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.     

The effect of small sample on optimal designs for logistic regression models

Asymptotic methods are commonly used in statistical inference for unknown parameters in binary data models. These methods are based on large sample theory, a condition which may be in conflict with small sample size and hence leads to poor results in the optimal designs theory. In this paper, we apply the second order expansions of the maximum likelihood estimator and derive a matrix formula for the mean square error (MSE) to obtain more precise optimal designs based on the MSE. Numerical results indicate the new optimal designs are more efficient than the optimal designs based on the information matrix.     

A BAYESIAN METHOD FOR THE CHOICE OF THE SAMPLE SIZE IN EQUIVALENCE TRIALS

In this paper we consider a Bayesian predictive approach to sample size determination in equivalence trials. Equivalence experiments are conducted to show that the unknown difference between two parameters is small. For instance, in clinical practice this kind of experiment aims to determine whether the effects of two medical interventions are therapeutically similar. We declare an experiment successful if an interval estimate of the effects‐difference is included in a set of values of the parameter of interest indicating a negligible difference between treatment effects (equivalence interval). We derive two alternative criteria for the selection of the optimal sample size, one based on the predictive expectation of the interval limits and the other based on the predictive probability that these limits fall in the equivalence interval. Moreover, for both criteria we derive a robust version with respect to the choice of the prior distribution. Numerical results are provided and an application is illustrated when the normal model with conjugate prior distributions is assumed.     

Cancer immunotherapy trial design with delayed treatment effect

A challenge arising in cancer immunotherapy trial design is the presence of a delayed treatment effect wherein the proportional hazard assumption no longer holds true. As a result, a traditional survival trial design based on the standard log‐rank test, which ignores the delayed treatment effect, will lead to substantial loss of statistical power. Recently, a piecewise weighted log‐rank test is proposed to incorporate the delayed treatment effect into consideration of the trial design. However, because the sample size formula was derived under a sequence of local alternative hypotheses, it results in an underestimated sample size when the hazard ratio is relatively small for a balanced trial design and an inaccurate sample size estimation for an unbalanced design. In this article, we derived a new sample size formula under a fixed alternative hypothesis for the delayed treatment effect model. Simulation results show that the new formula provides accurate sample size estimation for both balanced and unbalanced designs.     

Spectral Estimation of Covolatility from Noisy Observations Using Local Weights

We propose localized spectral estimators for the quadratic covariation and the spot covolatility of diffusion processes, which are observed discretely with additive observation noise. The appropriate estimation for time‐varying volatilities is based on an asymptotic equivalence of the underlying statistical model to a white‐noise model with correlation and volatility processes being constant over small time intervals. The asymptotic equivalence of the continuous‐time and discrete‐time experiments is proved by a construction with linear interpolation in one direction and local means for the other. The new estimator outperforms earlier non‐parametric methods in the literature for the considered model. We investigate its finite sample size characteristics in simulations and draw a comparison between various proposed methods.     

Editorial collaborators

Traditionally, the bioequivalence of a generic drug with the innovator's product is assessed by comparing their pharmacokinetic profiles determined from the blood or plasma concentration-time curves. This method may only be applicable to formulations where blood drug or metabolites levels adequately characterize absorption and metabolism. For non-systematic drugs categorized by the lack of systemic presence, such as metered dose inhalers (MDI), anti-ulcer agents and topical antifungals and vaginal antifungals, new definition of therapeutic equivalency and criteria for acceptance should be used. When pharmacologic effects of the drugs can be easily measured, pharmacodynamic effect studies can be used to assess the therapeutic equivalence of non-systemic drugs. When analytical methods or other tests cannot be developed to permit use of the pharmacodynamic method, clinical trials to compare one or several clinical endpoints may be the only suitable method to establishing therapeutic equivalence. In this paper we evaluate by Monte-Carlo simulations the fixed sample performances of some two one-sided tests procedures which may be used to assess the therapeutic equivalence of non-systemic drugs with binary clinical endpoints. Formulae of sample size determination for therapeutic equivalence clinical trials are also given.     

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.     

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.     

