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A mathematical approach to the temporal stationarity of background noise in MEG/EEG measurements.

The general spatiotemporal covariance matrix of the background noise in MEG/EEG signals is huge. To reduce the dimensionality of this matrix it is modeled as a Kronecker product of a spatial and a temporal covariance matrix. When the number of time samples is larger than, say, J = 500, the iterative Maximum Likelihood estimation of these two matrices is still too time-consuming to be useful on a routine basis. In this study we looked for methods to circumvent this computationally expensive procedure by using a parametric model with subject-dependent parameters. Such a model would additionally help with interpreting MEG/EEG signals. For the spatial covariance, models have been derived already and it has been shown that measured MEG/EEG signals can be understood spatially as random processes, generated by random dipoles. The temporal covariance, however, has not been modeled yet, therefore we studied the temporal covariance matrix in several subjects. For all subjects the temporal covariance shows an alpha oscillation and vanishes for large time lag. This gives rise to a temporal noise model consisting of two components: alpha activity and additional random noise. The alpha activity is modeled as randomly occurring waves with random phase and the covariance of the additional noise decreases exponentially with lag. This model requires only six parameters instead of 12 J(J + 1). Theoretically, this model is stationary but in practice the stationarity of the matrix is highly influenced by the baseline correction. It appears that very good agreement between the data and the parametric model can be obtained when the baseline correction window is taken into account properly. This finding implies that the background noise is in principle a stationary process and that nonstationarities are mainly caused by the nature of the preprocessing method. When analyzing events at a fixed sample after the stimulus (e.g., the SEF N20 response) one can take advantage of this nonstationarity by optimizing the baseline window to obtain a low noise variance at this particular sample.

Algorithms↗

A time-dependent discrimination index for survival data.

To derive models suitable for outcome prediction, a crucial aspect is the availability of appropriate measures of predictive accuracy, which have to be usable for a general class of models. The Harrell's C discrimination index is an extension of the area under the ROC curve to the case of censored survival data, which owns a straightforward interpretability. For a model including covariates with time-dependent effects and/or time-dependent covariates, the original definition of C would require the prediction of individual failure times, which is not generally addressed in most clinical applications. Here we propose a time-dependent discrimination index Ctd where the whole predicted survival function is utilized as outcome prediction, and the ability to discriminate among subjects having different outcome is summarized over time. Ctd is based on a novel definition of concordance: a subject who developed the event should have a less predicted probability of surviving beyond his/her survival time than any subject who survived longer. The predicted survival function of a subject who developed the event is compared to: (1) that of subjects who developed the event before his/her survival time, and (2) that of subjects who developed the event, or were censored, after his/her survival time. Subjects who were censored are involved in comparisons with subjects who developed the event before their observed times. The index reduces to the previous C in the presence of separation between survival curves on the whole follow-up. A confidence interval for Ctd is derived using the jackknife method on correlated one-sample U-statistics.The proposed index is used to evaluate the discrimination ability of a model, including covariates having time-dependent effects, concerning time to relapse in breast cancer patients treated with adjuvant tamoxifen. The model was obtained from 596 patients entered prospectively at Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano (INT). The model discrimination ability was validated on an independent testing data set of 175 patients provided by Centro Regionale Indicatori Biochimici di Tumore (CRIBT) in Venice.

Breast Neoplasms↗

In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises.

