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Models for the relationship between ambient temperature and daily mortality.

BACKGROUND: Ambient temperature is an important determinant of daily mortality that is of interest both in its own right and as a confounder of other determinants investigated using time-series regressions, in particular, air pollution. The temperature-mortality relationship is often found to be substantially nonlinear and to persist (but change shape) with increasing lag. We review and extend models for such nonlinear multilag forms. DEVELOPMENT: Popular models for mortality by temperature at given lag include polynomial and natural cubic spline curves, and the simple but more easily interpreted linear thresholds model, comprising linear relationships for temperatures below and above thresholds and a flat middle section. Most published analyses that have allowed the relationship to persist over multiple lags have done so by assuming that spline or threshold models apply to mean temperature in several lag strata (e.g., lags 0-1, 2-6, and 7-13). However, more flexible models are possible, and a modeling framework using products of basis functions ("cross-basis" functions) suggests a wide range, some used previously and some new. These allow for stepped or smooth changes in the model coefficients as lags increase. Applying a range of models to data from London suggest evidence for relationships up to at least 2 weeks' lag, with smooth models fitting best but lag-stratified threshold models allowing the most direct interpretation. CONCLUSIONS: A wide range of multilag nonlinear temperature-mortality relationships can be modeled. More awareness of options should improve investigation of these relationships and help control for confounding by them.

Humans↗

Statistical analyses of enzyme inhibitor kinetics: a hierarchical model-dependent approach.

Inference of the nature of an enzyme inhibitor and calculations of inhibitor constants from linear plots are prone to be unreliable when experimental error is significant. This may be minimised by a method of statistical analysis using nonlinear regression methods and modelling using the variance ratio test of a hierarchy of models of inhibitor behaviour.

Computer Simulation↗

The influence of weight with assay error on gentamicin pharmacokinetics using the Bayesian and nonlinear least square regression analysis in appendicitis patients.

The purpose of this study was to determine the influence of weight with gentamicin assay error on the Bayesian and nonlinear least squares regression analysis in 12 Korean appendicitis patients. Gentamicin was administered intravenously over 0.5 h every 8 h. Three specimens were collected 48 h after the first dose from all patients at the following times, just before the regularly scheduled infusion, at 0.5 h and 2 h after the end of the 0.5 h infusion. Serum gentamicin levels were analysed by fluorescence polarization immunoassay technique with TDxFLx. The standard deviation (SD) of the assay over its working range had been determined at the serum gentamicin concentrations of 0, 2, 4, 8, 12 and 16 microg/ml in quadruplicate. The polynominal equation of gentamicin assay error was found to be SD (microg/ml) = 0.0246-(0.0495C) + (0.00203C(2)). There were differences in the influence of weight with gentamicin assay error on pharmacokinetic parameters of gentamicin using the nonlinear least squares regression analysis but there were no differences on the Bayesian analysis. This polynominal equation can be used to improve the precision of fitting of pharmacokinetic models to optimize the process of model simulation both for population and for individualized pharmacokinetic models. The result would be improved dosage regimens and the better, safer care of patients receiving gentamicin.

Anti-Bacterial Agents↗

Input-output statistical independence in divisive normalization models of V1 neurons.

Simoncelli and co-workers have proposed statistically-derived nonlinear divisive normalization models of the primary visual cortex (V1) that are consistent with the hypothesis that sensory systems are adapted to the signals to which they are exposed. In this paper, we present a more rigorous mathematical formulation and analysis of these statistically-derived models in terms of mutual information as a metric for statistical independence. We prove that the ad hoc choice of divisive normalization parameters proposed by Simoncelli and co-workers does not guarantee statistical independence between the output responses, but interestingly such choice does guarantee that each output response is statistically independent of almost all the linear inputs. This holds for the two different models of natural image statistics analysed theoretically, and is consistent with empirical results obtained on a set of natural images.

Animals↗

Nonlinear cardio-respiratory interactions revealed by time-phase bispectral analysis.

Bispectral analysis based on high order statistics, introduced recently as a technique for revealing time-phase relationships among interacting noisy oscillators, has been used to study the nature of the coupling between cardiac and respiratory activity. Univariate blood flow signals recorded simultaneously by laser-Doppler flowmetry on both legs and arms were analysed. Coupling between cardiac and respiratory activity was also checked by use of bivariate data and computation of the cross-bispectrum between the ECG and respiratory signals. Measurements were made on six healthy males aged 25-27 years. Recordings were taken during spontaneous breathing (20 min), and during paced respiration at frequencies both lower and higher than that of spontaneous respiration (either two or three recordings with a constant frequency in the interval between 0.09 and 0.35 Hz). At each paced frequency recordings were taken for 12 min. It was confirmed that the dynamics of blood flow can usefully be considered in terms of coupled oscillators, and demonstrated that interactions between the cardiac and respiratory processes are weak and time-varying, and that they can be nonlinear. Nonlinear coupling was revealed to exist during both spontaneous and paced respiration. When present, it was detected in all four blood flow signals and in the cross-bispectrum between the ECG and respiratory signal. The episodes with nonlinear coupling were detected in 11 out of 22 recordings and lasted between 19 s in the case of high frequency (0.34 Hz) and 106 s in the case of low frequency paced respiration (0.11 Hz).

