Design and analysis of a 3‐arm noninferiority trial with a prespecified margin for the hazard ratio

A 3‐arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment. The inclusion of a placebo arm enables the assessment of assay sensitivity and internal validation, in addition to the testing of the noninferiority of the experimental treatment compared with the reference treatment. In 3‐arm noninferiority trials, various statistical test procedures have been considered to evaluate the following 3 hypotheses: (i) superiority of the experimental treatment over the placebo, (ii) superiority of the reference treatment over the placebo, and (iii) noninferiority of the experimental treatment compared with the reference treatment. However, hypothesis (ii) can be insufficient and may not accurately assess the assay sensitivity for the noninferiority of the experimental treatment compared with the reference treatment. Thus, demonstrating that the superiority of the reference treatment over the placebo is greater than the noninferiority margin (the nonsuperiority of the reference treatment compared with the placebo) can be necessary. Here, we propose log‐rank statistical procedures for evaluating data obtained from 3‐arm noninferiority trials to assess assay sensitivity with a prespecified margin Δ. In addition, we derive the approximate sample size and optimal allocation required to minimize the total sample size and that of the placebo treatment sample size, hierarchically.     

A Five-Decision Testing Procedure to Infer the Value of a Unidimensional Parameter

ABSTRACT

A statistical test can be seen as a procedure to produce a decision based on observed data, where some decisions consist of rejecting a hypothesis (yielding a significant result) and some do not, and where one controls the probability to make a wrong rejection at some prespecified significance level. Whereas traditional hypothesis testing involves only two possible decisions (to reject or not a null hypothesis), Kaiser’s directional two-sided test as well as the more recently introduced testing procedure of Jones and Tukey, each equivalent to running two one-sided tests, involve three possible decisions to infer the value of a unidimensional parameter. The latter procedure assumes that a point null hypothesis is impossible (e.g., that two treatments cannot have exactly the same effect), allowing a gain of statistical power. There are, however, situations where a point hypothesis is indeed plausible, for example, when considering hypotheses derived from Einstein’s theories. In this article, we introduce a five-decision rule testing procedure, equivalent to running a traditional two-sided test in addition to two one-sided tests, which combines the advantages of the testing procedures of Kaiser (no assumption on a point hypothesis being impossible) and Jones and Tukey (higher power), allowing for a nonnegligible (typically 20%) reduction of the sample size needed to reach a given statistical power to get a significant result, compared to the traditional approach.     

Randomization as a basis for inference in noninferiority trials

Noninferiority testing in clinical trials is commonly understood in a Neyman-Pearson framework, and has been discussed in a Bayesian framework as well. In this paper, we discuss noninferiority testing in a Fisherian framework, in which the only assumption necessary for inference is the assumption of randomization of treatments to study subjects. Randomization plays an important role in not only the design but also the analysis of clinical trials, no matter the underlying inferential field. The ability to utilize permutation tests depends on assumptions around exchangeability, and we discuss the possible uses of permutation tests in active control noninferiority analyses. The other practical implications of this paper are admittedly minor but lead to better understanding of the historical and philosophical development of active control noninferiority testing. The conclusion may also frame discussion of other complicated issues in noninferiority testing, such as the role of an intention to treat analysis.     

Precedence-type test based on Kaplan–Meier estimator of cumulative distribution function

In this paper, we introduce a precedence-type test based on Kaplan–Meier estimator of cumulative distribution function (CDF) for testing the hypothesis that two distribution functions are equal against a stochastically ordered hypothesis. This test is an alternative to the precedence life-test proposed first by Nelson (1963). After deriving the null distribution of the test statistic, we present its exact power function under the Lehmann alternative, and compare the exact power as well as simulated power (under location-shift) of the proposed test with other precedence-type tests. Next, we extend this test to the case of progressively Type-II censored data. Critical values for some combination of sample sizes and progressive censoring schemes are presented. We then examine the power properties of this test procedure and compare them to those of the weighted precedence and weighted maximal precedence tests under a location-shift alternative by means of Monte Carlo simulations. Finally, we present two examples to illustrate all the test procedures discussed here, and then make some concluding remarks.     

