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PubMed1990

Uncertainties in pharmacokinetic modeling for perchloroethylene. I. Comparison of model structure, parameters, and predictions for low-dose metabolism rates for models derived by different authors.

In recent years physiologically based pharmacokinetic models have come to play an increasingly important role in risk assessment for carcinogens. The hope is that they can help open the black box between external exposure and carcinogenic effects to experimental observations, and improve both high-dose to low-dose and interspecies projections of risk. However, to date, there have been only relatively preliminary efforts to assess the uncertainties in current modeling results. In this paper we compare the physiologically based pharmacokinetic models (and model predictions of risk-related overall metabolism) that have been produced by seven different sets of authors for perchloroethylene (tetrachloroethylene). The most striking conclusion from the data is that most of the differences in risk-related model predictions are attributable to the choice of the data sets used for calibrating the metabolic parameters. Second, it is clear that the bottom-line differences among the model predictions are appreciable. Overall, the ratios of low-dose human to bioassay rodent metabolism spanned a 30-fold range for the six available human/rat comparisons, and the seven predicted ratios of low-dose human to bioassay mouse metabolism spanned a 13-fold range. (The greater range for the rat/human comparison is attributable to a structural assumption by one author group of competing linear and saturable pathways, and their conclusion that the dangerous saturable pathway constitutes a minor fraction of metabolism in rats.) It is clear that there are a number of opportunities for modelers to make different choices of model structure, interpretive assumptions, and calibrating data in the process of constructing pharmacokinetic models for use in estimating "delivered" or "biologically effective" dose for carcinogenesis risk assessments. We believe that in presenting the results of such modeling studies, it is important for researchers to explore the results of alternative, reasonably likely approaches for interpreting the available data--and either show that any conclusions they make are relatively insensitive to particular interpretive choices, or to acknowledge the differences in conclusions that would result from plausible alternative views of the world.

Animals↗

PubMed1977

[Electronic measuring and calculating devices for arcogrammetric model diagnosis and for the interpretation of teleradiographs].

A newly developed method to mesure different parameters from plaster models of the teeth, from dental radiographs and from cephalometric X-rays by means of a 4-K minicomputer and on-line linear transducers are described. Programs in connection to Arcogrammetrics [Herren] are presented. The electronic devices allow storage of these parameters in order to make drawings of the actual dental arches and of predicted arches, as well as to trace growth and/or progress in orthodontic treatment.

Cephalometry↗

PubMedDate not supplied

[Motives for a revision of the physiology of labor and an updating of obstetric terminology].

During the second half of our century, revolutionary progress has been made in obstetrics in terms of care, prevention and technology, but curiously a number of doctrinal questions have been left unresolved which are more important in cultural and practical terms than is commonly thought. We refer in particular to the physiology of the mechanics of labour whose inveterate lacunae of interpretation and major conceptual inaccuracies would be easily resolved if tackled with sufficient interest. These are easy questions to resolve because the missing or incorrect aspects of the traditional model used to interpret the mechanics of labour are for the most part only caused by clashes with the basic principles of physical science. If the mechanics of labour are re-examined with a view to anchoring them rigorously and satisfactorily to the principles of physics, the traditional model of interpretation, which is currently in vogue, is completely invalidated and replaced by another based on a series of hydrodynamic phenomena of considerable obstetric interest. The advantages of these hydrodynamic phenomena are represented by the onset of the so-called "pelvic press", doubling the motor forces of labour during the release of the fetus, the constant maintenance of a balance of forces in the fetal environment, the rotary movements caused autonomously by a hydraulic and muscular system of fixing the womb during the release of the fetus, and above all by the equal interaction of the fetus in the mechanics of its own birth. Clearly, this new interpretative model calls for the use of partly updated and partly innovative obstetric terminology.

Female↗

PubMed1996

Estimability and interpretation of vaccine efficacy using frailty mixing models.