Adult↗

Initial reaction kinetics of succinate dehydrogenase in mouse liver studied with a real-time image analyser system.

The initial reaction kinetics of succinate dehydrogenase in situ were investigated in sections of mouse unfixed liver using an ARGUS-100 image analyser system. The sections were incubated on substrate-containing agarose gel films. Images of a section, illuminated with monochromatic light (584 nm), were captured with the image analyser in real time at intervals of 10 s during the incubation. The absorbances of selected hepatocytes in the successive images were determined as a function of time. In every cell, the absorbance increased nonlinearly after the first minute of incubation. The initial velocity of the dehydrogenase was calculated from the linear activities during the first 20 s of incubation. Hanes plots of the initial velocities and succinate concentration yielded the following mean kinetic constants. For periportal hepatocytes, the apparent Km = 1.2 +/- 0.8 mM and Vmax = 29 +/- 2 mumol hydrogen equivalents formed/cm3 hepatocyte cytoplasm per min. For pericentral hepatocytes, Km = 1.4 +/- 1.0 mM and Vmax = 21 +/- 2 mumol hydrogen equivalents/cm3 per min. The Km values are very similar to those determined previously from biochemical assays. These results, and the observed dependence of the initial velocity on the enzyme concentration, suggest that the technique reported here is valid for the histochemical assay of succinate dehydrogenase.

Animals↗

On discontinuities in motor learning: a longitudinal study of complex skill acquisition on a ski-simulator.

The qualitative behavioral reorganizations that occurred during the acquisition of a complex motor skill were examined. Five novice participants practiced for 39 sessions of ten 1-min trials on a modified version of the ski-simulator. Analyses focused on the motion of the apparatus platform, modeled as a self-sustained oscillator. At the beginning of the experiment, all participants adopted a behavior that could be modeled with a highly nonlinear stiffness function and a Rayleigh damping function. The behavior in the final part of the experiment was captured by a qualitatively different model, with a linear stiffness function and a van der Pol damping behavior. The transition from the initial to the final model was gradual and was marked in most cases by an abrupt increase of oscillation frequency. During the transition stage, the 2 damping behaviors seemed alternately exploited within each trial. The results are discussed in the framework of the dynamical systems approach to motor coordination and learning, considering motor skill acquisition as a phase transition.

Adult↗

[Investigations of empty body weight gain, on protein, fat and energy disposition as well as on utilization of metabolizable energy for energy deposition in black and white bulls. 1. Empty body weight gain].

Six series of individual feeding experiments (altogether 544 animals) with different energy supply and connected with steps slaughteries and whole-body analyses, constructed carried out and analysed upon the same aspects, were regression analytically interpreted with the aim of quantify the relation of empty body weight to live weight. The relation of empty body weight to live weight showed a nonlinear dependence on the live weight as well as on the age of animals. The assessment of the metabolizability of energy of the diet as an additional variable reduced the residual variation considerably. Therefore from the knowledge of live weight or age of the animals, and the metabolizability of energy of the diet the relation of empty body weight to live weight of black and white bulls could be calculated. Moreover, the relation of empty body weight gain to live weight gain in dependence on live weight and live weight gain was investigated.

Animal Feed↗

A delay-differential equation model of the feedback-controlled hypothalamus-pituitary-adrenal axis in humans.

The present work develops and analyses a model system of delay-differential equations which describes the core dynamics of the stress-responsive hypothalamus-pituitary-adrenal axis. This neuroendocrine ensemble exhibits prominent pulsatile secretory patterns governed by nonlinear and time-delayed feedforward and feedback signal interchanges. Formulation and subsequent bifurcation analysis of the model provide a qualitative and mathematical frame work for a better understanding of the delayed responsive mechanisms as well as the dynamic variations in different pathological situations.

Adrenocorticotropic Hormone↗

Assessment of bioavailability of soil-sorbed atrazine.

