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.     

论数学教育中的数学观念体系

本文从培养数学观念的角度，就数学教育如何培养人们的科学思维方式和形成良好的思维习惯作一论述。     

Bayesian modelling of catch in a north-west Atlantic fishery

Summary. We model daily catches of fishing boats in the Grand Bank fishing grounds. We use data on catches per species for a number of vessels collected by the European Union in the context of the Northwest Atlantic Fisheries Organization. Many variables can be thought to influence the amount caught: a number of ship characteristics (such as the size of the ship, the fishing technique used and the mesh size of the nets) are obvious candidates, but one can also consider the season or the actual location of the catch. Our database leads to 28 possible regressors (arising from six continuous variables and four categorical variables, whose 22 levels are treated separately), resulting in a set of 177 million possible linear regression models for the log-catch. Zero observations are modelled separately through a probit model. Inference is based on Bayesian model averaging, using a Markov chain Monte Carlo approach. Particular attention is paid to the prediction of catches for single and aggregated ships.     

Inference for the measurement of poverty in the presence of a stochastic weighting variable

Empirical applications of poverty measurement often have to deal with a stochastic weighting variable such as household size. Within the framework of a bivariate distribution function defined over income and weight, I derive the limiting distributions of the decomposable poverty measures and of the ordinates of stochastic dominance curves. The poverty line is allowed to depend on the income distribution. It is shown how the results can be used to test hypotheses concerning changes in poverty. The inference procedures are briefly illustrated using Belgian data. An erratum to this article can be found at     

话语含义的判别和听力理解

语义层面上语用含义的话语理解是大学英语教学的难点之所在。为加强薄弱环节,须从“会话含义”和“关联”理论出发,揭示话语中交际意图传递的规律和特征,并结合实例分析听力理解过程中可能出现的信息推理障碍及原因。     

Data tilting for time series

Summary. We develop a general methodology for tilting time series data. Attention is focused on a large class of regression problems, where errors are expressed through autoregressive processes. The class has a range of important applications and in the context of our work may be used to illustrate the application of tilting methods to interval estimation in regression, robust statistical inference and estimation subject to constraints. The method can be viewed as 'empirical likelihood with nuisance parameters'.     

Low dose risk estimation via simultaneous statistical inferences

Summary.  The paper develops and studies simultaneous confidence bounds that are useful for making low dose inferences in quantitative risk analysis. Application is intended for risk assessment studies where human, animal or ecological data are used to set safe low dose levels of a toxic agent, but where study information is limited to high dose levels of the agent. Methods are derived for estimating simultaneous, one-sided, upper confidence limits on risk for end points measured on a continuous scale. From the simultaneous confidence bounds, lower confidence limits on the dose that is associated with a particular risk (often referred to as a bench-mark dose ) are calculated. An important feature of the simultaneous construction is that any inferences that are based on inverting the simultaneous confidence bounds apply automatically to inverse bounds on the bench-mark dose.     

A note on interval‐censored lifetime data and the constant‐sum condition of oiler,gómez & calle (2004)

Oiler, Gomez & Calle (2004) give a constant sum condition for processes that generate interval‐censored lifetime data. They show that in models satisfying this condition, it is possible to estimate non‐parametrically the lifetime distribution based on a well‐known simplified likelihood. The author shows that this constant‐sum condition is equivalent to the existence of an observation process that is independent of lifetimes and which gives the same probability distribution for the observed data as the underlying true process.     

Direct and Indirect Causal Effects via Potential Outcomes*

Abstract. The use of the concept of ‘direct’ versus ‘indirect’ causal effects is common, not only in statistics but also in many areas of social and economic sciences. The related terms of ‘biomarkers’ and ‘surrogates’ are common in pharmacological and biomedical sciences. Sometimes this concept is represented by graphical displays of various kinds. The view here is that there is a great deal of imprecise discussion surrounding this topic and, moreover, that the most straightforward way to clarify the situation is by using potential outcomes to define causal effects. In particular, I suggest that the use of principal stratification is key to understanding the meaning of direct and indirect causal effects. A current study of anthrax vaccine will be used to illustrate ideas.     

数学证明中的推理问题

演绎推理和非演绎推理经常被运用到数学证明中。二者的共同之处在于:都是从前提推出结论、从已知达于未知;非演绎推理除归纳法之外,与演绎推理一样,只要前提都真,结论必真。不同之处在于:演绎推理从前提到结论之间的推理是逻辑推理,而非演绎推理的推理过程则是根据具体问题进行具体分析;演绎推理的前提与结论之间的关系必然能被数理逻辑的逻辑演算中的形式定理所反映,非演绎推理的前提与结论间的关系则不能;演绎推理对应着一个演绎推理规则,非演绎推理则无对应的推理规则。