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PubMed2007

Role of blood flow on RF exposure induced skin temperature elevations in rabbit ears.

In this in vivo study, we measured local temperature changes in rabbit pinnae, which were evoked by radiofrequency (RF) exposure for 20 min at localized SAR levels of 0 (sham exposure), 2.3, 10.0, and 34.3 W/kg over 1.0 g rabbit ear tissue. The effects of RF exposures on skin temperature were measured under normal blood flow and without blood flow in the ear. The results showed: (1) physiological blood flow clearly modified RF induced thermal elevation in the pinna as blood flow significantly suppressed temperature increases even at 34.3 W/kg; (2) under normal blood flow conditions, exposures at 2.3 and 10.0 W/kg, approximating existing safety limits for the general public (2 W/kg) and occupational exposure (10 W/kg), did not induce significant temperature rises in the rabbit ear. However, 2.3 W/kg induced local skin temperature elevation under no blood flow conditions. Our results demonstrate that the physiological effects of blood flow should be considered when extrapolating modeling data to living animals, and particular caution is needed when interpreting the results of modeling studies that do not include blood flow.

Animals↗

PubMed2003

A systems modeling approach to the study of retinoid function: implications for evaluation of retinoids in cancer chemoprevention and/or chemotherapy.

We have used a mathematical/compartmental modeling approach along with a number of rationally designed complementary in vivo and in vitro systems to investigate the effects of administration of various retinoids and/or drug combinations on normal physiological metabolism of native retinoids. The present paper focuses on our studies of the synthetic retinoid 4-HPR and our use of fairly simple mathematical/compartmental modeling techniques to investigate how this retinoid affects the metabolism of native retinoid overall, as well as in two specific tissues, the prostate and the eyes. We have presented our work with this particular retinoid and these tissues as an example of the type of studies we have been doing and to present some of the information that one can obtain using this approach. In addition, an important objective of this paper is to highlight the fact that a great deal of critical information can be derived from fairly simple mathematical/compartmental models. When used appropriately, such models provide a powerful tool to direct the design, conduct, and interpretation of experiments. The models we developed for the prostate and the eyes were used as hypotheses to direct our research efforts in both in vivo and in vitro systems. In the case of the eyes, we were able to elucidate the possible mechanisms involved in one of the most commonly reported complications (i.e., visual function abnormalities) associated with administration of an important chemopreventive and/or chemotherapeutic agent. We are in the process of further expanding our studies with the prostate as well as several other tissues in a similar manner. The immediate clinical relevance and application of our work with the eyes demonstrate the high translational potential of our approach. Without the use of the type of mathematical/compartmental modeling approach we used, which provided the basis for much of this work, we are not aware of any other way that we could have obtained the critical information that we did. We hope that the work presented here demonstrates the usefulness, power, and potential clinical applicability of a modeling approach to investigate different retinoid-based treatments as well as a variety of other chemopreventive and/or chemotherapeutic agents.

Animals↗

PubMedDate not supplied

Simulation of micropopulations in epidemiology: tutorial. 3. Simulation model evaluation methods. A series of tutorials illustrated by coronary heart disease models.

This is the third in a series of tutorials concerning the simulation of micropopulation models to support epidemiological research. The series emphasizes techniques used in studies at the National Micropopulation Simulation Resource at the University of Minnesota. For pedagogic purposes, applications to coronary heart disease (CHD) models are used to illustrate the principles and methodologies employed. All of the models presented are implemented using available software. A variety of tests and techniques are used to evaluate these models. This tutorial presents some of those methods stressing the advantages and limitations of the tests rather than the formal definitions. To make the evaluation methods more understandable, some of the risk factors for CHD models are introduced. The interpretation of the evaluation depends critically on the goals of the modeling effort. The subset of evaluation methods presented includes investigations of the epidemiological, mathematical and statistical aspects of the models.

Computer Simulation↗

PubMed1983

Arterial tonometry: review and analysis.

A review is presented of the field of arterial tonometry and of the problems involved with its application. A second generation model is developed which interprets most of the difficulties encountered in previous experimental work. The model also identifies barriers that must be overcome to allow tonometry to become a practical technique for obtaining measurement of continuous, absolute blood pressure. Problems addressed include those of calibration, positioning sensitivity, design standardization, material properties and vascular loading characteristics. Theoretical and experimental studies provide support for the application of basic biomechanical concepts for solution of these problems and suggest required design features.

