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PubMed1996

Evaluation of long-term survival: use of diagnostics and robust estimators with Cox's proportional hazards model.

We consider methodological problems in evaluating long-term survival in clinical trials. In particular we examine the use of several methods that extend the basic Cox regression analysis. In the presence of a long term observation, the proportional hazard (PH) assumption may easily be violated and a few long term survivors may have a large effect on parameter estimates. We consider both model selection and robust estimation in a data set of 474 ovarian cancer patients enrolled in a clinical trial and followed for between 7 and 12 years after randomization. Two diagnostic plots for assessing goodness-of-fit are introduced. One shows the variation in time of parameter estimates and is an alternative to PH checking based on time-dependent covariates. The other takes advantage of the martingale residual process in time to represent the lack of fit with a metric of the type 'observed minus expected' number of events. Robust estimation is carried out by maximizing a weighted partial likelihood which downweights the contribution to estimation of influential observations. This type of complementary analysis of long-term results of clinical studies is useful in assessing the soundness of the conclusions on treatment effect. In the example analysed here, the difference in survival between treatments was mostly confined to those individuals who survived at least two years beyond randomization.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Simulation of linear compartment models with application to nuclear medicine kinetic modeling.

Several techniques are evaluated for solving the linear ordinary differential equations arising from compartment models. The methods involve approximating the matrix exponential of the state matrix (i.e. the transition matrix). The computational efficiencies of these techniques, together with that of a general purpose differential equation solver, are compared for several models arising from radiopharmacokinetic studies. The matrix exponential calculations are performed using both Ward's Padé approximation method and an eigenvalue-eigenvector decomposition (QR factorization) of the matrix A. These two algorithms have been incorporated as simulation options into the programs of the ADAPT package. ADAPT consists of a set of high-level programs for simulation, parameter estimation and experiment design, developed primarily for basic and clinical research modeling and data analysis applications involving pharmacokinetic and pharmacodynamic processes. The advantages and disadvantages of these simulation strategies for solving linear kinetic models within a parameter estimation setting are illustrated and discussed.

Algorithms↗
PubMed2006

The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study.

BACKGROUND: Few data are available about how social networks reduce the risk of cognitive impairment in old age. We aimed to measure this effect using data from a large, longitudinal, epidemiological clinicopathological study. METHODS: 89 elderly people without known dementia participating in the Rush Memory and Aging Project underwent annual clinical evaluation. Brain autopsy was done at the time of death. Social network data were obtained by structured interview. Cognitive function tests were Z scored and averaged to yield a global and specific measure of cognitive function. Alzheimer's disease pathology was quantified as a global measure based on modified Bielschowsky silver stain. Amyloid load and the density of paired helical filament tau tangles were also quantified with antibody-specific immunostains. We used linear regression to examine the relation of disease pathology scores and social networks to level of cognitive function. FINDINGS: Cognitive function was inversely related to all measures of disease pathology, indicating lower function at more severe levels of pathology. Social network size modified the association between pathology and cognitive function (parameter estimate 0.097, SE 0.039, p=0.016, R(2)=0.295). Even at more severe levels of global disease pathology, cognitive function remained higher for participants with larger network sizes. A similar modifying association was observed with tangles (parameter estimate 0.011, SE 0.003, p=0.001, R(2)=0.454). These modifying effects were most pronounced for semantic memory and working memory. Amyloid load did not modify the relation between pathology and network size. The results were unchanged after controlling for cognitive, physical, and social activities, depressive symptoms, or number of chronic diseases. INTERPRETATION: These findings suggest that social networks modify the relation of some measures of Alzheimer's disease pathology to level of cognitive function.

Aged↗
PubMed2006

Ethnic differences in expectations for aging among older adults.

