Controlling type 1 error rate for sequential,bioequivalence studies with crossover designs

Sample size reestimation in a crossover, bioequivalence study can be a useful adaptive design tool, particularly when the intrasubject variability of the drug formulation under investigation is not well understood. When sample size reestimation is done based on an interim estimate of the intrasubject variability and bioequivalence is tested using the pooled estimate of intrasubject variability, type 1 error inflation will occur. Type 1 error inflation is caused by the pooled estimate being a biased estimator of the intrasubject variability. The type 1 error inflation and bias of the pooled estimator of variability are well characterized in the setting of a two‐arm, parallel study. The purpose of this work is to extend this characterization to the setting of a crossover, bioequivalence study with sample size reestimation and to propose an estimator of the intrasubject variability that will prevent type 1 error inflation.     

Adaptive and repeated cumulative meta‐analyses of safety data during a new drug development process

During a new drug development process, it is desirable to timely detect potential safety signals. For this purpose, repeated meta‐analyses may be performed sequentially on accumulating safety data. Moreover, if the amount of safety data from the originally planned program is not enough to ensure adequate power to test a specific hypothesis (e.g., the noninferiority hypothesis of an event of interest), the total sample size may be increased by adding new studies to the program. Without appropriate adjustment, it is well known that the type I error rate will be inflated because of repeated analyses and sample size adjustment. In this paper, we discuss potential issues associated with adaptive and repeated cumulative meta‐analyses of safety data conducted during a drug development process. We consider both frequentist and Bayesian approaches. A new drug development example is used to demonstrate the application of the methods. Copyright © 2015 John Wiley & Sons, Ltd.     

Stochastic Bounds with a Low Rank Decomposition

We investigate how we can bound a discrete time Markov chain (DTMC) by a stochastic matrix with a low rank decomposition. In the first part of the article, we show the links with previous results for matrices with a decomposition of size 1 or 2. Then we show how the complexity of the analysis for steady-state and transient distributions can be simplified when we take into account the decomposition. Finally, we show how we can obtain a monotone stochastic upper bound with a low rank decomposition.     

Saddlepoint Approximation for Sample and Bootstrap Quantiles

The paper gives the saddlepoint approximation for the distribution function of the sample quantile. A comparison of the saddlepoint approximations for the distribution functions of the sample quantile and the bootstrap quantile shows that the error of the bootstrap approximation to the distribution of the sample quantile obtained by Singh (1981) as an absolute error is actually a relative error.     

On inference for Kendall's τ within a longitudinal data setting

Kendall's τ is a non-parametric measure of correlation based on ranks and is used in a wide range of research disciplines. Although methods are available for making inference about Kendall's τ, none has been extended to modeling multiple Kendall's τs arising in longitudinal data analysis. Compounding this problem is the pervasive issue of missing data in such study designs. In this article, we develop a novel approach to provide inference about Kendall's τ within a longitudinal study setting under both complete and missing data. The proposed approach is illustrated with simulated data and applied to an HIV prevention study.     

The finite-time ruin probability in two non-standard renewal risk models with constant interest rate and dependent subexponential claims

This paper considers an ordinary renewal risk model and a compound renewal risk model with constant interest rate, subexponential claims and a general premium process. We derive some asymptotic results on the finite-time ruin probabilities.     

The generalized two-sided power distribution

The generalized standard two-sided power (GTSP) distribution was mentioned only in passing by Kotz and van Dorp Beyond Beta, Other Continuous Families of Distributions with Bounded Support and Applications, World Scientific Press, Singapore, 2004. In this paper, we shall further investigate this three-parameter distribution by presenting some novel properties and use its more general form to contrast the chronology of developments of various authors on the two-parameter TSP distribution since its initial introduction. GTSP distributions allow for J-shaped forms of its pdf, whereas TSP distributions are limited to U-shaped and unimodal forms. Hence, GTSP distributions possess the same three distributional shapes as the classical beta distributions. A novel method and algorithm for the indirect elicitation of the two-power parameters of the GTSP distribution is developed. We present a Project Evaluation Review Technique example that utilizes this algorithm and demonstrates the benefit of separate powers for the two branches of activity GTSP distributions for project completion time uncertainty estimation.     

On the asymptotic distribution of Cook's distance in logistic regression models

It sometimes occurs that one or more components of the data exert a disproportionate influence on the model estimation. We need a reliable tool for identifying such troublesome cases in order to decide either eliminate from the sample, when the data collect was badly realized, or otherwise take care on the use of the model because the results could be affected by such components. Since a measure for detecting influential cases in linear regression setting was proposed by Cook [Detection of influential observations in linear regression, Technometrics 19 (1977), pp. 15–18.], apart from the same measure for other models, several new measures have been suggested as single-case diagnostics. For most of them some cutoff values have been recommended (see [D.A. Belsley, E. Kuh, and R.E. Welsch, Regression Diagnostics: Identifying Influential Data and Sources of Collinearity, 2nd ed., John Wiley & Sons, New York, Chichester, Brisban, (2004).], for instance), however the lack of a quantile type cutoff for Cook's statistics has induced the analyst to deal only with index plots as worthy diagnostic tools. Focussed on logistic regression, the aim of this paper is to provide the asymptotic distribution of Cook's distance in order to look for a meaningful cutoff point for detecting influential and leverage observations.     

A comparison of classification models to identify the Fragile X Syndrome

The main models of machine learning are briefly reviewed and considered for building a classifier to identify the Fragile X Syndrome (FXS). We have analyzed 172 patients potentially affected by FXS in Andalusia (Spain) and, by means of a DNA test, each member of the data set is known to belong to one of two classes: affected, not affected. The whole predictor set, formed by 40 variables, and a reduced set with only nine predictors significantly associated with the response are considered. Four alternative base classification models have been investigated: logistic regression, classification trees, multilayer perceptron and support vector machines. For both predictor sets, the best accuracy, considering both the mean and the standard deviation of the test error rate, is achieved by the support vector machines, confirming the increasing importance of this learning algorithm. Three ensemble methods - bagging, random forests and boosting - were also considered, amongst which the bagged versions of support vector machines stand out, especially when they are constructed with the reduced set of predictor variables. The analysis of the sensitivity, the specificity and the area under the ROC curve agrees with the main conclusions extracted from the accuracy results. All of these models can be fitted by free R programs.