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PubMed1991

The specificity of the effects of stimulant medication on classroom learning-related measures of cognitive processing for attention deficit disorder children.

There appear to be beneficial effects of stimulant medication on daily classroom measures of cognitive functioning for Attention Deficit Disorder (ADD) children, but the specificity and origin of such effects is unclear. Consistent with previous results, 0.3 mg/kg methylphenidate improved ADD children's performance on a classroom reading comprehension measure. Using the Posner letting-matching task and four additional measures of phonological processing, we attempted to isolate the effects of methylphenidate to parameter estimates of (a) selective attention, (b) the basic cognitive process of retrieving name codes from permanent memory, and (c) a constant term that represented nonspecific aspects of information processing. Responses to the letter-matching stimuli were faster and more accurate with medication compared to placebo. The improvement in performance was isolated to the parameter estimate that reflected nonspecific aspects of information processing. A lack of medication effect on the other measures of phonological processing supported the Posner task findings in indicating that methylphenidate appears to exert beneficial effects on academic processing through general rather than specific aspects of information processing.

Arousal↗

PubMed1989

Segregation analysis of quantitative traits in nuclear families: comparison of three program packages.

Segregation analysis frequently is used to test for the presence of major gene effects and to estimate the various genetic and environmental components contributing to diseases. Recent advances in both theoretical models and computational algorithms have provided a number of new programs for performing segregation analyses. We compared two newer programs: REGC (part of the package "SAGE") and FISHER/MENDEL with an older established program (PAP) to determine relative accuracy in recovering parameter values and asymptotic standard errors, ability to discriminate between alternative transmission models, and execution speeds. Each program was applied to a set of computer simulations of a quantitative trait generated under a variety of genetic models. The results of these comparisons indicated that all the programs provided very similar parameter estimates, but that they differed in their abilities to identify the correct mode of transmission. In our simulations, PAP more often led to the selection of the correct transmission model, whereas REGC frequently indicated the presence of a major gene in simulations of purely polygenic transmission. Relative speeds for the programs differed, and their rank ordering varied with the complexity of the model being fitted. Although REGC was the fastest program for fitting a major gene or mixed model, it was by far the slowest program for estimating parameters in a sporadic or polygenic model.

Computer Simulation↗

PubMed2003

An evaluation of population D-optimal designs via pharmacokinetic simulations.

One goal of large scale clinical trials is to determine how a drug is processed by, and cleared from, the human body [i.e., its pharmacokinetic (PK) properties] and how these PK properties differ between individuals in a population (i.e., its population PK properties). Due to the high cost of these studies and the limited amount of data (e.g., blood samples) available from each study subject, it would be useful to know how many measurements are needed and when those measurements should be taken to accurately quantify population PK model parameters means and variances. Previous studies have looked at optimal design strategies of population PK experiments by developing an optimal design for an individual study (i.e., no interindividual variability was considered in the design), and then applying that design to each individual in a population study (where interindividual variability is present). A more algorithmically and informationally intensive approach is to develop a population optimal design, which inherently includes the assessment of interindividual variability. We present a simulation-based evaluation of these two design methods based on nonlinear Gaussian population PK models. Specifically, we compute standard individual and population D-optimal designs and compare population PK model parameter estimates based on simulated optimal design measurements. Our results show that population and standard D-optimal designs are not significantly different when both designs have the same number of samples per individual. However, population optimal designs allow for sampling schedules where the number of samples per individual is less than the number of model parameters, the theoretical limit allowed in standard optimal design. These designs with a low number of samples per individual are shown to be nearly as robust in parameter estimation as standard D-optimal designs. In the limit of just one sample per individual, however, population D-optimal designs are shown to be inadequate.

AIDS Vaccines↗

PubMed2004

Small-dose intrathecal clonidine and isobaric bupivacaine for orthopedic surgery: a dose-response study.