Arteries↗

PubMed2003

A simplified method to assess structurally identifiable parameters in Monod-based activated sludge models.

The first step in the estimation of parameters of models applied for data interpretation should always be an investigation of the identifiability of the model parameters. In this study the structural identifiability of the model parameters of Monod-based activated sludge models (ASM) was studied. In an illustrative example it was assumed that respirometric (dissolved oxygen or oxygen uptake rates) and titrimetric (cumulative proton production) measurements were available for the characterisation of nitrification. Two model structures, including the presence and absence of significant growth for description of long- and short-term experiments, respectively, were considered. The structural identifiability was studied via the series expansion methods. It was proven that the autotrophic yield becomes uniquely identifiable when combined respirometric and titrimetric data are assumed for the characterisation of nitrification. The most remarkable result of the study was, however, that the identifiability results could be generalised by applying a set of ASM1 matrix based generalisation rules. It appeared that the identifiable parameter combinations could be predicted directly based on the knowledge of the process model under study (in ASM1-like matrix representation), the measured variables and the biodegradable substrate considered. This generalisation reduces the time-consuming task of deriving the structurally identifiable model parameters significantly and helps the user to obtain these directly without the necessity to go too deeply into the mathematical background of structural identifiability.

Bacteria↗

PubMedDate not supplied

Statistical modeling of a ligand knowledge base.

A range of different statistical models has been fitted to experimental data for the Tolman electronic parameter (TEP) based on a large set of calculated descriptors in a prototype ligand knowledge base (LKB) of phosphorus(III) donor ligands. The models have been fitted by ordinary least squares using subsets of descriptors, principal component regression, and partial least squares which use variables derived from the complete set of descriptors, least angle regression, and the least absolute shrinkage and selection operator. None of these methods is robust against outliers, so we also applied a robust estimation procedure to the linear regression model. Criteria for model evaluation and comparison have been discussed, highlighting the importance of resampling methods for assessing the robustness of models and the scope for making predictions in chemically intuitive models. For the ligands covered by this LKB, ordinary least squares models of descriptor subsets provide a good representation of the data, while partial least squares, principal component regression, and least angle regression models are less suitable for our dual aims of prediction and interpretation. A linear regression model with robustly fitted parameters achieves the best model performance over all classes of models fitted to TEP data, and the weightings assigned to ligands during the robust estimation procedure are chemically intuitive. The increased model complexity when compared to the ordinary least squares linear model is justified by the reduced influence of individual ligands on the model parameters and predictions of new ligands. Robust linear regression models therefore represent the best compromise for achieving statistical robustness in simple, chemically meaningful models.

Algorithms↗

PubMed2005

Model inference or model selection: discussion of Klugkist, Laudy, and Hoijtink (2005).

I. Klugkist, O. Laudy, and H. Hoijtink (2005) presented a Bayesian approach to analysis of variance models with inequality constraints. Constraints may play 2 distinct roles in data analysis. They may represent prior information that allows more precise inferences regarding parameter values, or they may describe a theory to be judged against the data. In the latter case, the authors emphasized the use of Bayes factors and posterior model probabilities to select the best theory. One difficulty is that interpretation of the posterior model probabilities depends on which other theories are included in the comparison. The posterior distribution of the parameters under an unconstrained model allows one to quantify the support provided by the data for inequality constraints without requiring the model selection framework.

Analysis of Variance↗

PubMed1992

Developments in the meiotic analysis of hybrids. II. Amended models for tetraploids.

Amended models of meiotic behaviour in tetraploid species' hybrids have been constructed which better reflect the theory and assumptions about chromosome pairing necessary to conduct such analyses. In particular they correct problems concerning the distribution of chiasmata among and within chromosome configurations inherent in the earlier models of Kimber & Alonso (1981). In general these analyses give similar interpretations to the earlier models but in some cases call the previous conclusions into question.

Hybridization, Genetic↗

PubMed2006

Bayesian spatio-temporal approach for EEG source reconstruction: conciliating ECD and distributed models.

