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Effect of blood curve smearing on the accuracy of parameter estimates obtained for 82Rb/PET studies of blood-brain barrier permeability.

82Rb in conjunction with positron emission tomography (PET) has been used to estimate the blood to brain transport rate constant (K1) for Rb and the regional brain/tumour blood volume (Vb). Errors in K1 and Vb depend upon the accuracy of the measured arterial blood radioactivity and PET-monitored brain radioactivity. Arterial blood is usually sampled by placing a catheter in the radial artery and measuring the radioactivity in blood passing continuously in front of a detector or by counting discrete blood samples in a well scintillation detector. In either case, the passage of blood through catheter/pump tubing produces a smearing of the waveform as well as a delay in the arrival of radioactivity at the blood sampling site. The change in shape of the blood curve is significant for bolus-type injections and results in large errors in those model parameters which contribute substantially to the initial phase of the brain activity curve. We report here the results of computer simulations and an analysis of patient data which suggest that parameter estimation errors due to smearing and time shift may be large (greater than 50%) but that these errors can be minimised by the use of deconvolution techniques.

Blood-Brain Barrier

Parameter estimation and sensitivity analysis of a nonlinearly elastic static lung model.

A model for the static pressure-volume behavior of the lung parenchyma based on a pseudo-elastic strain energy function was tested. Values of the model parameters and their variances were estimated by an optimal least-squares fit of the model-predicted pressures to the corresponding data from excised, saline-filled dog lungs. Although the model fit data from twelve lungs very well, the coefficients of variation for parameter values differed greatly. To analyze the sensitivity of the model output to its parameters, we examined an approximate Hessian, H, of the least-squares objective function. Based on the determinant and condition number of H, we were able to set formal criteria for choosing the most reliable estimates of parameter values and their variances. This in turn allowed us to specify a normal range of parameter values for these dog lungs. Thus the model not only describes static pressure-volume data, but also uses the data to estimate parameters from a fundamental constitutive equation. The optimal parameter estimation and sensitivity analysis developed here can be widely applied to other physiologic systems.

Animals

Sensitivity analysis of the systemic circulation with a view to computer simulation and parameter estimation.

A sensitivity analysis study has been performed on a seven-parameter model of the systemic vascular bed in order to obtain structure reductions appropriate for simulation and estimation. This analysis considers separately the systolic and diastolic transfer functions between arterial and venous pressures in order to divide a non-linear problem in two distinct linear problems. The results obtained refer to nominal parameter values corresponding to normal circulatory conditions in man and supply guide-lines for an application-oriented selection of reduced models. Simple resistance-compliance models are preferred because the inertial effects appear to have only slight influence. In particular, the choice of a five-parameter model seems to be convenient for simulation purposes. An additional structure reduction is suggested to reach reliable results in parameter estimation problems. The resulting model is characterized by three elements: peripheral resistance, arterial compliance and venous compliance.

Blood Circulation

Parameter estimates for a QALY utility model.

This paper discusses a utility model for quality adjusted life years (QALY). According to this model, the utility of Y years of survival in health state Q is bYrH(Q), where b is a scaling constant and r and H(Q) are parameters. The parameter r is shown to be interpretable as a representation of a patient's risk attitude with respect to survival duration. The parameter H(Q) represents the proportionate reduction in the utility of survival when health state Q prevails. Methods are described for estimating these parameters from the results of an individual patient utility assessment. Results are then reported for empirical estimation of parameters r and H(Q) from the preference judgments of a sample of 46 coronary artery disease patients. In this empirical study, health state Q takes on two values--survival with angina pectoris and survival free from angina pectoris. Estimated values of parameters r and H(Q) are discussed in relation to the decision analysis of coronary artery bypass graft surgery. Finally, it is argued that the model deserves consideration as a medical utility model, despite some preliminary evidence that assumptions of the model are descriptively false, because it provides a simple representation of the utility of survival duration and health quality. These aspects of health outcomes are known to be critically important in the expected utility analysis of health decisions.

Angina Pectoris

Misclassification of a prognostic dichotomous variable: sample size and parameter estimate adjustment.

Under general conditions, Lagakos showed that for an explanatory variable observed with error, the asymptotic relative efficiency (ARE) when using the observed rather than the true values in linear models, logistic models and proportional hazards models for survival is the square of the correlation between the true and observed variables. The result is useful for sample size adjustment when this correlation is estimable. Often, one cannot observe correct values of the explanatory variable under any circumstances. We show, however, that under the models considered by Lagakos for a dichotomous explanatory variable, the ARE equals the kappa statistic in a read-reread protocol. Consequently, one need not know 'truth' in this situation to estimate the ARE and to adjust sample size to maintain desired power; divide the estimated sample size obtained with the assumption of no measurement error by the consistent estimate of the kappa statistic (which is unlikely to be zero or negative). We then develop heuristically an adjusted estimate of the beta parameter in a proportional hazards survival model. The work was motivated by analyses of the Childhood Brain Tumour Consortium database. Examples from this database illustrate the method.