We examined the dose-response relationship of intrathecal clonidine at small doses (<or=150 microg) with respect to prolonging bupivacaine spinal anesthesia. We aimed for establishing doses of intrathecal clonidine that would produce clinically relevant prolongation of spinal anesthesia and pain relief without significant side effects. Eighty orthopedic patients were randomly assigned to intrathecally receive isobaric 0.5% bupivacaine, 18 mg, plus saline (Group 1), clonidine 37.5 microg (Group 2), clonidine 75 microg (Group 3), and clonidine 150 microg (Group 4). Duration of the sensory block (regression below level L1) was increased in patients receiving intrathecal clonidine: 288 +/- 62 min (Group 1, control), 311 +/- 101 min in Group 2 (+8%), 325 +/- 69 min in Group 3 (+13%), and 337 +/- 78 min in Group 4 (+17%) (estimated parameter for dose 0.23 [95% confidence interval -0.05-0.50]). Duration of pain relief from intrathecal clonidine administration until the first request for supplemental analgesia was significantly prolonged: 295 +/- 80 min (Group 1, control), 343 +/- 75 min in Group 2 (+16%), 381 +/- 117 min in Group 3 (+29%), and 445 +/- 136 min in Group 4 (+51%) (estimated parameter for dose 1.02 [95% confidence interval 0.59-1.45]). Relative hemodynamic stability was maintained and there were no between-group differences in the sedation score. We conclude that small doses of intrathecal clonidine (<or=150 microg) significantly prolong the anesthetic and analgesic effects of bupivacaine in a dose-dependent manner and that 150 microg of clonidine seems to be the preferred dose, in terms of effect versus unwarranted side effects, when prolongation of spinal anesthesia is desired.

Adjuvants, Anesthesia↗

PubMedDate not supplied

Biokinetic evaluation and modeling of continuous thiocyanate biodegradation by Klebsiella sp.

Biokinetics for autotrophic degradation of thiocyanate using batch culture of Klebsiella sp. were evaluated both analytically and numerically. A sequential approach with an analytical method followed by a numerical approximation was used to evaluate and to ensure the accuracy of the parameter estimation. The nonlinear least-squares method with a 95% confidence interval was employed. The growth conditions were maintained at pH 7 and 38 degrees C for all experiments. With an automated incubation and turbidity reader, a total of 16 different initial thiocyanate concentrations, ranging from 10 to 300 mg L(-1), were used to develop a kinetic expression of specific growth rate as a function of substrate concentration. The biodegradation of thiocyanate with Klebsiella sp. followed a substrate inhibition pattern. Three identical automated bioreactors with working volumes of 1.5 L, equipped with sterilizable sampling ports, were also used for the numerical approximation of the biokinetic parameters in batch mode. A fourth order Runge-Kutta method was used to approximate the substrate inhibition kinetics of the Klebsiella sp. utilizing thiocyanate. Although the kinetic coefficients estimated by analytical and numerical methods were not statistically different at a 0.05 alpha level, model responses of numerical approximation generated a better prediction of changes in thiocyanate and cell mass concentrations. The hypothetical maximum growth rate, micro m, half saturation coefficient, Ks, microbial yield coefficient, Y, cell mass decay rate coefficient, kd, and substrate inhibition coefficient, Ksi, were evaluated as being 0.62 +/- 0.05 d(-1), 85 +/- 8 mg SCN- L(-1), 0.076 +/- 0.011 mg cell mass (mg SCN)(-1), 0.03 +/- 0.002 d(-1), and 131 +/- 22 mg SCN- L(-1), respectively. The calculated maximal substrate concentration, Sm, and apparent maximum specific growth rate, micro'm, were 105.5 +/- 8.7 mg SCN- L(-1) and 0.24 +/- 0.01 d(-1), respectively. Using these estimated parameters, the theoretical performance of the continuous operation was also illustrated, which depicts the residual thiocyanate and Klebsiella sp. concentrations in the non-steady and steady states at different hydraulic retention times (HRTs). Assuming the influent concentration of 250 mg SCN- L(-1), the expected treatment efficiency ranged from 94.9% to 69.4% between 20 and 5 days HRT, respectively. Klebsiella sp. was expected to be washed out at 4.8 days HRT, thus resulting in no treatment of thiocyanate.

