On power and sample size of the ANOVA-type rank test

When using nonparametric methods to analyze factorial designs with repeated measures, the ANOVA-type rank test has gained popularity due to its robustness and appropriate type I error control. This article proposes power and sample size calculation formulas under two scenarios where the nonparametric regression coefficients are known or they are unknown but a pilot study is available. When a pilot study is available, the formulas do not need any assumption on the underlying population distributions. Simulation results confirm the accuracy of the proposed methods. An STZ rat excisional wound study is used to demonstrate the application of the methods.     

Comparison of methods for incomplete repeated measures data analysis in small samples

This paper presents missing data methods for repeated measures data in small samples. Most methods currently available are for large samples. In particular, no studies have compared the performance of multiple imputation methods to that of non-imputation incomplete analysis methods. We first develop a strategy for multiple imputations for repeated measures data under a cell-means model that is applicable for any multivariate data with small samples. Multiple imputation inference procedures are applied to the resulting multiply imputed complete data sets. Comparisons to other available non-imputation incomplete data methods is made via simulation studies to conclude that there is not much gain in using the computer intensive multiple imputation methods for small sample repeated measures data analysis in terms of the power of testing hypotheses of parameters of interest.     

Assessing departure from dose linearity under a repeated measures incomplete block design

Dose proportionality/linearity is a desirable property in pharmacokinetic studies. Various methods have been proposed for its assessment. When dose proportionality is not established, it is of interest to evaluate the degree of departure from dose linearity. In this paper, we propose a measure of departure from dose linearity and derive an asymptotic test under a repeated measures incomplete block design using a slope approach. Simulation studies show that the proposed method has a satisfactory small sample performance in terms of size and power.     

Determination of hazard ratio for progression‐free survival considering the tumor assessment schedule in sample size calculation

Progression‐free survival is recognized as an important endpoint in oncology clinical trials. In clinical trials aimed at new drug development, the target population often comprises patients that are refractory to standard therapy with a tumor that shows rapid progression. This situation would increase the bias of the hazard ratio calculated for progression‐free survival, resulting in decreased power for such patients. Therefore, new measures are needed to prevent decreasing the power in advance when estimating the sample size. Here, I propose a novel calculation procedure to assume the hazard ratio for progression‐free survival using the Cox proportional hazards model, which can be applied in sample size calculation. The hazard ratios derived by the proposed procedure were almost identical to those obtained by simulation. The hazard ratio calculated by the proposed procedure is applicable to sample size calculation and coincides with the nominal power. Methods that compensate for the lack of power due to biases in the hazard ratio are also discussed from a practical point of view.     

Sample Size Calculation for Rank Tests Comparing K Survival Distributions

Rank tests, such as logrank or Wilcoxon rank sum tests, have been popularly used to compare survival distributions of two or more groups in the presence of right censoring. However, there has been little research on sample size calculation methods for rank tests to compare more than two groups. An existing method is based on a crude approximation, which tends to underestimate sample size, i.e., the calculated sample size has lower power than projected. In this paper we propose an asymptotically correct method and an approximate method for sample size calculation. The proposed methods are compared to other methods through simulation studies.     

Sample size calculations for time-averaged difference of longitudinal binary outcomes

In clinical trials with repeated measurements, the responses from each subject are measured multiple times during the study period. Two approaches have been widely used to assess the treatment effect, one that compares the rate of change between two groups and the other that tests the time-averaged difference (TAD). While sample size calculations based on comparing the rate of change between two groups have been reported by many investigators, the literature has paid relatively little attention to the sample size estimation for time-averaged difference (TAD) in the presence of heterogeneous correlation structure and missing data in repeated measurement studies. In this study, we investigate sample size calculation for the comparison of time-averaged responses between treatment groups in clinical trials with longitudinally observed binary outcomes. The generalized estimating equation (GEE) approach is used to derive a closed-form sample size formula, which is flexible enough to account for arbitrary missing patterns and correlation structures. In particular, we demonstrate that the proposed sample size can accommodate a mixture of missing patterns, which is frequently encountered by practitioners in clinical trials. To our knowledge, this is the first study that considers the mixture of missing patterns in sample size calculation. Our simulation shows that the nominal power and type I error are well preserved over a wide range of design parameters. Sample size calculation is illustrated through an example.     

