Statistical testing strategies for assessing treatment efficacy and marker accuracy in phase III trials

When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all‐comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker‐stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker‐defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker‐stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker‐defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker‐based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker‐negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker‐positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided.     

Blinded continuous monitoring in clinical trials with recurrent event endpoints

In studies with recurrent event endpoints, misspecified assumptions of event rates or dispersion can lead to underpowered trials or overexposure of patients. Specification of overdispersion is often a particular problem as it is usually not reported in clinical trial publications. Changing event rates over the years have been described for some diseases, adding to the uncertainty in planning. To mitigate the risks of inadequate sample sizes, internal pilot study designs have been proposed with a preference for blinded sample size reestimation procedures, as they generally do not affect the type I error rate and maintain trial integrity. Blinded sample size reestimation procedures are available for trials with recurrent events as endpoints. However, the variance in the reestimated sample size can be considerable in particular with early sample size reviews. Motivated by a randomized controlled trial in paediatric multiple sclerosis, a rare neurological condition in children, we apply the concept of blinded continuous monitoring of information, which is known to reduce the variance in the resulting sample size. Assuming negative binomial distributions for the counts of recurrent relapses, we derive information criteria and propose blinded continuous monitoring procedures. The operating characteristics of these are assessed in Monte Carlo trial simulations demonstrating favourable properties with regard to type I error rate, power, and stopping time, ie, sample size.     

A Graphical Tool for Interpreting Regression Coefficients of Trinomial Logit Models

Multinomial logit (also termed multi-logit) models permit the analysis of the statistical relation between a categorical response variable and a set of explicative variables (called covariates or regressors). Although multinomial logit is widely used in both the social and economic sciences, the interpretation of regression coefficients may be tricky, as the effect of covariates on the probability distribution of the response variable is nonconstant and difficult to quantify. The ternary plots illustrated in this article aim at facilitating the interpretation of regression coefficients and permit the effect of covariates (either singularly or jointly considered) on the probability distribution of the dependent variable to be quantified. Ternary plots can be drawn both for ordered and for unordered categorical dependent variables, when the number of possible outcomes equals three (trinomial response variable); these plots allow not only to represent the covariate effects over the whole parameter space of the dependent variable but also to compare the covariate effects of any given individual profile. The method is illustrated and discussed through analysis of a dataset concerning the transition of master’s graduates of the University of Trento (Italy) from university to employment.     

Properties of the weighted log‐rank test in the design of confirmatory studies with delayed effects

Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. This assumption not only affects the analysis part but also the sample size calculation. The presence of delayed effects causes a change in the hazard ratio while the trial is ongoing since at the beginning we do not observe any difference between treatment arms, and after some unknown time point, the differences between treatment arms will start to appear. Hence, the proportional hazards assumption no longer holds, and both sample size calculation and analysis methods to be used should be reconsidered. The weighted log‐rank test allows a weighting for early, middle, and late differences through the Fleming and Harrington class of weights and is proven to be more efficient when the proportional hazards assumption does not hold. The Fleming and Harrington class of weights, along with the estimated delay, can be incorporated into the sample size calculation in order to maintain the desired power once the treatment arm differences start to appear. In this article, we explore the impact of delayed effects in group sequential and adaptive group sequential designs and make an empirical evaluation in terms of power and type‐I error rate of the of the weighted log‐rank test in a simulated scenario with fixed values of the Fleming and Harrington class of weights. We also give some practical recommendations regarding which methodology should be used in the presence of delayed effects depending on certain characteristics of the trial.     

The context of employment discrimination: interpreting the findings of a field experiment

Although field experiments have documented the contemporary relevance of discrimination in employment, theories developed to explain the dynamics of differential treatment cannot account for differences across organizational and institutional contexts. In this article, I address this shortcoming by presenting the main empirical findings from a multi‐method research project, in which a field experiment of ethnic discrimination in the Norwegian labour market was complemented with forty‐two in‐depth interviews with employers who were observed in the first stage of the study. While the experimental data support earlier findings in documenting that ethnic discrimination indeed takes place, the qualitative material suggests that theorizing in the field experiment literature have been too concerned with individual and intra‐psychic explanations. Discriminatory outcomes in employment processes seems to be more dependent on contextual factors such as the number of applications received, whether requirements are specified, and the degree to which recruitment procedures are formalized. I argue that different contexts of employment provide different opportunity structures for discrimination, a finding with important theoretical and methodological implications.     

英国的刑事上诉制度研究

英国对刑事案件基本上实行两级上诉制度 :对于刑事法院的一审裁判可以依次向上诉法院和上议院上诉 ;对治安法院的裁判 ,可以分别向刑事法院或者高等法院以及上议院上诉 ,但是 ,二者的程序规则不完全相同。2 0世纪 70年代以来 ,英国上诉制度逐渐向大陆法系靠拢 ,最近英国政府再次提议进一步扩大控诉方的上诉权 ,英国上诉制度可能将发生重大变化。     

高速SDRAM控制器设计的FPGA实现

同步动态存储器(SDRAM)控制器通常用有限状态机实现,对于一般的设计方法,由于状态数量多,状态转换通常伴随大的组合逻辑而影响运行速度,因此,SDRAM控制器的速度限制了SDRAM存储器的访问速度。该文从结构优化入手来优化方法,利用状态机分解的思想将大型SDRAM控制状态机用若干小的子状态机实现,达到简化逻辑的目的,不仅提高了速度还节省了资源,对该类大型SDRAM控制器的实现有一定参考意义。     

三螺旋创新模式的理论探讨

基于非线性网状创新模型提出的“三螺旋场”和“三螺旋循环”概念进一步推进了三螺旋创新模式的理论研究。三螺旋场概念旨在解释在大学、产业和政府三股螺旋之间存在的相对独立和彼此作用的本质，说明三螺旋的生成原理、静态表现和动态演化特征。三螺旋的生成原理在于创新过程的非线性本质和多主体特征，静态表现为“内核外场模型”，而动态演化过程则在于纵向进化和横向循环。发生在三股螺旋之间的三螺旋循环揭示了在大学、产业和政府之间以人员、信息和产品流动为特征的相互作用和运行机制。     

A modified random-effect procedure for combining risk difference in sets of 2×2 tables from clinical trials

Summary Meta-analyses of sets of clinical trials often combine risk differences from several 2×2 tables according to a random-effects model. The DerSimonian-Laird random-effects procedure, widely used for estimating the populaton mean risk difference, weights the risk difference from each primary study inversely proportional to an estimate of its variance (the sum of the between-study variance and the conditional within-study variance). Because those weights are not independent of the risk differences, however, the procedure sometimes exhibits bias and unnatural behavior. The present paper proposes a modified weighting scheme that uses the unconditional within-study variance to avoid this source of bias. The modified procedure has variance closer to that available from weighting by ideal weights when such weights are known. We studied the modified procedure in extensive simulation experiments using situations whose parameters resemble those of actual studies in medical research. For comparison we also included two unbiased procedures, the unweighted mean and a sample-size-weighted mean; their relative variability depends on the extent of heterogeneity among the primary studies. An example illustrates the application of the procedures to actual data and the differences among the results. This research was supported by Grant HS 05936 from the Agency for Health Care Policy and Research to Harvard University.     

实数域及四元数除环上有平方根的方阵

给出了实数域及实四元数除环上方阵有平方根的充分必要条件．