Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

基于债务协商视角的债转股定量研究

针对我国政府、企业和银行等金融机构共同关注的债转股问题，基于债务协商谈判思想，建立部分债务股权互换模型，计算公司证券价格，探讨了债转股对公司价值、破产概率、破产损失成本和资本结构的影响，给出了银行等债权人愿意债转股的充分条件。结果表明：在事先破产清算协议贷款下，事后全部债转股总能提高公司股权价值，但并不一定能提高债券价值。只有其协商谈判能力满足一定条件，公司债权人才愿意事后选择债转股，实现帕累托改进、提高社会福利水平。其次，在公司股东协商谈判能力的一定范围内，部分债转股能提高公司价值，其最优转股债息比例随着公司资产风险的增大而增加。再次，债转股能降低公司破产风险和破产损失成本，但同时也提高了债券风险溢价。最后，随着股东谈判能力增强，最优协商转股债务比例、杠杆率都减少，而债券风险溢价增大。本文所得结果对我国政府、企业和银行如何实施债转股提供理论参考和实践指导。     

Confidence intervals,significance values,maximum likelihood estimates,etc. sharpened into Occam’s razors

Abstract

Confidence sets, p values, maximum likelihood estimates, and other results of non-Bayesian statistical methods may be adjusted to favor sampling distributions that are simple compared to others in the parametric family. The adjustments are derived from a prior likelihood function previously used to adjust posterior distributions.     

Hierarchical Bayesian Modeling of Post-Earthquake Ignition Probabilities Considering Inter-Earthquake Heterogeneity

Post-earthquake fires are high-consequence events with extensive damage potential. They are also low-frequency events, so their nature remains underinvestigated. One difficulty in modeling post-earthquake ignition probabilities is reducing the model uncertainty attributed to the scarce source data. The data scarcity problem has been resolved by pooling the data indiscriminately collected from multiple earthquakes. However, this approach neglects the inter-earthquake heterogeneity in the regional and seasonal characteristics, which is indispensable for risk assessment of future post-earthquake fires. Thus, the present study analyzes the post-earthquake ignition probabilities of five major earthquakes in Japan from 1995 to 2016 (1995 Kobe, 2003 Tokachi-oki, 2004 Niigata–Chuetsu, 2011 Tohoku, and 2016 Kumamoto earthquakes) by a hierarchical Bayesian approach. As the ignition causes of earthquakes share a certain commonality, common prior distributions were assigned to the parameters, and samples were drawn from the target posterior distribution of the parameters by a Markov chain Monte Carlo simulation. The results of the hierarchical model were comparatively analyzed with those of pooled and independent models. Although the pooled and hierarchical models were both robust in comparison with the independent model, the pooled model underestimated the ignition probabilities of earthquakes with few data samples. Among the tested models, the hierarchical model was least affected by the source-to-source variability in the data. The heterogeneity of post-earthquake ignitions with different regional and seasonal characteristics has long been desired in the modeling of post-earthquake ignition probabilities but has not been properly considered in the existing approaches. The presented hierarchical Bayesian approach provides a systematic and rational framework to effectively cope with this problem, which consequently enhances the statistical reliability and stability of estimating post-earthquake ignition probabilities.     

Empirical Non-Parametric Control Charts: Estimation Effects and Corrections

Owing to the extreme quantiles involved, standard control charts are very sensitive to the effects of parameter estimation and non-normality. More general parametric charts have been devised to deal with the latter complication and corrections have been derived to compensate for the estimation step, both under normal and parametric models. The resulting procedures offer a satisfactory solution over a broad range of underlying distributions. However, situations do occur where even such a large model is inadequate and nothing remains but to consider non- parametric charts. In principle, these form ideal solutions, but the problem is that huge sample sizes are required for the estimation step. Otherwise the resulting stochastic error is so large that the chart is very unstable, a disadvantage that seems to outweigh the advantage of avoiding the model error from the parametric case. Here we analyse under what conditions non-parametric charts actually become feasible alternatives for their parametric counterparts. In particular, corrected versions are suggested for which a possible change point is reached at sample sizes that are markedly less huge (but still larger than the customary range). These corrections serve to control the behaviour during in-control (markedly wrong outcomes of the estimates only occur sufficiently rarely). The price for this protection will clearly be some loss of detection power during out-of-control. A change point comes in view as soon as this loss can be made sufficiently small.     

首创全国普通高校策划学专业

西方的咨询业、策划业不断地向中国国内渗透,促使中国的策划业快速发展。面对越来越大的市场策划需求,三江学院抓住了激烈竞争的机遇,首创了策划学专业。五年来的策划学系形成了一整套的策划学的理论体系、教学体系和教学方法,特别是在理论教学和实践教学有机相结合中取得了最佳教学效果,从而培养出了一大批策划专业人才,得到了社会的认可和广泛好评。     

中国传统文化中的"尚三"理念对巴金《家·春·秋》创作的影响

巴金自称是受外国文学影响最多的作家之一,但是中国传统文化对他的创作在无形中的影响恐怕连他自己都没有意识到,在巴金的小说尤其是在长篇小说《家.春.秋》创作中就处处可见"尚三"传统的影响,形成了几种独特的创作现象:三事话语,三复情节,三变情节,三极建构,三而后成,传统文化与外来文化的相互渗透融合,是巴金能够成为文学大师的文化基础。     

实现祖国统一是历史赋予中国共产党的使命

祖国统一是中国历史发展的主流,是中国人民的基本要求,是中华民族的根本利益所在。本文主要论述了中国共产党以人民的需求和民族的利益作为自己的最高行动准则,他们顺应历史发展趋势,了解人民的愿望和要求,代表国家和民族的利益,把完成祖国统一大业看成是历史赋予中国共产党的神圣使命。     

Weak disintegrability as a form of preservation of coherence

Summary Weak disintegrations are investigated from various points of view. Kolmogorov's definition of conditional probability is critically analysed, and it is noted how the notion of disintegrability plays some role in connecting Kolmogorov's definition with the one given in line with de Finetti's coherence principle. Conditions are given, on the domain of a prevision, implying the equivalence between weak disintegrability and conglomerability. Moreover, weak sintegrations are characterized in terms of coherence, in de Finetti's sense, of, a suitable function. This fact enables us to give, an interpretation of weak disintegrability as a form of “preservation of coherence”. The previous results are also applied to a hypothetical inferential problem. In particular, an inference is shown to be coherent, in the sense of Heath and Sudderth, if and only if a suitable function is coherent, in de Finetti's sense. Research partially supported by: M.U.R.S.T. 40% “Problemi di inferenza pura”.     

人的全面发展与现代教育的使命

马克思主义关于人的全面发展理论是马克思主义教育思想的重要组成部分,早已成为制定教育方针、政策,确立社会主义教育目的的理论依据。从当前整个世界教育发展的总趋势以及教育理论与实践中存在的种种矛盾与困惑来看,重新论述和强调马克思主义关于人的全面发展思想,无论是对深入理解马克思主义教育思想,还是对重新认识现代教育的使命,指导社会主义教育实践,最终实现人的全面而自由的发展,都具有深远的意义。