The time‐dependent “cure‐death” model investigating two equally important endpoints simultaneously in trials treating high‐risk patients with resistant pathogens

A variety of primary endpoints are used in clinical trials treating patients with severe infectious diseases, and existing guidelines do not provide a consistent recommendation. We propose to study simultaneously two primary endpoints, cure and death, in a comprehensive multistate cure‐death model as starting point for a treatment comparison. This technique enables us to study the temporal dynamic of the patient‐relevant probability to be cured and alive. We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model. Traditional analyses using risk differences focus on one prespecified timepoint only. A restricted logrank‐based test of treatment effect is sensitive to ordered categories of responses and integrates information on duration of response. The pseudo‐value regression provides a direct regression model for examination of treatment effect via difference in transition probabilities. Applied to a topical real data example and simulation scenarios, we demonstrate advantages and limitations and provide an insight into how these methods can handle different kinds of treatment imbalances. The cure‐death model provides a suitable framework to gain a better understanding of how a new treatment influences the time‐dynamic cure and death process. This might help the future planning of randomised clinical trials, sample size calculations, and data analyses.     

A Bayesian sequential design with binary outcome

Several researchers have proposed solutions to control type I error rate in sequential designs. The use of Bayesian sequential design becomes more common; however, these designs are subject to inflation of the type I error rate. We propose a Bayesian sequential design for binary outcome using an alpha‐spending function to control the overall type I error rate. Algorithms are presented for calculating critical values and power for the proposed designs. We also propose a new stopping rule for futility. Sensitivity analysis is implemented for assessing the effects of varying the parameters of the prior distribution and maximum total sample size on critical values. Alpha‐spending functions are compared using power and actual sample size through simulations. Further simulations show that, when total sample size is fixed, the proposed design has greater power than the traditional Bayesian sequential design, which sets equal stopping bounds at all interim analyses. We also find that the proposed design with the new stopping for futility rule results in greater power and can stop earlier with a smaller actual sample size, compared with the traditional stopping rule for futility when all other conditions are held constant. Finally, we apply the proposed method to a real data set and compare the results with traditional designs.     

Multiphase experiments in practice: A look back

Multiphase experiments are introduced and an overview of their design and analysis as it is currently practised is given via an account of their development since 1955 and a literature survey. Methods that are available for designing and analysing them are outlined, with an emphasis on making explicit the role of the model in their design. The availability of software and its use is described in detail. Overall, while multiphase designs have been applied in areas such as plant breeding, plant pathology, greenhouse experimentation, product storage, gene expression studies, and sensory evaluation, their deployment has been limited.     

A powerful and efficient algorithm for breaking the links between aliased effects in asymmetric designs

Fractional factorial (FF) designs are no doubt the most widely used designs in experimental investigations due to their efficient use of experimental runs. One price we pay for using FF designs is, clearly, our inability to obtain estimates of some important effects (main effects or second order interactions) that are separate from estimates of other effects (usually higher order interactions). When the estimate of an effect also includes the influence of one or more other effects the effects are said to be aliased. Folding over an FF design is a method for breaking the links between aliased effects in a design. The question is, how do we define the foldover structure for asymmetric FF designs, whether regular or nonregular? How do we choose the optimal foldover plan? How do we use optimal foldover plans to construct combined designs which have better capability of estimating lower order effects? The main objective of the present paper is to provide answers to these questions. Using the new results in this paper as benchmarks, we can implement a powerful and efficient algorithm for finding optimal foldover plans which can be used to break links between aliased effects.     

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.     

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.     

就业为导向的高职英语课程设置——以广东培正学院为例

本文从培正学院为了突出学生就业的英语优势而采用的英语分级教学的课程实践入手,评价其教学模式的优劣,并提出了一些有待改进的建议。     

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.