Notes on the two-stage procedure under an incomplete block two-period crossover design

Abstract

Under an incomplete block crossover design with two periods, we derive the least-squares estimators for the period effect, treatment effects and carry-over effects in explicit formulae based on within-patient differences. Using the commonly-used strategy of searching a base model for making inferences in regression analysis, we define a two-stage test procedure in studying treatment effects. On the basis of Monte Carlo simulation, we evaluate the performance of the two-stage procedure for hypothesis testing, point and interval estimation of treatment effects in a variety of situations. We note that use of the two-stage procedure can be potentially misleading and hence one should not apply a test procedure to exclusively determine whether he/she needs to account for the carry-over effect in studying treatment effects. We use the double-blind crossover trial comparing two different doses of formoterol with placebo on the forced expiratory volume in 1 second (FEV₁) readings to illustrate the use of the two-stage procedure, as well as the distinction between use of two-stage procedure and the approach with assuming no carry-over effects based on one's subjective knowledge.     

Sample size determination for testing equality in frequency data under an incomplete block crossover design

When there are more than two treatments under comparison, we may consider the use of the incomplete block crossover design (IBCD) to save the number of patients needed for a parallel groups design and reduce the duration of a crossover trial. We develop an asymptotic procedure for simultaneously testing equality of two treatments versus a control treatment (or placebo) in frequency data under the IBCD with two periods. We derive a sample size calculation procedure for the desired power of detecting the given treatment effects at a nominal-level and suggest a simple ad hoc adjustment procedure to improve the accuracy of the sample size determination when the resulting minimum required number of patients is not large. We employ Monte Carlo simulation to evaluate the finite-sample performance of the proposed test, the accuracy of the sample size calculation procedure, and that with the simple ad hoc adjustment suggested here. We use the data taken as a part of a crossover trial comparing the number of exacerbations between using salbutamol or salmeterol and a placebo in asthma patients to illustrate the sample size calculation procedure.     

Notes on interval estimation of the proportion ratio under a three-treatment three-period crossover trial

When comparing two experimental treatments with a placebo, we focus our attention on interval estimation of the proportion ratio (PR) of patient responses under a three-period crossover design. We propose a random effects exponential multiplicative risk model and derive asymptotic interval estimators in closed form for the PR between treatments and placebo. Using Monte Carlo simulations, we compare the performance of these interval estimators in a variety of situations. We use the data comparing two different doses of an analgesic with placebo for the relief of primary dysmenorrhea to illustrate the use of these interval estimators and the difference in estimates of the PR and odds ratio (OR) when the underlying relief rates are not small.     

Sample size determination for testing equality in Poisson frequency data under an AB/BA crossover trial

Assuming that the frequency of occurrence follows the Poisson distribution, we develop sample size calculation procedures for testing equality based on an exact test procedure and an asymptotic test procedure under an AB/BA crossover design. We employ Monte Carlo simulation to demonstrate the use of these sample size formulae and evaluate the accuracy of sample size calculation formula derived from the asymptotic test procedure with respect to power in a variety of situations. We note that when both the relative treatment effect of interest and the underlying intraclass correlation between frequencies within patients are large, the sample size calculation based on the asymptotic test procedure can lose accuracy. In this case, the sample size calculation procedure based on the exact test is recommended. On the other hand, if the relative treatment effect of interest is small, the minimum required number of patients per group will be large, and the asymptotic test procedure will be valid for use. In this case, we may consider use of the sample size calculation formula derived from the asymptotic test procedure to reduce the number of patients needed for the exact test procedure. We include an example regarding a double‐blind randomized crossover trial comparing salmeterol with a placebo in exacerbations of asthma to illustrate the practical use of these sample size formulae. Copyright © 2013 John Wiley & Sons, Ltd.     

Exact unconditional testing procedures for comparing two independent Poisson rates

We consider seven exact unconditional testing procedures for comparing adjusted incidence rates between two groups from a Poisson process. Exact tests are always preferable due to the guarantee of test size in small to medium sample settings. Han [Comparing two independent incidence rates using conditional and unconditional exact tests. Pharm Stat. 2008;7(3):195–201] compared the performance of partial maximization p-values based on the Wald test statistic, the likelihood ratio test statistic, the score test statistic, and the conditional p-value. These four testing procedures do not perform consistently, as the results depend on the choice of test statistics for general alternatives. We consider the approach based on estimation and partial maximization, and compare these to the ones studied by Han (2008) for testing superiority. The procedures are compared with regard to the actual type I error rate and power under various conditions. An example from a biomedical research study is provided to illustrate the testing procedures. The approach based on partial maximization using the score test is recommended due to the comparable performance and computational advantage in large sample settings. Additionally, the approach based on estimation and partial maximization performs consistently for all the three test statistics, and is also recommended for use in practice.     