Characterizing the cortical activity sources of electroencephalography (EEG)/magnetoencephalography data is a critical issue since it requires solving an ill-posed inverse problem that does not admit a unique solution. Two main different and complementary source models have emerged: equivalent current dipoles (ECD) and distributed linear (DL) models. While ECD models remain highly popular since they provide an easy way to interpret the solutions, DL models (also referred to as imaging techniques) are known to be more realistic and flexible. In this paper, we show how those two representations of the brain electromagnetic activity can be cast into a common general framework yielding an optimal description and estimation of the EEG sources. From this extended source mixing model, we derive a hybrid approach whose key aspect is the separation between temporal and spatial characteristics of brain activity, which allows to dramatically reduce the number of DL model parameters. Furthermore, the spatial profile of the sources, as a temporal invariant map, is estimated using the entire time window data, allowing to significantly enhance the information available about the spatial aspect of the EEG inverse problem. A Bayesian framework is introduced to incorporate distinct temporal and spatial constraints on the solution and to estimate both parameters and hyperparameters of the model. Using simulated EEG data, the proposed inverse approach is evaluated and compared with standard distributed methods using both classical criteria and ROC curves.

Algorithms↗

PubMed1991

Actions of ketamine, phencyclidine and MK-801 on NMDA receptor currents in cultured mouse hippocampal neurones.

1. Stable N-methyl-D-aspartic acid (NMDA) receptor-mediated currents in cultured mouse hippocampal neurons were evoked by 20 ms pressure pulse applications of L-aspartate, repeatedly applied at 30 or 40 s intervals, to the cell body region of the neurone. We have characterized the voltage- and use-dependent blockade of the currents by three dissociative anaesthetics: ketamine, phencyclidine (PCP) and MK-801 in mouse hippocampal neurones grown in dissociated tissue culture. 2. We have used a simple model of the blockade, based on the 'guarded receptor hypothesis' to interpret our data. The model assumes that receptors are maximally activated at the peak of the response with an open probability (Po) approaching 1, that there is no desensitization and that the blocking drug only associates with, or dissociates from, receptor channels which have been activated by agonist (e.g. open channels). 3. The model allows us to estimate forward and reverse rate constants for binding of the blockers to open channels from measurements of the steady-state level of blockade and the rate of change of the current amplitude per pulse during onset and offset of blockade. As predicted by the model, the estimated reverse rate was independent of blocker concentration while the forward rate increased with concentration. Changing the level of positively charged ketamine (pKa 7.5) tenfold by changing pH from 6.5 to 8.5 caused a corresponding change in the forward rate while having no effect on the reverse rate. Most of the voltage dependence of the blockade could be accounted for by reduction of the reverse rate by depolarization. 4. Estimated forward rate constants for ketamine, PCP and MK-801 were similar to one another when measured under similar conditions and were 3 x 10(4) - 3 x 10(5) M-1 S-1. Most of the differences in potency of the three blockers could be accounted for by differences in the reverse rate constants which were approximately 0.2, 0.03 and 0.003 s-1 for ketamine, PCP and MK-801, respectively. The estimated rate constants actually are the product of the rate constants and 1/Po. Suggestions that maximum Po is much less than 1 for NMDA channels imply that both forward and reverse rate constants of blockade may in fact be larger than we have calculated. However, their magnitudes, relative to one another, are unaffected by this consideration. 5. The reverse rate constant of blockade increased at positive potentials. This increase was prevented when the neurone was loaded with N-methyl-D-glucamine, an impermeant cation which prevented outward currents.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2002

The economic burden of informal care.

OBJECTIVES: The great interest focused on home care technologies during the last decade resulted from its potential to cut costs. However, the reallocation of costs between healthcare providers and social welfare providers, and the indirect costs of informal care, are not as frequent topics of discussion. The aim of this paper is to discuss different models for estimating the costs of informal care in the home care setting in economic appraisals. METHODS: The outcome of using different models for estimating indirect costs was illustrated using empirical data regarding the time spent by informal caregivers in providing care in a group of home care patients (n = 59). The models used comprise different interpretations of the traditional human capital approach and the friction cost model. RESULTS AND CONCLUSIONS: Informal care is an important component in home care. The inclusion of indirect costs of informal care in economic appraisals will have implications for the cost-effectiveness of home care, since it will raise costs depending on the model used for estimating indirect costs. In this study we have shown that indirect costs estimated by the friction cost model only amount to 18% to 44% of the cost when the human capital approach is used. The results indicate that, regardless of the method used to estimate indirect costs, the cost of informal care in evaluations of home care programs is often underestimated due to the exclusion of indirect costs.

Aged↗

PubMed2003

Maximum information approach to scale description for affective measures based on the Rasch model.

