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At least 721 records · Page 40Linked to original sources

A spectral network model of pitch perception.

A model of pitch perception, called the spatial pitch network or SPINET model, is developed and analyzed. The model neurally instantiates ideas from the spectral pitch modeling literature and joins them to basic neural network signal processing designs to stimulate a broader range of perceptual pitch data than previous spectral models. The components of the model are interpreted as peripheral mechanical and neural processing stages, which are capable of being incorporated into a larger network architecture for separating multiple sound sources in the environment. The core of the new model transforms a spectral representation of an acoustic source into a spatial distribution of pitch strengths. The SPINET model uses a weighted "harmonic sieve" whereby the strength of activation of a given pitch depends upon a weighted sum of narrow regions around the harmonics of the nominal pitch value, and higher harmonics contribute less to a pitch than lower ones. Suitably chosen harmonic weighting functions enable computer simulations of pitch perception data involving mistuned components, shifted harmonics, and various types of continuous spectra including rippled noise. It is shown how the weighting functions produce the dominance region, how they lead to octave shifts of pitch in response to ambiguous stimuli, and how they lead to a pitch region in response to the octave-spaced Shepard tone complexes and Deutsch tritones without the use of attentional mechanisms to limit pitch choices. An on-center off-surround network in the model helps to produce noise suppression, partial masking, and edge pitch. Finally, it is shown how peripheral filtering and short-term energy measurements produce a model pitch estimate that is sensitive to certain component phase relationships.

Cochlea↗

Genetic manipulation of calcium-handling proteins in cardiac myocytes. II. Mathematical modeling studies.

We developed a mathematical model specific to rat ventricular myocytes that includes electrophysiological representation, ionic homeostasis, force production, and sarcomere movement. We used this model to interpret, analyze, and compare two genetic manipulations that have been shown to increase myocyte relaxation rates, parvalbumin (Parv) de novo expression, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) overexpression. The model was used to seek mechanistic insights into 1) the relative contribution of two mechanisms by which SERCA2a overexpression modifies Ca2+ sequestration, i.e., more pumps and an increase in the SERCA2a-to-phospholamban ratio, 2) the mechanisms behind postrest potentiation and how Parv and SERCA2a influence this response, and 3) why Parv myocytes retain their fast kinetics when endogenous SERCA2a is partially impaired by thapsigargin (a condition used to mimic diastolic dysfunction). The model was also utilized to predict whether Parv metal-binding characteristics might be modified to improve diastolic and systolic functions and whether Parv or SERCA2a might affect diastolic Ca2+ levels and myocyte energetics. One outcome of the model was to demonstrate a higher peak and total ATP consumption in SERCA2a myocytes and more even distribution of ATP throughout the cardiac cycle in Parv myocytes. This may have implications for failing hearts that are energetically compromised.

Animals↗

Characterization of mouse cysteinyl leukotriene receptors mCysLT1 and mCysLT2: differential pharmacological properties and tissue distribution.

Cysteinyl leukotrienes (LTs) are important proinflammatory mediators. Their precise roles in mice need to be elucidated to interpret mouse models of inflammatory diseases. For this purpose, we cloned and characterized mouse receptors for cysteinyl LTs, mCysLT(1) and mCysLT(2). mCysLT(1) and mCysLT(2) were composed of 339 amino acids with 87.3% identity and 309 amino acids with 73.4% identity to human orthologues, respectively. A pharmacological difference was noted between mouse and human CysLT(2). Pranlukast, a specific inhibitor for human CysLT(1), antagonized mCysLT(2) responses as determined by Ca(2+) elevation and receptor-induced promoter activation. The mRNA expressions of both mCysLTs were higher in C57BL/6 mice than in 129 mice. mCysLT(1) mRNA was expressed mainly in skin, lung, and small intestine. mCysLT(2) was seen more ubiquitously with high expressions in spleen, lung, and small intestine. By in situ hybridization we demonstrated for the first time that mCysLT(1) and mCysLT(2) were expressed in subcutaneous fibroblasts. The different pharmacological characteristics of CysLT(2) between human and mouse and the different distributions of CysLTs between mouse strains suggest that careful choice and interpretation are necessary for a study of CysLTs using animal models.

