SEARCH · PubMed Health

Results for “parameter estimation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,099 records · Page 61Linked to original sources

PubMedDate not supplied

A digital procedure for ground water recharge and discharge pattern recognition and rate estimation.

A digital procedure to estimate recharge/discharge rates that requires relatively short preparation time and uses readily available data was applied to a setting in central Wisconsin. The method requires only measurements of the water table, fluxes such as stream baseflows, bottom of the system, and hydraulic conductivity to delineate approximate recharge/discharge zones and to estimate rates. The method uses interpolation of the water table surface, recharge/discharge mapping, pattern recognition, and a parameter estimation model. The surface interpolator used is based on the theory of radial basis functions with thin-plate splines. The recharge/discharge mapping is based on a mass-balance calculation performed using MODFLOW. The results of the recharge/discharge mapping are critically dependent on the accuracy of the water table interpolation and the accuracy and number of water table measurements. The recharge pattern recognition is performed with the help of a graphical user interface (GUI) program based on several algorithms used in image processing. Pattern recognition is needed to identify the recharge/discharge zonations and zone the results of the mapping method. The parameter estimation program UCODE calculates the parameter values that provide a best fit between simulated heads and flows and calibration head-and-flow targets. A model of the Buena Vista Ground Water Basin in the Central Sand Plains of Wisconsin is used to demonstrate the procedure.

Automation↗

PubMed1998

Analysis of vinyl acetate metabolism in rat and human nasal tissues by an in vitro gas uptake technique.

Physiologically based pharmacokinetic (PBPK) models require estimates of catalytic rate constants controlling the metabolism of xenobiotics. Usually, these constants are derived from whole tissue homogenates wherein cellular architecture and enzyme compartmentation are destroyed. Since the nasal cavity epithelium is composed of a heterogeneous cell population measurement of xenobiotic metabolizing enzymes using homogenates could yield artifactual results. In this article a method for measuring rates of metabolism of vinyl acetate, a metabolism-dependent carcinogen, is presented that uses whole-tissue samples and PBPK modeling techniques to estimate metabolic kinetic parameters in tissue compartments. The kinetic parameter estimates were compared to those derived from homogenate experiments using two methods of tissue normalization. When the in vitro gas uptake constants were compared to homogenate-derived values, using a normalization procedure that does not account for tissue architecture, there was poor agreement. Homogenate-derived values from rat nasal tissue were 3- to 23-fold higher than those derived using the in vitro gas uptake method. When the normalization procedure for the rat homogenate-derived values took into account tissue architecture, a good agreement was observed. Carboxylesterase activity in homogenates of human nasal tissues was undetectable. Using the in vitro gas uptake technique, however, carboxylesterase activity was detected. Rat respiratory carboxylesterase and aldehyde dehydrogenase activities were about three and two times higher than those of humans, respectively. Activities of the rat olfactory enzymes were about equivalent to those of humans. K(m) values did not differ between species. The results suggest that the in vitro gas uptake technique is useful for deriving enzyme kinetic constants where effects of tissue architecture are preserved. Furthermore, the results suggest that caution should be exercised when scaling homogenate-derived values to whole-organ estimates, especially in organs of cellular heterogeneity.

Aged↗

PubMed1996

Using the EM-algorithm for survival data with incomplete categorical covariates.

Incomplete covariate data is a common occurrence in many studies in which the outcome is survival time. With generalized linear models, when the missing covariates are categorical, a useful technique for obtaining parameter estimates is the EM by the method of weights proposed in Ibrahim (1990). In this article, we extend the EM by the method of weights to survival outcomes whose distributions may not fall in the class of generalized linear models. This method requires the estimation of the parameters of the distribution of the covariates. We present a clinical trials example with five covariates, four of which have some missing values.

Algorithms↗

PubMed1994

Neuropsychological changes in children with cancer: the treatment of missing data in longitudinal studies.