The authors consider estimability and interpretation of vaccine efficacy based on time to event data, allowing that some of the population might have a very low probability of acquiring disease, and the rest have partial, possibly continuously distributed, susceptibility. The efficacy parameters of interest in the frailty mixing model include the fraction highly unlikely to acquire the infection or disease due to the vaccine, the degree of partial protection in those still susceptible, and the average protection or summary measure of efficacy under heterogeneity. The efficacy estimates can still be usefully interpreted when the heterogeneity results from heterogeneity in contact patterns, contact rates, or infectiousness of the contacts, as long as these are equal in the vaccinated and unvaccinated groups. A likelihood-based method allows estimation of the efficacy parameters of interest from grouped time to event data. Simulated vaccine studies assuming different levels and distributions of efficacy demonstrate that ignoring heterogeneity in susceptibility or exposure to infection generally results in underestimation of vaccine efficacy as well as incorrect interpretation of the estimates. The approach is also applicable to other covariates affecting susceptibility or exposure to infection in infectious diseases. Exploitation of the dependent happening structure of infectious diseases to obtain a shape for the baseline hazard may help identifiability. The authors recommend fitting several models to time to event data in vaccine studies.

Effect Modifier, Epidemiologic↗

PubMed1995

[Simulation as a method for solving medical technical problems].

The present paper first presents a comprehensive overview of the methodological aspects of simulation. It lists the various approaches to the modelling of real-world systems and emphasizes the respective constraints on the interpretation of model data. For this purpose, a classification of typical applications of simulation models is given, and is followed by a discussion of three structurally different ways of constructing a model. The correct matching of these modelling concepts to the particular application problem in hand is discussed, with special consideration being given to the drawing of conclusions from, and the interpretation of, the simulation results. To round of the classification, the simulation models are differentiated in accordance with the nature of their implementation. By defining application type, modelling concept and model implementation, an understanding of the validity and appropriate application of any industrial model is derived.

Computer Simulation↗

PubMed1994

How many screens does a CT workstation need?

A considerable number of prototype and commercial workstations have been developed during the last 10 years for electronic display of computed tomographic (CT) images during clinical interpretation. These CT workstations have varied widely in the number and size of monitors available for the display of the medical images ranging from a single 1,024 x 1,204-pixel monitor, to eight 2,500 x 2,000-pixel monitors. Image display times also have varied considerably, ranging from as fast as .11 seconds, to as slow as 26 seconds to fill a single monitor. No consensus has formed in the workstation community with regard to display area and response time requirements. To address this issue, we have constructed a time-motion model of CT interpretation. Model accuracy is experimentally verified with three workstations as well as with the film alternator. In general, CT interpretations with an electronic workstation become faster as display area increases and display time decreases. Results can be used by workstation designers and purchasers to roughly estimate differences in interpretation speeds among contending CT workstation designs.

Computer Peripherals↗

PubMed2001

Interpretability and robustness of sieve analysis models for assessing HIV strain variations in vaccine efficacy.

From data on HIV-1 characteristics measured on viruses isolated from vaccinated and unvaccinated persons infected while enrolled in preventive HIV-1 vaccine trials, interpretable inferences into strain variations of vaccine efficacy can be made with recently developed sieve analysis models. Four assumptions are needed for the parameters in these models to have meaningful interpretations in terms of vaccine-induced reductions in strain-specific per-contact transmission probabilities: (A1) vaccination impacts each strain-specific transmission probability homogeneously in vaccinated persons (leaky vaccine effect); (A2) for each strain biological susceptibility to infection given exposure is homogeneous among vaccinated trial participants and among unvaccinated trial participants; (A3) the distribution of exposure is equal in vaccinated and unvaccinated trial participants; (A4) the relative prevalence of circulating HIV-1 strains during the trial follow-up period is constant. Through theoretical considerations and simulations of an ongoing phase III HIV-1 vaccine efficacy trial in Bangkok, we evaluate the importance and necessity of these assumptions. We show that the models still provide estimates of biologically interpretable parameters when A1 is violated, but with bias the extent to which vaccine protection is heterogeneous. We also show that the models are highly robust to departures from A4, with implication that the time-independent models are adequate for applications. In addition, we suggest extensions of the sieve analysis models which incorporate random effects that account for unmeasured heterogeneity in infection risk. With these mixed models, usefully interpretable strain-specific vaccine efficacy parameters can be estimated without requiring A2. The conclusion is that A3, which is justified by randomization and blinding, is the essential assumption for the sieve models to provide reliable interpretable inferences into strain variations in vaccine efficacy.

AIDS Vaccines↗

PubMed2004

The effect of tightly bound water molecules on the structural interpretation of ligand-derived pharmacophore models.