Enzymes of the UDP-glucuronosyltransferase (UGT) superfamily are responsible for the metabolism of many drugs, environmental chemicals and endogenous compounds. Identification of the UGT(s) involved in the metabolism of a given compound ('reaction phenotyping') currently relies on multiple confirmatory approaches, which may be confounded by the dependence of UGT activity on enzyme source, incubation conditions, and the occurrence of atypical glucuronidation kinetics. However, the increasing availability of substrate and inhibitor 'probes' for the individual UGTs provides the prospect for reliable phenotyping of glucuronidation reactions using human liver microsomes or hepatocytes, thereby providing data directly relevant to drug metabolism in humans. While the feasibility of computational prediction of UGT substrate selectivity has been demonstrated, the development of easily interpretable and generalisable models requires further improvement in the datasets available for analysis. Quantitative prediction of the hepatic clearance of glucuronidated drugs and the magnitude of inhibitory interactions based on in vitro kinetic data is more problematic. Intrinsic clearance (CL(int)) values generated using human liver microsomes under-predict in vivo hepatic clearance, typically by an order of magnitude. In vivo clearances of glucuronidated drugs are also generally under-predicted by CL(int) values from human hepatocytes, but to a lesser extent than observed with the microsomal model. While it is anticipated that systematic analysis of the potential causes of under-prediction may provide more reliable in vitro-in vivo scaling strategies, mechanistic interpretation of in vitro-in vivo correlation more broadly awaits further advances in our understanding of the structural and cellular determinants of UGT activity.

Glucuronides↗

The law of perceptual stability: abastract foundations.

Confronted with an object of perception, an individual will spontaneously try to identify unambiguously and consistently all its parts; except in rare instances of "illusory phenomena," he will immediately succeed. This elementary fact is formalized in a law of visual perception. It is used to define sets of stable states for a sensory mode of a biological system. As characterized, stable states are to perception as quantum states are to atomic structure: they represent natural states of physical systems. They are shown to be observable and to have an exact mathematical representation.A class of bounded open subsets of a two-dimensional Euclidean space, whose boundaries are piecewise compact analytic arcs, is used to construct a nontrivial mathematical model for stable states. The finitely many components of this mathematical model of a stable state (image) are mapped onto an object of perception (icon) by perceptual judgments. These judgments, which include the judgment of stability, have an exact interpretation in this model. They unify and make precise such traditional notions of psychology as "Gestalt," "figureground," and "(visual) boundary."Postulates for a general theory of perception are given. They are used to establish a formal relationship between biological and subjective studies of sensory phenomena and so provide a framework in which subjective studies can be used to analyze (their associated) biological processes. In applying these methods to cases, all icons are divided into two classes (the static and dynamic cases). The static case is treated.

Animals↗

Stochastic dynamical model for stock-stock correlations.

We propose a model of coupled random walks for stock-stock correlations. The walks in the model are coupled via a mechanism that the displacement (price change) of each walk (stock) is activated by the price gradients over some underlying network. We assume that the network has two underlying structures, describing the correlations among the stocks of the whole market and among those within individual groups, respectively, each with a coupling parameter controlling the degree of correlation. The model provides the interpretation of the features displayed in the distribution of the eigenvalues for the correlation matrix of real market on the level of time sequences. We verify that such modeling indeed gives good fitting for the market data of US stocks.

Journal Article↗

Topic-vehicle interaction in metaphor comprehension.

Property comparison models of metaphor comprehension assume that the topic and vehicle terms in metaphors are both understood to be referring to their conventional literal referents. In contrast, the interactive property attribution model (Glucksberg, McGlone, & Manfredi, 1997) assumes that the vehicle is understood to be referring to a metaphoric category that includes the topic's literal referent as a member. A priming paradigm was used to test the implications of these different models. Prior to interpreting a metaphor, participants read (1) the topic or vehicle concept alone, (2) a sentence ascribing a metaphor-relevant property to one concept, or (3) a sentence ascribing a metaphor-irrelevant property to one concept. All of the prime types facilitated metaphor comprehension with the exception of sentences ascribing metaphor-irrelevant properties to vehicles. The failure of these sentences (but not their topic counterparts) to facilitate metaphor comprehension is attributable to their priming an inappropriate literal interpretation of the vehicle term. These results are consistent with the claim that irrelevant information is suppressed during language comprehension (Gernsbacher, 1990) and support the interactive property attribution model.