Researchers conducting longitudinal studies with children or adults are inevitably confronted with problems of attrition and missing data. Missing data in longitudinal studies is frequently handled by excluding from analyses those cases for whom data are incomplete. This approach to missing data is not optimal. On the one hand, if data are missing at random, then dropping incomplete cases ignores information collected on those cases that could be used to improve estimates of population parameters (e.g., means, variances, covariances, and growth rates) and improve the power of significance tests of statistical hypotheses. On the other hand, if data are not missing at random, then dropping incomplete cases leads to biased parameter estimates and hypothesis tests that may be internally and externally invalid. This study uses three years of follow-up data from a longitudinal investigation of neuropsychological outcomes of cancer in children to demonstrate the problems presented by missing data in repeated measures designs and some solutions. In evaluating potential biasing effects of attrition, the study extends previous research on neuropsychological outcomes in pediatric cancer by inclusion of patients whose disease had relapsed, and by comparison of surviving and nonsurviving patients. Although the data presented have specific relevance to the study of neuropsychological outcome in pediatric cancer, the problems of missing data and the solutions presented are relevant to a wide variety of diseases and conditions of interest to researchers in child and adult neuropsychology.

Adolescent↗

PubMed1990

A theoretical description of arterial pressure-flow relationships with verification in the isolated hindlimb of the dog.

We developed and tested a new two-compartment serial model of the arterial vasculature which unifies the capacitance (downstream arterial compliance) and waterfall (constant downstream pressure load) theories of blood flow through the arteries. In this model, blood drains from an upstream compliance through a resistance into a downstream compliance which empties into the veins through a downstream resistance which terminates in a constant pressure load. Using transient arterial pressure data obtained from an isolated canine hindlimb preparation, we tested this model, using a stop-flow technique. Numerical parameter estimation techniques were used to estimate the physiologic parameters of the model. The downstream compliance was found to be more than ten times larger than the upstream compliance and the constant pressure load was significantly above venous pressures but decreased in response to vasodilation. Our results support the applicability of both the capacitance and waterfall theories.

Animals↗

PubMed1999

Variation in the pattern of nucleotide substitution across sites.

A model of nucleotide substitution that allows the transition/transversion rate bias to vary across sites was constructed. We examined the fit of this model using likelihood-ratio tests by analyzing 13 protein coding genes and 1 pseudogene. Likelihood-ratio testing indicated that a model that allows variation in the transition/transversion rate bias across sites provided a significant improvement in fit for most protein coding genes but not for the pseudogene. When the analysis was repeated with parameters estimated separately for first, second, and third codon positions, strong heterogeneity was uncovered for the first and second codon positions; the variation in the transition/transversion rate was generally weaker at the third codon position. The transition rate bias and branch lengths are underestimated when variation in the transition/transversion rate was not accommodated, suggesting that it may be important to accommodate variation in the pattern of nucleotide substitution for accurate estimation of evolutionary parameters.

Animals↗

PubMed2004

Development of an optimal sampling strategy for clinical pharmacokinetic studies of the novel anthracycline disaccharide analogue MEN-10755.

AIM: MEN-10755 is a novel anthracycline analogue that has shown an improved therapeutic efficacy over doxorubicin in animal models, especially in gynaecological and lung cancers and is currently under clinical development for the treatment of solid tumours. The aim of the project was to develop an optimal sampling strategy for MEN-10755 to provide an efficient basis for future pharmacokinetic/pharmacodynamic investigations. METHODS: Data from 24 patients who participated in a phase I clinical pharmacokinetic study of MEN-10755 administered as a short i.v. infusion were included. Individual pharmacokinetic values were calculated by fitting the plasma concentration data to a two-compartment model using nonlinear least-squared regression (KINFIT, Ed 3.5). Population pharmacokinetic analysis was carried out using (a) the traditional standard two-stage method (STS) based on all data (KINFIT-ALL), (b) the iterative two-stage Bayesian (IT(2)B) population modelling algorithm (KINPOP), and (c) the STS method using KINFIT and using four optimally timed plasma concentrations (KINFIT-OSS4). Determinant (D) optimal sampling strategy (OSS) was used to evaluate the four most information-rich sampling times. The pharmacokinetic parameters V(c) (l), k(el) (h(-1)), k(12) (h(-1)) and k(21) (h(-1)) calculated using KINPOP served as a model for calculation of four D-optimal sampling times. D-optimal sampling data sets were analysed using KINFIT-OSS4 and compared with the population model obtained by the traditional standard two-stage approach for all data sets (KINFIT-ALL). RESULTS: The optimal sampling times were: the end of the infusion, and 1.5 h, 3.8 h and 24 h after the start of the infusion. The four-point D-optimal sampling design determined in this study gave individual parameter estimates close to the basic standard estimates using the full data set. CONCLUSION: Because accurate estimates of pharmacokinetic parameters were achieved, the four-point D-optimal sampling design may be very useful in future studies with MEN-10755.