Sample size calculation for testing non-inferiority and equivalence under Poisson distribution

When counting the number of chemical parts in air pollution studies or when comparing the occurrence of congenital malformations between a uranium mining town and a control population, we often assume Poisson distribution for the number of these rare events. Some discussions on sample size calculation under Poisson model appear elsewhere, but all these focus on the case of testing equality rather than testing equivalence. We discuss sample size and power calculation on the basis of exact distribution under Poisson models for testing non-inferiority and equivalence with respect to the mean incidence rate ratio. On the basis of large sample theory, we further develop an approximate sample size calculation formula using the normal approximation of a proposed test statistic for testing non-inferiority and an approximate power calculation formula for testing equivalence. We find that using these approximation formulae tends to produce an underestimate of the minimum required sample size calculated from using the exact test procedure. On the other hand, we find that the power corresponding to the approximate sample sizes can be actually accurate (with respect to Type I error and power) when we apply the asymptotic test procedure based on the normal distribution. We tabulate in a variety of situations the minimum mean incidence needed in the standard (or the control) population, that can easily be employed to calculate the minimum required sample size from each comparison group for testing non-inferiority and equivalence between two Poisson populations.     

Efficient sample size allocation with cost constraints for heterogeneous-variance group comparison

When conducting research with controlled experiments, sample size planning is one of the important decisions that researchers have to make. However, current methods do not adequately address this issue with regard to variance heterogeneity with some cost constraints for comparing several treatment means. This paper proposes a sample size allocation ratio in the fixed-effect heterogeneous analysis of variance when group variances are unequal and in cases where the sampling and/or variable cost has some constraints. The efficient sample size allocation is determined for the purpose of minimizing total cost with a designated power or maximizing the power with a given total cost. Finally, the proposed method is verified by using the index of relative efficiency and the corresponding total cost and the total sample size needed. We also apply our method in a pain management trial to decide an efficient sample size. Simulation studies also show that the proposed sample size formulas are efficient in terms of statistical power. SAS and R codes are provided in the appendix for easy application.     

A note on effective sample size for constructing confidence intervals for the difference of two proportions

Proportion differences are often used to estimate and test treatment effects in clinical trials with binary outcomes. In order to adjust for other covariates or intra-subject correlation among repeated measures, logistic regression or longitudinal data analysis models such as generalized estimating equation or generalized linear mixed models may be used for the analyses. However, these analysis models are often based on the logit link which results in parameter estimates and comparisons in the log-odds ratio scale rather than in the proportion difference scale. A two-step method is proposed in the literature to approximate the calculation of confidence intervals for the proportion difference using a concept of effective sample sizes. However, the performance of this two-step method has not been investigated in their paper. On this note, we examine the properties of the two-step method and propose an adjustment to the effective sample size formula based on Bayesian information theory. Simulations are conducted to evaluate the performance and to show that the modified effective sample size improves the coverage property of the confidence intervals.     

Sample size determination for the parallel model in a survey with sensitive questions

Recently, a new non-randomized parallel design is proposed by Tian (2013) for surveys with sensitive topics. However, the sample size formulae associated with testing hypotheses for the parallel model are not yet available. As a crucial component in surveys, the sample size formulae with the parallel design are developed in this paper by using the power analysis method for both the one- and two-sample problems. We consider both the one- and two-sample problems. The asymptotic power functions and the corresponding sample size formulae for both the one- and two-sided tests based on the large-sample normal approximation are derived. The performance is assessed through comparing the asymptotic power with the exact power and reporting the ratio of the sample sizes with the parallel model and the design of direct questioning. We numerically compare the sample sizes needed for the parallel design with those required for the crosswise and triangular models. Two theoretical justifications are also provided. An example from a survey on ‘sexual practices’ in San Francisco, Las Vegas and Portland is used to illustrate the proposed methods.     

