeeping procedures, Computation of Multivariate Normal and t Probabilities, Simultaneous confidence regions corresponding to Holm's stepdown procedure and other closed‐testing procedures, Alternative confidence regions for Bonferroni‐based closed‐testing procedures that are not alpha‐exhaustive, Confidence regions for Bonferroni‐based closed tests extended to more general closed tests, A simple sequentially rejective multiple test procedure, A stagewise rejective multiple test procedure based on a modified Bonferroni test, Powerful short‐cuts for multiple testing procedures with special reference to gatekeeping strategies, Some controversial multiple testing problems in regulatory applications, Challenges to multiple testing in clinical trials, A flexible fixed‐sequence testing method for hierarchically ordered correlated multiple endpoints in clinical trials, Addressing multiplicity issues of a composite endpoint and its components in clinical trials, R: A language for data analysis and graphics, Issues of Multiple Hypothesis Testing in Statistical Process Control, Testing non‐inferiority and superiority for two endpoints for several treatments with a control, An efficient method for accommodating potentially underpowered primary endpoints, Testing for efficacy in primary and secondary endpoints by partitioning decision paths, On closed testing procedure with special reference to ordered analysis of variance, Multiple and repeated testing of primary, co‐primary and secondary hypotheses, Multiple comparisons in drug clinical trials and preclinical assays: a‐priori ordered hypotheses, Biometrie in der Chemisch‐Pharmazeutischen Industrie, Chain procedures: A class of flexible closed testing procedures with clinical trial applications, Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance, R: A Language and Environment for Statistical Computing, Consonance and the closure method in multiple testing, Rectangular confidence regions for the means of multivariate normal distributions, An improved Bonferroni procedure for multiple tests of significance, Compatible simultaneous lower confidence bounds for the Holm procedure and other Bonferroni based closed tests, Optimally weighted, fixed sequence, and gatekeeping multiple testing procedures, Using prior information to allocate significance levels for multiple endpoints, A fixed sequence Bonferroni procedure for testing multiple endpoints, A Dunnett–Bonferroni‐based parallel gatekeeping procedure for dose‐response clinical trials with multiple endpoints, http://cran.r‐project.org/web/packages/gMCP/INSTALL. = Determination of cJ requires knowledge of the joint null distribution of the p‐values and computation of the corresponding multivariate cumulative distribution functions. + − {\displaystyle H_{1}=H_{(2)}} In that case the Simes test cannot reject Hi either and hence both remaining hypotheses must be retained. In this section we give details on different test procedures that could be employed to test the intersection hypotheses, including weighted Bonferroni tests, weighted min‐p tests accounting for the correlation between the test statistics, and weighted Simes' tests. = 0.05 ( 3 In addition, any two vertices Hi and Hj are connected through directed edges, where the associated weight gij indicates the fraction of the (local) significance level αi that is propagated to Hj once Hi (the hypothesis at the tail of the edge) has been rejected. {\displaystyle P_{(h)}\leq {\frac {\alpha }{m-h+1}}} to compute cJ=1.0783 for as well as for all and cJ=1 otherwise. {\displaystyle P_{(1)}} ~ are rejected at level − It provides a wide variety of statistical and graphical techniques, and is highly extensible. ( These recycling MTPs are closed testing procedures based on raw p-values associated with testing the individual null hypotheses, and the class of such MTPs includes, for example, serial and parallel gatekeeping, fallback and Holm procedures. … be the set of indices corresponding to the (unknown) true null hypotheses, having {\displaystyle H_{1}} = Section 3 introduces a stepwise version of the parallel Bonferroni gatekeeping procedure. as long as. α An improved Bonferroni procedure for multiple tests of significance BY R. J. SIMES Ludwig Institute for Cancer Research, University of Sydney, Sydney, N.S. 0 be the sorted p-values. {\displaystyle \alpha } Using graphical approaches, one can explore different test strategies together with the clinical team and thus tailor the multiple test procedure to the given study objectives. > cr[1,2] <‐ cr[2,1] <‐ cr[3,4] <‐ cr[4,3] <‐ 1/2, Finally, we perform the closed weighted parametric test at a specified significance