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Results for “parameter estimation”

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At least 811 records · Page 45Linked to original sources

PubMed1994

Tris(2-chloroethyl) phosphate pharmacokinetics in the Fischer 344 rat: a comparison of conventional methods and in vivo microdialysis coupled with tandem mass spectrometry.

The pharmacokinetics of tris(2-chloroethyl) phosphate (TRCP, 20 mg/kg, iv) were investigated in awake male and female and anesthetized male Fischer 344 (F344) rats by conventional (CONV) sampling/detection methods (blood withdrawal with sample workup and analysis for TRCP). TRCP pharmacokinetics were also investigated in anesthetized male F344 rats using a new sampling/detection technique, in vivo microdialysis coupled with tandem mass spectrometry (MD/MS/MS). The concentration of free TRCP in plasma versus time profiles were analyzed using noncompartmental methods to estimate pharmacokinetic parameters. Comparisons of mean parameter estimates were made for (1) awake males versus females in CONV studies (t test, no significant differences, p < or = 0.05) and (2) awake and anesthetized males in CONV studies and anesthetized males in MD/MS/MS studies. There were significant differences (Scheffe's test) for the three groups of male rats, most notably the free TRCP concentration in plasma at early time points in CONV versus MD/MS/MS studies. The contributions of an indwelling jugular cannula, the blood sampling regimen, and the in vitro MD/MS/MS standard calibration curve were investigated. It appears that quantitation of TRCP by mass spectrometry using an in vitro standard calibration is responsible for the difference.

Anesthesia↗

PubMed1990

Structural classification of multi-input nonlinear systems.

We present new structural classification and parameter estimation results that are applicable to multi-input nonlinear systems. The mathematical relationships between the self- and cross-(Volterra and Wiener) kernels are derived for a basic two-input nonlinear structure. These results are then used to develop classification methods for more complicated two-input structures. Algorithms for estimating the parameters (linear and nonlinear subsystems) of these structures are also presented.

Cybernetics↗

PubMed1983

The upper and lower bounds of rate constants for general mammillary compartment systems.

The upper and lower bounds of rate constants for general mammillary three and four compartment systems have been derived. It is further proposed that the midpoints of the bounds can be used as initial estimates for parameter estimation. Numerical examples are given demonstrating the closeness of the calculated midpoints to the "known" rate constants of both the three and four compartment systems.

Kinetics↗

PubMed2006

Monitoring dynamic systems with multiparameter fluorescence imaging.

A new general strategy based on the use of multiparameter fluorescence detection (MFD) to register and quantitatively analyse fluorescence images is introduced. Multiparameter fluorescence imaging (MFDi) uses pulsed excitation, time-correlated single-photon counting and a special pixel clock to simultaneously monitor the changes in the eight-dimensional fluorescence information (fundamental anisotropy, fluorescence lifetime, fluorescence intensity, time, excitation spectrum, fluorescence spectrum, fluorescence quantum yield, distance between fluorophores) in real time. The three spatial coordinates are also stored. The most statistically efficient techniques known from single-molecule spectroscopy are used to estimate fluorescence parameters of interest for all pixels, not just for the regions of interest. Their statistical significance is judged from a stack of two-dimensional histograms. In this way, specific pixels can be selected for subsequent pixel-based subensemble analysis in order to improve the statistical accuracy of the parameters estimated. MFDi avoids the need for sequential measurements, because the registered data allow one to perform many analysis techniques, such as fluorescence-intensity distribution analysis (FIDA) and fluorescence correlation spectroscopy (FCS), in an off-line mode. The limitations of FCS for counting molecules and monitoring dynamics are discussed. To demonstrate the ability of our technique, we analysed two systems: (i) interactions of the fluorescent dye Rhodamine 110 inside and outside of a glutathione sepharose bead, and (ii) microtubule dynamics in live yeast cells of Schizosaccharomyces pombe using a fusion protein of Green Fluorescent Protein (GFP) with Minichromosome Altered Loss Protein 3 (Mal3), which is involved in the dynamic cycle of polymerising and depolymerising microtubules.

