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.     

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.     

Journey towards independent living: a grounded theory investigation of leaving the care of Girls & Boys Town,South Africa

The journey out of care and towards independent living is a challenge for many care-leavers. There has been little research into the social processes involved in this care-leaving journey. This paper presents the results of a grounded theory investigation into the care-leaving journeys of nine young men who had, several years previously, been in the care of Girls & Boys Town in South Africa. Working from a resilience perspective, with an ecological emphasis, four central social processes emerged that together explain the care-leaving experiences of the participants. These processes are striving for authentic belonging; networking people for goal attainment; contextualised responsiveness and building hopeful and tenacious self-confidence. These four processes are located within contextual boundaries and at the social environmental interface. The paper presents these processes in detail, drawing on selected narratives of the participants and integrated with additional theory. It is hoped that this paper may contribute to theory building concerning care-leaving processes and enhance youth care practices for youth in care and leaving care.     

Kernel Estimation of Rate Function for Recurrent Event Data

Abstract.  Recurrent event data are largely characterized by the rate function but smoothing techniques for estimating the rate function have never been rigorously developed or studied in statistical literature. This paper considers the moment and least squares methods for estimating the rate function from recurrent event data. With an independent censoring assumption on the recurrent event process, we study statistical properties of the proposed estimators and propose bootstrap procedures for the bandwidth selection and for the approximation of confidence intervals in the estimation of the occurrence rate function. It is identified that the moment method without resmoothing via a smaller bandwidth will produce a curve with nicks occurring at the censoring times, whereas there is no such problem with the least squares method. Furthermore, the asymptotic variance of the least squares estimator is shown to be smaller under regularity conditions. However, in the implementation of the bootstrap procedures, the moment method is computationally more efficient than the least squares method because the former approach uses condensed bootstrap data. The performance of the proposed procedures is studied through Monte Carlo simulations and an epidemiological example on intravenous drug users.     

商业银行董事会治理的独立有效性研究

根据经济合作与发展组织、巴塞尔银行监管委员会和中国银行业监督管理委员会等组织关于公司治理的相关原则、指引和法律规定,对商业银行董事会的独立有效性进行了综合分析,得出商业银行董事会的独立有效性主要体现在独立董事的独立性,职能委员会的独立性以及独立董事占董事会成员的比例3个方面以及规范的独立董事、职能委员会的产生机制和明确的独立董事、职能委员会的责权利制度是确保商业银行董事会独立有效性基础的结论,并提出中国商业银行董事会的适度规模为11人,其中独立董事占董事会成员的合适比例为50％以上的建议。     

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。     

东汉庄园的兴起及其文化意蕴

西汉以自耕农为主体的经济结构到东汉以庄园为主体经济结构的转变 ,客观上形成了汉晋之际社会思潮变迁的重要依托。作为新兴的相对独立的社会经济单位 ,东汉庄园对士大夫的精神世界产生了重要影响。不仅使一部分士人从原有的大一统思想和依附地位中剥离出来 ,而且发展出了较为独立的群体性格、个体人格、思维方式和兴趣取向     

构建沈阳自主创新科技投融资体系的途径选择

建立创新型城市离不开多元化、多渠道、多层次的科技投融资体系。通过有效的政策安排,不断完善科技投融资体系,对加快沈阳的发展,加速科技创新进程和科技成果转化具有重要意义。本文提出了沈阳自主创新亟待投融资体系的完善,着重分析了沈阳自主创新科技投融资体系的现状和存在的问题,提出了促进沈阳自主创新科技投融资体系完善的途径。     

"专利权的地域性"评析

专利权的地域性是专利权法律冲突肯定说和否定说争议的焦点所在.文章通过分析专利权地域性的成因暨合理性,指出无论是国内法还是国际公约,适时地突破专利权地域性均不存在制度上的障碍.认为地域性并不是专利权的本质属性;随着各国政治、经济、文化环境的优化,专利权地域性的消失带有必然性;各国在处理涉外的专利权合同关系和侵权关系时,应突破地域性理论的窠臼,建立适宜的法律适用规则以解决存在的法律冲突.