Bioavailability of pesticides sorbed to soils is an important determinant of their environmental fate and impact. Mineralization of sorbed atrazine was studied in soil and clay slurries, and a desorption-biodegradation-mineralization (DBM) model was developed to quantitatively evaluate the bioavailability of sorbed atrazine. Three atrazine-degrading bacteria that utilized atrazine as a sole N source (Pseudomonas sp. strain ADP, Agrobacterium radiobacter strain J14a, and Ralstonia sp. strain M91-3) were used in the bioavailability assays. Assays involved establishing sorption equilibrium in sterile soil slurries, inoculating the system with organisms, and measuring the CO(2) production over time. Sorption and desorption isotherm analyses were performed to evaluate distribution coefficients and desorption parameters, which consisted of three desorption site fractions and desorption rate coefficients. Atrazine sorption isotherms were linear for mineral and organic soils but displayed some nonlinearity for K-saturated montmorillonite. The desorption profiles were well described by the three-site desorption model. In many instances, the mineralization of atrazine was accurately predicted by the DBM model, which accounts for the extents and rates of sorption/desorption processes and assumes biodegradation of liquid-phase, but not sorbed, atrazine. However, for the Houghton muck soil, which manifested the highest sorbed atrazine concentrations, enhanced mineralization rates, i.e., greater than those expected on the basis of aqueous-phase atrazine concentration, were observed. Even the assumption of instantaneous desorption could not account for the elevated rates. A plausible explanation for enhanced bioavailability is that bacteria access the localized regions where atrazine is sorbed and that the concentrations found support higher mineralization rates than predicted on the basis of aqueous-phase concentrations. Characteristics of high sorbed-phase concentration, chemotaxis, and attachment of cells to soil particles seem to contribute to the bioavailability of soil-sorbed atrazine.

Atrazine↗

Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes.

Particular intestinal bacteria metabolize the soy isoflavone daidzein to equol and O-desmethylangolensin (O-DMA), metabolites that can be identified in urine. Individuals that harbor bacteria capable of producing equol or O-DMA are known as equol producers (approximately 30%-50% of the population) and O-DMA producers (approximately 80%-90% of the population), respectively. The equol-producer phenotype has been associated with sex hormone-related outcomes in several studies. However, the bacteria responsible for these phenotypes have not yet been identified and factors that influence the manifestation of these phenotypes are not well understood. To evaluate familial clustering of and nongenetic factors associated with these phenotypes, 410 individuals from 112 families participated in phenotyping (3-day soy challenge and Day 4 spot urine collection). In segregation analyses of the equol-producer phenotype, the Mendelian dominant model provided the most parsimonious fit to the data, suggesting that the pattern of inheritance of the equol-producer phenotype is consistent with an autosomal dominant trait. This phenotype was positively associated with education (p trend = 0.01), but not with sex, smoking, or several dietary factors. Results of the segregation analyses of the O-DMA-producer phenotype were inconclusive; no other models provided a more parsimonious fit to the data than the general model. This phenotype was inversely associated with age in a nonlinear model (p = 0.01), positively associated with age- and sex-adjusted height (odds ratio [OR] 10-cm increase = 0.38, 95% confidence interval [CI] = 0.15, 0.95) and body mass index (kg/m(2)) (OR = 0.91, 95% CI = 0.85, 0.96), but not with sex, education, smoking, or several dietary factors. These results suggest the equol-producer phenotype may be under some degree of genetic control and that there are likely other environmental factors not evaluated in the present analysis that contribute to both of these phenotypes. These results provide a foundation for further work to refine our understanding of heritable and environmental determinants of daidzein-metabolizing phenotypes.

Female↗

New look at Bloch's law for contrast.

It has been commonly reported that the temporal integration of grating contrast proceeds more slowly as spatial frequency is increased. Such results have been based on the critical duration for sensitivity to contrast pulses varying in duration, but the analyses have not assumed full integration at short durations and have neglected the effects of probability summation over time. To take such effects into account, we discuss a class of analytical models based on nonlinear temporal integration. On the assumption that the temporal impulse response of the visual system determines contrast integration over time, we develop both a high-threshold model and a signal-detection approach involving multiple and independent nonlinear signal detectors with a time-limited integration span. The redefined critical durations predicted by the models and verified by the data are about 35 msec and vary by no more than 10 msec across spatial frequency. This variation is entirely attributable to a change in the strength of inhibition with spatial frequency, and the analysis implies that the excitatory component is constant at all spatial frequencies, contrary to previous accounts.

Humans↗

Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis.

OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.

Administration, Cutaneous↗

[EEG correlates of the change in information processing strategy in visual imagery].