Algorithms↗

PubMed2002

Effect of grapefruit juice intake on etoposide bioavailability.

PURPOSE: Oral administration of etoposide is limited by the high degree of unpredictable variation in systemic availability. This pilot study was conducted to evaluate the potential of pretreatment with grapefruit juice for improving the use of oral etoposide. METHODS: In a randomized crossover study, six patients were sequentially treated with 50 mg IV etoposide over 1 h, 50 mg orally, or 50 mg orally post grapefruit juice on day 1, day 4, and day 8. Blood samples were drawn up to 24 h after the end of infusion and oral drug administration. Plasma etoposide concentrations were determined by reversed-phase HPLC with UV detection. A two-compartment model was used for pharmacokinetic parameter estimation. Pharmacokinetic parameters were evaluated using descriptive statistics. RESULTS: Pretreatment with grapefruit juice resulted in an unexpected decrease of 26.2% in the AUC after oral treatment. Median absolute bioavailability with and without pretreatment with grapefruit juice was 52.4% and 73.2%, respectively. Interindividual variability was large in all treatment arms. CONCLUSION: Grapefruit juice seems to reduce rather than increase oral bioavailability of etoposide. Moreover, we did not observe a reduction in interpatient variability of bioavailability.

Administration, Oral↗

PubMed2001

Assessing variability by joint sampling of alignments and mutation rates.

When two sequences are aligned with a single set of alignment parameters, or when mutation parameters are estimated on the basis of a single "optimal" sequence alignment, the variability of both the alignment and the estimated parameters can be seriously underestimated. To obtain a more realistic impression of the actual uncertainty, we propose sampling sequence alignments and mutation parameters simultaneously from their joint posterior distribution given the two original sequences. We illustrate our method with human and orangutan sequences from the hyper variable region I and with gene-pseudogene pairs.

Animals↗

PubMed1998

Modelling and analysis of time-lags in some basic patterns of cell proliferation.

In this paper, we present a systematic approach for obtaining qualitatively and quantitatively correct mathematical models of some biological phenomena with time-lags. Features of our approach are the development of a hierarchy of related models and the estimation of parameter values, along with their non-linear biases and standard deviations, for sets of experimental data. We demonstrate our method of solving parameter estimation problems for neutral delay differential equations by analyzing some models of cell growth that incorporate a time-lag in the cell division phase. We show that these models are more consistent with certain reported data than the classic exponential growth model. Although the exponential growth model provides estimates of some of the growth characteristics, such as the population-doubling time, the time-lag growth models can additionally provide estimates of: (i) the fraction of cells that are dividing, (ii) the rate of commitment of cells to cell division, (iii) the initial distribution of cells in the cell cycle, and (iv) the degree of synchronization of cells in the (initial) cell population.

Animals↗

PubMed2006

Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model.

The plasma concentration-time profile of a drug is essential to explain the relationship between the administered dose and the kinetics of drug action. However, in some cases such as in pre-clinical pharmacology or phase-III clinical studies where it is not always possible to collect all the required PK information, this relationship can be difficult to establish. In these circumstances several authors have proposed simple models that can analyse and simulate the kinetics of the drug action in the absence of PK data. The present work further develops and evaluates the performance of such an approach. A virtual compartment representing the biophase in which the concentration is in equilibrium with the observed effect is used to extract the (pharmaco)kinetic component from the pharmacodynamic data alone. Parameters of this model are the elimination rate constant from the virtual compartment (KDE), which describes the equilibrium between the rate of dose administration and the observed effect, and the second parameter, named EDK(50) which is the apparent in vivo potency of the drug at steady state, analogous to the product of EC(50), the pharmacodynamic potency, and clearance, the PK "potency" at steady state. Using population simulation and subsequent (blinded) analysis to evaluate this approach, it is demonstrated that the proposed model usually performs well and can be used for predictive simulations in drug development. However, there are several important limitations to this approach. For example, the investigated doses should extend from those producing responses well below the EC(50) to those producing ones close to the maximum response, optimally reach steady state response and followed until the response returns to baseline. It is shown that large inter-individual variability on PK-PD parameters will produce biases as well as large imprecision on parameter estimates. It is also clear that extrapolations to dosage routes or schedules other than those used to estimate the parameters should be undertaken with great caution (e.g., in case of non-linearity or complex drug distribution). Consequently, it is advised to apply this approach only when the underlying structural PD and PK are well understood. In any case, K-PD model should definitively not be substituted for the gold standard PK-PD model when correct full model can and should be identified.

