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.     

A course for clinical trial personnel in clinical study designs, randomization, allocation schedules, and interactive response systems

This continuing education course for professionals involved in all areas of clinical trials integrates concepts related to the role of randomization in the scientific process. The course includes two interactive lecture and discussion sections and a workshop practicum. The first interactive lecture introduces basic clinical trial issues and statistical principles such as bias, blinding, randomization, control groups, and the importance of formulating clear and discriminating clinical and statistical hypotheses. It then focuses on the most commonly used clinical study designs and the corresponding patient randomization schemes. The second interactive lecture focuses on the implementation of randomization of patients and drug supply through allocation and component ID schedules. The workshop practicum, conducted in small groups, enables students to apply the lecture concepts to real clinical studies. Flexibility was built into the workshop practicum materials to allow the course content to be customized to specific audiences, and the interactive lecture sessions can be stretched to cover more advanced topics according to class interest and time availability.     

Maximum Likelihood Estimation for Multinomial‐Poisson Models: A Generalization of Birch's Numerical Invariance Results

Abstract. This study gives a generalization of Birch's log‐linear model numerical invariance result. The generalization is given in the form of a sufficient condition for numerical invariance that is simple to verify in practice and is applicable for a much broader class of models than log‐linear models. Unlike Birch's log‐linear result, the generalization herein does not rely on any relationship between sufficient statistics and maximum likelihood estimates. Indeed the generalization does not rely on the existence of a reduced set of sufficient statistics. Instead, the concept of homogeneity takes centre stage. Several examples illustrate the utility of non‐log‐linear models, the invariance (and non‐invariance) of fitted values, and the invariance (and non‐invariance) of certain approximating distributions.     

Characterization of dose‐response for count data using a generalized MCP‐Mod approach in an adaptive dose‐ranging trial

Understanding the dose–response relationship is a key objective in Phase II clinical development. Yet, designing a dose‐ranging trial is a challenging task, as it requires identifying the therapeutic window and the shape of the dose–response curve for a new drug on the basis of a limited number of doses. Adaptive designs have been proposed as a solution to improve both quality and efficiency of Phase II trials as they give the possibility to select the dose to be tested as the trial goes. In this article, we present a ‘shapebased’ two‐stage adaptive trial design where the doses to be tested in the second stage are determined based on the correlation observed between efficacy of the doses tested in the first stage and a set of pre‐specified candidate dose–response profiles. At the end of the trial, the data are analyzed using the generalized MCP‐Mod approach in order to account for model uncertainty. A simulation study shows that this approach gives more precise estimates of a desired target dose (e.g. ED70) than a single‐stage (fixed‐dose) design and performs as well as a two‐stage D‐optimal design. We present the results of an adaptive model‐based dose‐ranging trial in multiple sclerosis that motivated this research and was conducted using the presented methodology. Copyright © 2015 John Wiley & Sons, Ltd.     

A Class of Pseudolikelihood Ratio Tests for Homogeneity in Exponential Tilt Mixture Models

Mixture models are commonly used in biomedical research to account for possible heterogeneity in population. In this paper, we consider tests for homogeneity between two groups in the exponential tilt mixture models. A novel pairwise pseudolikelihood approach is proposed to eliminate the unknown nuisance function. We show that the corresponding pseudolikelihood ratio test has an asymptotic distribution as a supremum of two squared Gaussian processes under the null hypothesis. To maintain the appeal of simplicity for conventional likelihood ratio tests, we propose two alternative tests, both shown to have a simple asymptotic distribution of under the null. Simulation studies show that the proposed class of pseudolikelihood ratio tests performs well in controlling type I errors and having competitive powers compared with the current tests. The proposed tests are illustrated by an example of partial differential expression detection using microarray data from prostate cancer patients.     

A class of mixed models for recurrent event data

In this article, we propose a class of mixed models for recurrent event data. The new models include the proportional rates model and Box–Cox transformation rates models as special cases, and allow the effects of covariates on the rate functions of counting processes to be proportional or convergent. For inference on the model parameters, estimating equation approaches are developed. The asymptotic properties of the resulting estimators are established and the finite sample performance of the proposed procedure is evaluated through simulation studies. A real example with data taken from a clinic study on chronic granulomatous disease (CGD) is also illustrated for the use of the proposed methodology. The Canadian Journal of Statistics 39: 578–590; 2011. © 2011 Statistical Society of Canada     

A practical comparison of blinded methods for sample size reviews in survival data clinical trials

This paper presents practical approaches to the problem of sample size re-estimation in the case of clinical trials with survival data when proportional hazards can be assumed. When data are readily available at the time of the review, on a full range of survival experiences across the recruited patients, it is shown that, as expected, performing a blinded re-estimation procedure is straightforward and can help to maintain the trial's pre-specified error rates. Two alternative methods for dealing with the situation where limited survival experiences are available at the time of the sample size review are then presented and compared. In this instance, extrapolation is required in order to undertake the sample size re-estimation. Worked examples, together with results from a simulation study are described. It is concluded that, as in the standard case, use of either extrapolation approach successfully protects the trial error rates.     

A comparison of analysis procedures for correlated binary data in dedicated multi‐rater imaging trials

In this paper, three analysis procedures for repeated correlated binary data with no a priori ordering of the measurements are described and subsequently investigated. Examples for correlated binary data could be the binary assessments of subjects obtained by several raters in the framework of a clinical trial. This topic is especially of relevance when success criteria have to be defined for dedicated imaging trials involving several raters conducted for regulatory purposes. First, an analytical result on the expectation of the ‘Majority rater’ is presented when only the marginal distributions of the single raters are given. The paper provides a simulation study where all three analysis procedures are compared for a particular setting. It turns out that in many cases, ‘Average rater’ is associated with a gain in power. Settings were identified where ‘Majority significant’ has favorable properties. ‘Majority rater’ is in many cases difficult to interpret. Copyright © 2014 John Wiley & Sons, Ltd.     

Decomposition of Seasonality and Long‐term Trend in Seismological Data: A Bayesian Modelling of Earthquake Detection Capability

This study demonstrates the decomposition of seasonality and long‐term trend in seismological data observed at irregular time intervals. The decomposition was applied to the estimation of earthquake detection capability using cubic B‐splines and a Bayesian approach, which is similar to the seasonal adjustment model frequently used to analyse economic time‐series data. We employed numerical simulation to verify the method and then applied it to real earthquake datasets obtained in and around the northern Honshu island, Japan. With this approach, we obtained the seasonality of the detection capability related to the annual variation of wind speed and the long‐term trend corresponding to the recent improvement of the seismic network in the studied region.