Sample size estimation for a two-group comparison of repeated count outcomes using GEE

Randomized clinical trials with count measurements as the primary outcome are common in various medical areas such as seizure counts in epilepsy trials, or relapse counts in multiple sclerosis trials. Controlled clinical trials frequently use a conventional parallel-group design that assigns subjects randomly to one of two treatment groups and repeatedly evaluates them at baseline and intervals across a treatment period of a fixed duration. The primary interest is to compare the rates of change between treatment groups. Generalized estimating equations (GEEs) have been widely used to compare rates of change between treatment groups because of its robustness to misspecification of the true correlation structure. In this paper, we derive a sample size formula for comparing the rates of change between two groups in a repeatedly measured count outcome using GEE. The sample size formula incorporates general missing patterns such as independent missing and monotone missing, and general correlation structures such as AR(1) and compound symmetry (CS). The performance of the sample size formula is evaluated through simulation studies. Sample size estimation is illustrated by a clinical trial example from epilepsy.     

Phase II trial design with growth modulation index as the primary endpoint

Molecularly targeted, genomic‐driven, and immunotherapy‐based clinical trials continue to be advanced for the treatment of relapse or refractory cancer patients, where the growth modulation index (GMI) is often considered a primary endpoint of treatment efficacy. However, there little literature is available that considers the trial design with GMI as the primary endpoint. In this article, we derived a sample size formula for the score test under a log‐linear model of the GMI. Study designs using the derived sample size formula are illustrated under a bivariate exponential model, the Weibull frailty model, and the generalized treatment effect size. The proposed designs provide sound statistical methods for a single‐arm phase II trial with GMI as the primary endpoint.     

Sample size calculation for a proportional hazards mixture cure model with nonbinary covariates

Sample size calculation is a critical issue in clinical trials because a small sample size leads to a biased inference and a large sample size increases the cost. With the development of advanced medical technology, some patients can be cured of certain chronic diseases, and the proportional hazards mixture cure model has been developed to handle survival data with potential cure information. Given the needs of survival trials with potential cure proportions, a corresponding sample size formula based on the log-rank test statistic for binary covariates has been proposed by Wang et al. [25]. However, a sample size formula based on continuous variables has not been developed. Herein, we presented sample size and power calculations for the mixture cure model with continuous variables based on the log-rank method and further modified it by Ewell's method. The proposed approaches were evaluated using simulation studies for synthetic data from exponential and Weibull distributions. A program for calculating necessary sample size for continuous covariates in a mixture cure model was implemented in R.     

Formulas for counting acyclic digraph Markov equivalence classes

Multivariate Markov dependencies between different variables often can be represented graphically using acyclic digraphs (ADGs). In certain cases, though, different ADGs represent the same statistical model, thus leading to a set of equivalence classes of ADGs that constitute the true universe of available graphical models. Building upon the previously known formulas for counting the number of acyclic digraphs and the number of equivalence classes of size 1, formulas are developed to count ADG equivalence classes of arbitrary size, based on the chordal graph configurations that produce a class of that size. Theorems to validate the formulas as well as to aid in determining the appropriate chordal graphs to use for a given class size are included.     

CONFIDENCE INTERVALS FOR POWER,WITH SPECIAL REFERENCE TO MEDICAL TRIALS*

A technique is given for drawing valid inferences in cases where performance characteristics of statistical procedures (e.g. power for a test, or probability of a correct selection for a selection procedure) depend upon unknown parameters (e.g. an unknown variance). The technique is especially useful in situations where sample sizes are small (e.g. in many medical trials); the “usual” approximate procedures are found to be misleading in such cases.     

Notes on Kolassa’s Method for Estimating the Power of Wilcoxon–Mann–Whitney Test

The Kolassa method implemented in the nQuery Advisor software has been widely used for approximating the power of the Wilcoxon–Mann–Whitney (WMW) test for ordered categorical data, in which Edgeworth approximation is used to estimate the power of an unconditional test based on the WMW U statistic. When the sample size is small or when the sizes in the two groups are unequal, Kolassa’s method may yield quite poor approximation to the power of the conditional WMW test that is commonly implemented in statistical packages. Two modifications of Kolassa’s formula are proposed and assessed by simulation studies.     