Adenosine↗

PubMed1988

A chemical kinetic model for ligand binding to identical and independent binding sites in vivo.

In living systems, hormones bind to receptor proteins that are continuously synthesized and degraded. Since these systems cannot be described by equilibrium binding equations, we present a chemical kinetic model for the binding of a hormone to a receptor with identical and independent binding sites in which synthesis and degradation occur. We have derived, from the model, equations that can be used to calculate the bound ligand concentration and the total protein concentration as a function of the free ligand concentration and time. These results show that the methods for experimental measurements, parameter estimation, interpretation of the parameters, and error analysis that are commonly used for equilibrium binding to identical and independent binding sites can be adapted for the analysis of steady-state binding data. The equations we derived for the steady-state ligand binding permit determination of the total receptor protein concentration and the binding affinity from experimental data. In contrast, if an equilibrium model were used, the values of these parameters would not necessarily approximate the true values. A useful approximation to the total receptor concentration as a function of time was found that requires only three of the five rate constants required for exact description by the model. This approximation is shown to be accurate in the biologically relevant range by using previously published parameters estimated from steroid binding data, and adding perturbations to include experimental error and variations among biological systems. When complexities exist, such that the model does not describe the data, these analyses aid in assessing the types of additional components and interactions that may exist.

Binding Sites↗

PubMed1986

Non-linear fitting program for biological data.

A simple microcomputer program written in Microsoft Basic estimates pharmacokinetic parameters using the coordinate search technique to minimize the sum of squared errors. The program developed for portable computers combines a plot of data and curve fitting so as to find rapidly the initial parameters with the subsequent optimization of the parameter estimate.

Computers↗

PubMed1990

Use of hidden Markov models for electrocardiographic signal analysis.

Hidden Markov modelling (HMM) is a powerful stochastic modelling technique that has been successfully applied to automatic speech recognition problems. We are currently investigating the application of HMM to electrocardiographic signal analysis with the goal of improving ambulatory ECG analysis. The HMM approach specifies a Markov chain to model a "hidden" sequence that in this case is the underlying state of the heart. Each state of the Markov chain has an associated output function that describes the statistical characteristics of measurement samples generated during that state. Given a measurement sequence and HMM parameter estimates, the most likely underlying state sequence can be determined and used to infer beat classification. Advantages of this approach include resistance to noise, ability to model low-amplitude waveforms such as the P wave, and availability of an algorithm for automatically estimating model parameters from training data. We have applied the HMM approach to QRS complex detection and to arrhythmia analysis with encouraging results.

Algorithms↗

PubMed1981

Determination of the dissociation constant of carbonic anhydrase inhibitors: a computerized kinetic method based on esterase activity assay.

We evaluate a reliable procedure for in vitro determination of the dissociation constant, Ki, of carbonic anhydrase inhibitors. This pharmacologically important parameter is estimated, using a mathematical model derived from the Ackermann-Potter equation, by a computer-assisted nonlinear regression analysis of kinetic data from the enzyme-catalyzed hydrolysis of p-nitrophenyl acetate. The proposed method has the additional advantage, over the ones that require the use of only paper and pencil, of giving standard errors for the estimated parameters. Based on our findings, a comparison of the reported values for the inhibition of carbonic anhydrase by twelve sulfamoyl drugs is presented, and the difficulties associated with the determination of dissociation constants for carbonic anhydrase inhibitors are discussed.

