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.     

An overlook on statistical inference issues for stochastic damping hamiltonian systems under the fluctuation-dissipation condition

ABSTRACT

In this paper, we are interested in nonparametric inference issues for stochastic damping hamiltonian systems under the fluctuation-dissipation condition. This condition relates the magnitude of the dissipative term and the magnitude of the random term. The precise balance between the drift term which removes energy in average and the stochastic term provided by the fluctuation-dissipation relation insures that the canonical measure is preserved by the dynamics. In this framework, it is possible to give an explicit construction of a Lyapunov function and thus to prove exponential ergodicity. Then, we consider various estimation procedures and provide also a numerical section, where simulations are conducted.     

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.     

Exploratory Study on Drug Users’ Perspectives on Quality of Life: More than Health-Related Quality of Life?

In drug treatment outcome literature, a focus on objective and socially desirable indicators of change (e.g. no drug use) has predominated, while outcome indicators that are important for drug users themselves (e.g. quality of life, satisfaction with treatment) have largely been neglected. Nonetheless, Quality of Life (QoL) has become an important concept to evaluate effectiveness of treatment in mental health care research and disability studies. Given the almost exclusive focus on Health-related Quality of Life (HRQOL) in substance abuse research and the neglect of clients’ perspectives in this field, we explore in this study the concept of QoL as perceived by drug users. Focus group discussions (n = 9) were organised in various treatment settings and community services for drug users in the region of Ghent, Belgium to identify important dimensions of QoL and their interpretation by drug users. Data were clustered and analysed based on the theoretical framework of Robert Schalock (Quality of life. Volume 1: Conceptualization and measurement, 1996). The domains ‘personal relationships’, ‘social inclusion’ and ‘self-determination’ were discussed most frequently by the participants. They stressed the importance of a supportive social network in particular. It can be concluded that QoL is not primarily associated by drug users with health and it involves much more than the aspects typically represented in measures of HRQOL.     

On sequential closed testing dose groups with a control

Methods for a sequential test of a dose-response effect in pre-clinical studies are investigated. The objective of the test procedure is to compare several dose groups with a zero-dose control. The sequential testing is conducted within a closed family of one-sided tests. The procedures investigated are based on a monotonicity assumption. These closed procedures strongly control the familywise error rate while providing information about the shape of the dose-responce relationship. Performance of sequential testing procedures are compared via a Monte Carlo simulation study. We illustrae the procedures by application to a real data set.     

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.