Age-expectations of 611 non-Latino white, African-American, and Latino seniors recruited at 14 community-based senior centers in the greater Los Angeles region were compared. Participants completed the Expectations Regarding Aging (ERA-38) Survey, a self-administered instrument with previously demonstrated reliability and validity for measuring age-expectations. Analysis of variance was used to compare unadjusted differences between scores across ethnic groups. To examine whether observed differences persisted after adjusting for health and sociodemographic characteristics, a series of linear regression models was constructed, with the dependent variable being total ERA-38 score and the primary independent variables being African-American and Latino ethnicity (reference group=white), adjusting for age, sex, physical and mental health-related quality of life (HRQoL), medical comorbidity, activity of daily living (ADL) impairments, depression, and education. Latinos had significantly lower overall age-expectations than non-Latino whites or African Americans after adjusting for age and sex (parameter estimate=-3.4, P=.01); this difference persisted after adjusting for health variables including medical comorbidity, HRQoL, ADL impairments, and depression. After adjusting for education, being Latino was no longer significantly associated with lower age-expectations (parameter estimate=-1.9, P=.18). Being African American was not significantly associated with age-expectations in any of the adjusted models. Younger age and better HRQoL were associated with higher age-expectations in all models. In conclusion, of these 611 older adults recruited at senior centers in the greater Los Angeles region, Latinos had significantly lower age-expectations than non-Latino whites and African Americans, even after adjusting for health characteristics, but differences in educational levels explained this difference.

Black or African American↗
PubMed1982

Noninvasive chemical methods of estimating pharmacokinetic parameters.

Two noninvasive methods have been advocated for pharmacokinetic and bioavailability studies. The measurement of the salivary and urinary excretion of drugs and their metabolites may avoid sampling blood, particularly in introductory studies. The measurement of the salivary concentrations of drugs is of most value in studies on compounds which are little ionized at physiological pH values. Well studied examples where there is a good parallelism between salivary and plasma drug concentrations include the neutral drug, ethanol, the weakly acidic drugs, phenytoin and sulphapyridine, and the weakly basic drugs, carbamazepine and antipyrine. Data on the salivary secretion of more strongly acidic or basic drugs are often conflicting and further work is required to determine the usefulness of measuring the salivary secretion of such drugs in pharmacokinetic and biopharmaceutical studies. Studies on the rate of excretion or cumulative excretion of drugs and their metabolites in urine may provide good estimates of the terminal half lives of drugs. However, accurate determinations of the kinetic parameters of rapid processes are not obtainable from studies on urinary excretion. Reliable data can only be obtained if the timing of urine collections is precise and if there are no significant losses of urine.

Biotransformation↗
PubMed2005

Metabolic pathways reconstruction by frequency and amplitude response to forced glycolytic oscillations in yeast.

The hypothesis that frequency and amplitude response can be used in a complicated metabolic pathway kinetics model for optimal parameter estimation, as speculated by its successful prior usage for a mechanical oscillator and a heterogeneous chemical system, is tested here. Given the complexity of the glycolysis model of yeast chosen, this question is limited to three kinetics parameters of the 87 in the in vitro model developed in the literature. The direct application of the approach, used with the uninformed selection of operating conditions for the oscillation of external glucose concentration, led to miring the data assimilation process in local minima. Application of linear systems theory, however, identified two natural resonant frequencies that, when excited by external forced oscillations of the same frequency, result in the expression of many harmonics in the Fourier spectra, that is, information-rich experiments. A single such information-rich experiment at one of the resonant frequencies was sufficient to break away from the local minima to find the optimum kinetics parameter estimates. The resonant frequencies themselves represent oscillation modes in glycolysis akin to those previously observed. Furthermore, operation of the bioreactor with large amplitude oscillations of glucose feed (25%) leads to enhanced ethanol average yield by 1.6% at the resonant frequency.

Bioreactors↗
PubMed1997

A tracer interaction method for nonlinear pharmacokinetics analysis: application to evaluation of nonlinear elimination.

A drug tracer is most commonly applied to get information about the pharmacokinetics (PK) of a drug that is not confounded by an endogenously produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study of nonlinear PK behavior. In the present study a system analysis is applied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods are potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstrated in a simulation study and with real data in a specific implementation aimed at determining the Michaelis-Menten (MM) parameters of nonlinear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter evaluation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimation methodology proposed is ideally suitable for dynamic, non-steady-state conditions. Thus, it offers greater applicability and avoids the many problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination behavior of erythropoietin, a process that likely takes place via receptor-based endocytosis. Due to its high sensitivity, accuracy, and intrinsic nonlinearity the TIM may be suitable for in-vivo studies of receptor binding of the many biotechnology produced peptide drugs and endogenous compounds displaying receptor-mediated elimination.

Computer Simulation↗
PubMed1988

Computerized liver imaging: relationship with quantitatively estimated histological parameters in liver cirrhosis.