A guide to the design and analysis of small clinical studies

Clinical studies, which have a small number of patients, are conducted by pharmaceutical companies and research institutions. Examples of constraints that lead to a small clinical study include a single investigative site with a highly specialized expertise or equipment, rare diseases, and limited time and budget. We consider the following topics, which we believe will be helpful for the investigator and statistician working together on the design and analysis of small clinical studies: definitions of various types of small studies (exploratory, pilot, proof of concept); bias and ways to mitigate the bias; commonly used study designs for randomized and nonrandomized studies, and some less commonly used designs; potential ethical issues associated with small underpowered clinical studies; sample size for small studies; statistical analysis methods for different types of variables and multiplicity issues. We conclude the paper with recommendations made by an Institute of Medicine committee, which was asked to assess the current methodologies and appropriate situations for conducting small clinical studies.     

Consequences of effect size heterogeneity for meta-analysis: a Monte Carlo study

In this article we use Monte Carlo analysis to assess the small sample behaviour of the OLS, the weighted least squares (WLS) and the mixed effects meta-estimators under several types of effect size heterogeneity, using the bias, the mean squared error and the size and power of the statistical tests as performance indicators. Specifically, we analyse the consequences of heterogeneity in effect size precision (heteroskedasticity) and of two types of random effect size variation, one where the variation holds for the entire sample, and one where only a subset of the sample of studies is affected. Our results show that the mixed effects estimator is to be preferred to the other two estimators in the first two situations, but that WLS outperforms OLS and mixed effects in the third situation. Our findings therefore show that, under circumstances that are quite common in practice, using the mixed effects estimator may be suboptimal and that the use of WLS is preferable.     

A Note on Sample Size Determination for Akaike Information Criterion (AIC) Approach to Clinical Data Analysis

ABSTRACT

Because of its flexibility and usefulness, Akaike Information Criterion (AIC) has been widely used for clinical data analysis. In general, however, AIC is used without paying much attention to sample size. If sample sizes are not large enough, it is possible that the AIC approach does not lead us to the conclusions which we seek. This article focuses on the sample size determination for AIC approach to clinical data analysis. We consider a situation in which outcome variables are dichotomous and propose a method for sample size determination under this situation. The basic idea is also applicable to the situations in which outcome variables have more than two categories or outcome variables are continuous. We present simulation studies and an application to an actual clinical trial.     

Fixed effects ANOVA: an extension to samples with random size

In many relevant situations, such as in medical research, sample sizes may not be previously known. The aim of this paper is to extend one and more than one-way analysis of variance to those situations and show how to compute correct critical values. The interest of this approach lies in avoiding false rejections obtained when using the classical fixed size F-tests. Sample sizes are assumed as random and we then proceed with the application of this approach to a database on cancer.     

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.     

Some factors affecting statistical power of approximate tests in the linear mixed model for longitudinal data

Different longitudinal study designs require different statistical analysis methods and different methods of sample size determination. Statistical power analysis is a flexible approach to sample size determination for longitudinal studies. However, different power analyses are required for different statistical tests which arises from the difference between different statistical methods. In this paper, the simulation-based power calculations of F-tests with Containment, Kenward-Roger or Satterthwaite approximation of degrees of freedom are examined for sample size determination in the context of a special case of linear mixed models (LMMs), which is frequently used in the analysis of longitudinal data. Essentially, the roles of some factors, such as variance–covariance structure of random effects [unstructured UN or factor analytic FA0], autocorrelation structure among errors over time [independent IND, first-order autoregressive AR1 or first-order moving average MA1], parameter estimation methods [maximum likelihood ML and restricted maximum likelihood REML] and iterative algorithms [ridge-stabilized Newton-Raphson and Quasi-Newton] on statistical power of approximate F-tests in the LMM are examined together, which has not been considered previously. The greatest factor affecting statistical power is found to be the variance–covariance structure of random effects in the LMM. It appears that the simulation-based analysis in this study gives an interesting insight into statistical power of approximate F-tests for fixed effects in LMMs for longitudinal data.