Cognition↗

The biopsychosocial model of medicine revisited: a meta-theoretical excursion.

Engel's biopsychosocial model of medicine has been widely endorsed by contemporary medicine, at least in theory. Yet, whereas Engel's notion refers mainly to physician-patient communication, the prevalent interpretation of this model is mainly etiological. The present meta-theoretical study examines the relation between the different notions of the model. Using logical analysis and the theory of (critical) rationality, in particular Wettersten's theory of (complementary) styles of rationality, it is argued that the different notions of the model may be complementary, rather than contradictory or incommensurable as usually implied by those holding them.

Communication↗

[Establishment of a stochastic model for variation in fecal Schistosoma japonicum egg count and estimation of its parameters].

OBJECTIVE: To establish a stochastic model suitable for interpreting the variation in fecal Schistosoma japonicum egg count, and to estimate its parameters and to describe it. METHODS: Total variation in fecal egg count with a stochastic model can be divided into two kinds of sources, (1) inter-individual variation, and (2) intra-individual variation. Parameters in the model were estimated with the data collected in actual fecal egg count. RESULTS: Parameters M and r differed and k kept nearly the same in various age groups. The best cut-off point of r and M for age-splitting was at eight and 12 years, respectively. Parameter k was assumed the same in different age groups in the model E, and r differed in the groups of 2 - 7 years and 8 years of age, and M differed in the groups of 2 - 11 years and 12 years of age, with a minimum value of Akaike information criterion (AIC). CONCLUSION: Age may be an important factor contributing to the estimations of parameters M and r, and the model E was the best one.

Adolescent↗

The EINTHOVEN system: toward an improved cardiac arrhythmia monitor.

Contemporary cardiac arrhythmia monitors, used commonly in intensive care settings, are highly sensitive to artifact, resulting in high false alarm rates, inability to detect P waves reliably, and crude rhythm interpretation. We report on two new approaches that address these problems: a noise preprocessor that characterizes the type and degree of artifact in an ECG, and a model-based rhythm interpretation algorithm.

Algorithms↗

Regular folding chain conformation of the deoxyribonucleic acid in chromatin. X-ray diffraction and selforganization.

The following model is proposed for the structure of deoxyribonucleic acid (DNA) in chromatin: The DNA in a nucleosome is folded seven times to and fro on the surface of a cylindrical protein nucleus. There exist 3.5 DNA hairpins. The seven arms of the hairpins contain twenty DNA base pairs each. The six loops of the DNA hairpins contain ten DNA base pairs each. Consistently with the experiment, the model gives X-ray small-angle diffraction reflexes at 10.5 nm, 5.5 nm, 3.6 nm. The X-ray larg-angle diagram can also be interpreted by the model. Folding crystallization is the mechanism of supramolecular selfassembly giving condensation of DNA in the chromatin.

Chromatin↗

Why there is no gene for alcoholism.

The search for and recognition of biological and genetic markers of alcoholism are discussed in the context of a heuristic model of human alcoholism as a complex, multilocus, heterogeneous disorder. Implications of this model for the interpretation of results from both linkage and association studies are presented.

Alcoholism↗

Orogastric vaccination of guinea pigs with Helicobacter pylori sonicate and a high dose of cholera toxin lowers the burden of infection.

Guinea pigs were vaccinated orogastrically with Helicobacter pylori cell sonicate (CS) and 10 microg or 100 microg cholera toxin (CT) or CT only. Nai;ve animals were used as a control. In both experiments, vaccination primed the local IgG and IgA response, irrespective of the CT dose. After challenge, only the group of animals immunised with CS and 100 microg CT had a significantly lower number of H. pylori in the antral region of the stomach, but vaccination did not prevent H. pylori infection. This protective effect was not associated with a switch in IgG subclass, which remained predominantly IgG2. The levels of specific antibodies in serum and the gastric mucosa which were similar to naive unprotected animals. In conclusion, the ability of mucosal adjuvants such as CT to induce a protective immune response may be host dependent and findings in the Helicobacter-mouse model should be interpreted with caution.

