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.     

On Optimality of Bayesian Wavelet Estimators

Abstract.  We investigate the asymptotic optimality of several Bayesian wavelet estimators, namely, posterior mean, posterior median and Bayes Factor, where the prior imposed on wavelet coefficients is a mixture of a mass function at zero and a Gaussian density. We show that in terms of the mean squared error, for the properly chosen hyperparameters of the prior, all the three resulting Bayesian wavelet estimators achieve optimal minimax rates within any prescribed Besov space     for p  ≥ 2. For 1 ≤  p  < 2, the Bayes Factor is still optimal for (2 s +2)/(2 s +1) ≤  p  < 2 and always outperforms the posterior mean and the posterior median that can achieve only the best possible rates for linear estimators in this case.     

A Bayesian method for classification and discrimination

We discuss Bayesian analyses of traditional normal-mixture models for classification and discrimination. The development involves application of an iterative resampling approach to Monte Carlo inference, commonly called Gibbs sampling, and demonstrates routine application. We stress the benefits of exact analyses over traditional classification and discrimination techniques, including the ease with which such analyses may be performed in a quite general setting, with possibly several normal-mixture components having different covariance matrices, the computation of exact posterior classification probabilities for observed data and for future cases to be classified, and posterior distributions for these probabilities that allow for assessment of second-level uncertainties in classification.     

Deconvolution with supersmooth distributions

Nonparametric deconvolution problems require one to recover an unknown density when the data are contaminated with errors. Optimal global rates of convergence are found under the weighted L_p-loss (1 ≤ p ≤ ∞). It appears that the optimal rates of convergence are extremely low for supersmooth error distributions. To resolve this difficulty, we examine how high the noise level can be for deconvolution to be feasible, and for the deconvolution estimate to be as good as the ordinary density estimate. It is shown that if the noise level is not too high, nonparametric Gaussian deconvolution can still be practical. Several simulation studies are also presented.     

Modified cross-validation in density estimation

We propose a new modified (biased) cross-validation method for adaptively determining the bandwidth in a nonparametric density estimation setup. It is shown that the method provides consistent minimizers. Some simulation results are reported on which compare the small sample behavior of the new and the classical cross-validation selectors.     

密度分布非均匀的反馈控制Logistic单种群模型平衡态的稳定性

本文对种群密度在非均匀分布情形下,考虑了具反馈控制的滞后 Logistic 生态模型平衡位置的稳定性;分别给出了在常时滞和弱连续时滞以及强连续时滞情况下的稳定性条件;其结果是对 Gopalsamy 在密度均匀分布情形下相应结果的推广.     

Semi-parametric estimation of ROC curves based on binomial regression modelling

This paper presents a method of estimating a receiver operating characteristic (ROC) curve when the underlying diagnostic variable X is continuous and fully observed. The new method is based on modelling the probability of response given X , rather than the distribution of X given response. The method offers advantages in modelling flexibility and computational simplicity. The resulting ROC curve estimates are semi-parametric and can, in principle, take an infinite variety of shapes. Moreover, model selection can be based on standard methods within the binomial regression framework. Statistical accuracy of the curve estimate is provided by a simply implemented bootstrap approach.     

SHOULD WE ESTIMATE THE PROBABILITY OF CORRECT SELECTION?

Various authors, given k location parameters, have considered lower confidence bounds on (standardized) dserences between the largest and each of the other k - 1 parameters. They have then used these bounds to put lower confidence bounds on the probability of correct selection (PCS) in the same experiment (as was used for finding the lower bounds on differences). It is pointed out that this is an inappropriate inference procedure. Moreover, if the PCS refers to some later experiment it is shown that if a non-trivial confidence bound is possible then it is already possible to conclude, with greater confidence, that correct selection has occurred in the first experiment. The short answer to the question in the title is therefore ‘No’, but this should be qualified in the case of a Bayesian analysis.     

On the asymptotic normality of the L1- and L2-errors in histogram density estimation

The L₁ and L₂-errors of the histogram estimate of a density f from a sample X₁,X₂,…,Xn using a cubic partition are shown to be asymptotically normal without any unnecessary conditions imposed on the density f. The asymptotic variances are shown to depend on f only through the corresponding norm of f. From this follows the asymptotic null distribution of a goodness-of-fit test based on the total variation distance, introduced by Györfi and van der Meulen (1991). This note uses the idea of partial inversion for obtaining characteristic functions of conditional distributions, which goes back at least to Bartlett (1938).     

近代河南集市研究再思考

近代集市的发展不仅表现为数量方面的增加,也有集市数量不变而集市承载量增加的情况;考察集市分布密度以耕地面积为基础更有可比性,而且开市率的高低主要是人们传统习惯、人口规模、集市密度、商品化程度、经济发展状况等因素综合作用的结果,其中传统习惯对开市率的影响较大。