Algorithms↗

PubMed2005

Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients.

PURPOSE: The objectives of these population pharmacokinetic analyses were to (1) assess the overall disposition of pemetrexed, (2) characterize between-patient and within-patient variability and identify influential covariates with respect to pemetrexed pharmacokinetics; and, (3) provide individual empirical Bayesian estimates of pharmacokinetic parameters for use in a subsequent pharmacokinetic/pharmacodynamic evaluation of neutropenia following pemetrexed administration. PATIENTS AND METHODS: Data from 287 patients who received 441 cycles without folic acid or vitamin B12 supplementation during participation in one of ten phase II cancer trials were evaluated by population pharmacokinetic analysis using NONMEM. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area, administered as 10-min intravenous infusions every 21 days (1 cycle). The model was developed using data from eight of the ten studies. Predictive performance was evaluated using data from the other two studies. RESULTS: The population pharmacokinetics of pemetrexed administered as a 10-min intravenous infusion are well characterized by a two-compartment model. Typical values of total systemic clearance, central volume of distribution, distributional clearance, and peripheral volume of distribution were 91.6 ml/min, 12.9 l, 14.4 ml/min, and 3.38 l, respectively. Based on these parameter estimates, the terminal elimination half-life of pemetrexed was approximately 3.5 h. Renal function was identified as a covariate with respect to total systemic clearance, and body surface area as a covariate with respect to the central volume of distribution. CONCLUSION: Total systemic exposure (AUC) for a given dose of pemetrexed increases as renal function decreases. Since pharmacodynamic analyses have shown that AUC and not C (max) is the primary determinant of neutropenic response to pemetrexed, this suggests that dose adjustments based on renal function, rather than body surface area, might be considered for pemetrexed.

Adolescent↗

PubMed1993

Models for computer simulation studies of input functions for tracer kinetic modeling with positron emission tomography.

In tracer kinetic modeling with Positron Emission Tomography (PET), the direct measurement (piecewise linear approximation) of plasma time-activity curve of tracer (PTAC) is often used as the input function to estimate regional physiological parameters. However, no explicit general model is available for PTAC itself, which limits the further study of the effects of PTAC, such as PTAC measurement noise or PTAC sampling schedules, on the physiological parameters estimation. A PTAC model is proposed in this paper and compared with other four possible candidates. Eight sets of [18F]-fluoro-2-deoxy-D-glucose (FDG) experimental data were used to test the models and several statistical criteria were used to validate their adequacy. An application of the model to improve the estimation of local cerebral metabolic rate of glucose (LCMRGlc) is presented. This model is also expected to be useful for generating realistic PTAC curves in computer simulation studies of other tracers and their kinetic modeling characteristics.

Animals↗

PubMedDate not supplied

An improved hybrid HIV/AIDS model geared to specific public health data and decision making.

An improved version of a previously described compartmental dynamic model for the spread of the HIV virus and AIDS is presented in which the estimation of key parameters depends entirely on the use of good public health data. This means that practical applications to specific regions, using only local data, can be of great value to public health decision makers dealing with local problems. It is assumed that scientific support is available within an interdisciplinary operations research context. The improved model incorporates physicians' delays in reporting AIDS incidence, additional cases revealed by death certificate analysis, and a high-risk core group of HIV positives involving a limited residence time, followed by a low-risk group with extended residence, both groups leading to AIDS cases. The model is hybrid in character in the sense that the HIV infection process with large numbers is deterministic while the incubation process with small numbers initially is stochastic. Applications have been made to Switzerland. Key parameters estimated include, in particular, the actual sizes of the original core groups for gay men and intravenous drug users. Current numbers of circulating HIV positives are also obtained.

Acquired Immunodeficiency Syndrome↗

PubMed1986

Linkage disequilibria in finite populations.

Four-locus recombination frequencies are summarized into two-locus pair frequencies and three-locus frequencies, and further, into two-locus frequencies such that higher-order frequencies are linear functions of lower-order frequencies. Frequencies of gene combinations are defined according to their position on the same or distinct gametes, and linear functions of these provide the measures of linkage disequilibria. These concepts are utilized to derive the transitional behavior of the gene combinations frequencies and the linkage disequilibria in a finite monoecious population with random union of gametes for up to four loci. The transitions of lower-order disequilibria in a higher-order (more loci) setting involve the higher-order disequilibria which must be taken into account in arriving at the final (fixation) frequencies. The methods allow different initial conditions. Since corresponding data functions of the gene combination frequencies provide unbiased estimates of the parameters, estimators follow naturally.