Sample size calculations for single-arm survival studies using transformations of the Kaplan–Meier estimator

In single-arm clinical trials with survival outcomes, the Kaplan–Meier estimator and its confidence interval are widely used to assess survival probability and median survival time. Since the asymptotic normality of the Kaplan–Meier estimator is a common result, the sample size calculation methods have not been studied in depth. An existing sample size calculation method is founded on the asymptotic normality of the Kaplan–Meier estimator using the log transformation. However, the small sample properties of the log transformed estimator are quite poor in small sample sizes (which are typical situations in single-arm trials), and the existing method uses an inappropriate standard normal approximation to calculate sample sizes. These issues can seriously influence the accuracy of results. In this paper, we propose alternative methods to determine sample sizes based on a valid standard normal approximation with several transformations that may give an accurate normal approximation even with small sample sizes. In numerical evaluations via simulations, some of the proposed methods provided more accurate results, and the empirical power of the proposed method with the arcsine square-root transformation tended to be closer to a prescribed power than the other transformations. These results were supported when methods were applied to data from three clinical trials.     

A Bayesian sequential design with adaptive randomization for 2‐sided hypothesis test

Bayesian sequential and adaptive randomization designs are gaining popularity in clinical trials thanks to their potentials to reduce the number of required participants and save resources. We propose a Bayesian sequential design with adaptive randomization rates so as to more efficiently attribute newly recruited patients to different treatment arms. In this paper, we consider 2‐arm clinical trials. Patients are allocated to the 2 arms with a randomization rate to achieve minimum variance for the test statistic. Algorithms are presented to calculate the optimal randomization rate, critical values, and power for the proposed design. Sensitivity analysis is implemented to check the influence on design by changing the prior distributions. Simulation studies are applied to compare the proposed method and traditional methods in terms of power and actual sample sizes. Simulations show that, when total sample size is fixed, the proposed design can obtain greater power and/or cost smaller actual sample size than the traditional Bayesian sequential design. Finally, we apply the proposed method to a real data set and compare the results with the Bayesian sequential design without adaptive randomization in terms of sample sizes. The proposed method can further reduce required sample size.     

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.     

Optimal sample size planning for the Wilcoxon–Mann–Whitney and van Elteren tests under cost constraints

Sampling cost is a crucial factor in sample size planning, particularly when the treatment group is more expensive than the control group. To either minimize the total cost or maximize the statistical power of the test, we used the distribution-free Wilcoxon–Mann–Whitney test for two independent samples and the van Elteren test for randomized block design, respectively. We then developed approximate sample size formulas when the distribution of data is abnormal and/or unknown. This study derived the optimal sample size allocation ratio for a given statistical power by considering the cost constraints, so that the resulting sample sizes could minimize either the total cost or the total sample size. Moreover, for a given total cost, the optimal sample size allocation is recommended to maximize the statistical power of the test. The proposed formula is not only innovative, but also quick and easy. We also applied real data from a clinical trial to illustrate how to choose the sample size for a randomized two-block design. For nonparametric methods, no existing commercial software for sample size planning has considered the cost factor, and therefore the proposed methods can provide important insights related to the impact of cost constraints.     

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.     

Exact permutation inference for two sample repeated measures data

Experiments in which very few units are measured many times sometimes present particular difficulties. Interest often centers on simple location shifts between two treatment groups, but appropriate modeling of the error distribution can be challenging. For example, normality may be difficult to verify, or a single transformation stabilizing variance or improving normality for all units and all measurements may not exist. We propose an analysis of two sample repeated measures data based on the permutation distribution of units. This provides a distribution free alternative to standard analyses. The analysis includes testing, estimation and confidence intervals. By assuming a certain structure in the location shift model, the dimension of the problem is reduced by analyzing linear combinations of the marginal statistics. Recently proposed algorithms for computation of two sample permutation distributions, require only a few seconds for experiments having as many as 100 units and any number of repeated measures. The test has high asymptotic efficiency and good power with respect to tests based on the normal distribution. Since the computational burden is minimal, approximation of the permutation distribution is unnecessary.     

