Distribution of the two‐sample t‐test statistic following blinded sample size re‐estimation

We consider the blinded sample size re‐estimation based on the simple one‐sample variance estimator at an interim analysis. We characterize the exact distribution of the standard two‐sample t‐test statistic at the final analysis. We describe a simulation algorithm for the evaluation of the probability of rejecting the null hypothesis at given treatment effect. We compare the blinded sample size re‐estimation method with two unblinded methods with respect to the empirical type I error, the empirical power, and the empirical distribution of the standard deviation estimator and final sample size. We characterize the type I error inflation across the range of standardized non‐inferiority margin for non‐inferiority trials, and derive the adjusted significance level to ensure type I error control for given sample size of the internal pilot study. We show that the adjusted significance level increases as the sample size of the internal pilot study increases. Copyright © 2016 John Wiley & Sons, Ltd.     

Testing equality of two normal means using combined samples of paired and unpaired data

A test for equality of two normal means when the data consist of both paired and unpaired observations is proposed. The proposed test is compared with two other standard methods known in the literature with respect to the type I error rate and power using simulation results.     

Exact methods of testing the homogeneity of prevalences for correlated binary data

Correlated binary data arise in many ophthalmological and otolaryngological clinical trials. To test the homogeneity of prevalences among different groups is an important issue when conducting these trials. The equal correlation coefficients model proposed by Donner in 1989 is a popular model handling correlated binary data. The asymptotic chi-square test works well when the sample size is large. However, it would fail to maintain the type I error rate when the sample size is relatively small. In this paper, we propose several exact methods to deal with small sample scenarios. Their performances are compared with respect to type I error rate and power. The ‘M approach’ and the ‘E + M approach’ seem to outperform the others. A real work example is given to further explain how these approaches work. Finally, the computational efficiency of the exact methods is discussed as a pressing issue of future work.     

Sample size determinations when two binomial proportions are very small

Sample size determination for testing the hypothesis of equality of proportions with a specified type I and type I1 error probabilitiesis of ten based on normal approximation to the binomial distribution. When the proportionsinvolved are very small, the exact distribution of the test statistic may not follow the assumed distribution. Consequently, the sample size determined by the test statistic may not result in the sespecifiederror probabilities. In this paper the author proposes a square root formula and compares it with several existing sample size approximation methods. It is found that with small proportion (p≦.01) the squar eroot formula provides the closest approximation to the exact sample sizes which attain a specified type I and type II error probabilities. Thes quare root formula is simple inform and has the advantage that equal differencesare equally detectable.     

On the Exact Size of Tests of Treatment Effects in Multi‐Arm Clinical Trials

When testing treatment effects in multi‐arm clinical trials, the Bonferroni method or the method of Simes 1986) is used to adjust for the multiple comparisons. When control of the family‐wise error rate is required, these methods are combined with the close testing principle of Marcus et al. (1976). Under weak assumptions, the resulting p‐values all give rise to valid tests provided that the basic test used for each treatment is valid. However, standard tests can be far from valid, especially when the endpoint is binary and when sample sizes are unbalanced, as is common in multi‐arm clinical trials. This paper looks at the relationship between size deviations of the component test and size deviations of the multiple comparison test. The conclusion is that multiple comparison tests are as imperfect as the basic tests at nominal size α/m where m is the number of treatments. This, admittedly not unexpected, conclusion implies that these methods should only be used when the component test is very accurate at small nominal sizes. For binary end‐points, this suggests use of the parametric bootstrap test. All these conclusions are supported by a detailed numerical study.     

A permutation procedure for testing the equality of pattern hypotheses across groups involving correlation or covariance matrices

This paper describes a permutation procedure to test for the equality of selected elements of a covariance or correlation matrix across groups. It involves either centring or standardising each variable within each group before randomly permuting observations between groups. Since the assumption of exchangeability of observations between groups does not strictly hold following such transformations, Monte Carlo simulations were used to compare expected and empirical rejection levels as a function of group size, the number of groups and distribution type (Normal, mixtures of Normals and Gamma with various values of the shape parameter). The Monte Carlo study showed that the estimated probability levels are close to those that would be obtained with an exact test except at very small sample sizes (5 or 10 observations per group). The test appears robust against non-normal data, different numbers of groups or variables per group and unequal sample sizes per group. Power was increased with increasing sample size, effect size and the number of elements in the matrix and power was decreased with increasingly unequal numbers of observations per group.     

