Testing for bioequivalence of highly variable drugs from TR‐RT crossover designs with heterogeneous residual variances

Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR‐RTR‐RRT and TRTR‐RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR‐RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR‐RT designs. Under the assumption of zero subject‐by‐formulation interaction, this basic model is comparable to the FDA‐recommended model for TRR‐RTR‐RRT and TRTR‐RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real‐world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ‐based testing procedure that evaluates HV drugs under practical TR‐RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ‐based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.     

论“跨文化交际”课程设计模块化

利用美国学者陈国明先生的跨文化交际能力的模型,结合跨文化课程设计理论和国内研究数据,完成课程概念性的模块化设计,为国内同行提供一个课程设计的新思路。     

建筑抗震质量的设计与管理

地震灾害给人类社会生活带来重大影响。加强建筑工程质量管理,防止地震灾害,成为备受社会关注的热点问题。要从提高全民质量意识入手,建立健全有效的质量监督机制、提高建筑设计质量,加强施工质量控制．为人民安居乐业创造良好的环境。     

Analysis of robust design experiments with time-dependent ordinal response characteristics: a quality improvement study from the horticulture industry

An approach to the analysis of time-dependent ordinal quality score data from robust design experiments is developed and applied to an experiment from commercial horticultural research, using concepts of product robustness and longevity that are familiar to analysts in engineering research. A two-stage analysis is used to develop models describing the effects of a number of experimental treatments on the rate of post-sales product quality decline. The first stage uses a polynomial function on a transformed scale to approximate the quality decline for an individual experimental unit using derived coefficients and the second stage uses a joint mean and dispersion model to investigate the effects of the experimental treatments on these derived coefficients. The approach, developed specifically for an application in horticulture, is exemplified with data from a trial testing ornamental plants that are subjected to a range of treatments during production and home-life. The results of the analysis show how a number of control and noise factors affect the rate of post-production quality decline. Although the model is used to analyse quality data from a trial on ornamental plants, the approach developed is expected to be more generally applicable to a wide range of other complex production systems.     

论虚实关系在舞美设计中的运用

虚与实是艺术创作技巧的美学原则,在舞台美术设计中,更显示出虚实结合的独特性和必要性,具体来说,表现在几个方面:在布景设置上,要以实带虚,以虚衬实;在意境表达上,要虚实对比,和谐产生;在光色处理上,要虚实变幻,以景托人;在舞台布局上,要讲究整体,统筹协调.     

A variable-neighbourhood search algorithm for finding optimal run orders in the presence of serial correlation

The responses obtained from response surface designs that are run sequentially often exhibit serial correlation or time trends. The order in which the runs of the design are performed then has an impact on the precision of the parameter estimators. This article proposes the use of a variable-neighbourhood search algorithm to compute run orders that guarantee a precise estimation of the effects of the experimental factors. The importance of using good run orders is demonstrated by seeking D-optimal run orders for a central composite design in the presence of an AR(1) autocorrelation pattern.     

Cumulative correspondence analysis of ordered categorical data from industrial experiments

Most studies of quality improvement deal with ordered categorical data from industrial experiments. Accounting for the ordering of such data plays an important role in effectively determining the optimal factor level of combination. This paper utilizes the correspondence analysis to develop a procedure to improve the ordered categorical response in a multifactor state system based on Taguchi's statistic. Users may find the proposed procedure in this paper to be attractive because we suggest a simple and also popular statistical tool for graphically identifying the really important factors and determining the levels to improve process quality. A case study for optimizing the polysilicon deposition process in a very large-scale integrated circuit is provided to demonstrate the effectiveness of the proposed procedure.     

Doubly adaptive biased coin designs with heterogeneous responses

Doubly adaptive biased coin design (DBCD) is an important family of response-adaptive randomization procedures for clinical trials. It uses sequentially updated estimation to skew the allocation probability to favor the treatment that has performed better thus far. An important assumption for the DBCD is the homogeneity assumption for the patient responses. However, this assumption may be violated in many sequential experiments. Here we prove the robustness of the DBCD against certain time trends in patient responses. Strong consistency and asymptotic normality of the design are obtained under some widely satisfied conditions. Also, we propose a general weighted likelihood method to reduce the bias caused by the heterogeneity in the inference after a trial. Some numerical studies are also presented to illustrate the finite sample properties of DBCD.     

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.     

不忘初心：基于央视宣传片百年政党多模态形象建构研究

央视形象宣传片《我是谁》是中国共产党建党95周年以来的首部公益广告,具有重要的时代意义和研究价值.结合视觉设计语法、评价理论和“宣传片”的图像、文本和声音语料建立“宣传片”多模态形象诠释框架,探索“宣传片”建构党的形象的过程与范式.研究发现:一是“宣传片”图像的再现意义体现接地气的创意理念,互动意义展现与受众间的平等权势关系,构图意义揭示青年群体是目标受众的精准定位;二是“宣传片”文本重点建构人际意义的协商语义,从客观视角而不是主观情感刻画党员群体爱岗敬业的务实作风和百年政党一心为民的赤子之心;三是“宣传片”音乐、旁白等声音能够有效增强受众全方位了解党的形象塑造,从而尽快接受党为人民服务的不变“初心”.