Gene Frequency↗

PubMed1995

A simple, automatic method for morphometric analysis of the left ventricle in rats with myocardial infarction.

Induction of acute myocardial infarction in the rat is an established model for studying effects of therapeutic interventions. Images of sections of the rat left ventricle, stained with nitroblue tetrazolium, were digitized and several parameters estimated by dedicated software on an image analyzer (IBAS 2.0). The method was tested on 7 rats with 48-hr-old myocardial infarction and 4 sham-operated controls. Infarct size can be evaluated by two largely used methods, based on area or on angular extension of the lesion. Results of the two methods are linearly correlated, but area calculations give values half of those obtained from angular extension. Five minutes were needed for a complete evaluation of a section of the left ventricle. Estimates of the parameters showed a relatively low between- and within-operator variability and a good correlation with a classic, but time-consuming, planimetric method. The method simultaneously measures infarct size and left ventricular geometry in the rat. The advantages over previous nonautomatic methods are simplicity, good reproducibility, and speed of execution, which make it particularly useful in the evaluation of drug effects.

Analysis of Variance↗

PubMed2006

Dynamic modeling of chemical fate and transport in multimedia environments at watershed scale-I: theoretical considerations and model implementation.

A geo-referenced environmental fate model was developed for analyzing unsteady-state dispersion and distribution of chemicals in multimedia environmental systems. Chemical transport processes were formulated in seven environmental compartments of air, canopy, surface soil, root-zone soil, vadose-zone soil, surface water, and sediment. The model assumed that the compartments were completely mixed and chemical equilibrium was established instantaneously between the sub-compartments within each compartment. A fugacity approach was utilized to formulate the mechanisms of diffusion, advection, physical interfacial transport, and transformation reactions. The governing equations of chemical mass balances in the environmental compartments were solved simultaneously to reflect the interactions between the compartments. A geographic information system (GIS) database and geospatial analysis were integrated into the chemical transport simulation to provide spatially explicit estimations of model parameters at watershed scale. Temporal variations of the environmental properties and source emissions were also considered in the parameter estimations. The outputs of the model included time-dependent chemical concentrations in each compartment and its sub-compartments, and inter-media mass fluxes between adjacent compartments at daily time steps.

Computer Simulation↗

PubMed2004

Genetic parameters of multiple ovulation traits in Nellore females.

Variability in superovulatory response is a limiting factor for animal breeding programs using Multiple Ovulation and Embryo Transfer (MOET) nucleus schemes. To evaluate genetic factors affecting superovulory response, 1036 multiple ovulation records from 475 Brazilian Nellore embryo donors (daughters of 139 sires), 2.2-20.5-year olds, were analyzed. Traits used to evaluate superovulatory response included the number of palpable corpora lutea (CL), the total number of recovered structures (RS), and the number of viable embryos (VE). Two data sets were used: data from the first flush only or data from the first three flushes. Genetic parameter estimations were carried out using Restricted Maximum Likelihood (REML) methodology, with single- and multiple-trait animal models. According to the data set used, heritability estimates ranged from 0.47 to 0.57 for CL, from 0.20 to 0.65 for VE, and from 0 to 0.34 for RS, and were higher for the data set that used only the first flushing only. For the first flush, genetic correlations were 0.43 between CL and SF, 0.01 between CL and VE, and 0.73 between SF and VE. Repeatability estimates ranged from 0.47 to 0.51. In conclusion, the use of data from the first flush only might result in better estimates of genetic parameters for MOET traits in Nellore females. Furthermore, moderate to high values for repeatability suggested that selection for a high response to superovulation could be made after the first flush.

Animals↗

PubMed1999

In vitro characterization of the erythrocyte distribution of methazolamide: a model of erythrocyte transport and binding kinetics.

