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PubMed2005

Comparison of nonlinear dynamic methods and perturbation methods for voice analysis.

Nonlinear dynamic methods and perturbation methods are compared in terms of the effects of signal length, sampling rate, and noise. Results of theoretical and experimental studies quantitatively show that measurements representing frequency and amplitude perturbations are not applicable to chaotic signals because of difficulties in pitch tracking and sensitivity to initial state differences. Perturbation analyses are only reliable when applied to nearly periodic voice samples of sufficiently long signal lengths that were obtained at high sampling rates and low noise levels. In contrast, nonlinear dynamic methods, such as correlation dimension, allow the quantification of chaotic time series. Additionally, the correlation dimension method presents a more stable analysis of nearly periodic voice samples for shorter signal lengths, lower sampling rates, and higher noise levels. The correlation dimension method avoids some of the methodological issues associated with perturbation methods, and may potentially improve the ability for real time analysis as well as reduce costs in experimental designs for objectively assessing voice disorders.

Adult↗
PubMed2005

Heart rate variability in dairy cows-influences of breed and milking system.

Heart rate variability parameters in the time, frequency and nonlinear domains were investigated in two breeds of dairy cows (Austrian Simmental and Brown Swiss) milked either in an automatic milking system with partially forced cow traffic or in a herringbone milking parlour. Recordings were made of 24 cows (six of each breed and milking system) during lying, standing idle, and standing being milked, and analysed with linear mixed effects models taking the covariates time of day, live body weight, milk yield, stage of lactation and stage of pregnancy into account. Heart rate and nonlinear deterministic shares were higher, and heart rate variability in the time and frequency domains was lower, later in the day, in cows with higher body weight and in Simmental compared to Brown Swiss cows. Differences in the linear and nonlinear domains during lying indicated an increased level of chronic stress in cows in the automatic milking system with partially forced cow traffic, compared to cows milked in the herringbone milking parlour. No effects of milking system were found during milking, indicating that the stressor in the automatic milking system was not the milking process itself.

Analysis of Variance↗
PubMed1998

Statistical methods for population pharmacokinetic modelling.

A principal aim of population pharmacokinetic studies is to estimate the variance components associated with intra- and inter-individual variability in observed drug concentrations. The explanation of the inter-individual variability in terms of subject-specific covariates is also of great importance. Pharmacokinetic models are nonlinear in the parameters and estimation is not straightforward. Within this paper we review a number of estimation approaches which have been suggested for population pharmacokinetic analyses. We distinguish between Bayesian and non-Bayesian and fully-parametric, semi-parametric and nonparametric methods.

Analysis of Variance↗
PubMed1990

Linear calibration of radiographic mineral density using video-digitizing methods.

Radiographic images can provide quantitative as well as qualitative information if they are subjected to densitometric analysis. Using modern video-digitizing techniques, such densitometry can be readily accomplished using relatively inexpensive computer systems. However, such analyses are made more difficult by the fact that the density values read from the radiography have a complex, nonlinear relationship to bone mineral content. This article derives the relationship between these variables from the nature of the intermediate physical processes, and presents a simple mathematical method for obtaining a linear calibration function using a step wedge or other standard.

Animals↗
PubMed1981

Ethanol 'dose-dependent' elimination: Michaelis-Menten v classical kinetic analysis.

