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.     

A novel approach based on multiple correspondence analysis for monitoring social networks with categorical attributed data

In in most cases, the distribution of communications is unknown and one may summarize social network communications with categorical attributes in a contingency table. Due to the categorical nature of the data and a large number of features, there are many parameters to be considered and estimated in the model. Hence, the accuracy of estimators decreases. To overcome the problem of high dimensionality and unknown communications distribution, multiple correspondence analysis is used to reduce the number of parameters. Then the rescaled data are studied in a Dirichlet model in which the parameters should be estimated. Moreover, two control charts, Hotelling’s T² and multivariate exponentially weighted moving average (MEWMA), are developed to monitor the parameters of the Dirichlet distribution. The performance of the proposed method is evaluated through simulation studies in terms of average run length criterion. Finally, the proposed method is applied to a real case.     

Bayesian sample size determination for phase IIA clinical trials using historical data and semi‐parametric prior's elicitation

The Simon's two‐stage design is the most commonly applied among multi‐stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre‐trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design. In this work, we explore the Bayesian counterparts of the Simon's two‐stage design based on the predictive version of the single threshold design. This design requires specifying two prior distributions: the analysis prior, which is used to compute the posterior probabilities, and the design prior, which is employed to obtain the prior predictive distribution. While the usual approach is to build beta priors for carrying out a conjugate analysis, we derived both the analysis and the design distributions through linear combinations of B‐splines. The motivating example is the planning of the phase IIA two‐stage trial on anti‐HER2 DNA vaccine in breast cancer, where initial beliefs formed from elicited experts' opinions and historical data showed a high level of uncertainty. In a sample size determination problem, the impact of different priors is evaluated.     

存活式句法理论及其最简启示

主要阐述最简方案下存活式句法理论的主要内容,并对其优势和不足做出评价。从理论构建以及语言事实分析两个视角来看,与语段理论相比,存活理论更加符合最简句法的基本理念和要求,其理论设计更为合理,语料应用范围更为宽广。除此之外,以存活理论为基础,从核心句法操作、句法特征以及句法与其他语言模块的接口等角度反思最简方案下构建句法推导理论应该注意的问题。     

Phase I trial design for drug combinations with Bayesian model averaging

Various statistical models have been proposed for two‐dimensional dose finding in drug‐combination trials. However, it is often a dilemma to decide which model to use when conducting a particular drug‐combination trial. We make a comprehensive comparison of four dose‐finding methods, and for fairness, we apply the same dose‐finding algorithm under the four model structures. Through extensive simulation studies, we compare the operating characteristics of these methods in various practical scenarios. The results show that different models may lead to different design properties and that no single model performs uniformly better in all scenarios. As a result, we propose using Bayesian model averaging to overcome the arbitrariness of the model specification and enhance the robustness of the design. We assign a discrete probability mass to each model as the prior model probability and then estimate the toxicity probabilities of combined doses in the Bayesian model averaging framework. During the trial, we adaptively allocated each new cohort of patients to the most appropriate dose combination by comparing the posterior estimates of the toxicity probabilities with the prespecified toxicity target. The simulation results demonstrate that the Bayesian model averaging approach is robust under various scenarios. Copyright © 2015 John Wiley & Sons, Ltd.     

东营凹陷下始新统沙四段烃源岩有机相分析

目前,世界上新发现了众多深层油气藏,深层油气资源及成藏逐渐成为研究的热点。沉积有机相可以辅助对烃源岩的生烃潜力做出较好的评价,进而指导油气勘探。通过对东营凹陷下始新统沙四段烃源岩沉积特征及沉积环境、有机岩石学、有机地球化学、孢粉相等的分析,主要运用特殊元素比值、有机碳含量、镜质体发射率和孢粉相模式,将沙四段自下而上划分为盐下段的弱还原冲积扇沉积有机相、盐间段的强还原盐湖沉积有机相、盐上段的还原深湖—半深湖沉积有机相3 个有机相带。其中,以盐上段的还原深湖—半深湖沉积有机相烃源岩中保存的有机质最佳,具有良好的勘探前景,盐间段次之,盐下段较差。     