In liver cirrhosis, increased splenic uptake of radiocolloid, causing the liver-to-spleen (L/S) ratio to decrease, is a characteristic finding, especially during advanced illness. Histologically, advanced liver cirrhosis shows progressive replacement of hepatic parenchyma by fibrous tracts, making it possible to quantify both image and histological parameters. On this basis, the authors performed this study in 39 alcoholic cirrhotic patients in order to determine the relationship between the L/S ratio and right-to-left hepatic lobe ratio (RL/LL) and the degree of fibrosis, fat droplet area, total fat amount, and hepatocyte area. The authors tested if it is possible to predict the degree of fibrosis on the basis of image features or on a combination of image and biochemical parameters, using multiple correlation studies. The degree of fibrosis correlates with the L/S ratio (r = -0.48). The degree of correlation improved using prothrombin, gamma globulin and L/S ratio (r = 0.656), but not enough to allow an accurate estimation of the degree of fibrosis on the basis of a combination of imaging and biochemical data. Neither RL/LL nor L/S ratios significantly correlated with fatty infiltration, fat droplet area, or hepatocyte enlargement. Thus, liver imaging is not useful in quantifying the main histological changes observed in alcoholic liver cirrhosis.

Adult↗
PubMed1993

Hepatic disposition of acetaminophen and metabolites. Pharmacokinetic modeling, protein binding and subcellular distribution.

Successful pharmacokinetic modeling often requires the ability of a simple model to describe a complex series of physiological processes. However, a simple model may be inappropriate. Physiologically-relevant modeling may offer a more appropriate description, but requires further support from in vitro/in vivo data. A well-stirred hepatic model with linear processes was proposed to describe in vivo disposition of acetaminophen and metabolites after a 100 mg/kg bolus of acetaminophen to vehicle- or phenobarbital-pretreated, renal-ligated rats. Model simulations underpredicted acetaminophen glucuronide (AG) concentrations at early time points in serum, and were inconsistent with AG biliary excretion-rate profiles. Intracellular binding of AG by ligandin was hypothesized, and a cytosolic compartment with reversible binding was incorporated into the model. In this second model, only AG bound in the cytosolic compartment was available for excretion into bile. Model 2 better described the AG biliary excretion rate-time profiles based on calculated Akaike's information criterion values. However, no apparent change was observed in the underprediction of AG serum concentrations. Parameter estimates derived from the two models also were different. The rate constants regulating AG formation and sinusoidal egress were increased significantly after phenobarbital pretreatment according to model 1, while the AG biliary excretion rate constant was decreased significantly. Parameter estimates based on model 2 suggested that phenobarbital pretreatment impaired the cytosolic binding of AG but increased significantly the AG biliary excretion rate constant. The physiologic relevance of model 2 was not supported by a subsequent investigation of the protein binding and subcellular distribution of acetaminophen and metabolites. Acetaminophen, AG and acetaminophen sulfate (AS) were not bound extensively in hepatic cytosol (mean +/- SD unbound fractions were 0.90 +/- 0.08, 0.97 +/- 0.08, and 0.88 +/- 0.06, respectively). Phenobarbital pretreatment did not alter significantly the unbound fractions of acetaminophen, AG or AS in hepatic cytosol. Acetaminophen was distributed to a greater extent in lysosomes than in the nuclear, mitochondrial, microsomal and cytosolic fractions. Distribution of AS predominated in cytosolic and lysosomal fractions. AG was detected only in cytosol. Phenobarbital pretreatment decreased the content of acetaminophen, AG and AS in all hepatic fractions. This study demonstrates the utility of pharmacokinetic modeling in exploring mechanistic hypotheses. However, these results underscore the importance of obtaining pivotal data from in vitro/in vivo studies to validate hypothesized mechanisms.

Acetaminophen↗
PubMedDate not supplied

Testing and parameterizing a conceptual solute transport model in saturated fractured tuff using sorbing and nonsorbing tracers in cross-hole tracer tests.