Carbonic Anhydrase Inhibitors↗

PubMed1985

GFREG: a computer program for maximum likelihood regression using the Generalized F distribution.

A FORTRAN program is described for maximum likelihood estimation within the Generalized F family of distributions. It can be used to estimate regression parameters in a log-linear model for censored survival times with covariates, for which the error distribution may have a great variety of shapes, including most distributions of current use in biostatistics. The optimization is performed by an algorithm based on the generalized reduced gradient method. A stepwise variable search algorithm for covariate selection is included in the program. Output features include: model selection criteria, standard errors of parameter estimates, quantile and survival rates with their standard errors, residuals and several plots. An example based on data from Princess Margaret Hospital, Toronto, is discussed to illustrate the program's capabilities.

Biometry↗

PubMed1996

Body height changes with hyperextension.

OBJECTIVE: To automatize the lumbar physical examination with an acceptable rate of error. DESIGN: An external skin marker method for automatizing the physical examination was developed and its ability to discriminate between normal and abnormal subjects tested in a blind clinical trial. BACKGROUND: The low reproducibility of clinical findings, even among experienced doctors, has been well documented. This is of particular concern and may explain why there is such a wide variation in surgical rates across the USA (tenfold for disc herniation). Inconsistencies among physicians in the evaluation of benign low back conditions make standardization desirable. METHODS: A computerized physical examination was used to evaluate patients with low back pain and compare their results with a normative database obtained from a selection of healthy subjects. A high-resolution motion analysis system tracked the movement of skin markers placed on the midline and pelvis. Surface EMG electrodes placed above L(5) collected data from multifidus. From the kinematics of skin markers during flexion--extension with lifts up to 32 kg, and lateral bending with lifts up to 10 kg, the following parameters were estimated: lumbosacral angle and elongation, contribution of each lumbar segment to the lordosis reduction, relative pelvic/spine motion, and trunk velocity. First the average normal value for each estimated parameter was determined using 40 normal subjects. For each subject the difference between his parameter and the normal was processed by an expert system generating a normality index varying from zero (perfect abnormal) to one (perfect normal). To develop the expert system's rules, a preliminary group of 20 very abnormal subjects was used, such that the normality index separated them from the normals. For validation, a set of 29 back-sprain patients and another set of 42 discogram-positive patients were selected. Each subject was tested and his computerized normality index calculated without any clinician's input, then compared with the clinician's evaluation, which was taken to be the gold standard. The receiver operating characteristic technique was used to quantify the discrepancies. RESULTS: The expert system could detect clinically abnormal subjects with accuracy (sensitivity 83-91% and specificity > 90%) whele providing quantitative information on workers' functional capacities. CONCLUSIONS: Once a reference normative database is agreed upon, each patient can be compared with that reference according to the same rules, with the resulting machine classification being independent of the clinician. This eliminates the inter- and intra-clinician variability in patient follow-up. Because of the severity of the selection criteria, this study is based upon a relatively restricted number of subjects, as well as a limited normative database of 40 subjects. RELEVANCE: It is possible to automate the lumbar physical examination with an acceptable error rate. This technique permits the objective consistent assessment of lumbar function, and thus allows the comparison of different treatment regimes for lumbar dysfunction.

Journal Article↗

PubMed2005

Understanding agglomeration of indomethacin during the dissolution of micronised indomethacin mixtures through dissolution and de-agglomeration modeling approaches.

The purpose of this research was to correlate the state of agglomeration determined by the modeling of dissolution and de-agglomeration profiles, using mixtures of micronised indomethacin designed to have different dissolution rates and extents of particle agglomeration in dissolution media. Dissolution profiles were determined using the USP paddle method. De-agglomeration profiles were obtained from laser diffraction particle sizing of mixtures of indomethacin in dissolution media under non-sink conditions. Data were modeled and key parameters estimated using a non-linear least squares estimation algorithm. The key parameters of initial apparent volume concentrations as dispersed and agglomerated particles, and dissolution rate constants (for dissolution modeling), and the apparent volume concentrations of dispersible and non-dispersible agglomerates and the de-agglomeration rate constant (for de-agglomeration modeling) were related to indomethacin and sodium lauryl sulphate concentrations in the lactose-povidone mixtures. Micronised sodium lauryl sulphate added to the mixture was more effective in de-agglomeration than equivalent concentrations in the dissolution media. An excellent correlation existed between the total initial apparent volume concentration of agglomerates determined by dissolution and de-agglomeration (P=0.98). The use of key parameters estimated from the modeling of dissolution and de-agglomeration profiles provides a useful tool in dosage form development of formulations of poorly water soluble drugs.

