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.     

高性能可重构DSP处理器的数据通路设计

介绍了高性能定点可重构DSP处理器的数据通路设计。该数据通路以功能强大的16位定点计算单元为基础,搭建起高速16位数据处理平台;并能以单指令流多数据流的方式灵活支持多维向量运算;通过重构的方法有效地支持了32位数据处理。     

基于TMS320C40的FFT算法改进及应用

讨论了充分利用C4 0的硬件并行结构进行实数FFT的并行算法 ,并在地震勘探信号处理中得以应用     

超深亚微米信号串扰分析

芯片设计进入深亚微米后,互连线效应(主要是信号串扰)对集成电路的影响越来越大。该文针对这种影响进行了分析,讨论了在不考虑耦合电容和考虑耦合电容的两种情况下噪声产生机理,建立了一个耦合电容分析模型,得出了噪声产生的原因,并提出了解决噪声的策略。根据设计实例并结合建立的模型,提出了实际芯片设计中有效地控制串扰的方法,取得了良好的效果。     

采用二阶特征窗的语音盲分离方法

利用语音信号的短时平稳特性,提出了一种二阶特征窗语音盲分离方法。该方法采用新的联合差分相关矩阵白化算法去除有色噪声影响;用长度等于语音信号基音周期的等距特征窗连续分割预白化观测数据,在每个加窗的数据帧计算不同的时滞协方差矩阵。利用联合近似对角化时滞协方差矩阵集合得到旋转参数,最终达到语音信号的盲分离。该方法消除了有色噪声的影响,只需用到二阶信息就能很好地分离语音信号。仿真实验验证了该方法的有效性。     

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.     

电力系统同步网的建设与思考

数字同步网已经成为了通信网营运的重要支柱之一。针对电力系统通信业务面向市场开放的需求 ,阐述了建设电力系统同步网的重要性 ;研究和分析了同步网中时钟配置、链路选择和同步方式、网络管理等技术问题 ,并对电力系统中同步网的发展提出了一些建议。