Hydrolysis↗

PubMed1999

Spectral fitting of NMR spectra using an alternating optimization method with a priori knowledge.

As alternatives to the fast Fourier transform, advanced parametric methods based on the damped sinusoidal data model have been devised to better quantify the nuclear magnetic resonance (NMR) spectroscopy time-domain data. Previously, linear prediction (LP) fitting methods using Householder triangularization and singular value decomposition (SVD) techniques have been applied to the NMR spectroscopy data analysis. In this paper, we propose an alternating optimization method to quantify the time-domain NMR spectroscopy data. The proposed algorithm uses the a priori knowledge of the possible frequency intervals of the damped sinusoids to obtain more accurate parameter estimates when the NMR spectroscopy data are obtained under low signal-to-noise ratio conditions and the peaks are close together. None of the LP and SVD type of methods can use such approximate a priori knowledge. We have shown with measured NMR spectroscopy data that the proposed algorithm can be used to obtain accurate parameter estimates of frequencies, amplitudes, and damping ratios of the damped sinusoids and therefore the ultimate fit of the spectrum by using the a priori knowledge about the possible frequency intervals of the damped sinusoids.

Algorithms↗

PubMedDate not supplied

Software for experimental design: the computer program EXCAD.

A computer program (EXCAD) dedicated to the optimization of experimental designs to estimate parameters of a mathematical model, is presented. EXCAD computes D-optimal designs and sequentially augmented designs. D-optimal designs minimize the determinant of the variance-covariance matrix and parameters, thus obtaining the average most accurate estimate of parameters. D-optimal designs have generally as many support points as the number of parameters in the mathematical model, so sample scheduling is minimal, not extensive. Augmented designs add to an original design the point that maximizes the decrement of the determinant of the variance-covariance matrix. The general model, linearly or not linearly parametrized Y = F(X,P), that relates two independent variables and P parameters to different responses may be written in the program, while a set of prewritten models is provided.

Algorithms↗

PubMed1990

Pulmonary arterial compliance at rest and exercise in normal humans.

We evaluated the feasibility of determining pulmonary arterial compliance (Cp) by a parameter estimation procedure based on the three-element windkessel model. Eight normal patients studied with multisensor micromanometry technology had simultaneous rest and exercise pulmonary artery pressures (PAP) and flows recorded. These were submitted to the model and independent methods to determine Cp, pulmonary characteristic impedance (Zc), and pulmonary vascular resistance (PVR). Significant changes in heart rate, PAP, and stroke volume (P less than 0.05) occurred with exercise. In comparing rest and exercise Zc and PVR values determined by the model and independent methods, and in comparing each method for these values, there was no significant difference. Model-derived and independently derived estimates of Cp were significantly different at rest (P less than 0.04) and exercise (P less than 0.001). There was no significant difference between rest and exercise values of Cp by either method. The model estimates of PVR at rest (64 +/- 11 dyn.s.cm-5) and exercise (41 +/- 7 dyn.s.cm-5) (P = 0.06) and the model Zc value at rest (22 +/- 3 dyn.s.cm5) were appropriate. The model Cp values at rest (0.22 +/- 0.05 ml.mmHg-1.kg-1) correlated with previously reported normalized values in other species. This study reports the successful use of a parameter estimation procedure based on the three-element windkessel model to describe pulmonary artery compliance in normal humans.

Adult↗

PubMed1976

Estimation of parameters for a model of transmitter release at synapses.

We consider models for the release of transmitter in response to nerve impulses, where it is assumed that quanta of transmitter are released from some of n sites, the probability of release from any site being p. It is assumed that the quantal size is either a constant or is distributed as a normal or a gamma variate. Observations on both spontaneous potentials and evoked potentials are used to obtain moment estimated of n and p. Large sample estimates of the standard errors of these estimates are given.

Mathematics↗

PubMed2000

Validation of a population pharmacokinetic model for adjunctive lamotrigine therapy in children.