Using the Rasch model for ordered categories, this paper provides a method for qualitative interpretations of data from an affective measure such as an attitude scale or survey instrument. The Bock procedure is first used to partition the total item information to each response category. The location of each response category is determined by maximizing the information associated with this category. The response categories that cluster around a given point on the latent trait are then used to provide a qualitative description of this point. The description is explicit in terms of the behaviors or activities that are likely to be displayed by a respondent at this point. An illustration is provided using an alumni survey used at a large university in the southeast.

Attitude↗

PubMed2006

Bayesian mixed models and the phylogeny of pitvipers (Viperidae: Serpentes).

The subfamily Crotalinae (pitvipers) contains over 190 species of venomous snakes distributed in both the Old and New World. We incorporated an extensive sampling of taxa (including 28 of 29 genera), and sequences of four mitochondrial gene fragments (2.3kb) per individual, to estimate the phylogeny of pitvipers based on maximum parsimony and Bayesian phylogenetic methods. Our Bayesian analyses incorporated complex mixed models of nucleotide evolution that allocated independent models to various partitions of the dataset within combined analyses. We compared results of unpartitioned versus partitioned Bayesian analyses to investigate how much unpartitioned (versus partitioned) models were forced to compromise estimates of model parameters, and whether complex models substantially alter phylogenetic conclusions to the extent that they appear to extract more phylogenetic signal than simple models. Our results indicate that complex models do extract more phylogenetic signal from the data. We also address how differences in phylogenetic results (e.g., bipartition posterior probabilities) obtained from simple versus complex models may be interpreted in terms of relative credibility. Our estimates of pitviper phylogeny suggest that nearly all recently proposed generic reallocations appear valid, although certain Old and New World genera (Ovophis, Trimeresurus, and Bothrops) remain poly- or paraphyletic and require further taxonomic revision. While a majority of nodes were resolved, we could not confidently estimate the basal relationships among New World genera and which lineage of Old World species is most closely related to this New World group.

Animals↗

PubMed1999

Memories in context.

Context-dependent associative memories are models that allow the retrieval of different vectorial responses given a same vectorial stimulus, depending on the context presented to the memory. The contextualization is obtained by doing the Kronecker product between two vectorial entries to the associative memory: the key stimulus and the context. These memories are able to display a wide variety of behaviors that range from all the basic operations of the logical calculus (including fuzzy logics) to the selective extraction of features from complex vectorial patterns. In the present contribution, we show that a context-dependent memory matrix stores a large amount of possible virtual associative memories, that awaken in the presence of a context. We show how the vectorial context allows a memory matrix to be representable in terms of its singular-value decomposition. We describe a neural interpretation of the model in which the Kronecker product is performed on the same neurons that sustain the memory. We explored, with numerical experiments, the reliability of chains of contextualized associations. In some cases, random disconnection produces the emergence of oscillatory behaviors of the system. Our results show that associative chains retain their performances for relatively large dimensions. Finally, we analyze the properties of some modules of context-dependent autoassociative memories inserted in recursive nets: the perceptual autoorganization in the presence of ambiguous inputs (e.g. the disambiguation of the Necker's cube figure), the construction of intersection filters, and the feature extraction capabilities.

Memory↗

PubMedDate not supplied

Combining sequence and time series expression data to learn transcriptional modules.

Our goal is to cluster genes into transcriptional modules--sets of genes where similarity in expression is explained by common regulatory mechanisms at the transcriptional level. We want to learn modules from both time series gene expression data and genome-wide motif data that are now readily available for organisms such as S. cereviseae as a result of prior computational studies or experimental results. We present a generative probabilistic model for combining regulatory sequence and time series expression data to cluster genes into coherent transcriptional modules. Starting with a set of motifs representing known or putative regulatory elements (transcription factor binding sites) and the counts of occurrences of these motifs in each gene's promoter region, together with a time series expression profile for each gene, the learning algorithm uses expectation maximization to learn module assignments based on both types of data. We also present a technique based on the Jensen-Shannon entropy contributions of motifs in the learned model for associating the most significant motifs to each module. Thus, the algorithm gives a global approach for associating sets of regulatory elements to "modules" of genes with similar time series expression profiles. The model for expression data exploits our prior belief of smooth dependence on time by using statistical splines and is suitable for typical time course data sets with relatively few experiments. Moreover, the model is sufficiently interpretable that we can understand how both sequence data and expression data contribute to the cluster assignments, and how to interpolate between the two data sources. We present experimental results on the yeast cell cycle to validate our method and find that our combined expression and motif clustering algorithm discovers modules with both coherent expression and similar motif patterns, including binding motifs associated to known cell cycle transcription factors.