Exact sample-size determination in testing non-inferiority under a simple crossover trial

For testing the non-inferiority (or equivalence) of an experimental treatment to a standard treatment, the odds ratio (OR) of patient response rates has been recommended to measure the relative treatment efficacy. On the basis of an exact test procedure proposed elsewhere for a simple crossover design, we develop an exact sample-size calculation procedure with respect to the OR of patient response rates for a desired power of detecting non-inferiority at a given nominal type I error. We note that the sample size calculated for a desired power based on an asymptotic test procedure can be much smaller than that based on the exact test procedure under a given situation. We further discuss the advantage and disadvantage of sample-size calculation using the exact test and the asymptotic test procedures. We employ an example by studying two inhalation devices for asthmatics to illustrate the use of sample-size calculation procedure developed here.     

Crossover design in clinical trials for binary response

In this paper, we consider a binary response model for the analysis of the two-treatment, two-period and four-sequence crossover design. We have introduced intra-patient drug dependency parameter in the model and provide two tests for the hypothesis of equality of treatment effects. We employ Monte Carlo simulation to compare our tests and a test that works under parallel design on the basis of type I error rate and power. We find that our procedures are dominant over the competitor with respect to power. Finally, we use a data set to illustrate the applicability of our procedure.     

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.     

Adaptive two-treatment two-period crossover design for binary treatment responses incorporating carry-over effects

Adaptive designs are sometimes used in a phase III clinical trial with the goal of allocating a larger number of patients to the better treatment. In the present paper we use some adaptive designs in a two-treatment two-period crossover trial in the presence of possible carry-over effects, where the treatment responses are binary. We use some simple designs to choose between the possible treatment combinations AA, AB, BA or BB. The goal is to use the better treatment a larger proportion of times. We calculate the allocation proportions to the possible treatment combinations and their standard deviations. We also investigate related inferential problems, for which related asymptotics are derived. The proposed procedure is compared with a possible competitor. Finally we use real data sets to illustrate the applicability of our proposed design.     

Non parametric hypothesis tests for comparing reliability functions

In reliability and related disciplines, comparing reliability functions of two (or more) aging processes is a crucial step in the process of determining reliability and understanding an aging process. The aim of this paper is to propose a non parametric statistical methodology to compare two populations based on their mean residual life function and expected inactivity time function. We introduce some novel hypothesis testing procedures that involve both Cramér–von Mises- and Kolmogorov–Smirnov-type test statistics and their decision rules are constructed based on the asymptotic distributions of these test statistics and bootstrapping method. We study the practical behavior of the proposed testing procedures extensively through simulations. The results reveal that the proposed hypothesis testing procedures perform efficiently in identifying small and large differences. Two real-life examples are discussed to demonstrate the practical utility of the tests.     

Bootstrap methods for the nonparametric assessment of population bioequivalence and similarity of distributions

A completely nonparametric approach to population bioequivalence in crossover trials has been suggested by Munk and Czado (1999). It is based on the Mallows (1972) metric as a nonparametric distance measure which allows the comparison between the entire distribution functions of test and reference formulations. It was shown that a separation between carry-over and period effects is not possible in the nonparametric setting. However when carry-over effects can be excluded, treatment effects can be assessed when period effects are or not. Munk and Czado (1999) proved bootstrap limit laws of the corresponding test statistics because estimation of the limiting variance of the test statistic is very cumbersome. The purpose of this paper is to investigate the small sample behavior of various bootstrap methods and to compare it with the asymptotic test obtained by estimation of the limiting variance. The percentile (PC) and bias correct- ed and accelerated (BCA) bootstrap were compared for multivariate normal and nonnormal populations. From the simulation results presented, the BCA bootstrap is found to be less conservative and provides higher power compared to the PC bootstrap, especially when skewed multivariate populations are present.     

Testing treatment‐by‐period interaction in four‐period crossover trials

Statistical analyses of crossover clinical trials have mainly focused on assessing the treatment effect, carryover effect, and period effect. When a treatment‐by‐period interaction is plausible, it is important to test such interaction first before making inferences on differences among individual treatments. Considerably less attention has been paid to the treatment‐by‐period interaction, which has historically been aliased with the carryover effect in two‐period or three‐period designs. In this article, from the data of a newly developed four‐period crossover design, we propose a statistical method to compare the effects of two active drugs with respect to two response variables. We study estimation and hypothesis testing considering the treatment‐by‐period interaction. Constrained least squares is used to estimate the treatment effect, period effect, and treatment‐by‐period interaction. For hypothesis testing, we extend a general multivariate method for analyzing the crossover design with multiple responses. Results from simulation studies have shown that this method performs very well. We also illustrate how to apply our method to the real data problem.     