Chemistry, Pharmaceutical↗

PubMed2005

Characterizing the amplitude dynamics of the human core-temperature circadian rhythm using a stochastic-dynamic model.

Two measures, amplitude and phase, have been used to describe the characteristics of the endogenous human circadian pacemaker, a biological clock located in the hypothalamus. Although many studies of change in circadian phase with respect to different stimuli have been conducted, the physiologic implications of the amplitude changes (dynamics) of the pacemaker are unknown. It is known that phase changes of the human circadian pacemaker have a significant impact on sleep timing and content, hormone secretion, subjective alertness and neurobehavioral performance. However, the changes in circadian amplitude with respect to different stimuli are less well documented. Although amplitude dynamics of the human circadian pacemaker are observed in physiological rhythms such as plasma cortisol, plasma melatonin and core temperature data, currently methods are not available to accurately characterize the amplitude dynamics from these rhythms. Of the three rhythms core temperature is the only reliable variable that can be monitored continuously in real time with a high sampling rate. To characterize the amplitude dynamics of the circadian pacemaker we propose a stochastic-dynamic model of core temperature data that contains both stochastic and dynamic characteristics. In this model the circadian component that has a dynamic characteristic is represented as a perturbation solution of the van der Pol equation and the thermoregulatory response in the data that has a stochastic characteristic is represented as a first-order autoregressive process. The model parameters are estimated using data with a maximum likelihood procedure and the goodness-of-fit measures along with the associated standard error of the estimated parameters provided inference about the amplitude dynamics of the pacemaker. Using this model we analysed core temperature data from an experiment designed to exhibit amplitude dynamics. We found that the circadian pacemaker recovers slowly to an equilibrium level following amplitude suppression. In humans this reaction to perturbation from equilibrium value has potential physiological implications.

Body Temperature Regulation↗

PubMed2006

Model identification for DNA sequence-structure relationships.

We investigate the use of algebraic state-space models for the sequence dependent properties of DNA. By considering the DNA sequence as an input signal, rather than using an all atom physical model, computational efficiency is achieved. A challenge in deriving this type of model is obtaining its structure and estimating its parameters. Here we present two candidate model structures for the sequence dependent structural property Slide and a method of encoding the models so that a recursive least squares algorithm can be applied for parameter estimation. These models are based on the assumption that the value of Slide at a base-step is determined by the surrounding tetranucleotide sequence. The first model takes the four bases individually as inputs and has a median root mean square deviation of 0.90 A. The second model takes the four bases pairwise and has a median root mean square deviation of 0.88 A. These values indicate that the accuracy of these models is within the useful range for structure prediction. Performance is comparable to published predictions of a more physically derived model, at significantly less computational cost.

Crystallography, X-Ray↗

PubMed2005

Sample size determination for estimation of the accuracy of two conditionally independent tests in the absence of a gold standard.

We developed an Excel spreadsheet template (available at http://www.epi.ucdavis.edu/diagnostictests/) to calculate sample sizes to estimate sensitivity and specificity with desired precision in the absence of a gold standard. Calculations are predicated on the use of two conditionally independent tests for screening animals from two populations and are based on the methods of Hui and Walter(1980). Sample size calculations rely on asymptotic normality of maximum likelihood (ML) estimates of parameters. Spreadsheets for calculating standard errors for the parameter estimates and for providing ML estimates using cross-tabulated data also are included. An example of application of the methods to bovine paratuberculosis is presented.

Animals↗