Inference on Polychotomous Responses in Finite Populations

Abstract. A model‐based predictive estimator is proposed for the population proportions of a polychotomous response variable, based on a sample from the population and on auxiliary variables, whose values are known for the entire population. The responses for the non‐sample units are predicted using a multinomial logit model, which is a parametric function of the auxiliary variables. A bootstrap estimator is proposed for the variance of the predictive estimator, its consistency is proved and its small sample performance is compared with that of an analytical estimator. The proposed predictive estimator is compared with other available estimators, including model‐assisted ones, both in a simulation study involving different sampling designs and model mis‐specification, and using real data from an opinion survey. The results indicate that the prediction approach appears to use auxiliary information more efficiently than the model‐assisted approach.     

Testing the equality of several multivariate normal mean vectors under heteroscedasticity: A fiducial approach and an approximate test

We consider the problem of testing the equality of several multivariate normal mean vectors under heteroscedasticity. We first construct a fiducial confidence region (FCR) for the differences between normal mean vectors and we then propose a fiducial test for comparing mean vectors by inverting the FCR. We also propose a simple approximate test that is based on a modification of the χ² approximation. This simple test avoids the complications of simulation-based inference methods. We show that the proposed fiducial test has correct type one error rate asymptotically. We compare the proposed fiducial and approximate tests with the parametric bootstrap test in terms of controlling the type one error rate via an extensive simulation study. Our simulation results show that the proposed fiducial and approximate tests control the type one error rate, while there are cases that the parametric bootstrap test is out of control. We also discuss the power performance of the tests. Finally, we illustrate with a real example how our proposed methods are applicable in analyzing repeated measure designs including a single grouping variable.     

Robust Small Sample Inference for Generalised Estimating Equations: An Application of the Anova‐type Test

Asymptotically, the Wald‐type test for generalised estimating equations (GEE) models can control the type I error rate at the nominal level. However in small sample studies, it may lead to inflated type I error rates. Even with currently available small sample corrections for the GEE Wald‐type test, the type I error rate inflation is still serious when the tested contrast is multidimensional. This paper extends the ANOVA‐type test for heteroscedastic factorial designs to GEE and shows that the proposed ANOVA‐type test can also control the type I error rate at the nominal level in small sample studies while still maintaining robustness with respect to mis‐specification of the working correlation matrix. Differences of inference between the Wald‐type test and the proposed test are observed in a two‐way repeated measures ANOVA model for a diet‐induced obesity study and a two‐way repeated measures logistic regression for a collagen‐induced arthritis study. Simulation studies confirm that the proposed test has better control of the type I error rate than the Wald‐type test in small sample repeated measures models. Additional simulation studies further show that the proposed test can even achieve larger power than the Wald‐type test in some cases of the large sample repeated measures ANOVA models that were investigated.     

A Bayesian sequential design with binary outcome

Several researchers have proposed solutions to control type I error rate in sequential designs. The use of Bayesian sequential design becomes more common; however, these designs are subject to inflation of the type I error rate. We propose a Bayesian sequential design for binary outcome using an alpha‐spending function to control the overall type I error rate. Algorithms are presented for calculating critical values and power for the proposed designs. We also propose a new stopping rule for futility. Sensitivity analysis is implemented for assessing the effects of varying the parameters of the prior distribution and maximum total sample size on critical values. Alpha‐spending functions are compared using power and actual sample size through simulations. Further simulations show that, when total sample size is fixed, the proposed design has greater power than the traditional Bayesian sequential design, which sets equal stopping bounds at all interim analyses. We also find that the proposed design with the new stopping for futility rule results in greater power and can stop earlier with a smaller actual sample size, compared with the traditional stopping rule for futility when all other conditions are held constant. Finally, we apply the proposed method to a real data set and compare the results with traditional designs.     

