A convenient formula for sample size calculations in clinical trials with multiple co-primary continuous endpoints

The clinical efficacy of a new treatment may often be better evaluated by two or more co-primary endpoints. Recently, in pharmaceutical drug development, there has been increasing discussion regarding establishing statistically significant favorable results on more than one endpoint in comparisons between treatments, which is referred to as a problem of multiple co-primary endpoints. Several methods have been proposed for calculating the sample size required to design a trial with multiple co-primary correlated endpoints. However, because these methods require users to have considerable mathematical sophistication and knowledge of programming techniques, their application and spread may be restricted in practice. To improve the convenience of these methods, in this paper, we provide a useful formula with accompanying numerical tables for sample size calculations to design clinical trials with two treatments, where the efficacy of a new treatment is demonstrated on continuous co-primary endpoints. In addition, we provide some examples to illustrate the sample size calculations made using the formula. Using the formula and the tables, which can be read according to the patterns of correlations and effect size ratios expected in multiple co-primary endpoints, makes it convenient to evaluate the required sample size promptly.     

Curtailed two-stage designs with two dependent binary endpoints

When phase I clinical trials were found to be unable to precisely estimate the frequency of toxicity, Brayan and Day proposed incorporating toxicity considerations into two-stage designs in phase II clinical trials. Conaway and Petroni further pointed out that it is important to evaluate the clinical activity and safety simultaneously in studying cancer treatments with more toxic chemotherapies in a phase II clinical trial. Therefore, they developed multi-stage designs with two dependent binary endpoints. However, the usual sample sizes in phase II trials make these designs difficult to control the type I error rate at a desired level over the entire null region and still have sufficient power against reasonable alternatives. Therefore, the curtailed sampling procedure summarized by Phatak and Bhatt will be applied to the two-stage designs with two dependent binary endpoints in this paper to reduce sample sizes and speed up the development process for drugs.     

三国两晋讲武考

三国两晋时期,政权割据更替,战事发生频繁,统治者更重视武力,史籍讲武记载渐多。考索文献、援引事件发现,此期讲武仍属形成发展中。讲武主要有两种形式,一为显耀朝廷威武之典礼仪式,一为练兵备战之实际训练。朝廷之讲武礼,虽粗具章法程序,然因时兴废,未成国家常典。练兵备战之讲武,既非国家礼仪,则其举行随需而定,不限古法。     

Two‐stage phase II survival trial design

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression‐free survival or event‐free survival is often a primary endpoint for the trial design. However, methods to evaluate two‐stage single‐arm phase II trials with a time‐to‐event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two‐stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two‐stage design can be routinely used for single‐arm phase II trial designs with a time‐to‐event endpoint as a complement to the commonly used Simon's two‐stage design for the binary outcome.     

Inference on the ratio of two coefficients of variation of two lognormal distributions

The coefficient of variation (CV) can be used as an index of reliability of measurement. The lognormal distribution has been applied to fit data in many fields. We developed approximate interval estimation of the ratio of two coefficients of variation (CsV) for lognormal distributions by using the Wald-type, Fieller-type, log methods, and method of variance estimates recovery (MOVER). The simulation studies show that empirical coverage rates of the methods are satisfactorily close to a nominal coverage rate for medium sample sizes.     

Transmuted two-parameter Lindley distribution

In this study, we propose a new distribution using the quadratic rank transmutation map named as transmuted two-parameter Lindley distribution (TTLD). This distribution is more flexible than the two-parameter Lindley distribution (TLD). The properties of the TTLD are examined, and estimation methods for the parameters of this distribution are discussed. The usefulness of the TTLD is demonstrated on some real data.     

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.     

论“两型社会”背景下大学生环境教育的普及

大学生是未来社会建设和发展的生力军,其环保素质直接影响着未来环境事业的发展与成败,进而影响到"两型社会"建设与和谐社会的构建。当前大学生环境教育存在以下问题:重专业,轻普及;教育内容和形式不够丰富;课程体系不够健全;缺乏教育环境的支持。在普及大学生环境教育的过程中要加强认识,将环境教育列入教学计划;整合资源,完善课程体系;丰富形式,重视第二课堂教育。     

A review and re‐interpretation of a group‐sequential approach to sample size re‐estimation in two‐stage trials

In this paper, we review the adaptive design methodology of Li et al. (Biostatistics 3 :277–287) for two‐stage trials with mid‐trial sample size adjustment. We argue that it is closer in principle to a group sequential design, in spite of its obvious adaptive element. Several extensions are proposed that aim to make it even more attractive and transparent alternative to a standard (fixed sample size) trial for funding bodies to consider. These enable a cap to be put on the maximum sample size and for the trial data to be analysed using standard methods at its conclusion. The regulatory view of trials incorporating unblinded sample size re‐estimation is also discussed. © 2014 The Authors. Pharmaceutical Statistics published by John Wiley & Sons, Ltd.     

契约参照点、高管才能与高管薪酬——来自中国情景下行业属性和产权性质的经验证据

采用Demerjian 等的DEA-TOBIT两阶段模型来估算高管才能,从行业属性和产权性质角度分析了契约参照点、高管才能与高管薪酬之间的关系,并使用2008-2013年我国上市公司的样本数据进行实证检验。分析结果显示：（1）高管才能越高,其薪酬水平越高;（2）高管薪酬契约中存在参照点效应,而国有企业和被保护行业更可能利用契约参照点来提升高管薪酬水平;（3）高管薪酬契约参照点效应中存在着高管才能高低的差异,拥有高才能高管的国有企业和被保护行业利用契约参照点拉动高管薪酬增长的倾向更明显。