A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials

Patient heterogeneity may complicate dose‐finding in phase 1 clinical trials if the dose‐toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose‐toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup‐specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within‐subgroup dose‐toxicity curves. The simulations show that the hierarchical model‐based method is recommended in settings where the dose‐toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.     

Adaptive phase I/II clinical trials for drug combination assessment in oncology using the outcomes of each cycle

Many new anticancer agents can be combined with existing drugs, as combining a number of drugs may be expected to have a better therapeutic effect than monotherapy owing to synergistic effects. Furthermore, to drive drug development and to reduce the associated cost, there has been a growing tendency to combine these as phase I/II trials. With respect to phase I/II oncology trials for the assessment of dose combinations, in the existing methodologies in which efficacy based on tumor response and safety based on toxicity are modeled as binary outcomes, it is not possible to enroll and treat the next cohort of patients unless the best overall response has been determined in the current cohort. Thus, the trial duration might be potentially extended to an unacceptable degree. In this study, we proposed a method that randomizes the next cohort of patients in the phase II part to the dose combination based on the estimated response rate using all the available observed data upon determination of the overall response in the current cohort. We compared the proposed method to the existing method using simulation studies. These demonstrated that the percentage of optimal dose combinations selected in the proposed method is not less than that in the existing method and that the trial duration in the proposed method is shortened compared to that in the existing method. The proposed method meets both ethical and financial requirements, and we believe it has the potential to contribute to expedite drug development.     

A simple two-stage design for quantitative responses with application to a study in diabetic neuropathic pain

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to be stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase II and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail.     

语段理论下汉语存现句的生成机制研究

存现句是一种特殊的句式,具有跨语言的性质,一般认为其下位句型包括存在甸与隐现句。对汉语存现句相关问题的研究也一直是国内外生成语言学者研究关注的热门话题,通过对汉语存现句的研究进行回顾,发现以往对汉语存现句的研究大多是在管约论框架下进行的,研究的主要问题包括以下几个方面：1．存现句的生成机制;2．句首处所名词组的语法地位;3．存现动词的性质;4．动词后名词组的赋格问题。其中存现句的生成机制问题是最为根本的问题,生成语言学者对此也是各持己见。本文尝试在语段理论的框架下,对汉语存现句的推导生成做尝试性探究,力图寻求汉语存现句统一的生成机制。     

试论中华民族多元一体格局发展的阶段划分

本文通过解析多元一体格局的内涵及其演变,探寻多元一体格局发展的轨迹,将中华民族多元一体格局的发展划分为四个阶段.从中看出,多元一体格局、中华民族(中国境内)、统一多民族中国三者之间虽然范畴不同,却三位一体,多元一体格局本身的形成、稳定与危机,同中华民族、中国统一多民族国家的命运息息相关.     

A two phases queueing system with Bernoulli vacation schedule under multiple vacation policy

This paper deals with a single server Poisson arrival queue with two phases of heterogeneous service along with a Bernoulli schedule vacation model, where after two successive phases service the server either goes for a vacation with probability p (0≤p≤1) or may continue to serve the next unit, if any, with probability q(=1−p). Further the concept of multiple vacation policy is also introduced here. We obtained the queue size distributions at a departure epoch and at a random epoch, Laplace Stieltjes Transform of the waiting time distribution and busy period distribution along with some mean performance measures. Finally we discuss some statistical inference related issues.     

Identifying the most successful dose (MSD) in dose-finding studies in cancer

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not     

聚乙二醇-硫酸铵双水相体系萃取分离食用色素的研究

研究了硫酸铵-聚乙二醇（PEG）双水相体系中,PEG浓度、（NH4）2SO4用量、Trition X-100用量、溶液酸度等因素对常见食用色素叶绿素铜钠盐（SCC）萃取率的影响。研究表明,在50mL的总体积中,聚乙二醇的浓度为30％,10％的SCC溶液的体积为1mL,（NH4）2SO4用量为10．0g,表面活性剂Trition X-100的用量为1．0mL,在中性或微碱性条件下,叶绿素铜钠盐的萃取率达97．98％。叶绿素铜钠盐最大吸收峰位于632nm,实验测定其溶液体积在0—1．2mL范围内符合比耳定律,标准工作曲线为Y=1．0117x＋0．0055,R=0．9999。在实验条件下,金属离子Zn^2＋、Mn^2＋、Mg^2＋、Fe^2＋、Ni^2＋、Cu^2＋对SCC的萃取均不干扰。     

碱、表面活性剂和聚合物为主的三元复合驱油体系相行为研究

通过研究不同浓度Na2 CO3、KPS存在的条件下复合驱油体系的相行为变化 ,找到了形成中相最佳区的条件 ,揭示了相行为与油水界面张力及表面活性剂在不同相间分配量大小的相关性 ,从临界胶束浓度变化对相态转变机理给予合理解释。     

互动在认知建构中的定位

认知在互动过程中不断趋同,又不断分化与超越。互动使各种不同表征的认知系统相互作用,联结建构成具有差异的统一体。在互动过程中,互动个体的认知状态经历了＂初始建构者＂＂孤独建构者＂和＂社会建构者＂三个不同阶段。互动建构的知识并非都是真理。互动所形成的稳定语境,即具有排他性,也具有保护性。权力强加于社会,迫使个体参与权力规训的社会互动,使社会语境发生了根本性的改变,但有时权力无法抗拒原有社会语境从而默认原有社会语境的存在。