Goodness-of-fit tests for one-shot device accelerated life testing data

In this article, we develop a formal goodness-of-fit testing procedure for one-shot device testing data, in which each observation in the sample is either left censored or right censored. Such data are also called current status data. We provide an algorithm for calculating the nonparametric maximum likelihood estimate (NPMLE) of the unknown lifetime distribution based on such data. Then, we consider four different test statistics that can be used for testing the goodness-of-fit of accelerated failure time (AFT) model by the use of samples of residuals: a chi-square-type statistic based on the difference between the empirical and expected numbers of failures at each inspection time; two other statistics based on the difference between the NPMLE of the lifetime distribution obtained from one-shot device testing data and the distribution specified under the null hypothesis; as a final statistic, we use White's idea of comparing two estimators of the Fisher Information (FI) to propose a test statistic. We then compare these tests in terms of power, and draw some conclusions. Finally, we present an example to illustrate the proposed tests.     

Notes on estimation of the intraclass correlation under the AB/BA crossover trial

Under the AB/BA crossover trial, we focus our attention on estimation of the intraclass correlation in normal data. We develop both point and interval estimators in closed form for the intraclass correlation. We employ Monte Carlo simulation to study the performance of these estimators in a variety of situations. We note that the estimators developed here for the intraclass correlation remain valid even when there are possibly unexpected carry-over effects.     

Notes on Test Homogeneity of the Odds Ratio in Matched Pairs Under Stratified Sampling: A Monte Carlo Evaluation

Using Monte Carlo simulation, we compare the performance of five asymptotic test procedures and a randomized permutation test procedure for testing the homogeneity of odds ratio under the stratified matched-pair design. We note that the weighted-least-square test procedure is liberal, while Pearson's goodness-of-fit (PGF) test procedure with the continuity correction is conservative. We note that PGF without the continuity correction, the conditional likelihood ratio test procedure, and the randomized permutation test procedure can generally perform well with respect to Type I error. We use the data taken from a case–control study regarding the endometrial cancer incidence published elsewhere to illustrate the use of these test procedures.     

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.     

Testing bioequivalence for multiple formulations with power and sample size calculations

Bioequivalence (BE) trials play an important role in drug development for demonstrating the BE between test and reference formulations. The key statistical analysis for BE trials is the use of two one‐sided tests (TOST), which is equivalent to showing that the 90% confidence interval of the relative bioavailability is within a given range. Power and sample size calculations for the comparison between one test formulation and the reference formulation has been intensively investigated, and tables and software are available for practical use. From a statistical and logistical perspective, it might be more efficient to test more than one formulation in a single trial. However, approaches for controlling the overall type I error may be required. We propose a method called multiplicity‐adjusted TOST (MATOST) combining multiple comparison adjustment approaches, such as Hochberg's or Dunnett's method, with TOST. Because power and sample size calculations become more complex and are difficult to solve analytically, efficient simulation‐based procedures for this purpose have been developed and implemented in an R package. Some numerical results for a range of scenarios are presented in the paper. We show that given the same overall type I error and power, a BE crossover trial designed to test multiple formulations simultaneously only requires a small increase in the total sample size compared with a simple 2 × 2 crossover design evaluating only one test formulation. Hence, we conclude that testing multiple formulations in a single study is generally an efficient approach. The R package MATOST is available at https://sites.google.com/site/matostbe/ . Copyright © 2012 John Wiley & Sons, Ltd.     

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 Powerful Method of Assessing the Fit of the Lognormal Distribution

When faced with the problem of goodness-of-fit to the Lognormal distribution, testing methods typically reduce to comparing the empirical distribution function of the corresponding logarithmic data to that of the normal distribution. In this article, we consider a family of test statistics which make use of the moment structure of the Lognormal law. In particular, a continuum of moment conditions is employed in the construction of a new statistic for this distribution. The proposed test is shown to be consistent against fixed alternatives, and a simulation study shows that it is more powerful than several classical procedures, including those utilizing the empirical distribution function. We conclude by applying the proposed method to some, not so typical, data sets.     

Some inferential procedures in randomized repeated measurement design for binary response

We consider a two-treatment two-period crossover design in the presence of possible carryover effects, where the treatment responses are binary. We provide some simple probability models incorporating the possible carryover effects. Asymptotic distributions of the estimates of the parameters under the proposed models are derived. We carry out tests for treatment difference and carryover effects. Finally we use a data set to illustrate the applicability of the proposed procedures.