1 To compare classical linear regression techniques and a Michaelis-Menten elimination model eight normal human volunteers each received three intravenous doses (0.375, 0.5, and 0.75 g/kg) of ethanol and four of the subjects each received four oral doses (0.5, 0.65, 0.95, 1.25 g/kg) of ethanol. 2 Computerized analysis of the time-plasma concentration profiles using a two-compartment Michaelis-Menton elimination model yielded a median absorption constant of 1.29 h-1; volume of distribution of 0.47 l/kg; Vmax of 0.12 g h-1 kg-1; and Km of 0.03 g/l. Classical techniques resulted in a slope of 0.20 g l-1 h-1, volume of distribution of 0.55 l/kg, and a B60 of 0.11 g h-1 kg-1. 3 Transient post-prandial decreases in elimination slope occurred at higher oral doses. A trend of increasing slope with increasing oral dose was seen at concentrations well above the Km. Time to sobriety (0.8 g/l) increased nonlinearly with increasing peak concentration. 4 Maximal ethanol elimination rates are determined equally well by the two techniques. Classical analyses overestimate the volume of distribution of ethanol by 17%. Neither technique helps explain the post-prandial changes in slope or increasing slope with dose at high concentrations.

Adult↗
PubMed2006

Effect of target dynamics on pharmacokinetics of a novel therapeutic antibody against the epidermal growth factor receptor: implications for the mechanisms of action.

The epidermal growth factor receptor (EGFR) is overexpressed on many solid tumors and represents an attractive target for antibody therapy. Here, we describe the effect of receptor-mediated antibody internalization on the pharmacokinetics and dose-effect relationship of a therapeutic monoclonal antibody (mAb) against EGFR (2F8). This mAb was previously found therapeutically active in mouse tumor models by two dose-dependent mechanisms of action: blockade of ligand binding and induction of antibody-dependent cell-mediated cytotoxicity. In vitro studies showed 2F8 to be rapidly internalized by EGFR-overexpressing cells. In vivo, accelerated 2F8 clearance was observed in cynomolgus monkeys at low doses but not at high doses. This enhanced clearance seemed to be receptor dependent and was included in a pharmacokinetic model designed to explain its nonlinearity. Receptor-mediated clearance was also found to affect in situ antibody concentrations in tumor tissue. Ex vivo analyses of xenograft tumors of 2F8-treated nude mice revealed that relatively high antibody plasma concentrations were required for maximum EGFR saturation in high-EGFR-expressing human A431 tumors, in contrast to lower-EGFR-expressing human xenograft tumors. In summary, receptor-mediated antibody internalization and degradation provides a saturable route of clearance that significantly affects pharmacokinetics, particularly at low antibody doses. EGFR saturation in normal tissues does not predict saturation in tumor tissue as local antibody concentrations in EGFR-overexpressing tumors may be more rapidly reduced by antibody internalization. Consequently, antibody saturation of the receptor may be affected, thereby affecting the local mechanism of action.

Animals↗
PubMed1994

Nonlinear phonology: introduction and clinical application.

The purpose of this tutorial is to introduce a recent advance in phonological theory, "nonlinear phonology," which differs fundamentally from previous theories by focusing on the hierarchical nature of relationships among phonological units. We first introduce the basic concepts and assumptions of nonlinear phonological theory and then demonstrate clinical applications of the theory for assessment and intervention. Data from a child with a severe phonological disorder are used to illustrate aspects of nonlinear theory. The data are first analyzed in terms of phonological processes in order to provide the readers with a familiar starting point for comprehension and comparison. The nonlinear frameworks are shown to provide a deeper analysis of the child's phonological system than the phonological process analyses and to lead to a more clearly defined intervention plan.

Articulation Disorders↗
PubMed2006

Internal versus external intrapartum foetal heart rate monitoring: the effect on linear and nonlinear parameters.