Adjuvants, Immunologic↗

Molecular modeling of triazine type MDR modulators using CoMFA and CoMSIA approaches.

In the present study a series of 30 triazine derivatives was investigated by 3D QSAR methods with respect to their MDR reversing activity in vitro. Two approaches were applied and compared: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Molecular models with good predictive power were derived using steric, electrostatic and hydrophobic fields of the compounds. The results indicated the dominant role of the electrostatic and hydrophobic fields for MDR reversing activity of the investigated modulators. The obtained statistical parameters (Qcv2, Qpr2) showed that the CoMFA and CoMSIA models have similar predictivity. The CoMSIA models were slightly better than the CoMFA ones and obtained with lower number of principal components. The models were graphically interpreted using CoMFA and CoMSIA contour plots. The structural regions responsible for the differences in anti-MDR activity were analyzed in respect to their electrostatic and hydrophobic nature. An easier interpretation of the CoMSIA contour plots was noticed.

Drug Resistance, Multiple↗

Dynamic simulation of protein complex formation on a genomic scale.

MOTIVATION: One of the central questions in the post-genomic era is the understanding of protein-protein interactions and of protein complex formation. It has been observed that protein complex size distributions of the yeast Saccharomyces cerevisiae decay exponentially. The shape of these size distributions reflects mechanisms of protein complex association and dissociation. RESULTS: We present the most simple dynamic model that is able to reproduce the observed protein complex size distribution for yeast. This protein association-dissociation model (PAD-model) simulates the dynamics of protein complex formation on a genomic scale for about 50 million protein molecules. By ruling out different model variants it is possible to elucidate fundamental features of the protein complex dynamics, e.g. complex association is independent of complex size. In addition, the PAD-model provides information about the complexity of the yeast proteome and it gives an idea of how many complexes could not be identified during the measurements. AVAILABILITY: All programs used for this publication are available on request from the authors. CONTACT: beyer@imb-jena.de SUPPLEMENTARY INFORMATION: Supplementary information about the model and its interpretation can be downloaded from http://www.imb-jena.de/tsb/pad.

Computer Simulation↗

Enantiophore modeling in 3D-QSAR. A data mining application on Whelk-O1 chiral stationary phase.

A combination of the enantiophore concept described in a previous study and a quantitative structure enantioselective relationship (QSER) based on partial least squares (PLS) analysis is presented. In the present study, a comprehensive approach for describing the enantioselective binding properties of the Whelk-O1 chiral HPLC receptor is achieved using molecular descriptors calculated by the GRID program. The GRID descriptors allow us to describe the molecules in terms of their ability to form favorable interactions with independent chemical groups (probes) that can be related to receptor sites. For each molecule, we compute 120 enantiophore descriptors representing the energy contributions from all possible pairwise combinations of probes. The overall procedure was simplified by considering only the most energetically favorable locations and converting selected grid-point energies into alignment-independent descriptors. By using a training set of 143 diverse chiral compounds, an optimal PLS model requiring seven components was chosen by using the cross-validation method resulting in a correlation coefficient R2= 0.88 and a cross validated correlation coefficient Q2= 0.85. An interpretation of the model is proposed based upon a visual inspection of the regression coefficient plots. From these plots, the influence of particular molecular features for selective binding of solutes was estimated and used to outline the chiral recognition sites in the Whelk-O1 receptor. The predictive power of our model has been estimated by means of an external data set emphasizing the suitability of the procedure also for predictive aims.

Journal Article↗

Reforming health care for the elderly--the example of Vorarlberg.