Amino Acid Sequence↗

Cirrhosis of the liver and receptor-mediated function in vascular smooth muscle.

Altered regulation of receptors on the vascular smooth muscle has been proposed as one of the mechanisms that may account for the vascular abnormalities in patients with cirrhosis of the liver. Impaired contractility and down-regulation of contractile receptors have been demonstrated in cirrhotic patients and animal models, although interpretation of the literature is hampered by methodological variation and conflicting results. There is little evidence, however, that receptor down-regulation is the cause of contractile dysfunction in either patients or animal models. Receptor desensitisation may contribute to impaired contraction in human arteries, but further investigation is required to confirm this possibility.

Animals↗

Molecular genetic analysis of diabetes in mice.

Transgenic and 'knockout' models are increasingly used to study the role of the immune system, insulin signaling and beta-cell gene transcription in diabetes. Mice and humans have similar genetics, developmental biology and physiology. In interpreting these models, however, one needs to be mindful of some differences that exist between mice and humans.

Animals↗

Computer simulation of metabolism of glucose-perfused rat heart in a work-jump.

A computer model of glycolysis, the tricarboxylic acid cycle, and related amino acid metabolism, is described for a glucose-perfused experimental rat heart preparation suddenly switched from low work load (Langendorff perfusion) to high work load (left atrial perfusion). Glycolytic intermediate measurements suggest activation of phosphofructokinase within a few seconds. This activation, and also that of other glycolytic enzymes, is calculated as due to a sharp increase in cytoplasmic Mg2+ level, which overcomes the inhibitory effects of a rapid fall in cytoplasmic pH to 6.77 (calculated from a rapid fall in creatine phosphate). Increased glycolytic substrate is initially supplied by glycogenolysis mediated by phosphorylase b (activated by an early rise in cytoplasmic AMP), followed by increased glucose uptake from the perfusate. Testable predictions are made by the model, especially that lactate production rate should peak early. Additional experiments are described that verify these predictions and fill gaps in the original measurements. The role of modeling in interpreting such experiments is discussed.

Amino Acids↗

Analysis of correlated data in human biomonitoring studies. The case of high sister chromatid exchange frequency cells.

Sister chromatid exchange (SCE) analysis in peripheral blood lymphocytes is a well established technique that aims to evaluate human exposure to toxic agents. The individual mean value of SCE per cell had been the only recommended index to measure the extent of this cytogenetic damage until the early 1980's, when the concept of high frequency cells (HFC) was introduced to increase the sensitivity of the assay. All statistical analyses proposed thus far to handle these data are based on measures which refer to the individual mean values and not to the single cell. Although this approach allows the use of simple statistical methods, part of the information provided by the distribution of SCE per single cell within the individual is lost. Using the appropriate methods developed for the analysis of correlated data, it is possible to exploit all the available information. In particular, the use of random-effects models seems to be very promising for the analysis of clustered binary data such as HFC. Logistic normal random-effects models, which allow modelling of the correlation among cells within individuals, have been applied to data from a large study population to highlight the advantages of using this methodology in human biomonitoring studies. The inclusion of random-effects terms in a regression model could explain a significant amount of variability, and accordingly change point and/or interval estimates of the corresponding coefficients. Examples of coefficients that change across different regression models and their interpretation are discussed in detail. One model that seems particularly appropriate is the random intercepts and random slopes model.

Adult↗

The interpretation of random-effects meta-analysis in decision models.