The effect of foetal heart rate (FHR) acquisition mode on linear and nonlinear parameters is still largely unknown. In 33 normal labouring women, FHR signals were acquired simultaneously by an external ultrasound sensor applied to the maternal abdomen and an internal scalp electrode, in the minutes preceding delivery. For each case, the initial and final 5, 10 and 20 min segments were analysed, considering FHR signals at a frequency of 4 Hz (the frequency at which they are transmitted by the majority of commercialized foetal monitors). Several time and frequency domain linear and nonlinear FHR indices were computed in these segments, namely mean FHR, very low frequency (VLF), low frequency (LF), high frequency (HF), approximate entropy (ApEn) and sample entropy (SampEn). Parametric confidence intervals, statistical tests and correlation coefficients were calculated in order to evaluate the effect of internal versus external FHR monitoring modes on the considered indices. The whole evaluation was repeated using FHR signals at a frequency of 2 Hz. Most time domain linear indices were similar with external and internal monitoring in the initial and final segments of the tracings. However, linear frequency domain indices were poorly correlated in the final segments and had significantly different mean values in the initial segments. Nonlinear indices were significantly different in both initial and final segments. The correlation between 4 and 2 Hz sampled parameters was high for both linear and nonlinear indices (most correlation coefficient values ranging between 0.95 and 1) but nonlinear index values were significantly higher at 2 Hz. In conclusion, the mode used to acquire FHR signals and the sampling rate employed can significantly affect most FHR indices.

Algorithms↗
PubMed2002

On the use of generalized additive models in time-series studies of air pollution and health.

The widely used generalized additive models (GAM) method is a flexible and effective technique for conducting nonlinear regression analysis in time-series studies of the health effects of air pollution. When the data to which the GAM are being applied have two characteristics--1) the estimated regression coefficients are small and 2) there exist confounding factors that are modeled using at least two nonparametric smooth functions--the default settings in the gam function of the S-Plus software package (version 3.4) do not assure convergence of its iterative estimation procedure and can provide biased estimates of regression coefficients and standard errors. This phenomenon has occurred in time-series analyses of contemporary data on air pollution and mortality. To evaluate the impact of default implementation of the gam software on published analyses, the authors reanalyzed data from the National Morbidity, Mortality, and Air Pollution Study (NMMAPS) using three different methods: 1) Poisson regression with parametric nonlinear adjustments for confounding factors; 2) GAM with default convergence parameters; and 3) GAM with more stringent convergence parameters than the default settings. The authors found that pooled NMMAPS estimates were very similar under the first and third methods but were biased upward under the second method.

Air Pollution↗
PubMedDate not supplied

Pharmacokinetic analyses with RUGFIT: an interactive pharmacokinetic computer program.

RUGFIT is an interactive computer program to fit polyexponential equations to experimental points without the need of assumptions about the number of exponential terms and without the need of initial parameter estimates. The fitting is performed by iterative stripping minimizing the sum of squared residuals. This procedure leads to multiple model equations describing the profile of the y-value in time, that are compared with the test of Boxenbaum et al. The examples analysed in this paper are: a plasma decay curve after an intravenous bolus injection and one after an oral gift, a dA/dt versus time curve with a lag time and a curve possibly reflecting an entero-hepatic recirculation. The outcomes are, where possible, compared with the outcomes obtained with the computer programs CFT3, NONLIN, and NONLINEAR (SPSS). The latter three programs sometimes run into a local minimum, as the outcomes obtained with RUGFIT were close to the best ones obtained with the other programs. The analyses with RUGFIT show that a choice of an inadequate model equation can lead to a marked error in the value of the area under the curve that may result in a marked error of, for instance, the bioavailability. The procedures of RUGFIT are illustrated in the Appendix. RUGFIT also contains options to calculate microparameters, to simulate dosage regimes, to calculate exponents and intercepts from rate constants and to analyse time effect relationships.

Animals↗
PubMed2002

Extrapolation of cardiac index from analysis of the left ventricular outflow velocities in children: implication of the relationship between aortic size and body surface area.