多孔介质内流体相态特征超声波探测研究进展

目前有关烃类流体相态的研究已较为成熟,能为油气田的高效开发提供相应的理论指导和技术支持。但研究成果大多忽略多孔介质对流体相态的影响。为此,在充分考虑流体与多孔介质相互作用的基础上,开展多孔介质内流体相态特征的研究十分必要。随着研究的不断深入,超声波探测技术不受压力温度限制、不改变流体成分、检测成本低、对人体无害等优点逐渐得到重视,并在多孔介质内相态研究领域逐渐得到了应用。在参考国内外相关文献资料的基础上,简述了超声波的探测机理,重点综述了超声波探测在多孔介质内天然气水合物、凝析油气相态特征研究的应用进展,并指出了目前存在的主要问题及今后的研究重点。     

开发区发展阶段识别及差异化调控对策研究——以湖南省为例

在文献回顾及相关专家访谈基础上,提出开发区成长指数、成长速度、成长累积的概念,并设计出计算方法,以此对湖南省开发区发展阶段及调控对策进行实证研究。首先划定几个临界值识别开发区发展阶段;然后说明湖南开发区发展呈现的明显的不均匀性;最后基于不同发展阶段特征提出相关差异化调控对策。     

Risk factors for severe perineal trauma during vaginal childbirth: A Western Australian retrospective cohort study

AimTo determine rates and risk factors for third and fourth degree perineal tears (severe perineal trauma) in a Western Australian context.Design and settingA retrospective hospital-based cohort study was performed using computerised data for 10,408 singleton vaginal deliveries from 28 weeks gestation.MethodsWomen with severe perineal trauma were compared to those without. Logistic regression analysis, stratified by parity, was used to assess demographic and obstetric factors associated with perineal trauma.ResultsSevere perineal trauma incidence was 3% (338/10408), 5.4% (239/4405) for primiparas and 1.7% (99/5990) for multiparas (p < 0.001). Adjusted risk factors associated with trauma and common across parity included Asian or Indian ethnicity, shoulder dystocia and assisted delivery. Epidural analgesia (OR 0.72, 95% CI 0.54–0.96), preterm birth (OR 0.40, 95% CI 0.23–0.72) and episiotomy (OR 0.54, 95% CI 0.39–0.74) were protective in primiparas, while episiotomy was associated with increased risk in multiparas (OR 2.01, 95% CI 1.18–3.45). Additional factors among primiparas were occipito posterior (OP) delivery (OR 3.35, 95% CI 1.75–6.41) and prolonged second stage (OR 1.98, 95% CI 1.46–2.68), and among multiparas included gestational diabetes (OR 1.78, 95% CI 1.04–3.03) and birth weight >4000 g (OR 1.86, 95% CI 1.10–3.15).ConclusionParity differences in risk factors such as episiotomy, infant weight, OP delivery, gestational diabetes and prolonged second stage warrant investigation into clinical management. Although rates differ internationally, and replication evidence has confirmed consistency for certain demographic and obstetric factors, the development of internationally endorsed clinical guidelines and further research around interventions to protect the perineum are recommended.     

空气中多种醛酮液相色谱法侧定的研究

本文研究了空气中多种醛酮的测定。目前国内仅对空气中甲醛的测定研究较多,国外报导的方法需用萃取、浓缩等一系列前处理过程,方法麻烦,易引入杂质造成污染。本文报导的方法系采用2.4—二硝基苯肼的甲醇强酸溶液吸收空气中醛酮直接注入液相色谱仪中进行分离测定。研究表明:本法分离效果好,重复性好,方法简便,速度快,测定的精密度和准确度符合微量分析误差的要求。