Small sample equivalence tests for exponentiality

We consider small sample equivalence tests for exponentialy. Statistical inference in this setting is particularly challenging since equivalence testing procedures typically require much larger sample sizes, in comparison with classical “difference tests,” to perform well. We make use of Butler's marginal likelihood for the shape parameter of a gamma distribution in our development of small sample equivalence tests for exponentiality. We consider two procedures using the principle of confidence interval inclusion, four Bayesian methods, and the uniformly most powerful unbiased (UMPU) test where a saddlepoint approximation to the intractable distribution of a canonical sufficient statistic is used. We perform small sample simulation studies to assess the bias of our various tests and show that all of the Bayes posteriors we consider are integrable. Our simulation studies show that the saddlepoint-approximated UMPU method performs remarkably well for small sample sizes and is the only method that consistently exhibits an empirical significance level close to the nominal 5% level.     

Nonparametric equivalence testing with respect to the median difference

The problem of comparing two independent groups of univariate data in the sense of testing for equivalence is considered for a fully nonparametric setting. The distribution of the data within each group may be a mixture of both a continuous and a discrete component, and no assumptions are made regarding the way in which the distributions of the two groups of data may differ from each other – in particular, the assumption of a shift model is avoided. The proposed equivalence testing procedure for this scenario refers to the median of the independent difference distribution, i.e. to the median of the differences between independent observations from the test group and the reference group, respectively. The procedure provides an asymptotic equivalence test, which is symmetric with respect to the roles of ‘test’ and ‘reference’. It can be described either as a two‐one‐sided‐tests (TOST) approach, or equivalently as a confidence interval inclusion rule. A one‐sided variant of the approach can be applied analogously to non‐inferiority testing problems. The procedure may be generalised to equivalence testing with respect to quantiles other than the median, and is closely related to tolerance interval type inference. Copyright © 2009 John Wiley & Sons, Ltd.     

Tests for noncorrelation of two multivariate ARMA time series

In many situations, we want to verify the existence of a relationship between multivariate time series. In this paper, we generalize the procedure developed by Haugh (1976) for univariate time series in order to test the hypothesis of noncorrelation between two multivariate stationary ARMA series. The test statistics are based on residual cross-correlation matrices. Under the null hypothesis of noncorrelation, we show that an arbitrary vector of residual cross-correlations asymptotically follows the same distribution as the corresponding vector of cross-correlations between the two innovation series. From this result, it follows that the test statistics considered are asymptotically distributed as chi-square random variables. Two test procedures are described. The first one is based on the residual cross-correlation matrix at a particular lag, whilst the second one is based on a portmanteau type statistic that generalizes Haugh's statistic. We also discuss how the procedures for testing noncorrelation can be adapted to determine the directions of causality in the sense of Granger (1969) between the two series. An advantage of the proposed procedures is that their application does not require the estimation of a global model for the two series. The finite-sample properties of the statistics introduced were studied by simulation under the null hypothesis. It led to modified statistics whose upper quantiles are much better approximated by those of the corresponding chi-square distribution. Finally, the procedures developed are applied to two different sets of economic data.     

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.     

Testing the difference of two exponential means using generalized p-values

There are no exact fixed-level tests for testing the null hypothesis that the difference of two exponential means is less than or equal to a prespecified value θ₀. For this testing problem, there are several approximate testing procedures available in the literature. Using an extended definition of p-values, Tsui and Weerahandi (1989) gave an exact significance test for this testing problem. In this paper, the performance of that procedure is investigated and is compared with approximate procedures. A size and power comparison is carried out using a simulation study. Its findings show that the test based on the generalized p-value guarantees the intended size and that it is either as good as or outperforms approximate procedures available in the literature, both in power and in size.     

A weighted bootstrap approximation for comparing the error distributions in nonparametric regression

Several procedures have been proposed for testing the equality of error distributions in two or more nonparametric regression models. Here we deal with methods based on comparing estimators of the cumulative distribution function (CDF) of the errors in each population to an estimator of the common CDF under the null hypothesis. The null distribution of the associated test statistics has been approximated by means of a smooth bootstrap (SB) estimator. This paper proposes to approximate their null distribution through a weighted bootstrap. It is shown that it produces a consistent estimator. The finite sample performance of this approximation is assessed by means of a simulation study, where it is also compared to the SB. This study reveals that, from a computational point of view, the proposed approximation is more efficient than the one provided by the SB.     