AIMS: This analysis was performed to validate a previously developed population pharmacokinetic model for lamotrigine in order to establish a basis for dosage recommendations for children. METHODS: (a) The importance of the covariates in the final model was confirmed using the model validation dataset. Population and individual (Bayesian estimate) pharmacokinetic parameters were estimated using both the initial model, which included none of the covariates, and the final model. Accuracy and precision of parameter estimation and of concentration prediction were compared between the two models. (b) The performance in predicting the validation concentrations by the final model parameters obtained previously from the model development dataset was assessed. (c) The parameters of the final model were refined using a dataset combining both the development and validation data. RESULTS: Prediction performance of the final pharmacostatistical model was superior to that of the initial model. The results of the validation confirmed that concomitant antiepileptic drugs that increased or reduced lamotrigine clearance in adults had similar effects in children. The validation also verified the linear relationship between weight and clearance. The previously seen small sex effect on clearance was found statistically insignificant. CONCLUSIONS: The current analysis confirmed the previous findings. To achieve the same concentrations, children receiving enzyme-inducing antiepileptic drugs without valproate require higher doses than those receiving valproate; and heavier children require higher doses.

Adolescent↗

PubMed2006

Multiple imputation of missing genotype data for unrelated individuals.

The objective of this study was to investigate the performance of multiple imputation of missing genotype data for unrelated individuals using the polytomous logistic regression model, focusing on different missingness mechanisms, percentages of missing data, and imputation models. A complete dataset of 581 individuals, each analysed for eight biallelic polymorphisms and the quantitative phenotype HDL-C, was used. From this dataset one hundred replicates with missing data were created, in different ways for different scenarios. The performance was assessed by comparing the mean bias in parameter estimates, the root mean squared standard errors, and the genotype-imputation error rates. Overall, the mean bias was small in all scenarios, and in most scenarios the mean did not differ significantly from 'no bias'. Including polymorphisms that are highly correlated in the imputation model reduced the genotype-imputation error rate and increased precision of the parameter estimates. The method works well for data that are missing completely at random, and for data that are missing at random. In conclusion, our results indicate that multiple imputation with the polytomous logistic regression model can be used for association studies to deal with the problem of missing genotype data, when attention is paid to the imputation model and the percentage of missing data.

Cholesterol, HDL↗

PubMed1988

Frequency response analysis of human saccadic eye movements: estimation of stochastic muscle forces.

A frequency response method is used to estimate parameters of a fourth-order model of the oculomotor system and the active state tensions during a saccadic eye movement. The lateral and medial rectus muscle of each eye is modeled as a parallel combination of an active state tension generator with a viscosity and elastic element, connected to a series elastic element. The eyeball is modeled as a sphere connected to a viscosity and elastic element. Each of these elements is assumed to be ideal and linear. The active state tension for each muscle is modeled by a low-pass filtered pulse-step waveform. Initial estimates of the oculomotor mechanical components are based on physiological evidence. Initial estimates of the active state tension are based on an extrapolation of the eye movement trajectory. Horizontal saccadic eye movements were recorded from infrared signals reflected from the anterior surface of the cornea and then digitized. Parameter estimates were calculated for the model by using a conjugate gradient search program which minimizes the integral of the absolute value of the squared error between the model and the data. The predictions of the model are shown to be in good agreement with the data. Final estimates of motoneuronal activity demonstrate that the agonist muscle is maximally stimulated during the early portion of a saccadic eye movement regardless of the amplitude of the saccade; only the duration of the maximal stimulation affects the size of the saccade. The antagonist muscle is completely inhibited during the period of maximum agonist muscle stimulation. Furthermore, it is demonstrated that saccade motoneuronal activity is a stochastic phenomenon.

Elasticity↗

PubMed1985

A kinetic analysis of enzyme inactivation as applied to the covalent modification of Na+ + K+ -ATPase and Ca2+ -ATPase.