Vorarlberg--Austria's most western province with a population of about 325,000--has always implemented forms of social policy in which the principles of subsidiarity and solidarity play an important role. This is reflected in the structure of the organizations traditionally providing social services as well as in the more recent programmes the government has developed for social policy. This paper discusses two cases in point: the private associations for home care (Krankenpflegerverbände)--which now exist in 65 Vorarlberg communities and cover 85% of the population in the province--offering nursing services at home to members or to persons who are willing to join the organization when they need care, and the new organizational model, called Gesunder Lebensraum Vorarlberg (GLV), which is successfully operating in a few pilot communities. GLV has spawned umbrella organizations, run by volunteers, and offering a variety of social services relevant to the elderly, for example visiting services or neighbourhood help in case of emergencies. The volunteers get organizational help from a profit-making firm financed by the government. The Vorarlberg models can be interpreted as a step towards demedicalization and deinstitutionalization of health care for the elderly. Nevertheless, they also show the problems that arise when professionals and volunteers must cooperate. The models may lead to savings for the governments involved, although details are still subject to future empirical investigations.

Aged↗

Kinetic analysis of pulmonary neutrophil retention in vivo using the multiple-indicator-dilution technique.

Multiple-indicator-dilution experiments were performed in the lungs of 13 anesthetized dogs by simultaneous bolus injection of 111In-labeled neutrophils, 51Cr-labeled red blood cells, and Evans blue-labeled albumin. Concomitant counts of unlabeled neutrophils were similar in pulmonary artery and aortic blood samples, demonstrating a dynamic balance across the lungs in the physiological state. Outflow profiles of labeled neutrophils were analyzed on the basis of a recirculatory pharmacokinetic model of labeled albumin. The outflow profiles of the recovered neutrophils were composed of a throughput component of circulating neutrophils and a component of reversibly marginated neutrophils. They were interpreted by a model incorporating neutrophil margination (transfer coefficient = 0.195 +/- 0.081 s-1), rapid demargination (0.054 +/- 0.027 s-1), and transfer to a slow marginated pool (0.023 +/- 0.018 s-1). It will be interesting to apply the analysis in future studies aimed at determining whether it could be a useful research tool to investigate the interactions between the pulmonary endothelium and neutrophils in physiological and diseased states.

Albumins↗

Do antidepressants cause suicidality in children? A Bayesian meta-analysis.

BACKGROUND: To quantify the risk of suicidal behavior/ideation (suicidality) for children who use antidepressants, the FDA collected randomized placebo-controlled trials of antidepressant efficacy in children. Although none of the 4487 children completed suicide, 1.7% exhibited suicidality. The FDA meta-analyzed these studies and found sufficient evidence of an increased risk to require a black-box warning on antidepressants for children. PURPOSE: The FDA considered different drug formulations and psychiatric diagnoses to be equivalent in their effect on suicidality. If this assumption does not hold, the FDA analysis may have underestimated the variance of the risk estimate. We investigate the consequences of relaxing these assumptions. METHODS: We extend the FDA analysis using a Bayesian hierarchical model that allows for a study-level component of variability and facilitates extensive sensitivity analyses. RESULTS: We found an association between antidepressant use and an increased risk of suicidality in studies where the diagnosis was major depressive disorder (odds ratio 2.3 [1.3, 3.8]), and where the antidepressant was an SSRI (odds ratio 2.2 [1.3, 3.6]). We did not find evidence for such an association in the complement sets of trials. Although the results based on the hierarchical model are insensitive to model perturbations, the robustness of the FDA's meta-analysis to model assumptions is less clear. These data have limited generalizability due to exclusion of patients with baseline risk of suicide and the use of relatively short duration trials. CONCLUSIONS: Because of model specification and interpretation issues raised in this paper, we conclude that the evidence supporting a causal link between antidepressant use and suicidality in children is weak. The use of Bayesian hierarchical models for meta-analysis has facilitated the incorporation of potentially important sources of variability and the use of sensitivity analysis to assess the consequences of model specifications and their impact on important regulatory decisions.

Antidepressive Agents↗