The importance of the consideration of water molecules in the structural interpretation of ligand-derived pharmacophore models is explored. We compare and combine results from recently introduced methods for bound-water molecule identification in protein binding sites and ligand-superposition-based pharmacophore derivation, for the interpretation of ligand-derived pharmacophore models. In the analysis of thymidine kinase (HSV-1) and poly (ADP-ribose) polymerase (PARP), the concurrent application of both methods leads to an agreement in the prediction of tightly bound water molecules as key pharmacophoric points in the binding site of these proteins. This agreement has implications for approaching binding site analysis and consensus drug design, as it highlights how pharmacophore-based models of binding sites can include interaction features not only with protein groups but also with bound water molecules.

Ligands↗

PubMed2005

Evaluation of the orthogonal projection on latent structure model limitations caused by chemical shift variability and improved visualization of biomarker changes in 1H NMR spectroscopic metabonomic studies.

In general, applications of metabonomics using biofluid NMR spectroscopic analysis for probing abnormal biochemical profiles in disease or due to toxicity have all relied on the use of chemometric techniques for sample classification. However, the well-known variability of some chemical shifts in 1H NMR spectra of biofluids due to environmental differences such as pH variation, when coupled with the large number of variables in such spectra, has led to the situation where it is necessary to reduce the size of the spectra or to attempt to align the shifting peaks, to get more robust and interpretable chemometric models. Here, a new approach that avoids this problem is demonstrated and shows that, moreover, inclusion of variable peak position data can be beneficial and can lead to useful biochemical information. The interpretation of chemometric models using combined back-scaled loading plots and variable weights demonstrates that this peak position variation can be handled successfully and also often provides additional information on the physicochemical variations in metabonomic data sets.

3-Hydroxybutyric Acid↗

PubMed2005

Preferential urn model and nongrowing complex networks.

A preferential urn model, which is based on the concept "the rich get richer," is proposed. From a relationship between a nongrowing model for complex networks and the preferential urn model in regard to degree distributions, it is revealed that a fitness parameter in the nongrowing model is interpreted as an inverse local temperature in the preferential urn model. Furthermore, it is clarified that the preferential urn model with randomness generates a fat-tailed occupation distribution; the concept of the local temperature enables us to understand the fat-tailed occupation distribution intuitively. Since the preferential urn model is a simple stochastic model, it can be applied to research on not only the nongrowing complex networks, but also many other fields such as econophysics and social sciences.

Journal Article↗

PubMed2006

Developing quantitative, multiscale models for microgravity crystal growth.

Crystal growth conducted under microgravity conditions has had a profound impact on improving our understanding of melt crystal growth processes. Here, we present a brief history of microgravity crystal growth and discuss the development of appropriate models to interpret and optimize these growth experiments. The need for increased model realism and predictive capability demands new approaches for describing phenomena important at several disparate length scales. Of special importance is the ability to represent three-dimensional and transient continuum transport (flows, heat, and mass transfer), phase-change phenomena (thermodynamics and kinetics), and system design (such as furnace heat transfer during melt growth). An overview of mathematical models and numerical algorithms employed to represent such multiscale effects is presented.

Journal Article↗

PubMed2000

[Introduction to regression models].

Regression models are widely used. They are viewed by clinicians as a passport for a publication in major journals. The expressions: multivariate, logistic regression and Cox model are synonymous with complexity and appear both magical and seductive. Altogether, most clinicians do not read the results of regression models with a critical eye. Our aim is to describe the most common regression models in a unifying framework, and to explain how to interpret each model. We hope that investigators will then be able to discuss the models with the statisticians.

Logistic Models↗

PubMed1993

Parathyroid hormone, ionised calcium, and potentially interacting variables in plasma of an Old World primate.

Bone turnover and calcium homeostasis in man can only be modelled validly in Old World nonhuman primates. In order to interpret the models it is necessary to establish endocrine and biochemical parameters of bone mineral metabolism. This report is probably the first description of acute phase parathyroid responses to manipulations of blood ionised calcium, and of reference values for potentially interacting variables, in vervet monkeys. Plasma parathyroid hormone concentrations were measured in vervets under defined conditions, and ranges reported as normal for other nonhuman primates and man are summarised.

Animals↗

PubMed2005

Orthogonal signal correction used for noise elimination of open path Fourier transform infrared spectra.

