Properties of the weighted log‐rank test in the design of confirmatory studies with delayed effects

Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. This assumption not only affects the analysis part but also the sample size calculation. The presence of delayed effects causes a change in the hazard ratio while the trial is ongoing since at the beginning we do not observe any difference between treatment arms, and after some unknown time point, the differences between treatment arms will start to appear. Hence, the proportional hazards assumption no longer holds, and both sample size calculation and analysis methods to be used should be reconsidered. The weighted log‐rank test allows a weighting for early, middle, and late differences through the Fleming and Harrington class of weights and is proven to be more efficient when the proportional hazards assumption does not hold. The Fleming and Harrington class of weights, along with the estimated delay, can be incorporated into the sample size calculation in order to maintain the desired power once the treatment arm differences start to appear. In this article, we explore the impact of delayed effects in group sequential and adaptive group sequential designs and make an empirical evaluation in terms of power and type‐I error rate of the of the weighted log‐rank test in a simulated scenario with fixed values of the Fleming and Harrington class of weights. We also give some practical recommendations regarding which methodology should be used in the presence of delayed effects depending on certain characteristics of the trial.     

审计定价管制与交易剩余——2010年审计定价管制失效的自然实验

在经济下行压力加大、资本市场进一步开放的新形势下,厘清审计市场交易——监管机制,完善审计服务市场尤为必要。借由2010 年审计定价管制政策失效的自然实验,本文通过嵌入双边随机边界模型,得到审计双方的定价交易剩余指标,运用双重差分模型解析价格管制与交易定价的作用机制。研究发现,定价管制失效的原因不在于规制俘获,而在于价格管制与当前的市场效率不匹配。下限管制尽管能够提高审计师剩余,但同时会放大交易定价风险,增加剩余的错配,扰乱交易秩序。上限管制则进一步固化市场的低价竞争。进一步研究发现审计师剩余与盈余质量显著相关,2014年的放开定价管制政策提高了审计师剩余。研究厘清了审计市场交易机制,有利于未来研究审计交易机制的微观影响及与盈余质量的关联,为在新时代把握审计市场交易——监管规律、培育自发良性交易的审计市场提供有益借鉴。     

Comparison of Four New General Classes of Search Designs

A factor screening experiment identifies a few important factors from a large list of factors that potentially influence the response. If a list consists of m factors each at three levels, a design is a subset of all possible 3 ^m runs. This paper considers the problem of finding designs with small numbers of runs, using the search linear model introduced in Srivastava (1975). The paper presents four new general classes of these 'search designs', each with 2 m −1 runs, which permit, at most, two important factors out of m factors to be searched for and identified. The paper compares the designs for 4 ≤ m ≤ 10, using arithmetic and geometric means of the determinants, traces and maximum characteristic roots of particular matrices. Two of the designs are found to be superior in all six criteria studied. The four designs are identical for m = 3 and this design is an optimal design in the class of all search designs under the six criteria. The four designs are also identical for m = 4 under some row and column permutations.     

Examples of the use of an equivalence theorem in constructing optimum experimental designs for random-effects nonlinear regression models

The problem considered is that of finding an optimum measurement schedule to estimate population parameters in a nonlinear model when the patient effects are random. The paper presents examples of the use of sensitivity functions, derived from the General Equivalence Theorem for D-optimality, in the construction of optimum population designs for such schedules. With independent observations, the theorem applies to the potential inclusion of a single observation. However, in population designs the observations are correlated and the theorem applies to the inclusion of an additional measurement schedule. In one example, three groups of patients of differing size are subject to distinct schedules. Numerical, as opposed to analytical, calculation of the sensitivity function is advocated. The required covariances of the observations are found by simulation.     

Efficient designs based on orthogonal arrays of type I and type II for experiments using units ordered over time or space

For a wide variety of applications, experiments are based on units ordered over time or space. Models for these experiments generally may include one or more of: correlations, systematic trends, carryover effects and interference effects. Since the standard optimal block designs may not be efficient in these situations, orthogonal arrays of type I and type II, which were introduced in 1961 by C.R. Rao [Combinatorial arrangements analogous to orthogonal arrays, Sankhya A 23 (1961) 283–286], have been recently used to construct optimal and efficient designs for many of these experiments. Results in this area are unified and the salient features are outlined.     

Robustness of a Class of Partial Diallel Cross Designs to the Unavailability of a Complete Block of Observations

Complete and partial diallel cross designs are examined as to their construction and robustness against the loss of a block of observations. A simple generalized inverse is found for the information matrix of the line effects, which allows evaluation of expressions for the variances of the line-effect differences with and without the missing block. A-efficiencies, based on average variances of the elementary contrasts of the line-effects, suggest that these designs are fairly robust. The loss of efficiency is generally less than 10%, but it is shown that specific comparisons might suffer a loss of efficiency of as much as 40%.     

A semi-parametric approach to robust parameter design

Parameter design or robust parameter design (RPD) is an engineering methodology intended as a cost-effective approach for improving the quality of products and processes. The goal of parameter design is to choose the levels of the control variables that optimize a defined quality characteristic. An essential component of RPD involves the assumption of well estimated models for the process mean and variance. Traditionally, the modeling of the mean and variance has been done parametrically. It is often the case, particularly when modeling the variance, that nonparametric techniques are more appropriate due to the nature of the curvature in the underlying function. Most response surface experiments involve sparse data. In sparse data situations with unusual curvature in the underlying function, nonparametric techniques often result in estimates with problematic variation whereas their parametric counterparts may result in estimates with problematic bias. We propose the use of semi-parametric modeling within the robust design setting, combining parametric and nonparametric functions to improve the quality of both mean and variance model estimation. The proposed method will be illustrated with an example and simulations.     

Analysis of a continuous-time proportional hazard model using discrete duration data

Many economic duration variables are often available only up to intervals, and not up to exact points. However, continuous time duration models are conceptually superior to discrete ones. Hence, in duration analyses, one faces a situation with discrete data and a continuous model. This paper discusses (i) the asymptotic bias of a conventional approximation procedure in which a discrete duration is treated as an exact observation; and (ii) the efficiency of a correct maximum likelihood estimator which appropriately accounts for the discrete nature of the data.     

Horwitz's rule, transforming both sides and the design of experiments for mechanistic models

Summary. The paper develops methods for the design of experiments for mechanistic models when the response must be transformed to achieve symmetry and constant variance. The power transformation that is used is partially justified by a rule in analytical chemistry. Because of the nature of the relationship between the response and the mechanistic model, it is necessary to transform both sides of the model. Expressions are given for the parameter sensitivities in the transformed model and examples are given of optimum designs, not only for single-response models, but also for experiments in which multivariate responses are measured and for experiments in which the model is defined by a set of differential equations which cannot be solved analytically. The extension to designs for checking models is discussed.     

Detection and correction of artificial shifts in climate series

Summary.  Many long instrumental climate records are available and might provide useful information in climate research. These series are usually affected by artificial shifts, due to changes in the conditions of measurement and various kinds of spurious data. A comparison with surrounding weather-stations by means of a suitable two-factor model allows us to check the reliability of the series. An adapted penalized log-likelihood procedure is used to detect an unknown number of breaks and outliers. An example concerning temperature series from France confirms that a systematic comparison of the series together is valuable and allows us to correct the data even when no reliable series can be taken as a reference.