Some robustness issues for comparing multiple logistic regression slopes to a control for small samples

For comparing several logistic regression slopes to that of a control for small sample sizes, Dasgupta et al. (2001) proposed an "asymptotic" small-sample test and a "pivoted" version of that test statistic. Their results show both methods perform well in terms of Type I error control and marginal power when the response is related to the explanatory variable via a logistic regression model. This study finds, via Monte Carlo simulations, that when the underlying relationship is probit, complementary log-log, linear, or even non-monotonic, the "asymptotic" and the "pivoted" small-sample methods perform fairly well in terms of Type I error control and marginal power. Unlike their large sample competitors, they are generally robust to departures from the logistic regression model.     

The cross-product ratio in bivariate lognormal and gamma distributions,with an application to non-randomized trials

Non-randomized trials can give a biased impression of the effectiveness of any intervention. We consider trials in which incidence rates are compared in two areas over two periods. Typically, one area receives an intervention, whereas the other does not. We outline and illustrate a method to estimate the bias in such trials under two different bivariate models. The illustrations use data in which no particular intervention is operating. The purpose is to illustrate the size of the bias that could be observed purely due to regression towards the mean (RTM). The illustrations show that the bias can be appreciably different from zero, and even when centred on zero, the variance of the bias can be large. We conclude that the results of non-randomized trials should be treated with caution, as interventions which show small effects could be explained as artefacts of RTM.     

Parallelizing computation of expected values in recombinant binomial trees

Recombinant binomial trees are binary trees where each non-leaf node has two child nodes, but adjacent parents share a common child node. Such trees arise in option pricing in finance. For example, an option can be valued by evaluating the expected payoffs with respect to random paths in the tree. The cost to exactly compute expected values over random paths grows exponentially in the depth of the tree, rendering a serial computation of one branch at a time impractical. We propose a parallelization method that transforms the calculation of the expected value into an embarrassingly parallel problem by mapping the branches of the binomial tree to the processes in a multiprocessor computing environment. We also discuss a parallel Monte Carlo method and verify the convergence and the variance reduction behavior by simulation study. Performance results from R and Julia implementations are compared on a distributed computing cluster.     

Zero-inflated models and estimation in zero-inflated Poisson distribution

In this paper, we briefly overview different zero-inflated probability distributions. We compare the performance of the estimates of Poisson, Generalized Poisson, ZIP, ZIGP and ZINB models through Mean square error (MSE), bias and Standard error (SE) when the samples are generated from ZIP distribution. We propose a new estimator referred to as probability estimator (PE) of inflation parameter of ZIP distribution based on moment estimator (ME) of the mean parameter and compare its performance with ME and maximum likelihood estimator (MLE) through a simulation study. We use the PE along with ME and MLE to fit ZIP distribution to various zero-inflated datasets and observe that the results do not differ significantly. We recommend using PE in place of MLE since it is easy to calculate and the simulation study in this paper demonstrates that the PE performs as good as MLE irrespective of the sample size.     

Distributions of statistics describing concentration of runs in non homogeneous Markov-dependent trials

In the first n, n ? 3, trials of a non homogeneous zero-one Markov chain of first order, we consider runs of ones of length exceeding a threshold. The article deals with statistics denoting, the length and the position of the shortest segment of the chain in which all such runs of ones are concentrated. The study provides recursive schemes for conditional distributions of these statistics. Numerical examples illustrate the theoretical results.     

Two-stage phase II trials with early stopping for effectiveness and safety as well as ineffectiveness or harm

This article proposes new optimal and minimax designs, which allow early stopping not only for ineffectiveness or toxicity but also for sufficient effectiveness and safety. These designs may facilitate effective drug development by detecting sufficient effectiveness and safety at an early stage or by detecting ineffectiveness or excessive toxicity at an early stage. The proposed design has advantage over other designs in the sense that it can control the type I error rate and is robust against the real association parameter. Comparing to Jin's design, it is always advantageous in terms of expected sample size.     

Are Private Interests Clouding the Peer-Review Process of the WHO Bulletin? A Case Study

Readers’ trust on the medical literature has been eroded, and journal editors and some editorial boards are taking measures to ensure that authors fully and accurately report research findings and disclose conflicts of interest. This article describes a case study in which the papers editor of the World Health Organization (WHO) Bulletin influenced the content of an article that had been approved by the external reviewers. The editor objected to the publication of the large price differentials of the new molecular entities (NMEs) across the Latin American countries where they had been tested and the limited added therapeutic value of the NMEs that had been assessed by independent drug bulletins. This article summarizes the exchanges with WHO staff and posits the hypothesis that the WHO Bulletin might be affected by the shifts in WHO financing. Several authors have raised concern about the impact of financial conflicts of interest in WHO activities in the field of nutrition, intellectual property, and in the emergency response to the flu pandemic. Moreover, it has been reported that powerful WHO contributors pressured WHO into revising its publication policy. This is the first time that authors question if these conflicts of interest are also affecting the editorial independence of the WHO Bulletin.     

Adaptive Isotonic Estimation of the Minimum Effective and Peak Doses in the Presence of Covariates

We consider a problem of estimating the minimum effective and peak doses in the presence of covariates. We propose a sequential strategy for subject assignment that includes an adaptive randomization component to balance the allocation to placebo and active doses with respect to covariates. We conclude that either adjusting for covariates in the model or balancing allocation with respect to covariates is required to avoid bias in the target dose estimation. We also compute optimal allocation to estimate the minimum effective and peak doses in discrete dose space using isotonic regression.     

Prediction of accrual closure date in multi-center clinical trials with discrete-time Poisson process models

In a phase III multi‐center cancer clinical trial or a large public health study, sample size is predetermined to achieve desired power, and study participants are enrolled from tens or hundreds of participating institutions. As the accrual is closing to the target size, the coordinating data center needs to project the accrual closure date on the basis of the observed accrual pattern and notify the participating sites several weeks in advance. In the past, projections were simply based on some crude assessment, and conservative measures were incorporated in order to achieve the target accrual size. This approach often resulted in excessive accrual size and subsequently unnecessary financial burden on the study sponsors. Here we proposed a discrete‐time Poisson process‐based method to estimate the accrual rate at time of projection and subsequently the trial closure date. To ensure that target size would be reached with high confidence, we also proposed a conservative method for the closure date projection. The proposed method was illustrated through the analysis of the accrual data of the National Surgical Adjuvant Breast and Bowel Project trial B‐38. The results showed that application of the proposed method could help to save considerable amount of expenditure in patient management without compromising the accrual goal in multi‐center clinical trials. Copyright © 2012 John Wiley & Sons, Ltd.     

Seven useful designs

When designing a clinical trial there is a need to design a study that achieves the objectives of a trial both efficiently and with minimum resources. This paper describes seven trial designs that could possibly be used in clinical development and highlights how a design although not optimal for an individual study may be optimal for a wider clinical program.