Open path Fourier transform infrared (OP-FTIR) spectroscopy is qualified in detecting mixtures by multivariate calibration methods such as partial least squares (PLS); however, its applications are still restricted by background noise, which is unavoidable for OP-FTIR spectra and cannot be resolved solely by multivariate calibration methods. Hence OP-FTIR spectra are often pretreated before the data are subjected to the multivariate calibration model. A new preprocessing technique, orthogonal signal correction (OSC), was presented in this paper. The principle of OSC is to remove the part in X orthogonal to Y, and it is implemented based on PLS and nonlinear iterative partial least squares (NIPALS) algorithm. The approach was applied to three different data sets of PLS model. It performed much better than classical PLS when handling data with noise but comparably when processing on the simulated data. Moreover, OSC could reduce the complexity of model, which would facilitate the interpretation of the models. The results reveal that the proposed method gives much better prediction than the classical PLS and is very promising for the wide use of OP-FTIR. The preprocessing technique, auto-scaling, and second-order derivatives (SOD) were also considered.

Air Pollutants↗

PubMed1995

Standardized estimates from categorical regression models.

We consider the problem of interpreting categorical regression models, such as the polytomous logistic model, the continuation-ratio model, the stereotype model, and the cumulative-odds model. We present a method to convert categorical regression coefficients into estimates of standardized fitted probabilities, probability differences and probability ratios. We use a delta-method approach to estimate standard errors. We then present a small simulation study to compare different transforms for setting confidence limits, and provide an illustration of our approach in an observational study of drug therapy of polymyositis.

Algorithms↗

PubMed1997

Homology modeling of Neurospora crassa geranylgeranyl pyrophosphate synthase: structural interpretation of mutant phenotypes.

A model of the tertiary structure of the Neurospora crassa carotenogenic prenyltransferase, geranylgeranyl pyrophosphate synthase (GGPPS), is presented, based on structural homology with other prenyltransferases and on the crystal structure of recombinant avian farnesyl pyrophosphate synthase (FPPS). The conserved aspartate-rich motifs DDxx(xx)D and associated basic residues, considered to be the active sites for binding and catalysis in all prenyltransferases, are highly conserved in the N. crassa GGPPS protein, while other regions display a lower degree of sequence homology; thus the GGPPS model structure is predicted to be highly reliable in the active site region. A number of carotene-deficient mutants have been generated utilizing the repeat-induced point mutation (RIP) mechanism: mutant al-3RIP1 carries a Ser-to-Asn mutation in position 336 which falls within the predicted active site of the enzyme. Analysis of the model structure of this mutant indicates that Ser336 may be involved in substrate uptake. Two other mutants, al-3RIP3 and al-3RIP6, carry mutations in positions in the GGPPS protein, homologous to regions of the avian FPPS enzyme proposed to be involved in enzyme dimerization and substrate uptake, respectively, suggesting an explanation for the reduced carotene content of these mutants.

Alkyl and Aryl Transferases↗

PubMed1989

Variability of safe dose estimates when using complicated models of the carcinogenic process. A case study: methylene chloride.

Advances in understanding carcinogenesis have led to the development of mathematical models that have biologically interpretable parameters. These models utilize more of the available scientific data than the empirical models routinely employed for quantifying carcinogenic risk. They also require consideration of sources of uncertainty in risk estimates that were previously ignored, such as animal-to-animal variability of physiological and pharmacological constants. A numerical technique is proposed for studying the consequences of incorporating the intrapopulation variability of biologically interpretable parameters into the risk assessment process. To demonstrate the technique, the variability of safe dose estimates for exposure to methylene chloride is considered. The results suggest that intrapopulation variability of the model parameters can increase the variability of safe dose estimates an appreciable amount.

Animals↗

PubMed1984

Multiexponential, multicompartmental, and noncompartmental modeling. I. Methodological limitations and physiological interpretations.

Multiexponential, multicompartmental, and noncompartmental analysis methods are conventional modeling tools in life science areas, and, on occasion, a number of facets of each are misunderstood, misused, or misinterpreted. We critically examine some of the assumptions, subtleties, and properties of each of these methodologies, with emphasis on their applicability and their interpretation in physiological terms. We discuss the similarities and differences in noncompartmental and compartmental approaches, their relationships with multiexponential models, and several important assumptions that must be satisfied in the practical application of these techniques. A key issue is the highly restricted structure of the noncompartmental model, limiting its applicability quite severely. Noncompartmental analysis is not model independent, as it is often called. Another issue is the importance and manner of choosing a suitable multicompartmental topology, consistent with system structure and modeling goals, when a physiological mapping of specific model parameters is desired.

Models, Biological↗