Brain Neoplasms

A relation between the Akaike criterion and reliability of parameter estimates, with application to nonlinear autoregressive modelling of ictal EEG.

The Akaike minimum information criterion provides a means to determine the appropriate number of lags in a linear autoregressive model of a time series. We show that the Akaike criterion is closely related to the reliability estimates of successively determined parameters of a linear autoregressive (LAR) model. A similar criterion may be applied to determine whether the addition of a nonlinear term to an LAR model provides a statistically significant improvement in the description of the time series. As an example, we use this method to identify quadratic contributions to a nonlinear autoregressive characterization of a typical 3/s spike and wave seizure discharge.

Data Interpretation, Statistical

Program to estimate parameters of linear systems without numerical differentiation.

This paper describes a computer program for estimating the parameters of a linear differential equation systen with constant coefficients by use of a nonlinear least-squares method. For minimization the sum of squares of an existing standard program, the Gauss-Newton gradient procedure, is employed. The differential equation system is solved by the Taylor expansion method. The advantage of this approach is that the derivatives with respect to the parameters are available without numerical differentiation. Therefore the inaccuracy inherent in numerical differentiation and the problem of choosing the modification of the parameters are eliminated. The given procedure is applicable for all the first order gradient methods. The presented method was tested with generated data from a four-compartmental model.

Computers

Twin-family studies of perceptual speed ability. II. Parameter estimation.

Offspring of monozygotic (MZ) twins form half-ships that permit a direct test of maternal effects and differentiate several sources of between-family environmental variance. Combined with conventional twin data, these genetic half-sibships provide a unique data set for estimating sources of variation in quantitative traits. To illustrate, genetic and environmental parameters were estimated for Identical Pictures Test data obtained from children of MZ twin parents and an (approximate) age-matched cohort of like-sex twins. Analyses of variance of the data, standardized for age and sex, yield 12 mean squares to which gene-environment models were fit. Maximum-likelihood estimation revealed a complete absence of maternal influences and shared environmental effects; a simple two-parameter model, assuming random mating and attributing variation in test scores to additive genes and within-family environment, adequately accounts for the familial data.

Adolescent

Parameter estimation for a prosthetic ankle.

The mechanical parameters of a model of an energy storage and return ankle prosthesis are estimated for normal level walking by means of an optimization procedure. The walking cycle is divided into six fields, such that the power does not change sign within each field; the transition between successive fields occurs at zero power. The optimal spring stiffness as a function of time, is found by optimizing a quadratic cost function to minimize the difference between the estimated ankle moments and the moments in normal walking. The optimization is subjected to four continuous constraints within each field and to two continuity constraints for the transitions between successive fields. The time-varying spring stiffness and the implications of additional external energy are discussed and are presented as recommendations for the designer.

Ankle Joint

Identifiability: the first step in parameter estimation.

The observations in an experiment define a set of observational parameters that are functions of the basic kinetic parameters of the model of the system. The problem of identifiability is concerned with whether the observational parameters uniquely specify the basic kinetic parameters. As such, it depends only on the functional relation between the two levels of parameters and not on errors of observation and the estimation procedure. It should be checked before doing the experiment. Given initial estimates of the basic kinetic parameters, identifiability can be checked, in a local sense, from data generated by simulating the experiment on the model.

Computer Simulation

Relationships among growth hormone and prolactin secretory parameter estimates in Holstein bulls and their predicted differences for lactational traits.

Selection of dairy sires is based on the production records of their female ancestors, half-sibs and daughters. No trait expressed by the sire is used. Concentrations of growth hormone (GH) and prolactin (PRL), hormones produced in both males and females that are fundamental in lactation, may be correlated with production. A study was conducted to determine whether measures of these hormones in the sire would be useful predictors of lactational ability of daughters. Blood samples were collected at 15-min intervals for 8 h from 26 Holstein bulls (5.5 yr of age) that had one progeny summary available. Plasma concentrations of GH and PRL were quantified and the mean and baseline concentrations and the frequency and mean amplitude of the secretory peaks were determined for each bull. Concentrations among these values and bulls' predicted differences (PD) were determined. Significant negative correlations were detected for frequency of GH peaks and PD for yield of milk, fat and protein; correlations were positive for PRL baseline concentrations and PD for fat and protein (P less than .10), and correlations were negative for frequency of PRL peaks and PD for milk, fat and protein (P less than .10). Addition of estimates of bull hormone secretory parameters to breeding values based on performance of relatives considerably improved the accuracy (R2) for predicting progeny performance from sire information. Certain characteristics of the patterns of GH and PRL secretion may be heritable and aid in identification of superior dairy animals.

Animals

Transducer characterization from pressure amplitude distribution measurements using a Kalman filter as parameter estimation algorithm.

