Bayesian adaptive dose‐escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy

The main purpose of dose‐escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose‐escalation designs that incorporate both the dose‐limiting events and dose‐limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose‐escalation strategies. The first type of procedures, called “single objective,” aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called “dual objective,” aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose‐escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual‐objective designs give better results in terms of identifying the 2 real target doses compared to the single‐objective designs.     

Computer-Assisted Screening and Intervention for Alcohol Problems in Primary Care

ABSTRACT

The effectiveness of a bilingual (English/Spanish) computer-assisted alcohol screening/intervention for hazardous and harmful alcohol use, the Health Habits Survey (HHS) was tested in primary care settings. Assessment-only patients were compared with patients exposed to the HHS. Of the 2053 recruited, 151 (7.4%) screened positive on the Alcohol Use Disorders Identification Test (AUDIT) and were re-contacted six months later for follow-up. Significant alcohol reduction was observed in both conditions. No between-group differences were observed. Computer-assisted screening and intervention are feasible in primary care settings and may be a realistic provider-extender when traditional screening is absent or inconsistently implemented.     

Sequential estimation problems for negative exponential populations

The literature on sequential estimation problems for negative exponential populations has been reviewed here, We attempt to bring in all the published and unpublished materials known to us in a fairly coherent fashion. Both the concepts and theoretical findings are discussed.     

Social Work with the Osteoporotic Woman

A chronic, progressive, and potentially debilitating condition, osteoporosis has a multitude of currently untapped implications for effective social work practice. A working knowledge of the medical framework of the disease process itself is a prerequisite to informed practice. This article presents such information, along with the psychological and social components, in order to provide the social worker with the comprehensive biopsyehosaial knowledge base necessary for effective practice with the osteoporotic woman and her family.     

信息不对称下医药营销服务外包契约设计

为了缩减销售成本,一些制药企业将营销服务外包给合约销售公司(contract sales organization,CSO).由于CSO的营销努力不可合同化,制药企业需要基于市场销量来激励CSO的营销努力.然而,市场销量受制药企业定价决策的影响,因此CSO将面临制药企业提高定价的道德风险.此外,药品营销难度信息可能是CSO的私人信息,这使得制药企业面临逆向选择问题.当制药企业将营销服务外包给多个CSO时,由于制药企业针对同一药品在不同市场的售价相同,其定价决策对多个CSO所服务市场的销量具有共同的影响.相对绩效的激励契约能够消除共同不确定因素对代理人产出的影响,从而更有利于激励代理人付出高水平的努力.因此依据信息甄别的博弈模型,分析基于个体绩效与基于相对绩效的激励契约的有效性.研究发现:1)药品营销难度信息对称时,基于相对绩效的激励契约占优于基于个体绩效的激励契约,且可以获得全局最优的营销努力和期望利润;2)药品营销难度信息不对称时,两种激励契约均不能获得全局最优的营销努力和期望利润.数值分析表明,药品营销难度的先验概率,市场价格敏感性和高低类型药品营销难度差异的变化会影响制药企业的契约选择,较高的市场价格敏感性和较低的高低类型药品营销难度差异使得基于相对绩效的激励契约更有效.     

减刑假释实行申请制之倡导

根据我国刑法规定,减刑假释程序是由执行机关提出减刑假释意见书,法院组成合议庭作出裁定。现有制度存在很大不合理性,犯罪人作为减刑假释的直接获益人,被排斥在程序之外并不能保障犯罪人的利益,而且会导致假释使用率被执行机关人为降低。减刑假释本质都应采用权利说,二者本质上并无差别,且优劣互补,只是具体执行方式不同,因此减刑假释应当实行申请制,由犯罪人根据自身情况自由选择减刑或者假释并先行提出申请,执行机关提出意见书,法院居中裁定。减刑假释实行申请制有利于司法机关选择真正适合犯罪人的执行措施,提高犯罪人改造的积极性,使得对犯罪人的改造更加有效、更加彻底,同时也保障了犯罪人的合法权益。     

Randomization tests in recursive response-adaptive randomization procedures

In a randomized clinical trial, response-adaptive randomization procedures use the information gathered, including the previous patients' responses, to allocate the next patient. In this setting, we consider randomization-based inference. We provide an algorithm to obtain exact p-values for statistical tests that compare two treatments with dichotomous responses. This algorithm can be applied to a family of response adaptive randomization procedures which share the following property: the distribution of the allocation rule depends only on the imbalance between treatments and on the imbalance between successes for treatments 1 and 2 in the previous step. This family includes some outstanding response adaptive randomization procedures. We study a randomization test to contrast the null hypothesis of equivalence of treatments and we show that this test has a similar performance to that of its parametric counterpart. Besides, we study the effect of a covariate in the inferential process. First, we obtain a parametric test, constructed assuming a logit model which relates responses to treatments and covariate levels, and we give conditions that guarantee its asymptotic normality. Finally, we show that the randomization test, which is free of model specification, performs as well as the parametric test that takes the covariate into account.     

Factor screening in nonregular two-level designs based on projection-based variable selection

In this paper, we focus on the problem of factor screening in nonregular two-level designs through gradually reducing the number of possible sets of active factors. We are particularly concerned with situations when three or four factors are active. Our proposed method works through examining fits of projection models, where variable selection techniques are used to reduce the number of terms. To examine the reliability of the methods in combination with such techniques, a panel of models consisting of three or four active factors with data generated from the 12-run and the 20-run Plackett–Burman (PB) design is used. The dependence of the procedure on the amount of noise, the number of active factors and the number of experimental factors is also investigated. For designs with few runs such as the 12-run PB design, variable selection should be done with care and default procedures in computer software may not be reliable to which we suggest improvements. A real example is included to show how we propose factor screening can be done in practice.     

中国宪法非讼化原因探析

中国宪法呈现为非讼化特征是有其历史必然性的。其主要原因在于 :前苏联宪法模式及其苏维埃宪法意识的影响 ,宪法章程化、宪法纲领化和宪法问题政治化等中国现代宪法观念的作用 ,以及中国社会民主意识和公民宪法权利意识的限制     

Family violence in gambling help-seeking populations

Elevated rates of family violence among treatment-seeking problem gamblers compared to general population estimates have been reported in Spain, Canada and Australia. This study examined the occurrence of family violence among 454 problem gambling help-seeking clients (370 gamblers, 84 affected others) recruited through 3 national gambling treatment services in New Zealand. Measures used were the Problem Gambling Severity Index, and a modified version of the HITS Scale which assessed physical, emotional, verbal and sexual abuse. Past-year family violence among gamblers in this sample was 46.8% for victimization, 41.2% for perpetration and 55.0% for any form of family violence. Among affected others the occurrence was 65.5% for victimization, 57.1% for perpetration and 71.4% for any form of violence. The most common type of violence was verbal intimate partner violence. Affected others and women gamblers reported higher rates of violence victimization and perpetration. These findings underscore the importance of screening gambling help-seeking clients for family violence, and the development of prevention and treatment programmes to address violence in this population, with particular attention to affected others and women gamblers. Future research should assess coercive control and the gendered nature of family violence among problem gambling help-seekers.