Equal‐tailed confidence intervals for comparison of rates

Several methods are available for generating confidence intervals for rate difference, rate ratio, or odds ratio, when comparing two independent binomial proportions or Poisson (exposure‐adjusted) incidence rates. Most methods have some degree of systematic bias in one‐sided coverage, so that a nominal 95% two‐sided interval cannot be assumed to have tail probabilities of 2.5% at each end, and any associated hypothesis test is at risk of inflated type I error rate. Skewness‐corrected asymptotic score methods have been shown to have superior equal‐tailed coverage properties for the binomial case. This paper completes this class of methods by introducing novel skewness corrections for the Poisson case and for odds ratio, with and without stratification. Graphical methods are used to compare the performance of these intervals against selected alternatives. The skewness‐corrected methods perform favourably in all situations—including those with small sample sizes or rare events—and the skewness correction should be considered essential for analysis of rate ratios. The stratified method is found to have excellent coverage properties for a fixed effects analysis. In addition, another new stratified score method is proposed, based on the t‐distribution, which is suitable for use in either a fixed effects or random effects analysis. By using a novel weighting scheme, this approach improves on conventional and modern meta‐analysis methods with weights that rely on crude estimation of stratum variances. In summary, this paper describes methods that are found to be robust for a wide range of applications in the analysis of rates.     

Testing the equality of several log-normal means based on a computational approach

In this study, we propose a new test based on a computational approach to test the equality of several log-normal means. We compare this test with some existing methods in terms of the type-I error rate and power using Monte Carlo simulations for varying values of number of groups and sample sizes. The simulation results indicate that the proposed test could be suggested as a good alternative for testing the equality of several log-normal means.     

Blinded sample size re‐estimation in crossover bioequivalence trials

In drug development, bioequivalence studies are used to indirectly demonstrate clinical equivalence of a test formulation and a reference formulation of a specific drug by establishing their equivalence in bioavailability. These studies are typically run as crossover studies. In the planning phase of such trials, investigators and sponsors are often faced with a high variability in the coefficients of variation of the typical pharmacokinetic endpoints such as the area under the concentration curve or the maximum plasma concentration. Adaptive designs have recently been considered to deal with this uncertainty by adjusting the sample size based on the accumulating data. Because regulators generally favor sample size re‐estimation procedures that maintain the blinding of the treatment allocations throughout the trial, we propose in this paper a blinded sample size re‐estimation strategy and investigate its error rates. We show that the procedure, although blinded, can lead to some inflation of the type I error rate. In the context of an example, we demonstrate how this inflation of the significance level can be adjusted for to achieve control of the type I error rate at a pre‐specified level. Furthermore, some refinements of the re‐estimation procedure are proposed to improve the power properties, in particular in scenarios with small sample sizes. Copyright © 2014 John Wiley & Sons, Ltd.     

Adaptive designs for single‐arm phase II trials in oncology

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two‐stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two‐stage design proposed by Chang et al. (Biometrics 1987; 43:865–874). However, the new design allows the use of mid‐course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology. Copyright © 2012 John Wiley & Sons, Ltd.     

Outlier Robust Small‐Area Estimation Under Spatial Correlation

Modern systems of official statistics require the estimation and publication of business statistics for disaggregated domains, for example, industry domains and geographical regions. Outlier robust methods have proven to be useful for small‐area estimation. Recently proposed outlier robust model‐based small‐area methods assume, however, uncorrelated random effects. Spatial dependencies, resulting from similar industry domains or geographic regions, often occur. In this paper, we propose an outlier robust small‐area methodology that allows for the presence of spatial correlation in the data. In particular, we present a robust predictive methodology that incorporates the potential spatial impact from other areas (domains) on the small area (domain) of interest. We further propose two parametric bootstrap methods for estimating the mean‐squared error. Simulations indicate that the proposed methodology may lead to efficiency gains. The paper concludes with an illustrative application by using business data for estimating average labour costs in Italian provinces.     