On optimal tests for general interval-hypotheses

Optimal statistical tests, using the normality assumptions for general interval hypotheses including equivalence testing and testing for nonzero difference (or for non-unit) are presented. These tests are based on the decision theory for Polya Type distributions and are compared with usual confidence tests and with ’two one-sided tests’- procedures. A formal relationship between some optimal tests and the Anderson and Hauck procedure as well as a procedure recommended by Patel and Gupta is given. A new procedure for a generalisation of Student's test as well as for equivalence testing for thet-statistics is shown.     

On Testing the Mean Equivalence of Treatments from Correlated Normal Populations

Let there be k equally correlated treatment populations under consideration, a Studentized range test is proposed to test the hypothesis of average mean equivalence against the alternative hypothesis of inequivalence. The maximum level and minimum power at some least favorable configurations of means are used to calculate the critical value and the required sample size simultaneously when testing a null against an alternative hypothesis. The range test is applied to a real world problem to find out if the stress levels among children at four time periods due to a newly built nearby airport are equivalent.     

Tracking interval for selecting between non-nested models: An investigation for Type II right censored data

In this paper, we consider the setting where the observed data is incomplete. For the general situation where the number of gaps as well as the number of unobserved values in some gaps go to infinity, the asymptotic behavior of maximum likelihood estimator is not clear. We derive and investigate the asymptotic properties of maximum likelihood estimator under censorship and drive a statistic for testing the null hypothesis that the proposed non-nested models are equally close to the true model against the alternative hypothesis that one model is closer when we are faced with a life-time situation. Furthermore rewrite a normalization of a difference of Akaike criterion for estimating the difference of expected Kullback–Leibler risk between the distributions in two different models.     

RAO'S SCORE TESTS IN SURVIVAL ANALYSIS: EXAMPLES AND BARTLETT TYPE ADJUSTMENTS

Score method in hypothesis testing is one of Professor C. R. Rao's great contributions to statistics. It provides a simple and unified way to test some simple and composite hypotheses in many statistical problems. Some popular tests in statistical practice derived with the help of intuitions can be shown as score tests under some statistical models. The subject-years test and log-rank test in survival analysis are two of the examples. In this paper, we first introduce these two examples. After formulating these two tests as score tests, we then review some recent results on the Bartlett type adjustments for these tests.     

The split sample permutation t-tests

Without the exchangeability assumption, permutation tests for comparing two population means do not provide exact control of the probability of making a Type I error. Another drawback of permutation tests is that it cannot be used to test hypothesis about one population. In this paper, we propose a new type of permutation tests for testing the difference between two population means: the split sample permutation t-tests. We show that the split sample permutation t-tests do not require the exchangeability assumption, are asymptotically exact and can be easily extended to testing hypothesis about one population. Extensive simulations were carried out to evaluate the performance of two specific split sample permutation t-tests: the split in the middle permutation t-test and the split in the end permutation t-test. The simulation results show that the split in the middle permutation t-test has comparable performance to the permutation test if the population distributions are symmetric and satisfy the exchangeability assumption. Otherwise, the split in the end permutation t-test has significantly more accurate control of level of significance than the split in the middle permutation t-test and other existing permutation tests.     

Towards a theory of point optimal testing

This paper puts the case for the inclusion of point optimal tests in the econometrician's repertoire. They do not suit every testing situation but the current evidence, which is reviewed here, indicates that they can have extremely useful Small-sample power properties. As well as being most powerful at a nominated point in the alternative hypothesis parameter space, they may also have optimum power at a number of other points and indeed be uniformly most powerful when such a test exists. Point optimal tests can also be used to trace out the maxemum attainable power envelope for a given testing problem, thus providing a benchmark against which test procedures can be evaluated. In some cases, point optimal tests can be constructed from tests of simple null hypothesis against a simple alternative. For a wide range of models of interst to econometricians, this paper shows how one can check whether a point optimal test can be constructed in this way. When it cannot, one may wish to consider approximately point optimal tests. As an illustration, the approach is applied to the non-nested problem of testing for AR(1) distrubances against MA(1) distrubances in the linear regression model.     