A kinetic analysis of enzyme inactivation due to the covalent binding of chemically modified ligands is presented. Reaction schemes similar to the Michaelis-Menten scheme have been studied as well as schemes with two states of the enzyme or two binding sites. The resulting kinetic equations lead to time courses of inactivation which can be represented by two exponential functions at least in a quasi-steady state approximation. These curves are frequently encountered in inactivation experiments. Since rapid methods for model selection and parameter estimation are desirable, but not available, a technique for a preliminary analysis of the experimental data is presented. A mere glance at the time courses shows what reaction schemes are inapplicable. For each family of inactivation curves, the construction of a line of intersections is proposed. This line contains essential kinetic information and can further be utilized for a rough parameter estimation. The technique is illustrated for three sets of experimental data where Na+ + K+ -ATPase and Ca2+ -ATPase have been inactivated by ATP-analogs.

Adenosine Triphosphate↗

PubMed1992

Multiple dipole modeling and localization from spatio-temporal MEG data.

An array of biomagnetometers may be used to measure the spatio-temporal neuromagnetic field or magnetoencephalogram (MEG) produced by neural activity in the brain. A popular model for the neural activity produced in response to a given sensory stimulus is a set of current dipoles, where each dipole represents the primary current associated with the combined activation of a large number of neurons located in a small volume of the brain. An important problem in the interpretation of MEG data from evoked response experiments is the localization of these neural current dipoles. We present here a linear algebraic framework for three common spatio-temporal dipole models: i) unconstrained dipoles, ii) dipoles with a fixed location, and iii) dipoles with a fixed orientation and location. In all cases, we assume that the location, orientation, and magnitude of the dipoles are unknown. With a common model, we show how the parameter estimation problem may be decomposed into the estimation of the time invariant parameters using nonlinear least-squares minimization, followed by linear estimation of the associated time varying parameters. A subspace formulation is presented and used to derive a suboptimal least-squares subspace scanning method. The resulting algorithm is a special case of the well-known MUltiple SIgnal Classification (MUSIC) method, in which the solution (multiple dipole locations) is found by scanning potential locations using a simple one dipole model. Principal components analysis (PCA) dipole fitting has also been used to individually fit single dipoles in a multiple dipole problem. Analysis is presented here to show why PCA dipole fitting will fail in general, whereas the subspace method presented here will generally succeed. Numerically efficient means of calculating the cost functions are presented, and problems of model order selection and missing moments are discussed. Results from a simulation and a somatosensory experiment are presented.

Algorithms↗

PubMed1990

Clinical pharmacology of imipenem and cilastatin in premature infants during the first week of life.

The first-dose and multidose pharmacokinetics of imipenem and cilastatin were evaluated in 41 premature infants during their first week of life. Premature infants (gestational age, less than or equal to 37 weeks) were assigned to receive 10-, 15-, 20-, or 25-mg/kg doses of imipenem-cilastatin (1:1) as a single- or multiple-dose regimen. A total of 39 infants received a single dose, whereas 18 infants received multiple doses. No differences were observed in pharmacokinetic parameter estimates for either agent relative to the dose administered or infant body weight; thus, the data were pooled. Elimination half-life, steady-state volume of distribution, and body clearance averaged 2.5 h, 0.5 liter/kg, and 2.5 ml/min per kg, respectively, for imipenem and 9.1 h, 0.4 liter/kg, and 0.5 ml/min per kg, respectively, for cilastatin. Similar values for these parameter estimates were observed after multidose administration, although substantial accumulation of cilastatin in serum was observed. A total of 21% of the imipenem and 43% of the cilastatin were excreted unchanged in the urine over a 12-h collection period. Corresponding renal clearances averaged 0.4 and 0.2 ml/min per kg for imipenem and cilastatin, respectively. Substantial differences were observed in the route by which imipenem was cleared from the body compared with data from adult volunteers. These data suggest that infants should receive an imipenem dose of 20 mg/kg administered every 12 h for the treatment of bacterial infections outside the central nervous system.

Cilastatin↗

PubMed1997

Evaluation of a sparse sampling strategy for determining vancomycin pharmacokinetics in preterm neonates: application of optimal sampling theory.