Two cross-hole tracer tests involving the simultaneous injection of two nonsorbing solute tracers with different diffusion coefficients (bromide and pentafluorobenzoate) and one weakly sorbing solute tracer (lithium ion) were conducted in two different intervals at the C-wells complex near the site of a potential high-level nuclear waste repository at Yucca Mountain, NV. The tests were conducted to (1) test a conceptual radionuclide transport model for saturated, fractured tuffs near Yucca Mountain and (2) obtain transport parameter estimates for predictive modeling of radionuclide transport. The differences between the responses of the two nonsorbing tracers and the sorbing tracer (when normalized to injection masses) were consistent with a dual-porosity transport system in which matrix diffusion was occurring. The concentration attenuation of the sorbing tracer relative to the nonsorbing tracers suggested that diffusion occurred primarily into matrix pores, not simply into stagnant water within the fractures. The K(d) values deduced from the lithium responses were generally larger than K(d) values measured in laboratory batch sorption tests using crushed C-wells cores. This result supports the use of laboratory-derived K(d) values for predicting sorbing species transport at the site, as the laboratory K(d) values would result in underprediction of sorption and hence conservative transport predictions. The tracer tests also provided estimates of effective flow porosity and longitudinal dispersivity at the site. The tests clearly demonstrated the advantages of using multiple tracers of different physical and chemical characteristics to distinguish between alternative conceptual transport models and to obtain transport parameter estimates that are better constrained than can be obtained using only a single tracer or using multiple nonsorbing tracers without a sorbing tracer.

Benzoates↗
PubMed1987

Modeling of respiratory system impedances in dogs.

Mechanical impedances between 4 and 64 Hz of the respiratory system in dogs have been reported (A.C. Jackson et al. J. Appl. Physiol. 57: 34-39, 1984) previously by this laboratory. It was observed that resistance (the real part of impedance) decreased slightly with frequency between 4 and 22 Hz then increased considerably with frequency above 22 Hz. In the current study, these impedance data were analyzed using nonlinear regression analysis incorporating several different lumped linear element models. The five-element model of Eyles and Pimmel (IEEE Trans. Biomed. Eng. 28: 313-317, 1981) could only fit data where resistance decreased with frequency. However, when the model was applied to these data the returned parameter estimates were not physiologically realistic. Over the entire frequency range, a significantly improved fit was obtained with the six-element model of DuBois et al. (J. Appl. Physiol. 8: 587-594, 1956), since it could follow the predominate frequency-dependent characteristic that was the increase in resistance. The resulting parameter estimates suggested that the shunt compliance represents alveolar gas compressibility, the central branch represents airways, and the peripheral branch represents lung and chest wall tissues. This six-element model could not fit, with the same set of parameter values, both the frequency-dependent decrease in Rrs and the frequency-dependent increase in resistance. A nine-element model recently proposed by Peslin et al. (J. Appl. Physiol. 39: 523-534, 1975) was capable of fitting both the frequency-dependent decrease and the frequency-dependent increase in resistance. However, the data only between 4 and 64 Hz was not sufficient to consistently determine unique values for all nine parameters.

Airway Resistance↗
PubMed2001

Methodological issues of using observational human data in lung dosimetry models for particulates.

INTRODUCTION: The use of human data to calibrate and validate a physiologically based pharmacokinetic (PBPK) model has the clear advantage of pertaining to the species of interest, namely humans. A challenge in using these data is their often sparse, heterogeneous nature, which may require special methods. Approaches for evaluating sources of variability and uncertainty in a human lung dosimetry model are described in this study. METHODS: A multivariate optimization procedure was used to fit a dosimetry model to data of 131 U.S. coal miners. These data include workplace exposures and end-of-life particle burdens in the lungs and hilar lymph nodes. Uncertainty in model structure was investigated by fitting various model forms for particle clearance and sequestration of particles in the lung interstitium. A sensitivity analysis was performed to determine which model parameters had the most influence on model output. Distributions of clearance parameters were estimated by fitting the model to each individual's data, and this information was used to predict inter-individual differences in lung particle burdens at given exposures. The influence of smoking history, race and pulmonary fibrosis on the individual's estimated clearance parameters was also evaluated. RESULTS: The model structure that provided the best fit to these coal miner data includes a first-order interstitialization process and no dose-dependent decline in alveolar clearance. The parameter that had the largest influence on model output is fractional deposition. Race and fibrosis severity category were statistically significant predictors of individual's estimated alveolar clearance rate coefficients (P < 0.03 and P < 0.01-0.06, respectively), but smoking history (ever, never) was not (P < 0.4). Adjustments for these group differences provided some improvement in the dosimetry model fit (up to 25% reduction in the mean squared error), although unexplained inter-individual differences made up the largest source of variability. Lung burdens were inversely associated with the miners' estimated clearance parameters, e.g. individuals with slower estimated clearance had higher observed lung burdens. CONCLUSIONS: The methods described in this study were used to examine issues of uncertainty in the model structure and variability of the miners' estimated clearance parameters. Estimated individual clearance had a large influence on predicted lung burden, which would also affect disease risk. These findings are useful for risk assessment, by providing estimates of the distribution of lung burdens expected under given exposure conditions.