The amplitude and frequency contents of a received ultrasound pulse depends on the spatial pressure amplitude distribution of the sound field, as produced by the transducer in the medium, and on the position and orientation of the reflecting surface in this field. Often, the geometry of the reflecting surface and the acoustical properties of the medium are known or can be estimated. Then it is practical to determine the transducer parameters in order to calculate the distortion of a reflected ultrasound pulse. Apart from geometrical parameters such as size and mechanical focusing, the surface velocity amplitude distribution (SVAD) of a transducer is of major importance. For some transducer configurations this SVAD may be described with a limited number of parameters. This paper presents a method, based on a Kalman filter algorithm, to assess the transducer parameters by measurement of the spatial sound field pressure amplitude distribution in various planes for different emission frequencies. Comparison of the measured pressure amplitudes with those calculated using the estimated values of the parameters shows that this method yields reliable results.

Acoustics

Identifiability and parameter estimation.

In experiments on biological systems one often cannot measure all state variables (compartments). Given a particular experiment of that type, a basic kinetic parameter may have no effect on the observations; such a parameter is an insensible parameter for that experiment. A parameter may influence the observations and not be uniquely determinable; such a parameter is nonidentifiable for that experiment. Only identifiable parameters can be estimated uniquely, by that experiment. I review the basic theory to check identifiability for a nominal value of a parameter (local identifiability), and present some examples of problems that may arise in estimation.

Kinetics

Simulation of calcium homeostasis: modeling and parameter estimation.

The system that regulates plasma calcium in the bird has been formalized into a model based on a series of differential equations and solved by computer simulation. Bone, kidney, and intestine have been considered as the control subsystems, with parathyroid hormone and 1,25-dihydroxycholecalciferol as the regulating hormones. The parameters used in the simulation model have been computed either from published results or by specifically designed experiments described here. For the estimation of parameters, an iterative procedure has been developed that was designed to minimize the sum of square errors between observed and system-simulated values. Parameters of 1,25-dihydroxycholecalciferol metabolism were experimentally obtained from the kinetic behavior of the 3H-labeled hormone in rachitic birds after a single dose. Model parameters have been adjusted using the results of in vivo calcium loading and validated by an EDTA infusion experiment. The simulation model has been used to study the hierarchy of the activities of the three control subsystems and of the regulating hormones, at different calcium intakes. Positive or negative errors in plasma calcium resulted in an asymmetry in the activities of the controlling systems, bone and kidney, whereas the intestine is characterized by its relatively long response time.

Animals

A model of intestinal iron absorption and plasma iron kinetics: optimal parameter estimates for normal dogs.

A multicompartment model describing the physiological processes of intestinal iron absorption has been developed. The model accounts for uptake by the intestinal mucosa of iron in the lumen, followed by either iron incorporation into a mucosal storage pool (presumably ferritin) or direct iron transfer to the plasma. To enable analysis of iron absorption from noninvasive measurements, plasma iron kinetics were also analyzed. The model was validated in studies of three beagle dogs given oral 59Fe-citrate and intravenous 55Fe-transferrin simultaneously. Model parameters were estimated from the best (least-squares) fit of the model outputs to the tracer iron activity in venous blood samples and in the whole body. The parameter values show that both incorporation of iron into the mucosal storage pool and transfer of iron from the mucosa to the plasma occur at rates approximately 100 times greater than mucosal uptake of iron from the gut lumen. Further, release of iron from mucosal storage, while measurable, occurs at a slow rate. The study demonstrates the practicality of this noninvasive approach for the simultaneous study of iron absorption and plasma iron kinetics.

Animals

Hemodynamic parameter estimation from ocular fluorescein angiograms.

BACKGROUND: A method is proposed for parameterizing choroidal blood flow from fluorescein angiograms. METHODS: After digitizing and aligning the angiographic sequence, the intensity build-up curves of fluorescence are analysed per pixel (approx. 10 microns in fundo). Two models are compared. A one-compartment model predicts an exponential build-up curve, from which the following parameters are estimated: maximum fluorescence, dye appearance time and local perfusion rate (reciprocal of the time constant of the exponential). To account for the contribution of the systemic circulation to the shape of the build-up curve, a two-compartment model is used which predicts a bi-exponential curve. RESULTS: Introduction of the second (systemic) compartment resulted in a significant improvement of fit in 37 of 48 patients studied. The rate constants of the systemic compartment found were mainly in the range of 0.30-1.00 s-1. CONCLUSION: For the individual patient, the local perfusion rates may vary strongly, with lower perfusion rates possibly being of prognostic value for ocular diseases such as glaucoma or diabetic retinopathy.

Blood Flow Velocity

HPLC-analysis and preliminary pharmacokinetic parameter estimations of chloroquine.

An HPLC method for the separate determination of chloroquine and its major metabolites has been developed. Separation was on an octadecyl RP column. Fluorimetric detection followed after on-line post-column buffering of the mobile phase to pH = 9.25. The method is highly selective for the compounds of interest with a detection limit down to 1 ng/ml. Preliminary data on the pharmacokinetics of chloroquine are reported, as obtained with this method. Kinetic parameters were estimated with the aid of the non-linear regression computer programme NON-LIN.

Chloroquine