Estimation of Metabolic Rate Constants in PBPK‐Models from Liver Slice Experiments: What Are the Experimental Needs?

A mechanistic model is presented describing the clearance of a compound in a precision-cut liver slice that is incubated in a culture medium. The problem of estimating metabolic rate constants in PBPK models from liver slice experiments is discussed using identifiability analysis. From the identifiability problem analysis, it appears that in addition to the clearance, the compound's free fraction in the slice and the diffusion rate of the exchange of the compound between culture medium and liver slice should be identified. In addition, knowledge of the culture medium volume, the slice volume, the compound's free fraction, and octanol-water-based partition between medium and slice is presupposed. The formal solution for identification is discussed from the perspective of experimental practice. A formally necessary condition for identification is the sampling of parent compound in liver slice or culture medium. However, due to experimental limitations and errors, sampling the parent compound in the slice together with additional sampling of metabolite pooled from the medium and the slice is required for identification in practice. Moreover, it appears that identification results are unreliable when the value of the intrinsic clearance exceeds the value of the diffusion coefficient, a condition to be verified a posteriori.     

一类非线性混合整规划的无约束连续化解法

将整系数多项式 0 - 1混合整规划问题化成无约束多项式规划问题。通过解该问题 ,能得到原问题的近似解。处理方法的特点是能够直接处理不等式约束情形 ,而不需要先将不等式约束化成等式约束再来处理     

Sums of powers of binomial coefficients

An asymptotic series for sums of powers of binomial coefficients is derived, the general term being defined and usable with a computer symbolic language. Sums of squares of coefficients in the symmetric case are shown to have a link with classical moment problems, but this property breaks down for cubes and higher powers. Problems of remainders for the asymptotic series are mentioned. Using the reflection formula for I'(.), a continuous form for a binomial function is set up, and this becomes oscillatory outstde the usual range. A new contmued fraction emerges for the logarithm of an adjusted sum of binomial squares. The note is a contribution to the problem of the interpretation of asymptotic series and processes for their convergence acceleration.     

A model with long-term survivors: negative binomial Birnbaum-Saunders

Abstract

We propose a cure rate survival model by assuming that the number of competing causes of the event of interest follows the negative binomial distribution and the time to the event of interest has the Birnbaum-Saunders distribution. Further, the new model includes as special cases some well-known cure rate models published recently. We consider a frequentist analysis for parameter estimation of the negative binomial Birnbaum-Saunders model with cure rate. Then, we derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes. We illustrate the usefulness of the proposed model in the analysis of a real data set from the medical area.     

Group sequential monitoring based on the weighted log‐rank test statistic with the Fleming–Harrington class of weights in cancer vaccine studies

In recent years, immunological science has evolved, and cancer vaccines are now approved and available for treating existing cancers. Because cancer vaccines require time to elicit an immune response, a delayed treatment effect is expected and is actually observed in drug approval studies. Accordingly, we propose the evaluation of survival endpoints by weighted log‐rank tests with the Fleming–Harrington class of weights. We consider group sequential monitoring, which allows early efficacy stopping, and determine a semiparametric information fraction for the Fleming–Harrington family of weights, which is necessary for the error spending function. Moreover, we give a flexible survival model in cancer vaccine studies that considers not only the delayed treatment effect but also the long‐term survivors. In a Monte Carlo simulation study, we illustrate that when the primary analysis is a weighted log‐rank test emphasizing the late differences, the proposed information fraction can be a useful alternative to the surrogate information fraction, which is proportional to the number of events. Copyright © 2016 John Wiley & Sons, Ltd.     

Unified multivariate survival model with a surviving fraction: an application to a Brazilian customer churn data

In this paper we propose a new lifetime model for multivariate survival data in presence of surviving fractions and examine some of its properties. Its genesis is based on situations in which there are m types of unobservable competing causes, where each cause is related to a time of occurrence of an event of interest. Our model is a multivariate extension of the univariate survival cure rate model proposed by Rodrigues et al. [37 J. Rodrigues, V.G. Cancho, M. de Castro, and F. Louzada-Neto, On the unification of long-term survival models, Statist. Probab. Lett. 79 (2009), pp. 753–759. doi: 10.1016/j.spl.2008.10.029[Crossref], [Web of Science ®] , [Google Scholar]]. The inferential approach exploits the maximum likelihood tools. We perform a simulation study in order to verify the asymptotic properties of the maximum likelihood estimators. The simulation study also focus on size and power of the likelihood ratio test. The methodology is illustrated on a real data set on customer churn data.     

Influence diagnostics for the Weibull-Negative-Binomial regression model with cure rate under latent failure causes

In this paper, we propose a flexible cure rate survival model by assuming that the number of competing causes of the event of interest follows the Negative Binomial distribution and the time to event follows a Weibull distribution. Indeed, we introduce the Weibull-Negative-Binomial (WNB) distribution, which can be used in order to model survival data when the hazard rate function is increasing, decreasing and some non-monotonous shaped. Another advantage of the proposed model is that it has some distributions commonly used in lifetime analysis as particular cases. Moreover, the proposed model includes as special cases some of the well-know cure rate models discussed in the literature. We consider a frequentist analysis for parameter estimation of a WNB model with cure rate. Then, we derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes and present some ways to perform global influence analysis. Finally, the methodology is illustrated on a medical data.     

A general long-term aging model with different underlying activation mechanisms: Modeling,Bayesian estimation,and case influence diagnostics

In this paper we propose a general cure rate aging model. Our approach enables different underlying activation mechanisms which lead to the event of interest. The number of competing causes of the event of interest is assumed to follow a logarithmic distribution. The model is parameterized in terms of the cured fraction which is then linked to covariates. We explore the use of Markov chain Monte Carlo methods to develop a Bayesian analysis for the proposed model. Moreover, some discussions on the model selection to compare the fitted models are given, as well as case deletion influence diagnostics are developed for the joint posterior distribution based on the ψ-divergence, which has several divergence measures as particular cases, such as the Kullback–Leibler (K-L), J-distance, L₁ norm, and χ²-square divergence measures. Simulation studies are performed and experimental results are illustrated based on a real malignant melanoma data.     

高新技术与旅游业可持续发展

从发展趋势看 ,高新技术必将成为我国旅游业可持续发展的新动力。因为高新技术是旅游业可持续发展的技术支撑 ,是增强国际旅游市场竞争力的重要手段。然而目前我国旅游业发展中无论在旅游科技基础、旅游经营管理、旅游环境保护、还是在旅游产品开发等方面 ,高新技术应用程度都较低 ,与旅游发达国家差距较大。为实现我国旅游业可持续发展 ,必须提高旅游业创新能力 ,搞好旅游环境保护 ,变革管理和运作方式 ,全面参与国际竞争 ,提高从业人员素质