level α=0.025, say, by calling, > res <‐ gMCP(graph, p, corr = cr, alpha = 0.025), This returns an object of class gMCPResult providing information on which hypotheses are rejected, > res@rejected H1 H2 H3 H4 TRUE FALSE TRUE FALSE, We conclude from the output that both H1 and H3 can be rejected. Bonferroni procedure, closed testing procedure, adjusted p-value. The closed testing principle. {\displaystyle m} {\displaystyle H_{(1)}} ) However, the Hochberg procedure requires the hypotheses to be independent or under certain forms of positive dependence, whereas Holm–Bonferroni can be applied without such assumptions. Nevertheless, for a given weighting strategy, this procedure is uniformly more powerful than an associated Bonferroni‐based procedure from Section 3.1. Related gatekeeping procedures addressing the problem of comparing several doses with a control for multiple hierarchical endpoints were described, among others, by Dmitrienko et al. Let α α or less, while the number of all intersections of null hypotheses to be tested is of order For clinical trials with multiple treatment arms or endpoints a variety of sequentially rejective, weighted Bonferroni‐type tests have been proposed, such as gatekeeping procedures, fixed sequence tests, and fallback procedures. Special Issue: Special Topic: Multiplicity Issues in Clinical Trials. Figure 3 displays the initial graph together with a possible rejection sequence. ≤ 1 α α . m 1 Similar to Algorithm 1, the results in Bretz et al. , The simple Bonferroni correction rejects only null hypotheses with p-value less than ≤ α H m Alternatively, the numerical information can be entered into the transition matrix and other fields on the right‐hand side of the GUI. Note that we can immediately improve that test procedure by connecting the secondary hypotheses H3 and H4 with the primary hypotheses H1 and H2 through the ε‐edges introduced in Bretz et al. h {\displaystyle {\frac {\alpha }{m_{0}}}} and Dmitrienko and Tamhane (2009) used this example to illustrate the truncated Holm procedure described in Dmitrienko et al. ( ( defining weighted directed graphs one also defines a weighting strategy for all subsets of null hypotheses. Different buttons are available in the icon panel of the GUI to create a new graph. … 0 m 0.02 1 m Über … The same applies for each − α These authors contributed equally to this work. (2009) to the graphical weighting strategies as follows. "The use of the Boole inequality within multiple inference theory is usually called the Bonferroni technique, and for this reason we will call our test the sequentially rejective Bonferroni test. H We first define the related transition matrix G and the weights wi(I), i∈I, through, > G[1,3] <‐ G[2,4] <‐ G[3,2] <‐ G[4,1] <‐ 1, The function matrix2graph then converts the matrix G and the vector w into an object of type graphMCP. In Section 4, we describe the gMCP package in R which implements some of the methods discussed in this paper and illustrate it with a clinical trial example using a truncated Holm procedure. {\displaystyle H_{(1)}\ldots H_{(m)}} (2009). Setting δ=δ*, we obtain the local significance levels for procedure (C) in Table 2. derived from the Bonferroni test, was proposed in Dmitrienko et al. 1 Mentioning: 108 - The confirmatory analysis of pre-specified multiple hypotheses has become common in pivotal clinical trials. In statistics, the Holm–Bonferroni method,[1] also called the Holm method or Bonferroni–Holm method, is used to counteract the problem of multiple comparisons. 3 1 ( Note that even though • Closed Testing Procedure (CTP) ... (sequentially rejective) graphical methods using: o Weighted Bonferroni tests o Weighted parametric tests for greater power o Simes tests for greater power • Concluding Remarks (Part I) Huque 2015 4. {\displaystyle H_{(1)}} ( 0.04 If pi<α, one would have rejected already all hypotheses in step (ii) and stopped the procedure because for all other hypotheses than Hi necessarily pj≤α. As shown in this paper, consonance can be enforced and related sequentially rejective graphs established at least in some simple situations. p Since the procedure is step-down, we first test is not rejected since For the weighting strategy from Example 1, the resulting closed weighted Simes test will reject more hypotheses than the related closed weighted Bonferroni test only if all four p‐values are less than or equal to α (Maurer et al., 2011). This condition is often violated by the weighted parametric tests above. Weighting strategies are formally defined through the weights wi (I), i∈I, for the global null hypothesis HI and the transition matrix G=(gij), where 0≤gij≤1, gii=0, and for all i, j∈I. English Deutsch. Otherwise, cJ=1 and condition (4) is trivially satisfied. Let Let us assume that we wrongly reject a true hypothesis. 