Body Burden↗
PubMed1985

Comparison of models describing the sorption of nitroglycerin and diazepam by plastic infusion systems: diffusion and compartment models.

The time course of sorption of diazepam and nitroglycerin from aqueous solutions into plastic materials has been represented by the diffusion and compartmental models for a variety of storage conditions. The diffusion model seemed to be the more satisfactory model in respect to both description and prediction of the drug uptake for all conditions. The compartment model appeared to be useful for describing the drug uptake at earlier times, giving a satisfactory fit to the data and reliable final parameter estimates. However, that model was not able to describe the loss as equilibrium was approached or accurately predict the disappearance profiles for these solutes with alterations in solution volume or infusion bag size. Approximations of the diffusion model gave parameter estimates consistent with those obtained by nonlinear regression using the full equations.

Adsorption↗
PubMed1999

Pharmacokinetic curve fitting using numerical inverse Laplace transformation.

The combination of the nonlinear regression program ADAPT II with Talbot's method of numerical Laplace transformation, that allows parameter estimation when the model function is given only in the Laplace domain, is described and successfully applied to pharmacokinetic problems. The accuracy and precision of the method has been found satisfactory; its performance is comparable to that achieved in parameter estimation based on functions defined in the time domain.

Algorithms↗
PubMed2006

Assessment of the validity of a population pharmacokinetic model for epirubicin.

AIMS: The aim of this study was to evaluate a population model for epirubicin clearance using internal and external validation techniques. METHODS: Jackknife samples were used to identify outliers in the population dataset and individuals influencing covariate selection. Sensitivity analyses were performed in which serum aspartate transaminase (AST) values (a covariate in the population model) or epirubicin concentrations were randomly changed by +/-10%. Cross-validation was performed five times, on each occasion using 80% of the data for model development and 20% to assess the performance of the model. External validation was conducted by assessing the ability of the population model to predict concentrations and clearances in a separate group of 79 patients. RESULTS: Structural parameter estimates from all jackknife samples were within 7.5% of the final population estimates and examination of log likelihood values indicated that the selection of AST in the final model was not due to the presence of outliers. Alteration of AST or epirubicin concentrations by +/-10% had a negligible effect on population parameter estimates and their precision. In the cross-validation analysis, the precision of clearance estimates was better in patients with AST concentrations>150 U l-1. In the external validation, epirubicin concentrations were over-predicted by 81.4% using the population model and clearance values were also poorly predicted (imprecision 43%). CONCLUSIONS: The results of internal validation of population pharmacokinetic models should be interpreted with caution, especially when the dataset is relatively small.

Adult↗
PubMed1984

A calculator program for individualizing factor VIII dosage.

We developed a calculator program to individualize Factor VIII dosage on the basis of the concentration-time data obtained after a single test-dose. The program is designed for the Hewlett-Packard 41-CV calculator. The calculation procedure is the 1977 version of the Sawchuk and Zaske method. The program performs model parameter estimation through a nonlinear iterative least-squares technique (the modified Gauss-Newton method). We tested our program in three patients with classic hemophilia who required multiple-dose treatment with Factor VIII. In each patient, individual kinetic parameters were estimated from the serial plasma levels measured after the test-dose. The predicted concentration-time curve resulting from all the administered doses was calculated based on the estimated kinetic parameters. Good agreement between predicted and measured levels during the multiple-dose regimen was observed in all patients.

Computers↗
PubMed1996

A comparison of a Bayesian population method with two methods as implemented in commercially available software.

In this paper we describe and discuss three specific estimation procedures that are available within commercially available population software packages. The first version of NONMEM (l) was released in 1979 and later versions are the standard analysis tools in both industry and academia. Recently, two commercially available pieces of software have become available. PPHARM was released during 1994 and POPKAN was released in 1995. We provide descriptions and critique the FOCE method within NONMEM, the two-step algorithm within PPHARM and the Markov chain Monte Carlo method that is utilized by POPKAN. We use simulated data generated from a monoexponential model to evaluate the parameter estimation capabilities of these methods within the three software tools. In particular we investigate the effect on parameter estimation of increasing both interindividual and intraindividual variability.

Bayes Theorem↗