BACKGROUND: It has recently been reported in critically ill patients that a linear relationship exists between cardiac index (CI) measured with thermodilution and mean aortic blood flow velocity (MAFV). This hypothesis can be validated mathematically only if the aortic area (AA index) indexed to body surface area (BSA) remains constant and if the relationship between aortic diameter (PhiAo) and BSA is nonlinear. However, several other equations have described the relationship between BSA and, respectively, PhiAo and aortic area (AA) in children. The aim of this study was to determine if the relationships calculated between BSA and aortic size in children (without left ventricular outflow tract abnormality) could validate the hypothesis that MAFV and CI are well linked linearly, leading to its use to determine CI. METHODS: Two hundred and thirty-two measurements performed in 126 children and infants were retrospectively analysed. PhiAo was measured in the long axis view at the annulus using two-dimensional mode echocardiography with a 5-MHz transducer. Various linear and nonlinear relationships between BSA and, respectively, PhiAo, PhiAoindex, AA and AAindex were determined based on a nonlinear regression method with a model as follows: y=a(xc) + b. The comparisons between regressions were conducted based on the estimation error. RESULTS: The relationships between PhiAo and BSA appeared nonlinear and was well described by: PhiAo=2.96(BSA1/4) - 1.31 with a non-zero y-intercept and PhiAo=1.64(BSA1/2) with a zero y-intercept. In contrast, the relationships between AA and BSA were linear. The AAindex was not linked to BSA and can be considered as constant. The coefficient a of the equation appeared similar to those obtained mathematically with the relationship previously described between MAFV and CI. CONCLUSIONS: The hypothesis that CI can be extrapolated to the measurement of MAFV appears valid as regards the relationships calculated between aortic size and BSA in children without left ventricular outflow tract abnormality.

Adolescent↗
PubMed2004

Adaptive neural control of uncertain MIMO nonlinear systems.

In this paper, adaptive neural control schemes are proposed for two classes of uncertain multi-input/multi-output (MIMO) nonlinear systems in block-triangular forms. The MIMO systems consist of interconnected subsystems, with couplings in the forms of unknown nonlinearities and/or parametric uncertainties in the input matrices, as well as in the system interconnections without any bounding restrictions. Using the block-triangular structure properties, the stability analyses of the closed-loop MIMO systems are shown in a nested iterative manner for all the states. By exploiting the special properties of the affine terms of the two classes of MIMO systems, the developed neural control schemes avoid the controller singularity problem completely without using projection algorithms. Semiglobal uniform ultimate boundedness (SGUUB) of all the signals in the closed-loop of MIMO nonlinear systems is achieved. The outputs of the systems are proven to converge to a small neighborhood of the desired trajectories. The control performance of the closed-loop system is guaranteed by suitably choosing the design parameters. The proposed schemes offer systematic design procedures for the control of the two classes of uncertain MIMO nonlinear systems. Simulation results are presented to show the effectiveness of the approach.

Neural Networks, Computer↗
PubMed2007

Experimental investigations of nonlinearities and destruction mechanisms of an experimental phospholipid-based ultrasound contrast agent.

OBJECTIVES: We sought to characterize the acoustical behavior of the experimental ultrasound contrast agent BR14 by determining the acoustic pressure threshold above which nonlinear oscillation becomes significant and investigating microbubble destruction mechanisms. MATERIALS AND METHODS: We used a custom-designed in vitro setup to conduct broadband attenuation measurements at 3.5 MHz varying acoustic pressure (range, 50-190 kPa). We also performed granulometric analyses on contrast agent solutions to accurately measure microbubble size distribution and to evaluate insonification effects. RESULTS: Attenuation did not depend on acoustic pressure less than 100 kPa, indicating this pressure as the threshold for the appearance of microbubble nonlinear behavior. At the lowest excitation amplitude, attenuation increased during insonification, while, at higher excitation levels, the attenuation decreased over time, indicating microbubble destruction. The destruction rate changed with pressure amplitude suggesting different destruction mechanisms, as it was confirmed by granulometric analysis. CONCLUSIONS: Microbubbles showed a linear behavior until 100 kPa, whereas beyond this value significant nonlinearities occurred. Observed destruction phenomena seem to be mainly due to gas diffusion and bubble fragmentation mechanisms.

Contrast Media↗
PubMed1977

Use of pharmacological data for bioavailability and pharmacokinetic analyses.

