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.     

A Comparison of Partially Adaptive and Reweighted Least Squares Estimation

The small sample performance of least median of squares, reweighted least squares, least squares, least absolute deviations, and three partially adaptive estimators are compared using Monte Carlo simulations. Two data problems are addressed in the paper: (1) data generated from non-normal error distributions and (2) contaminated data. Breakdown plots are used to investigate the sensitivity of partially adaptive estimators to data contamination relative to RLS. One partially adaptive estimator performs especially well when the errors are skewed, while another partially adaptive estimator and RLS perform particularly well when the errors are extremely leptokur-totic. In comparison with RLS, partially adaptive estimators are only moderately effective in resisting data contamination; however, they outperform least squares and least absolute deviation estimators.     

On the asymptotic normality of the L1- and L2-errors in histogram density estimation

The L₁ and L₂-errors of the histogram estimate of a density f from a sample X₁,X₂,…,Xn using a cubic partition are shown to be asymptotically normal without any unnecessary conditions imposed on the density f. The asymptotic variances are shown to depend on f only through the corresponding norm of f. From this follows the asymptotic null distribution of a goodness-of-fit test based on the total variation distance, introduced by Györfi and van der Meulen (1991). This note uses the idea of partial inversion for obtaining characteristic functions of conditional distributions, which goes back at least to Bartlett (1938).     

“over”空间组合关系的隐喻延伸

本文探究“over”所体现的意象图式，重点讨论空间组合关系向隐喻延伸的转换。     

清纯下女、"藐姑仙子"或"畸形的恶兽"——中国现代留日作家小说中日本女性的三个类型

1912至1936年间，尤其是1920年代，中国现代留日作家小说中塑造了大量个性复杂多样的日本女性形象。在中国文学史上这是第一次大规模地塑造以日本现实为基础的日本人形象．并占据了日本题材小说创作的主流地位，具有重要的开拓意义。     

Nonresponse weighting adjustment using estimated response probability

To reduce nonresponse bias in sample surveys, a method of nonresponse weighting adjustment is often used which consists of multiplying the sampling weight of the respondent by the inverse of the estimated response probability. The authors examine the asymptotic properties of this estimator. They prove that it is generally more efficient than an estimator which uses the true response probability, provided that the parameters which govern this probability are estimated by maximum likelihood. The authors discuss variance estimation methods that account for the effect of using the estimated response probability; they compare their performances in a small simulation study. They also discuss extensions to the regression estimator.     

On Rates of Convergence for Bayesian Density Estimation

Abstract.  We consider the problem of estimating a compactly supported density taking a Bayesian nonparametric approach. We define a Dirichlet mixture prior that, while selecting piecewise constant densities, has full support on the Hellinger metric space of all commonly dominated probability measures on a known bounded interval. We derive pointwise rates of convergence for the posterior expected density by studying the speed at which the posterior mass accumulates on shrinking Hellinger neighbourhoods of the sampling density. If the data are sampled from a strictly positive, α -Hölderian density, with α  ∈ ( 0,1] , then the optimal convergence rate n^{− α / (2 α +1)} is obtained up to a logarithmic factor. Smoothing histograms by polygons, a continuous piecewise linear estimator is obtained that for twice continuously differentiable, strictly positive densities satisfying boundary conditions attains a rate comparable up to a logarithmic factor to the convergence rate n ^−4/5 for integrated mean squared error of kernel type density estimators.     

On an adaptive version of the Metropolis–Hastings algorithm with independent proposal distribution

In this paper, we present a general formulation of an algorithm, the adaptive independent chain (AIC), that was introduced in a special context in Gåsemyr et al . [ Methodol. Comput. Appl. Probab. 3 (2001)]. The algorithm aims at producing samples from a specific target distribution Π, and is an adaptive, non-Markovian version of the Metropolis–Hastings independent chain. A certain parametric class of possible proposal distributions is fixed, and the parameters of the proposal distribution are updated periodically on the basis of the recent history of the chain, thereby obtaining proposals that get ever closer to Π. We show that under certain conditions, the algorithm produces an exact sample from Π in a finite number of iterations, and hence that it converges to Π. We also present another adaptive algorithm, the componentwise adaptive independent chain (CAIC), which may be an alternative in particular in high dimensions. The CAIC may be regarded as an adaptive approximation to the Gibbs sampler updating parametric approximations to the conditionals of Π.     

Improved Monte Carlo inference for models with additive error

Some statistical models defined in terms of a generating stochastic mechanism have intractable distribution theory, which renders parameter estimation difficult. However, a Monte Carlo estimate of the log-likelihood surface for such a model can be obtained via computation of nonparametric density estimates from simulated realizations of the model. Unfortunately, the bias inherent in density estimation can cause bias in the resulting log-likelihood estimate that alters the location of its maximizer. In this paper a methodology for radically reducing this bias is developed for models with an additive error component. An illustrative example involving a stochastic model of molecular fragmentation and measurement is given.     

Confidence Intervals for Current Status Data

Abstract.  The likelihood ratio statistic for testing pointwise hypotheses about the survival time distribution in the current status model can be inverted to yield confidence intervals (CIs). One advantage of this procedure is that CIs can be formed without estimating the unknown parameters that figure in the asymptotic distribution of the maximum likelihood estimator (MLE) of the distribution function. We discuss the likelihood ratio-based CIs for the distribution function and the quantile function and compare these intervals to several different intervals based on the MLE. The quantiles of the limiting distribution of the MLE are estimated using various methods including parametric fitting, kernel smoothing and subsampling techniques. Comparisons are carried out both for simulated data and on a data set involving time to immunization against rubella. The comparisons indicate that the likelihood ratio-based intervals are preferable from several perspectives.