This article shows that the interpretation of the random-effects models used in meta-analysis to summarize heterogeneous treatment effects can have a marked effect on the results from decision models. Sources of variation in meta-analysis include the following: random variation in outcome definition (amounting to a form of measurement error), variation between the patient groups in different trials, variation between protocols, and variation in the way a given protocol is implemented. Each of these alternatives leads to a different model for how the heterogeneity in the effect sizes previously observed might relate to the effect size(s) in a future implementation. Furthermore, these alternative models require different computations and, when the net benefits are nonlinear in the efficacy parameters, result in different expected net benefits. The authors' analysis suggests that the mean treatment effect from a random-effects meta-analysis will only seldom be an appropriate representation of the efficacy expected in a future implementation. Instead, modelers should consider either the predictive distribution of a future treatment effect, or they should assume that the future implementation will result in a distribution of treatment effects. A worked example, in a probabilistic, Bayesian posterior framework, is used to illustrate the alternative computations and to show how parameter uncertainty can be combined with variation between individuals and heterogeneity in meta-analysis.

Cholesterol↗

Kinetics of lactose fermentation using a recombinant Saccharomyces cerevisiae strain.

This work presents a multi-route, non-structural kinetic model for interpretation of ethanol fermentation of lactose using a recombinant flocculent Saccharomyces cerevisiae strain expressing both the LAC4 (coding for beta-galactosidase) and LAC12 (coding for lactose permease) genes of Kluyveromyces lactis. In this model, the values of different metabolic pathways are calculated applying a modified Monod equation rate in which the growth rate is proportional to the concentration of a key enzyme controlling the single metabolic pathway. In this study, three main metabolic routes for S. cerevisiae are considered: oxidation of lactose, reduction of lactose (producing ethanol), and oxidation of ethanol. The main bioprocess variables determined experimentally were lactose, ethanol, biomass, and dissolved oxygen concentrations. Parameters of the proposed kinetic model were established by fitting the experimental data obtained in a small lab-scale fermentor with the initial lactose concentrations ranging from 5 g/dm3 to 50 g/dm3. A very good agreement between experimental data and simulated profiles of the main variables (lactose, ethanol, biomass, and dissolved oxygen concentrations) was achieved.

Bioreactors↗

Environments and evolution: interactions between stress, resource inadequacy and energetic efficiency.

Evolutionary change is interpreted in terms of the near-universal ecological scenario of stressful environments. Consequently, there is a premium on the energetically efficient exploitation of resources in a resource-inadequate world. Under this environmental model, fitness can be approximated to energetic efficiency especially towards the limits of survival. Furthermore, fitness at one stage of the life-cycle should correlate with fitness at other stages, especially for development time, survival and longevity; 'good genotypes' under stress should therefore be at a premium. Conservation in the wild depends primarily on adaptation to abiotically changing habitats since towards the limits of survival, genomic variation is rarely restrictive. The balance between energetic costs under variable environments and energy from resources provides a model for interpreting evolutionary stasis, punctuational and gradual change, and specialist diversification. Ultimately, a species should be in an equilibrium between the physiology of an organism and its adaptation to the environment. The primary key to understanding evolutionary change should therefore be ecological, highlighting energy availability in a stressed world; this approach is predictive for various patterns of evolutionary change in the living and fossil biota.

Adaptation, Physiological↗

Cluster formation in two-Yukawa fluids.

We present a different and efficient method for implementing the analytical solution of Ornstein-Zernike equation for two-Yukawa fluids in the mean spherical approximation. We investigate, in particular, the conditions for the formation of an extra low-Q peak in the structure factor, which we interpret as due to cluster formation in the two-Yukawa fluid when the interparticle potential is composed of a short-range attraction and a long-range repulsion. We then apply this model to interpret the small angle neutron scattering data for protein solutions at moderate concentrations and find out that the presence of a peak centered at Q=0 (zero-Q peak) besides the regular interaction peak due to charged proteins implies an existence of long-range attractive interactions besides the charge repulsion.

Journal Article↗

Photosystem I, an improved model of the stromal subunits PsaC, PsaD, and PsaE.