The use of pharmacological responses such as pupil diameter for dosage individualization, bioavailability, and pharmacokinetic analyses is becoming more widespread. Attempts to use pupil diameter to assess morphine bioavailability illuminate the fact that multiple responses, nonlinearities, and the condition of the subject can produce misleading results unless the applicability of the method is confirmed.

Animals↗
PubMed1995

A nonparametric subject-specific population method for deconvolution: I. Description, internal validation, and real data examples.

In a pharmacokinetics context deconvolution facilitates the following: (i) Given data obtained after intravascular (generally intravenous) input one may estimate the disposition function; (ii) given the disposition function and data obtained after extravascular administration one may estimate the extravascular to vascular input rate function. In general if the data can be represented by the convolution of two functions, of which one is unknown, deconvolution allows the estimation of the unknown one. Attention has been given in the past to deconvolution and in particular to its nonparametric variants. However, in a population context (multiple observations collected in each of a group of subjects) the use of nonparametric deconvolution is limited to either analyzing each subject separately or to analyzing the aggregate response from the population without specifying subject-specific characteristics. To our knowledge a fully nonparametric deconvolution method in which subject specificity is explicitly taken into account has not been reported. To do so we use so-called "longitudinal splines." A longitudinal spline is a nonparametric function composed of a template spline, in common to all subjects, and of a distortion spline representing the difference of the subject's function from the template. Using longitudinal splines for input rate or disposition function one obtains a solution to the problem of taking subject specificity into account in a nonparametric deconvolution context. To obtain estimates of longitudinal splines we consider three different methods: (1) parametric nonlinear mixed effect, (2) least squares, and (3) two-stage. Results obtained in one simulated and two real data analyses are shown.

Least-Squares Analysis↗
PubMed2005

EEG synchronisation during sleep-related epileptic seizures as a new tool to discriminate confusional arousals from paroxysmal arousals: preliminary findings.

Confusional arousals, paroxysmal arousals (as part of the nocturnal frontal lobe epilepsy) and normal arousals and awakenings from NREM sleep are frequently a challenge for differential diagnosis. In this article we describe the course of synchronisation between different EEG channels during nocturnal seizures in 3 patients with sleep-related epileptic seizures and in 1 patient with sleep terrors. The functional interactions between the different EEG channels during the nocturnal seizures were analysed by means of the so-called synchronisation likelihood (SL). SL is a measure of the dynamical (linear and nonlinear) interdependencies between a time series (EEG channel) and one or more other time series. The main results of our study are the confirmation of a significant increase in EEG synchronisation during sleep-related seizures and the indication that clinically similar ictal motor patterns might be generated by different neurophysiological mechanisms, characterised by different patterns of synchronisation involving multiple or single frequency bands. This new approach might be useful to differentiate motor seizures, emerging from NREM sleep, from parasomnias (arousal disorders) when both ictal and interictal EEGs are uninformative.

Adult↗
PubMed1987

Relation of blood pressure during exercise to anaerobic metabolism.

To determine the effects of anaerobic metabolism on blood pressure (BP), 25 subjects were studied for BP response to graded and continuous leg-crank ergometry under both aerobic and anaerobic conditions. Measurements obtained during exercise also included ventilatory equivalents for oxygen and carbon dioxide to determine anaerobic threshold. Systolic and diastolic BP responses to exercise before anaerobic threshold were compared with responses after anaerobic threshold by linear regression analyses. The systolic BP response to graded exercise was significantly accelerated (p less than 0.01) after anaerobic threshold, demonstrating a nonlinear response to proportionately graded exercise demand. Comparison of the slopes or rates of change in diastolic BP before and after anaerobic threshold also indicated a significant difference (p less than 0.01) under these 2 different metabolic conditions. It is concluded that in contrast to the linear response of BP under conditions of aerobic metabolism, BP responds nonlinearly during anaerobic metabolism.

Anaerobiosis↗