Physiologically Based Liver Modeling and Risk Assessment

Because of the inherent complexity of biological systems, there is often a choice between a number of apparently equally applicable physiologically based models to describe uptake and metabolism processes in toxicology or risk assessment. These models may fit the particular data sets of interest equally well, but may give quite different parameter estimates or predictions under different (extrapolated) conditions. Such competing models can be discriminated by a number of methods, including potential refutation by means of strategic experiments, and their ability to suitably incorporate all relevant physiological processes. For illustration, three currently used models for steady-state hepatic elimination--the venous equilibration model, the parallel tube model, and the distributed sinusoidal perfusion model--are reviewed and compared with particular reference to their application in the area of risk assessment. The ability of each of the models to describe and incorporate such physiological processes as protein binding, precursor-metabolite relations and hepatic zones of elimination, capillary recruitment, capillary heterogeneity, and intrahepatic shunting is discussed. Differences between the models in hepatic parameter estimation, extrapolation to different conditions, and interspecies scaling are discussed, and criteria for choosing one model over the others are presented. In this case, the distributed model provides the most general framework for describing physiological processes taking place in the liver, and has so far not been experimentally refuted, as have the other two models. These simpler models may, however, provide useful bounds on parameter estimates and on extrapolations and risk assessments.     

Optimal sampling for repeated binary measurements

The authors consider the optimal design of sampling schedules for binary sequence data. They propose an approach which allows a variety of goals to be reflected in the utility function by including deterministic sampling cost, a term related to prediction, and if relevant, a term related to learning about a treatment effect To this end, they use a nonparametric probability model relying on a minimal number of assumptions. They show how their assumption of partial exchangeability for the binary sequence of data allows the sampling distribution to be written as a mixture of homogeneous Markov chains of order k. The implementation follows the approach of Quintana & Müller (2004), which uses a Dirichlet process prior for the mixture.     

A modification of Honoré's triple-link model in the synoptic problem

Summary.  In New Testament studies, the synoptic problem is concerned with the relationships between the gospels of Matthew, Mark and Luke. In an earlier paper a careful specification in probabilistic terms was set up of Honoré's triple-link model. In the present paper, a modification of Honoré's model is proposed. As previously, counts of the numbers of verbal agreements between the gospels are examined to investigate which of the possible triple-link models appears to give the best fit to the data, but now using the modified version of the model and additional sets of data.     

Goodness‐of‐fit methods for matched case‐control studies

The authors propose graphical and numerical methods for checking the adequacy of the logistic regression model for matched case‐control data. Their approach is based on the cumulative sum of residuals over the covariate or linear predictor. Under the assumed model, the cumulative residual process converges weakly to a centered Gaussian limit whose distribution can be approximated via computer simulation. The observed cumulative residual pattern can then be compared both visually and analytically to a certain number of simulated realizations of the approximate limiting process under the null hypothesis. The proposed techniques allow one to check the functional form of each covariate, the logistic link function as well as the overall model adequacy. The authors assess the performance of the proposed methods through simulation studies and illustrate them using data from a cardiovascular study.     

Markov Properties for Acyclic Directed Mixed Graphs

We consider acyclic directed mixed graphs, in which directed edges ( x → y ) and bi-directed edges ( x ↔ y ) may occur. A simple extension of Pearl's d -separation criterion, called m -separation, is applied to these graphs. We introduce a local Markov property which is equivalent to the global property resulting from the m -separation criterion for arbitrary distributions.     

Almost Consistent Estimation of Panel Probit Models with “Small” Fixed Effects

We propose four different GMM estimators that allow almost consistent estimation of the structural parameters of panel probit models with fixed effects for the case of small Tand large N. The moments used are derived for each period from a first order approximation of the mean of the dependent variable conditional on explanatory variables and on the fixed effect. The estimators differ w.r.t. the choice of instruments and whether they use trimming to reduce the bias or not. In a Monte Carlo study, we compare these estimators with pooled probit and conditional logit estimators for different data generating processes. The results show that the proposed estimators outperform these competitors in several situations.     

Block external bootstrap in partially linear models with nonstationary strong mixing error terms

The authors extend the block external bootstrap to partially linear regression models with strongly mixing, nonstationary error terms. In addition to providing an approximate distribution for the semiparametric least square estimator of the parametric component, they propose a consistent estimator of the co‐variance matrix of this estimator.     

A Non-parametric Frailty Model for Temporally Clustered Multivariate Failure Times

Abstract A model is introduced here for multivariate failure time data arising from heterogenous populations. In particular, we consider a situation in which the failure times of individual subjects are often temporally clustered, so that many failures occur during a relatively short age interval. The clustering is modelled by assuming that the subjects can be divided into ‘internally homogenous’ latent classes, each such class being then described by a time‐dependent frailty profile function. As an example, we reanalysed the dental caries data presented earlier in Härkänen et al. [Scand. J. Statist. 27 (2000) 577], as it turned out that our earlier model could not adequately describe the observed clustering.     

A Unified Approach to the Characterization of Equivalence Classes of DAGs, Chain Graphs with no Flags and Chain Graphs

Abstract.  A Markov property associates a set of conditional independencies to a graph. Two alternative Markov properties are available for chain graphs (CGs), the Lauritzen–Wermuth–Frydenberg (LWF) and the Andersson–Madigan– Perlman (AMP) Markov properties, which are different in general but coincide for the subclass of CGs with no flags . Markov equivalence induces a partition of the class of CGs into equivalence classes and every equivalence class contains a, possibly empty, subclass of CGs with no flags itself containing a, possibly empty, subclass of directed acyclic graphs (DAGs). LWF-Markov equivalence classes of CGs can be naturally characterized by means of the so-called largest CGs , whereas a graphical characterization of equivalence classes of DAGs is provided by the essential graphs . In this paper, we show the existence of largest CGs with no flags that provide a natural characterization of equivalence classes of CGs of this kind, with respect to both the LWF- and the AMP-Markov properties. We propose a procedure for the construction of the largest CGs, the largest CGs with no flags and the essential graphs, thereby providing a unified approach to the problem. As by-products we obtain a characterization of graphs that are largest CGs with no flags and an alternative characterization of graphs which are largest CGs. Furthermore, a known characterization of the essential graphs is shown to be a special case of our more general framework. The three graphical characterizations have a common structure: they use two versions of a locally verifiable graphical rule. Moreover, in case of DAGs, an immediate comparison of three characterizing graphs is possible.     

Mapping water quality by local scoring

The mean density of bacteria in a water body is commonly monitored using quantal assay. This paper describes the use of local scoring in estimating the spatial distribution of mean density from quantal assay results at a set of point locations. An application to estimating the mean density of fecal conform bacteria in a coastal pond is presented. Model diagnostics based on a parametric bootstrap are also presented.