3 ( So let us define the random variable A typical case in practice is to assume (or show) that the test statistics have a joint multivariate normal distribution with non‐negative correlations. 3 Screenshot of the GUI from the gMCP package. , 3 ( 1 = … P Conflict of interest The authors have declared no conflict of interest. ) This allows one to first derive suitable weighting strategies that reflect the given study objectives and subsequently apply appropriate test procedures, such as weighted Bonferroni tests, weighted parametric tests accounting for the correlation between the test statistics, or weighted Simes tests. The latter is not the case for the numerical example in Section 3.1, because, for example, p3=0.1>0.025=α and hence no further hypothesis can be rejected. 0.01 . In what follows, we assume that the hypotheses H1,…,Hm satisfy the free combination condition (Holm, 1979). + If in the previous example the correlations are all 0.5 (corresponding to a Dunnett test in a balanced one‐way layout with known variance), we have and . α 4 (2011) provided SAS/IML code to perform the resulting Bonferroni‐based sequentially rejective multiple test procedures. Because p2≤α, we reject H2 and the procedure stops. The gMCP package offers a GUI to conveniently create and perform Bonferroni‐based graphical test procedures, such as the one for the test procedure above. Using (1), the right hand side is at most p ) ) Graphical displays and a concise algebraic notation are provided for such MTPs. = 0.06 {\displaystyle P_{(2)}\leq \alpha /(m-1)} ⋯ {\displaystyle I_{0}} This conclusion remains true if the common variance is unknown and Dunnett t tests or individual t tests are used. 0.005 The local level tests in gMCP are weighted tests, where the weights are derived from a directed weighted graph G I. , m Assume that for the test of the intersection of any two hypotheses the weights are 1/3 and 2/3. p {\displaystyle h} The paper is organized as follows. {\displaystyle H_{(2)}} = {\displaystyle \leq \alpha } ) It is a shortcut procedure since practically the number of comparisons to be made equal to k 2 H In particular, we discuss in Section 2 how a separation between the weighting strategy and the test procedure facilitates the application of a graphical approach beyond Bonferroni‐based test procedures. ≤ 1 Statistics in Medicine. We refer to the installation instructions at http://cran.r‐project.org/web/packages/gMCP/INSTALL and the accompanying vignette for a description of the full functionality (Rohmeyer and Klinglmueller, 2011). 1 Note that this condition is not always easy to verify or even justify in practice. Therefore, pi>α and one cannot reject Hi. , {\displaystyle {\frac {\alpha }{m}}} {\displaystyle m} The resulting decisions are identical to those obtained with Algorithm 4, because for any given weighting strategy, any hypothesis rejected by the closed weighted Bonferroni test procedure is also rejected by the associated closed weighted Simes test procedure. In this paper, we investigate extensions of the original ideas. P For example, if , and p4=0.01, the initial graph from Figure 3 rejects H1 and H3, whereas the consonant weighted parametric test procedure from Figure 4 with δ=0.0783 rejects only H1. Let p(1)α for all i∈I, stop and retain all m hypotheses. In the following, we give only a brief illustration of the gMCP package. {\displaystyle H_{4}} The closure principle introduced by Marcus et al. is rejected – while controlling the family-wise error rate of ≤ H Note that if the weights are not exhaustive, step (ii) may no longer be valid and should be skipped. ) (2) does not provide the only possible definition of a weighted parametric test. P The gMCP function takes objects of the type graphMCP as its input together with a vector of p‐values and performs the specified multiple test procedure. m To get the Bonferroni corrected/adjusted p value, divide the original α-value by the number of analyses on the dependent variable. Hung and Wang (2009, 2010) considered some controversial multiple test problems, with emphasis on regulatory applications, and pointed out illogical problems that may arise with recently developed multiple test procedures. [4]. Each intersection is tested using the simple Bonferroni test. are controlled at level of family-wise error rate of In the cardiovascular study example, the hypotheses in are only tested, if at least one of the hypotheses in are rejected.

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