Estimates of subgroup treatment effects in overall nonsignificant trials: To what extent should we believe in them?

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall “failed” trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial of limited value to design the replication trial. An empirical Bayesian shrinkage method is suggested to minimize this overestimation. The proposed estimator appears to offer either a good or a conservative correction to the observed subgroup treatment effect hence provides a more reliable subgroup treatment effect estimate for adequate planning of future studies.     

A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials

Patient heterogeneity may complicate dose‐finding in phase 1 clinical trials if the dose‐toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose‐toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup‐specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within‐subgroup dose‐toxicity curves. The simulations show that the hierarchical model‐based method is recommended in settings where the dose‐toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.     

主体在“忧患意识”中觉悟

牟宗三建构的道德形上学是以儒家传统的主体性为理论支点,而这种道德主主体性真正奠基于主体在“忧患意识”中的觉悟,忧患意识是在对人的忧患负责中形成的,主体的觉悟意味着责任意识的产生。从原始的本能到主体的觉悟,以“心性”范畴为核心的道德哲学成了中学文化的主流,这也是现代新儒家以“道统”自居的理论依据。     

独立学院学生大学英语学习心理与学习行为的调查研究

本文对独立学院学生在大学英语学习心理与学习行为方面的群体特点和存在的问题加以论述。     

中国高等教育中的自主招生与人才选拔：来自北大、清华和人大的发现

本文通过对“首都大学生成长追踪调查”中三所精英大学（北京大学、清华大学和中国人民大学）具有代表性样本的数据分析,从教育公平和人才选拔效率两个角度检验了自主招生政策实施的效果。研究结果表明,从教育公平的方面来讲,获得自主招生破格录取的学生更有可能来自父母受过高等教育的家庭、城市家庭和好的重点高中。从人才选拔效率的角度来讲,获得自主招生破格录取学生的学业表现、社会活动能力、非认知能力、毕业后的计划和实际去向与统招学生却并无显著差别。本文的发现对于如何完善自主招生政策、促进教育公平、科学选拔和培养优秀人才等议题具有重要的政策启示意义。     

Notes on testing carry-over effects in continuous data under an incomplete block crossover design

We consider hypothesis testing and estimation of carry-over effects in continuous data under an incomplete block crossover design when comparing two experimental treatments with a placebo. We develop procedures for testing differential carry-over effects based on the weighted-least-squares (WLS) method. We apply Monte Carlo simulations to evaluate the performance of these test procedures in a variety of situations. We use the data regarding the forced expiratory volume in one second (FEV₁) readings taken from a double-blind crossover trial comparing two different doses of formoterol with a placebo to illustrate the use of test procedures proposed here.     

Optimal and lead-in adaptive allocation for binary outcomes: A comparison of Bayesian methods

We compare posterior and predictive estimators and probabilities in response-adaptive randomization designs for two- and three-group clinical trials with binary outcomes. Adaptation based upon posterior estimates are discussed, as are two predictive probability algorithms: one using the traditional definition, the other using a skeptical distribution. Optimal and natural lead-in designs are covered. Simulation studies show that efficacy comparisons lead to more adaptation than center comparisons, though at some power loss, skeptically predictive efficacy comparisons and natural lead-in approaches lead to less adaptation but offer reduced allocation variability. Though nuanced, these results help clarify the power-adaptation trade-off in adaptive randomization.     

Sample size estimation for comparing rates of change in K-group repeated count outcomes

Sample size estimation for comparing the rates of change in two-arm repeated measurements has been investigated by many investigators. In contrast, the literature has paid relatively less attention to sample size estimation for studies with multi-arm repeated measurements where the design and data analysis can be more complex than two-arm trials. For continuous outcomes, Jung and Ahn (2004 Jung, S., Ahn, C. (2004). K-sample test and sample size calculation for comparing slopes in data with repeated measurements. Biometrical J. 46(5):554–564.[Crossref], [Web of Science ®] , [Google Scholar]) and Zhang and Ahn (2013 Zhang, S., Ahn, C. (2013). Sample size calculation for comparing time-averaged responses in k-group repeated measurement studies. Comput. Stat. Data Anal. 58:283–291.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) have presented sample size formulas to compare the rates of change and time-averaged responses in multi-arm trials, using the generalized estimating equation (GEE) approach. To our knowledge, there has been no corresponding development for multi-arm trials with count outcomes. We present a sample size formula for comparing the rates of change in multi-arm repeated count outcomes using the GEE approach that accommodates various correlation structures, missing data patterns, and unbalanced designs. We conduct simulation studies to assess the performance of the proposed sample size formula under a wide range of designing configurations. Simulation results suggest that empirical type I error and power are maintained close to their nominal levels. The proposed method is illustrated using an epileptic clinical trial example.     

网络环境下大学英语自主学习教学模式探讨

教育部发起的新一轮大学英语教学改革指出,大学英语教学的目标是培养大学生的英语综合应用能力和自主学习能力。实现这一教学目标的关键是要修正当前偏离大学英语教学目标和语言学习规律的传统课堂教学模式,积极抓住现代信息技术带采的契机,探索自主学习教学的新模式。本文就浙江树人大学英语教学模式改革,对构建新型自主学习教学模式的背景、理论依据、改革内容、初步成果及改革启示等进行尝试性探讨。