Cnanger of the spatial organization of biopotentials (spatial synchronization and disorder, spectral power and coherence) were analyzed during mental creating of visual images from two simple elements: the angle the oblique line. With the transition from the first to the fourth task, the total number of used elements increased from the number suitable for simultaneous presentation and conscious processing (less than 7 +/- 2) to a much higher number. Changes in the characteristics of the spatial organization of biopotentials associated with the increase in the number of the elements can be explained by a change in the information processing strategy, transformation of information processing strategy, i.e. the transition from the left-hemispheric successive (conscious) analyses to the right-hemispheric simultaneous (unconscious) processing. It was shown that this change in the information processing strategy was accompanied by an increase in the index of spatial disorder sensitive to complicated nonlinear processes. Subjects were divided in two groups with different forms of the reorganization of interhemispheric and fronto-occipital relationships of biopotentials. These data are interpreted in terms of different involvement of the unconscious intellectual processes of different layers (subconsciousness and superconsciousness) in the change in information processing strategy.

Adult↗

Computational subunits of visual cortical neurons revealed by artificial neural networks.

A crucial step toward understanding visual processing is to obtain a comprehensive description of the relationship between visual stimuli and neuronal responses. Many neurons in the visual cortex exhibit nonlinear responses, making it difficult to characterize their stimulus-response relationships. Here, we recorded the responses of primary visual cortical neurons of the cat to spatiotemporal random-bar stimuli and trained artificial neural networks to predict the response of each neuron. The random initial connections in the networks consistently converged to regular patterns. Analyses of these connection patterns showed that the response of each complex cell to the random-bar stimuli could be well approximated by the sum of a small number of subunits resembling simple cells. The direction selectivity of each complex cell measured with drifting gratings was also well predicted by the combination of these subunits, indicating the generality of the model. These results are consistent with a simple functional model for complex cells and demonstrate the usefulness of the neural network method for revealing the stimulus-response transformations of nonlinear neurons.

Animals↗

Mechanical behaviour of hamstring muscles in low-back pain patients and control subjects.

The purpose of this study was to measure and compare the passive elastic moment, the stiffness and the damping coefficient of the hip joint, as functions of the hip and knee joint angles in men with and without low-back pain. Two conventional tests, the straight-leg-raising test and the trunk forward flexion, were also performed and compared between these subjects. The passive elastic moment was measured using an isokinetic device in the passive mode. This device raised the lower limb from the horizontal position to the straight-leg-raising angle at a slow and constant angular velocity. A custom-made splint connected with the lever arm of the isokinetic device maintained the knee in extension and the ankle in the neutral position. The damping coefficient of the hip joint was measured for 0, 15, 45, 60, 75 and 90% of straight leg raising angle of each subject, using the suspension method based on small oscillation theory. To ensure that muscles were inactive during the passive hip moment tests, muscle activity was monitored with surface EMG. The stiffness was computed as the ratio of the change in passive elastic moment to the change in the hip angle. The passive elastic moment, the stiffness and the normalized trunk flexion were significantly different between the two groups respectively. There was, however, no difference between the two groups in the results of straight-leg-raise and damping coefficient of the hip. The passive elastic moment was a nonlinear function of the hip flexion angle and showed large intersubject differences, especially as the joint limit was approached. The damping coefficient was a polynomial function of the hip flexion angle. The measured variables were analysed using a discriminant function and it was shown that the two groups were clearly discriminable in a meaningful manner.

Journal Article↗

Analysis of concentration-response relationships by seemingly unrelated nonlinear regression (SUNR) technique.

In performing statistical evaluation of concentration-response relationship in pharmacological studies, all the commercially available statistical packages assume each data point is an independent measure of the drug response, and do not account for the dependence between the multiple measurements taken from the same subject (tissue, animal, or sample). Seemingly unrelated nonlinear regression (SUNR) is a statistical technique that takes into account both within-and between-subject variance. This technique has been implemented in an SAS-based interactive program called SUNR. The statistical analyses are based upon the original work by Gallant (Gallant, 1975, J Econometrics 3:35-50; Gallant and Goebel, 1976, JASA 71:961-967), which has been further developed by Muller and Helms (1984) (Presented at ASA meeting in Washington, D.C.) To test this program, we have analyzed both simulated and actual data with SUNR, comparing our results to those of several popular statistical programs. All the programs yielded essentially the same estimates for the EC50, minimum and maximum response in both the simulated and experimental data sets. However, our results differed markedly from the commercial packages in the estimates of standard errors associated with the estimated maxima. When analyzing simulated data, which were far less noisy than the experimental data, differences between the analyses were minimal. However, in the analyses of experimental data, the standard errors calculated by the commercial programs appear to significantly underestimate the standard error. Using SUNR, however, the 95% confidence limits on the maxima are markedly wider, and, importantly, always cover the observed actual data range.

Animals↗