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.     

Nonparametric Shrinkage Estimation for Aalen's Additive Hazards Model

Aalen's nonparametric additive model in which the regression coefficients are assumed to be unspecified functions of time is a flexible alternative to Cox's proportional hazards model when the proportionality assumption is in doubt. In this paper, we incorporate a general linear hypothesis into the estimation of the time‐varying regression coefficients. We combine unrestricted least squares estimators and estimators that are restricted by the linear hypothesis and produce James‐Stein‐type shrinkage estimators of the regression coefficients. We develop the asymptotic joint distribution of such restricted and unrestricted estimators and use this to study the relative performance of the proposed estimators via their integrated asymptotic distributional risks. We conduct Monte Carlo simulations to examine the relative performance of the estimators in terms of their integrated mean square errors. We also compare the performance of the proposed estimators with a recently devised LASSO estimator as well as with ridge‐type estimators both via simulations and data on the survival of primary billiary cirhosis patients.     

Production and changeover control policies of a class of failure prone buffered flow-shops

This article deals with a stochastic optimal control problem for a class of buffered multi-parts flow-shops manufacturing system. The involved machines are subject to random breakdowns and repairs. The flow-shop under consideration is not completely flexible and hence requires setup time and cost in order to switch the production from a part type to another, this changeover is carried on the whole line. Our objective is to find the production plan and the sequence of setups that minimise the cost function, which penalises inventories/backlogs and setups. A continuous dynamic programming formulation of the problem is presented. Then, a numerical scheme is adopted to solve the obtained optimality conditions equations for a two buffered serial machines two parts case. A complete heuristic policy, based on the numerical observations which describe the optimal policies in system states, is developed. It will be shown that the obtained policy is a combination of a KANBAN/CONWIP and a modified hedging corridor policy. Moreover, based on our observations and existent research studies extension to cover more complex flow-shops is henceforth possible. The robustness of such a policy is illustrated through sensitivity analysis.     

Graphical and Numerical Methods for Detecting Influential Observations in Complex Bingham Data

We describe methods to detect influential observations in a sample of pre-shapes when the underlying distribution is assumed to be complex Bingham. One of these methods is based on Cook's distance, which is derived from the likelihood of the complex Bingham distribution. Other method is related to the tangent space, which is based on the local influence for the multivariate normal distribution. A method to detect outliers is also explained. The application of the methods is illustrated in both a real dataset and a simulated sample.     

The Multi-dimensional Characteristics of Wellbeing: How Different Aspects of Wellbeing Interact and Do Not Interact with Each Other

Because wellbeing is a multi-varied and dynamic phenomenon, social scientists need to better understand how different aspects of people’s wellbeing are tied together and how these ties differ between individuals at one point in time and within individuals over time. The paper outlines a general model that considers the multidimensional structure of wellbeing. We utilize the potential of latent variable modelling on a unique Swedish database: the Panel Survey of Ageing and the Elderly (PSAE). An inclusive and flexible model that considers the interactions between semi-autonomous domains (material resources, health, psychosocial factors, lifestyle, etc.) is developed. Our empirical study is based on cross-sectional PSAE data and focuses on people 55 years or older (N = 5,374). The analysis takes advantage of recent developments in statistical theory in the field of latent variable modelling to bring about a more dynamic and theory confirming analysis of a multifaceted phenomenon such as wellbeing.     

Testing the Granger Noncausality Hypothesis in Stationary Nonlinear Models of Unknown Functional Form

In this article, we propose a general method for testing the Granger noncausality hypothesis in stationary nonlinear models of unknown functional form. These tests are based on a Taylor expansion of the nonlinear model around a given point in the sample space. We study the performance of our tests by a Monte Carlo experiment and compare these to the most widely used linear test. Our tests appear to be well-sized and have reasonably good power properties.     

Simulating space-time random fields with nonseparable Gneiting-type covariance functions

Statistics and Computing - Two algorithms are proposed to simulate space-time Gaussian random fields with a covariance function belonging to an extended Gneiting class, the definition of which...     

Model averaging inconcentration–QT analyses

This article describes how a frequentist model averaging approach can be used for concentration–QT analyses in the context of thorough QTc studies. Based on simulations, we have concluded that starting from three candidate model families (linear, exponential, and Emax) the model averaging approach leads to treatment effect estimates that are quite robust with respect to the control of the type I error in nearly all simulated scenarios; in particular, with the model averaging approach, the type I error appears less sensitive to model misspecification than the widely used linear model. We noticed also few differences in terms of performance between the model averaging approach and the more classical model selection approach, but we believe that, despite both can be recommended in practice, the model averaging approach can be more appealing because of some deficiencies of model selection approach pointed out in the literature. We think that a model averaging or model selection approach should be systematically considered for conducting concentration–QT analyses. Copyright © 2016 John Wiley & Sons, Ltd.     

Comparison of hazard rates for dependent random variables

In this paper, we define and study a new notion for the comparison of the hazard rates of two random variables taking into account their mutual dependence. Properties, applications and the comparison for a data set are given.     

Testing Hypotheses in Nonparametric Models of Production

Data envelopment analysis (DEA) and free disposal hull (FDH) estimators are widely used to estimate efficiency of production. Practitioners use DEA estimators far more frequently than FDH estimators, implicitly assuming that production sets are convex. Moreover, use of the constant returns to scale (CRS) version of the DEA estimator requires an assumption of CRS. Although bootstrap methods have been developed for making inference about the efficiencies of individual units, until now no methods exist for making consistent inference about differences in mean efficiency across groups of producers or for testing hypotheses about model structure such as returns to scale or convexity of the production set. We use central limit theorem results from our previous work to develop additional theoretical results permitting consistent tests of model structure and provide Monte Carlo evidence on the performance of the tests in terms of size and power. In addition, the variable returns to scale version of the DEA estimator is proved to attain the faster convergence rate of the CRS-DEA estimator under CRS. Using a sample of U.S. commercial banks, we test and reject convexity of the production set, calling into question results from numerous banking studies that have imposed convexity assumptions. Supplementary materials for this article are available online.