Comparison of methods for analyzing binary repeated measures data: A simulation-based study (comparison of methods for binary repeated measures)

In this study, some methods suggested for binary repeated measures, namely, Weighted Least Squares (WLS), Generalized Estimating Equations (GEE), and Generalized Linear Mixed Models (GLMM) are compared with respect to power, type 1 error, and properties of estimates. The results indicate that with adequate sample size, no missing data, the only covariate being time effect, and a relatively limited number of time points, the WLS method performs well. The GEE approach performs well only for large sample sizes. The GLMM method is satisfactory with respect to type I error, but its estimates have poorer properties than the other methods.     

Sample size determination for cluster randomization phase II trials of dichotomous data

One of the main goals for a phase II trial is to screen and select the best treatment to proceed onto further studies in a phase III trial. Under the flexible design proposed elsewhere, we discuss for cluster randomization trials sample size calculation with a given desired probability of correct selection to choose the best treatment when one treatment is better than all the others. We develop exact procedures for calculating the minimum required number of clusters with a given cluster size (or the minimum number of patients with a given number of repeated measurements) per treatment. An approximate sample size and the evaluation of its performance for two arms are also given. To help readers employ the results presented here, tables are provided to summarize the resulting minimum required sample sizes for cluster randomization trials with two arms and three arms in a variety of situations. Finally, to illustrate the sample size calculation procedures developed here, we use the data taken from a cluster randomization trial to study the association between the dietary sodium and the blood pressure.     

Power and Sample Size for Fixed-Effects Inference in Reversible Linear Mixed Models

ABSTRACT

Despite the popularity of the general linear mixed model for data analysis, power and sample size methods and software are not generally available for commonly used test statistics and reference distributions. Statisticians resort to simulations with homegrown and uncertified programs or rough approximations which are misaligned with the data analysis. For a wide range of designs with longitudinal and clustering features, we provide accurate power and sample size approximations for inference about fixed effects in the linear models we call reversible. We show that under widely applicable conditions, the general linear mixed-model Wald test has noncentral distributions equivalent to well-studied multivariate tests. In turn, exact and approximate power and sample size results for the multivariate Hotelling–Lawley test provide exact and approximate power and sample size results for the mixed-model Wald test. The calculations are easily computed with a free, open-source product that requires only a web browser to use. Commercial software can be used for a smaller range of reversible models. Simple approximations allow accounting for modest amounts of missing data. A real-world example illustrates the methods. Sample size results are presented for a multicenter study on pregnancy. The proposed study, an extension of a funded project, has clustering within clinic. Exchangeability among the participants allows averaging across them to remove the clustering structure. The resulting simplified design is a single-level longitudinal study. Multivariate methods for power provide an approximate sample size. All proofs and inputs for the example are in the supplementary materials (available online).     

Multiple-arm superiority and non-inferiority designs with various endpoints

Multiple-arm dose-response superiority trials are widely studied for continuous and binary endpoints, while non-inferiority designs have been studied recently in two-arm trials. In this paper, a unified asymptotic formulation of a sample size calculation for k-arm (k>0) trials with different endpoints (continuous, binary and survival endpoints) is derived for both superiority and non-inferiority designs. The proposed method covers the sample size calculation for single-arm and k-arm (k> or =2) designs with survival endpoints, which has not been covered in the statistic literature. A simple, closed form for power and sample size calculations is derived from a contrast test. Application examples are provided. The effect of the contrasts on the power is discussed, and a SAS program for sample size calculation is provided and ready to use.