Alternatives to post‐processing posterior predictive p values

The posterior predictive p value (ppp) was invented as a Bayesian counterpart to classical p values. The methodology can be applied to discrepancy measures involving both data and parameters and can, hence, be targeted to check for various modeling assumptions. The interpretation can, however, be difficult since the distribution of the ppp value under modeling assumptions varies substantially between cases. A calibration procedure has been suggested, treating the ppp value as a test statistic in a prior predictive test. In this paper, we suggest that a prior predictive test may instead be based on the expected posterior discrepancy, which is somewhat simpler, both conceptually and computationally. Since both these methods require the simulation of a large posterior parameter sample for each of an equally large prior predictive data sample, we furthermore suggest to look for ways to match the given discrepancy by a computation‐saving conflict measure. This approach is also based on simulations but only requires sampling from two different distributions representing two contrasting information sources about a model parameter. The conflict measure methodology is also more flexible in that it handles non‐informative priors without difficulty. We compare the different approaches theoretically in some simple models and in a more complex applied example.     

Which Measure Should be Used for Testing in a Paired Design: Simple Difference,Percent Change,or Symmetrized Percent Change?

We aimed to determine the most proper change measure among simple difference, percent, or symmetrized percent changes in simple paired designs. For this purpose, we devised a computer simulation program. Since distributions of percent and symmetrized percent change values are skewed and bimodal, paired t-test did not give good results according to Type I error and the test power. To be to able use percent change or symmetrized percent change as change measure, either the distribution of test statistics should be transformed to a known theoretical distribution by transformation methods or a new test statistic for these values should be developed.     

Two-stage k-sample designs for the ordered alternative problem

In preclinical studies and clinical dose-ranging trials, the Jonckheere-Terpstra test is widely used in the assessment of dose-response relationships. Hewett and Spurrier (1979) presented a two-stage analog of the test in the context of large sample sizes. In this paper, we propose an exact test based on Simon's minimax and optimal design criteria originally used in one-arm phase II designs based on binary endpoints. The convergence rate of the joint distribution of the first and second stage test statistics to the limiting distribution is studied, and design parameters are provided for a variety of assumed alternatives. The behavior of the test is also examined in the presence of ties, and the proposed designs are illustrated through application in the planning of a hypercholesterolemia clinical trial. The minimax and optimal two-stage procedures are shown to be preferable as compared with the one-stage procedure because of the associated reduction in expected sample size for given error constraints.     

Properties of the weighted log‐rank test in the design of confirmatory studies with delayed effects

Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. This assumption not only affects the analysis part but also the sample size calculation. The presence of delayed effects causes a change in the hazard ratio while the trial is ongoing since at the beginning we do not observe any difference between treatment arms, and after some unknown time point, the differences between treatment arms will start to appear. Hence, the proportional hazards assumption no longer holds, and both sample size calculation and analysis methods to be used should be reconsidered. The weighted log‐rank test allows a weighting for early, middle, and late differences through the Fleming and Harrington class of weights and is proven to be more efficient when the proportional hazards assumption does not hold. The Fleming and Harrington class of weights, along with the estimated delay, can be incorporated into the sample size calculation in order to maintain the desired power once the treatment arm differences start to appear. In this article, we explore the impact of delayed effects in group sequential and adaptive group sequential designs and make an empirical evaluation in terms of power and type‐I error rate of the of the weighted log‐rank test in a simulated scenario with fixed values of the Fleming and Harrington class of weights. We also give some practical recommendations regarding which methodology should be used in the presence of delayed effects depending on certain characteristics of the trial.     

Bayesian estimates of predictive value and related parameters of a diagnostic test

Bayesian analysis of predictive values and related parameters of a diagnostic test are derived. In one case, the estimates are conditional on values of the prevalence of the disease; in the second case, the corresponding unconditional estimates are presented. Small-sample point estimates, posterior moments, and credibility intervals for all related parameters are obtained. Numerical methods of solution are also discussed.