Algorithms↗

PubMed2001

Parametric modelling of neonatal mortality in relation to size at birth.

We use a richly parameterized model to analyse the effects of shortness and thinness at birth on neonatal mortality in Swedish live-born singletons. The model captures the hazard of neonatal mortality according to the function alpha x exp(-gamma x t) + delta, where t represents age. Covariates are allowed to simultaneously influence the initial excess hazard, the rate of decay, and the long-term hazard. Among term newborns, birth length for gestational age had a stronger effect on the long-term hazard and a weaker effect on the initial excess hazard than the Ponderal index. The initial excess hazard associated with a low Ponderal index tended to decay quickly. Among preterm newborns, a higher birth length for gestational age was associated with lower initial and long-term hazards, and with a faster rate of decay of the initial excess hazard. In contrast, the Ponderal index was not associated with the long-term hazard. We discuss the interpretability of the model and its potential use in neonatology and medical demography. We also compare the model to a Cox model with time-dependent covariates.

Analysis of Variance↗

PubMed1997

A numerical study of the critical line of Kauffman networks.

Kauffman networks were introduced in 1969 as a model of genetic regulatory systems. One of the most striking successes of this model is its ability to reproduce, for a critical value of its parameters, the observed scaling laws of the average cell replication time and of the average number of cell types in a given organism vs. the number of genes. Yet, the numerical evidence for such scaling laws in the model is still unsatisfactory, and restricted to a particular critical point, while we expect that the scaling behaviour is universal along the critical line. In this paper we try to sharpen the evidence for the scaling behaviour of critical systems, carrying on a detailed numerical investigation of their properties. We measure the length of the cycles (which in the model represents the period of cell cycles) and their number (which represents the number of cell types) for a point of the critical line different from the only one previously studied. Our results seem to confirm that such quantities scale as radicalN for all critical systems, at least for lengths and numbers small enough. On the other hand, we found that their probability distributions are very broad (power-law like) and become broader with system size. This means that there is an effective scale of the length and of the number of cycles that increases much faster than radicalN, and in the infinite size limit the biological analogy found by Kauffman may be lost. A numerical study of the modular structure of critical networks supports this conclusion. The implications of this fact for the biological interpretation of the model are briefly discussed. Finally, we found that the typical weight of the attraction basins tends to zero as a power law in the infinite size limit, with an exponent which seems to be universal along the whole critical line.

Animals↗

PubMedDate not supplied

[Non-canonical nucleotide exchange catalyzed by Escherichia coli DNA-polymerase I and the two-center model of the mechanism of action of this enzyme].

It is shown, that DNA hydrolysis catalyzed by E. coli DNA polymerase I is inhibited, when a reaction mixture contains one type of deoxynucleoside 5'-triphosphate (dNTP). When the reaction mixture contains [32P]dNTP, then [32P] is incorporated into DNA and v. v. (32P) from DNA is transferred into dNTP. The nucleotide exchange between DNA and dNTP in the assay mixture is observed only in the case, when the chemical nature of nucleotide residue of dNTP and that of the 3'-terminus of DNA is the same. Analysis of products of DNA hydrolysis in the presence of one type of dNTP using electrophoresis in polyacrylamide gel shows that most of the DNA molecules are terminated at the 3'-termini by the dNMP residue of the same chemical nature as the dNTP in the assay mixture. However, in some cases DNA molecules contain one additional nucleotide residue. This phenomenon can be explained by incorporation of one additional dNMP residue originating from dNTP only in those cases, when a non-typical base pairing of this nucleotide residue with a template residue readily takes place. The above-mentioned facts can be interpreted within the model for DNA hydrolysis with involvement of two intermediate covalent forms of dNMP residues with DNA polymerase I; one dNMP-intermediate should be placed at the elongation center and the other--at the hydrolysis center. The DNA hydrolysis by 3'----5' exonuclease activity of DNA polymerase I proceeds through these two covalent forms. DNA polymerases alpha from calf thymus and T4 phage do not catalyze the nucleotide exchange between DNA and dNTP from the reaction media.

Binding Sites↗