A test statistic based on ranked set sampling for two normal means

In this study, we considered a hypothesis test for the difference of two population means using ranked set sampling. We proposed a test statistic for this hypothesis test with more than one cycle under normality. We also investigate the performance of this test statistic, when the assumptions hold and are violated. For this reason, we investigate the type I error and power rates of tests under normality with equal and unequal variances, non-normality with equal and unequal variances. We also examine the performance of this test under imperfect ranking case. The simulation results show that derived test performs quite well.     

The evaluation of bioequivalence using nonparametric procedures

Applications of nonparametric methods to the evaluation of bioequiv-alence for two treatments are presented for independent samples and for a crossover design. Included are procedures for testing for equivalence in location, in dispersion, and in general. Also presented are procedures for the calculation of confidence limits. A general strategy for the evaluation of bioequivalence is developed which involves both hypothesis testing and the calculation of confidencelimits for parameters which characterize departures from equivalene.     

Invariant tests based on M-estimators,estimating functions,and the generalized method of moments

We study the invariance properties of various test criteria which have been proposed for hypothesis testing in the context of incompletely specified models, such as models which are formulated in terms of estimating functions (Godambe, 1960) or moment conditions and are estimated by generalized method of moments (GMM) procedures (Hansen, 1982), and models estimated by pseudo-likelihood (Gouriéroux, Monfort, and Trognon, 1984b,c) and M-estimation methods. The invariance properties considered include invariance to (possibly nonlinear) hypothesis reformulations and reparameterizations. The test statistics examined include Wald-type, LR-type, LM-type, score-type, and C(α)?type criteria. Extending the approach used in Dagenais and Dufour (1991), we show first that all these test statistics except the Wald-type ones are invariant to equivalent hypothesis reformulations (under usual regularity conditions), but all five of them are not generally invariant to model reparameterizations, including measurement unit changes in nonlinear models. In other words, testing two equivalent hypotheses in the context of equivalent models may lead to completely different inferences. For example, this may occur after an apparently innocuous rescaling of some model variables. Then, in view of avoiding such undesirable properties, we study restrictions that can be imposed on the objective functions used for pseudo-likelihood (or M-estimation) as well as the structure of the test criteria used with estimating functions and generalized method of moments (GMM) procedures to obtain invariant tests. In particular, we show that using linear exponential pseudo-likelihood functions allows one to obtain invariant score-type and C(α)?type test criteria, while in the context of estimating function (or GMM) procedures it is possible to modify a LR-type statistic proposed by Newey and West (1987) to obtain a test statistic that is invariant to general reparameterizations. The invariance associated with linear exponential pseudo-likelihood functions is interpreted as a strong argument for using such pseudo-likelihood functions in empirical work.     

CONSTRUCTING MORE POWERFUL EXACT TESTS OF EQUIVALENCE FROM BINARY MATCHED PAIRS

In randomized clinical trials, it is often necessary to demonstrate that a new medical treatment does not substantially differ from a standard reference treatment. Formal testing of such ‘equivalence hypotheses’ is typically done by combining two one‐sided tests (TOST). A quite different strand of research has demonstrated that replacing nuisance parameters with a null estimate produces P‐values that are close to exact ( Lloyd 2008a ) and that maximizing over the residual dependence on the nuisance parameter produces P‐values that are exact and optimal within a class ( Röhmel & Mansmann 1999 ; Lloyd 2008a ). The three procedures – TOST, estimation and maximization of a nuisance parameter – can each be expressed as a transformation of an approximate P‐value. In this paper, we point out that TOST‐based P‐values will generally be conservative, even if based on exact and optimal one‐sided tests. This conservatism is avoided by applying the three transforms in a certain order – estimation followed by TOST followed by maximization. We compare this procedure with existing alternatives through a numerical study of binary matched pairs where the two treatments are compared by the difference of response rates. The resulting tests are uniformly more powerful than the considered competitors, although the difference in power can range from very small to moderate.