The rate and extent of binding of methazolamide to human erythrocytes was studied in vitro. All experiments were carried out at physiological temperature (37 C) and pH (7.4). Methazolamide (MTZ) buffer concentrations were analyzed by HPLC. Distributional equilibrium between buffer and washed red blood cells was achieved after 1 hr. Results of equilibrium studies were consistent with two classes of binding sites for MTZ within the erythrocyte: a low affinity, high capacity site (CA-I) and a high affinity, low capacity site (CA-II). A two-binding site model was fitted to experimental data generating estimates for binding parameters Ka1 (0.0017 +/- 0.00022 microM-1) nM1 (636 +/- 5.23 microM), Ka2(0.46 +/- 0.0083 microM-1), and nM2(80.9 +/- 0.389 microM). Based upon these findings, kinetic studies were performed in order to characterize the rate of drug distribution. The rate of erythrocyte uptake of MTZ was mathematically modeled using a series of differential equations describing drug diffusion across the red blood cell membrane and subsequent complexation with intracellular binding sites. The model assumed that penetration of MTZ into the red blood cells was passive but drug binding to the carbonic anhydrase isozymes was not instantaneous. Using a novel curve fitting technique, parameter estimates of RBC membrane permeability (0.0102 +/- 0.000618 cm/min), and binding rate constants k-1(0.254 +/- 0.0213 min-1), k1 (0.0022 +/- 0.00020 ml/microgram-min), k-2(1.59 +/- 0.0358 min-1), and k2(3.1 +/- 0.035 ml/microgram-min) were obtained. The model characterized the observed biphasic decline of MTZ buffer concentrations over time and may help explain the prolonged residence of MTZ in vivo.

Binding Sites↗

PubMed2003

Sample size for multiple regression: obtaining regression coefficients that are accurate, not simply significant.

An approach to sample size planning for multiple regression is presented that emphasizes accuracy in parameter estimation (AIPE). The AIPE approach yields precise estimates of population parameters by providing necessary sample sizes in order for the likely widths of confidence intervals to be sufficiently narrow. One AIPE method yields a sample size such that the expected width of the confidence interval around the standardized population regression coefficient is equal to the width specified. An enhanced formulation ensures, with some stipulated probability, that the width of the confidence interval will be no larger than the width specified. Issues involving standardized regression coefficients and random predictors are discussed, as are the philosophical differences between AIPE and the power analytic approaches to sample size planning.

Humans↗

PubMed1997

Pharmacokinetic-pharmacodynamic modelling of the anti-lipolytic and anti-ketotic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine in rats.

1. The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals. 2. After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and beta-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3. The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 microg kg[-1] in 5 min and 15 min, and 120 microg kg[-1] in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+/-s.e., n=19) were Emax: -80+/-2% (% change from baseline), EC50: 22+/-2 ng ml(-1), and Hill factor: 2.2+/-0.2. 4. In another group, given 400 microg kg(-1) SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal Emax model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC50 values (mean+/-s.e., n=6) were 131+/-31 ng ml(-1) and 20+/-3 ng ml(-1) for heart rate and NEFA lowering effect, respectively. 5. In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

3-Hydroxybutyric Acid↗

PubMed2003

Complete curve fitting of extraction profiles for estimating uncertainties in recovery estimates.

This paper reports the use of improved numerical approaches to modelling extraction profiles, and shows that the approach substantially reduces statistical prediction uncertainties compared to those obtained on the basis of a three-point extrapolation from the later part of the extraction curve. Numerical fitting of manually obtained polycyclic aromatic hydrocarbon extraction data to a spherical particle diffusion model showed uncertainties typically reduced by a factor of three (with extremes at 1.02 and 770). Application to pressurised fluid extraction study of pelletised poly(vinylchloride) containing 30 mass% di(2-ethylhexyl)phthalate also showed good improvements. However, this high precision data showed small but significant lack of fit resulting in residual correlation and visibly biased prediction (more so than simple extrapolation). Re-fitting and uncertainty estimation using a first-order autoregression approximation to the covariance matrix produced more realistic uncertainty estimates and closer parameter estimates and is accordingly recommended for treating residual correlation from other causes, but did not entirely alleviate the problem. Different shape models (spherical, plane sheet and cylindrical) were applied without accounting fully for fitting error, and particle size effects were eliminated by modelling a simple size distribution. However, an approximate model based on linearly concentration-dependent diffusion coefficient showed excellent fit, confirming concentration-dependence as the most likely cause. This semiempirical model led to an uncertainty in total extractable material, at 0.2% of the total extractable value (with allowance for correlation). This is potentially good enough for recovery estimation and correction in certification of reference materials for validation purposes.

Journal Article↗