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.     

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.     

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。     

Data skeletons: simultaneous estimation of multiple quantiles for massive streaming datasets with applications to density estimation

We consider the problem of density estimation when the data is in the form of a continuous stream with no fixed length. In this setting, implementations of the usual methods of density estimation such as kernel density estimation are problematic. We propose a method of density estimation for massive datasets that is based upon taking the derivative of a smooth curve that has been fit through a set of quantile estimates. To achieve this, a low-storage, single-pass, sequential method is proposed for simultaneous estimation of multiple quantiles for massive datasets that form the basis of this method of density estimation. For comparison, we also consider a sequential kernel density estimator. The proposed methods are shown through simulation study to perform well and to have several distinct advantages over existing methods.     

Predictive Bayesian Microbial Dose-Response Assessment Based on Suggested Self-Organization in Primary Illness Response: Cryptosporidium parvum

The probability of illness caused by very low doses of pathogens cannot generally be tested due to the numbers of subjects that would be needed, though such assessments of illness dose response are needed to evaluate drinking water standards. A predictive Bayesian dose-response assessment method was proposed previously to assess the unconditional probability of illness from available information and avoid the inconsistencies of confidence-based approaches. However, the method uses knowledge of the conditional dose-response form, and this form is not well established for the illness endpoint. A conditional parametric dose-response function for gastroenteric illness is proposed here based on simple numerical models of self-organized host-pathogen systems and probabilistic arguments. In the models, illnesses terminate when the host evolves by processes of natural selection to a self-organized critical value of wellness. A generalized beta-Poisson illness dose-response form emerges for the population as a whole. Use of this form is demonstrated in a predictive Bayesian dose-response assessment for cryptosporidiosis. Results suggest that a maximum allowable dose of 5.0 x 10(-7) oocysts/exposure (e.g., 2.5 x 10(-7) oocysts/L water) would correspond with the original goals of the U.S. Environmental Protection Agency Surface Water Treatment Rule, considering only primary illnesses resulting from Poisson-distributed pathogen counts. This estimate should be revised to account for non-Poisson distributions of Cryptosporidium parvum in drinking water and total response, considering secondary illness propagation in the population.     

Causal Reasoning from Longitudinal Data*

Abstract. This paper reviews some of the key statistical ideas that are encountered when trying to find empirical support to causal interpretations and conclusions, by applying statistical methods on experimental or observational longitudinal data. In such data, typically a collection of individuals are followed over time, then each one has registered a sequence of covariate measurements along with values of control variables that in the analysis are to be interpreted as causes, and finally the individual outcomes or responses are reported. Particular attention is given to the potentially important problem of confounding. We provide conditions under which, at least in principle, unconfounded estimation of the causal effects can be accomplished. Our approach for dealing with causal problems is entirely probabilistic, and we apply Bayesian ideas and techniques to deal with the corresponding statistical inference. In particular, we use the general framework of marked point processes for setting up the probability models, and consider posterior predictive distributions as providing the natural summary measures for assessing the causal effects. We also draw connections to relevant recent work in this area, notably to Judea Pearl's formulations based on graphical models and his calculus of so‐called do‐probabilities. Two examples illustrating different aspects of causal reasoning are discussed in detail.