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.     

Dietary and Inhalation Intake of Lead and Estimation of Blood Lead Levels in Adults and Children in Kanpur, India

This research was initiated to study lead levels in various food items in the city of Kanpur, India, to assess the dietary intake of lead and to estimate blood lead (PbB) levels, a biomarker of lead toxicity. For this purpose, sampling of food products, laboratory analysis, and computational exercises were undertaken. Specifically, six food groups (leafy vegetables, nonleafy vegetables, fruits, pulses, cereals, and milk), drinking water, and lead air concentration were considered for estimating lead intake. Results indicated highest lead content in leafy vegetables followed by pulses. Fruits showed low lead content and drinking water lead levels were always within tolerable limits. It was estimated that average daily lead intake through diet was about 114 microg/day for adults and 50 microg/day in children; tolerable limit is 250 microg/day for adults and 90 microg/day for children. The estimated lead intakes were translated into the resultant PbB concentrations for children and adults using a physiologically-based pharmacokinetic (PBPK) model. Monte Carlo simulation of PbB level variations for adults showed that probability of exceeding the tolerable limit of PbB (i.e.,10 microg/dL) was 0.062 for the pre-unleaded and 0.000328 for the post-unleaded gasoline period. The probability of exceeding tolerable limits in PbB level was reduced by a factor of 189 in the post-unleaded scenario. The study also suggested that in spite of the introduction of unleaded gasoline, children continue to be at a high risk (probability of exceeding 10 microg/dL = 0.39) because of a high intake of lead per unit body weight.     

Estimation of Benchmark Dose of Lifetime Cadmium Intake for Adverse Renal Effects Using Hybrid Approach in Inhabitants of an Environmentally Exposed River Basin in Japan

The aim of this study is to estimate the reference level of lifetime cadmium intake (LCd) as the benchmark doses (BMDs) and their 95% lower confidence limits (BMDLs) for various renal effects by applying a hybrid approach. The participants comprised 3,013 (1,362 men and 1,651 women) and 278 (129 men and 149 women) inhabitants of the Cd‐polluted and nonpolluted areas, respectively, in the environmentally exposed Kakehashi River basin. Glucose, protein, aminonitrogen, metallothionein, and β₂‐microglobulin in urine were measured as indicators of renal dysfunction. The BMD and BMDL that corresponded to an additional risk of 5% were calculated with background risk at zero exposure set at 5%. The obtained BMDLs of LCd were 3.7 g (glucose), 3.2 g (protein), 3.7 g (aminonitrogen), 1.7 g (metallothionein), and 1.8 g (β₂‐microglobulin) in men and 2.9 g (glucose), 2.5 g (protein), 2.0 g (aminonitrogen), 1.6 g (metallothionein), and 1.3 g (β₂‐microglobulin) in women. The lowest BMDL was 1.7 g (metallothionein) and 1.3 g (β₂‐microglobulin) in men and women, respectively. The lowest BMDL of LCd (1.3 g) was somewhat lower than the representative threshold LCd (2.0 g) calculated in the previous studies. The obtained BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure.     

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 Content Analysis of Intake Paperwork: An Exploration of How Clinicians Ask About Gender,Sex, and Sexual/Affectual Orientation

In the United States, the transgender and gender nonconforming (TGNC) population has increased twofold since 2011. Although counseling professionals are called to provide competent services to TGNC clients, no empirical studies exist that examine one of the first points of contact: Intake paperwork. The authors conducted a content analysis (N = 128) of intake paperwork and assessed how and if clinicians asked for gender, sex, and sexual/affectual orientation, and whether they conflated these constructs. Findings indicate adjustments need to be made for intakes to be more inclusive of these constructs. The authors offer clinical implications and avenues for future research.     

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.