An improved electron density map of photosystem I (PSI) calculated at 4-A resolution yields a more detailed structural model of the stromal subunits PsaC, PsaD, and PsaE than previously reported. The NMR structure of the subunit PsaE of PSI from Synechococcus sp. PCC7002 (Falzone, C. J., Kao, Y.-H., Zhao, J., Bryant, D. A., and Lecomte, J. T. J. (1994) Biochemistry 33, 6052-6062) has been used as a model to interpret the region of the electron density map corresponding to this subunit. The spatial orientation with respect to other subunits is described as well as the possible interactions between the stromal subunits. A first model of PsaD consisting of a four-stranded beta-sheet and an alpha-helix is suggested, indicating that this subunit partly shields PsaC from the stromal side. In addition to the improvements on the stromal subunits, the structural model of the membrane-integral region of PSI is also extended. The current electron density map allows the identification of the N and C termini of the subunits PsaA and PsaB. The 11-transmembrane alpha-helices of these subunits can now be assigned uniquely to the hydrophobic segments identified by hydrophobicity analyses.

Amino Acid Sequence↗

Human endotoxemia: a model for mechanistic insight and therapeutic targeting.

The diversity of phenotypic manifestations, comorbidities, and therapeutic algorithms in patients with severe inflammation have confounded efforts to translate mechanistic insights from the bench top to the bedside. This dilemma has negatively impacted upon many therapeutic interventions that exhibited seemingly well-reasoned preclinical portfolios. Prudence urges the assessment of potent immunoregulatory therapies, wherever possible, in models that replicate the clinical phenotype absent overt manifestations of genetically or environmentally modified processes. The healthy human model of endotoxin administration (systemic or endobronchial) provides such an opportunity and has been used to great advantage for gaining insight into mechanisms of disease and for determination of therapeutic signal strength. When thoughtfully interpreted, the model may provide proof of principle as well as lessen the unpredictability of clinical responses. Although the broad characteristics of this model are well described in the literature, it is recognized that this model does not fully replicate the magnitude of initial inflammatory stress nor the latent spectrum of inflammation/sepsis-inducible organ system pathologies. Nevertheless, the similarities between the early, transient clinical phenotype, inducible physiochemical change, and biochemical pathway activation of this model to the early hyperdynamic phase of resuscitated injury and infection are striking. Rational testing of a therapeutic mechanism requires a quantifiable and reproducibly altered marker of the hypothetical mechanism. Given the modest nature of endotoxin induced insult, interventions that demonstrate target specific efficacy in conjunction with attenuated phenotype responses are more likely to exhibit efficacy within lower risk patient populations. By contrast, the model cannot predict clinical efficacy among higher risk patients nor in those who have endured extended periods of inflammatory stress.

Endotoxemia↗

The prediction of human skin responses by using the combined in vitro fluorescein leakage/Alamar Blue (resazurin) assay.

A range of cosmetics formulations with human patch-test data were supplied in a coded form, for the examination of the use of a combined in vitro permeability barrier assay and cell viability assay to generate, and then test, a prediction model for assessing potential human skin patch-test results. The target cells employed were of the Madin Darby canine kidney cell line, which establish tight junctions and adherens junctions able to restrict the permeability of sodium fluorescein across the barrier of the confluent cell layer. The prediction model for interpretation of the in vitro assay results included initial effects and the recovery profile over 72 hours. A set of the hand-wash, surfactant-based formulations were tested to generate the prediction model, and then six others were evaluated. The model system was then also evaluated with powder laundry detergents and hand moisturisers: their effects were predicted by the in vitro test system. The model was under-predictive for two of the ten hand-wash products. It was over-predictive for the moisturisers, (two out of six) and eight out of ten laundry powders. However, the in vivo human patch test data were variable, and 19 of the 26 predictions were correct or within 0.5 on the 0-4.0 scale used for the in vivo scores, i.e. within the same variable range reported for the repeat-test hand-wash in vivo data.