OBJECTIVE: To use optimal sampling theory to determine the fewest vancomycin concentrations required and the appropriate sampling times to calculate vancomycin pharmacokinetic parameters in neonates. DESIGN: Unblinded evaluation in neonates with presumed sepsis. SETTING: Level 3 community-based neonatal intensive care unit. PATIENTS: Eleven neonates with presumed sepsis. INTERVENTIONS: Twelve courses of intravenous vancomycin 20 mg/kg were administered. Blood samples were collected 3 and 9 hours after initiation of a 1-hour infusion of the first dose. MEASUREMENTS AND MAIN RESULTS: A two-compartment model was fit to vancomycin concentrations using iterative two-stage analysis. Pharmacokinetic parameter estimates were used for determination of optimal sampling times for two-, three-, and four-sample strategies with subsequent generation of two-, three-, and four-sample concentration data for 100 cases. Relative performance of strategies was compared through calculation and comparison of D efficiency for the determined strategies. Bias (median percent error) and precision (median percent absolute error) of pharmacokinetic parameter estimates for each strategy in the 100 simulated cases were determined. CONCLUSIONS: For estimation of total clearance and volume in the central and peripheral compartments, all strategies performed similarly with no difference in efficiency or bias and precision of estimates. Our results suggest that for clinical evaluations two appropriately timed samples (0.5 h after a 1-h infusion, trough concentration) are adequate for estimation of vancomycin clearance in neonates.

Aminoglycosides↗

PubMedDate not supplied

Probabilistic linkage of large public health data files.

Probabilistic linkage technology makes it feasible and efficient to link large public health databases in a statistically justifiable manner. The problem addressed by the methodology is that of matching two files of individual data under conditions of uncertainty. Each field is subject to error which is measured by the probability that the field agrees given a record pair matches (called the m probability) and probabilities of chance agreement of its value states (called the u probability). Fellegi and Sunter pioneered record linkage theory. Advances in methodology include use of an EM algorithm for parameter estimation, optimization of matches by means of a linear sum assignment program, and more recently, a probability model that addresses both m and u probabilities for all value states of a field. This provides a means for obtaining greater precision from non-uniformly distributed fields, without the theoretical complications arising from frequency-based matching alone. The model includes an iterative parameter estimation procedure that is more robust than pre-match estimation techniques. The methodology was originally developed and tested by the author at the U.S. Census Bureau for census undercount estimation. The more recent advances and a new generalized software system were tested and validated by linking highway crashes to Emergency Medical Service (EMS) reports and to hospital admission records for the National Highway Traffic Safety Administration (NHTSA).

Adult↗

PubMed2001

Formation kinetics of hydroxymethylfurfural, lactulose and furosine in milk heated under isothermal and non-isothermal conditions.

A detailed kinetic study of hydroxymethylfurfural, lactulose and furosine formation was performed upon heating milk at temperatures between 90 degrees C and 140 degrees C. In case of prolonged heating, formation kinetics could be described by a fractional conversion model. Considering only the first phase of the model, kinetics could be simplified to a pseudo-zero order model. A first assessment of kinetic parameters was made by isothermal experiments. Data were analysed using both a 2-step linear and a 1-step non-linear regression method. Only for furosine, did the global 1-step regression approach seem to give better results than the individual 2-step regression approach. Next, the estimated parameters k(ref) and Ea were re-evaluated under non-isothermal conditions by subjecting milk to a time variable temperature profile. Given the complexity of Maillard reaction, it seemed better to estimate kinetic parameters under non-isothermal conditions when using a simplified model. Formation of hydroxymethylfurfural, lactulose and furosine was characterized by an Ea value of 90.2 kJ/mol (k(110 degrees C) = 1.2 micromol/l, min), 99.1 kJ/mol (k(110 degrees C) = 51.5 mg/l, min) and 88.7 kJ/mol (k(110 degrees C) = 16.3 mg/100 g protein, min) respectively. Additionally, 90% joint confidence regions were constructed in order to obtain an accurate representation of the statistical confidence associated with the simultaneously estimated parameters.

Animals↗