Animal Testing Alternatives↗

Mathematical modelling of cell cycle and chronobiology: preliminary results.

A mathematical model taking into account the observed diurnal variations in cell kinetics is presented. The principle of the method is to divide each phase of the cell cycle in a definite number of compartments and to assume that the fluxes into and out of the compartments corresponding to the G1 phase are the only varying parameters through the day. Theoretical evolutions of percentages of cells in M and S phase, theoretical curves for percentage labelled mitosis experiment are derived. Preliminary results of the applications of the model to interpretation of published experimental data obtained in hamster cheek pouch epithelium are shown.

Cell Division↗

Current knowledge and recent developments in consumer exposure assessment of pesticides: a UK perspective.

Techniques employed in the assessment of consumer exposure to pesticides are currently being reviewed in the UK. This is not a formal process as is happening in the USA. However, the advent of probabilistic approaches and sophisticated computer models has prompted regulators, industry and other stakeholders in the UK to recognize the need for refinements in the risk-assessment process. Sources of information and data necessary to explore such refinements are disparate. This review aims to collate the information to present a coherent picture of the current knowledge, the data available and the stakeholders involved. It can then be used as a resource with which to investigate further more specific issues. Although focussing on the UK, the European context is included and reference is made to US models and developments that should be investigated. Factors hampering progress include the lack of sufficient data on which to base quantitative analysis, especially in the residential pesticides sector, and lack of experience in using and interpreting probabilistic models. At present, such techniques are being approached with some caution in the UK and in Europe, although their utility for cumulative assessment is accepted. Communicating results to both risk managers and consumers will be a considerable challenge.

Community Participation↗

A model to describe growth patterns of the mammary gland during pregnancy and lactation.

Extensive proliferation and death of cells in the mammary gland occur during pregnancy and lactation. In this study, a mechanistic model was developed that yielded a single equation to describe the pattern of mammary growth of mammals throughout pregnancy and lactation. The model contains a single pool, which is the cell population of the mammary gland; one influx, representing cell proliferation; and one efflux, representing cell death. The parameters of the equation lend themselves to direct physiological interpretation. The model fitted data on mammary gland DNA adequately and can be related to current knowledge on factors and inhibitors of mammary gland growth. A unique definition of the parameters of the model can be difficult because of the high degree of variation among animals, an improper number of observations, or timing, as indicated by analyses of simulated data. The model can also be applied to the study of the entire lactation curve. The widely applied gamma equation and the equation that was developed in this study were compared using weekly production data from dairy cows. The new model performed well, particularly when a sharp peak in milk production occurred. The model has the advantage of providing, for the first time, a simple biological description of the lactation curve that can be used to discriminate changes in lactational performance that are associated with experimental treatments.

Animals↗

Removable partial denture design: a photoelastic study.

Quantifiable frozen-stress photoelastic techniques were used to analyze stresses induced in mandibular models by a conventional free-end saddle removable partial denture. Four quasi-anatomical mandibular models were constructed for processing, together with their respective calibration specimens, through identical time/temperature stress-freezing cycles. After processing and slicing, an unloaded control model demonstrated some low-order fringes adjacent to the coronal third of the abutment tooth roots, but was otherwise stress free. A lower bilateral free-end saddle partial denture was constructed and fitted in turn to each of the remaining three models. Each denture/model combination was then loaded and processed through a stress-freezing cycle. After processing, 6-mm slices were cut from selected regions for analysis for the presence of stresses. Using a polariscope with circular polarized, monochromatic light, values for maximum shear stress were calculated at selected points in the slices taken from the three loaded models. Variations up to 28% of the mean were obtained for the three experimental models as compared with the consistent results for the material fringe values obtained from the calibration specimens. The study pointed out the problems involved in using photoelastic stress analysis on complicated anatomical models. The interpretation of the results from such studies should be approached with caution.

Denture, Partial↗