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Application of the covariance function approach with an iterative two-stage algorithm to the estimation of parameters of a random regression test day model for dairy production traits.

The covariance function approach with an iterative two-stage algorithm of LIU et al. (2000) was applied to estimate parameters for the Polish Black-and-White dairy population based on a sample of 338 808 test day records for milk, fat, and protein yields. A multiple trait sire model was used to estimate covariances of lactation stages. A third-order Legendre polynomial was subsequently fitted to the estimated (co)variances to derive (co)variances of random regression coefficients for both additive genetic and permanent environment effects. Daily and 305-day heritability estimates obtained are consistent with several studies which used both fixed and random regression test day models. Genetic correlations between any two days in milk (DIM) of the same lactation as well as genetic correlations between the same DIM of two lactations were within a biologically acceptable range. It was shown that the applied estimation procedure can utilise very large data sets and give plausible estimates of (co)variance components.

Journal Article↗

Prednisolone: limited sampling strategies for estimating pharmacokinetic parameters.

To develop limited-sampling strategy (LSS) models for estimating prednisolone's area under plasma concentration versus time curve (AUC(0-infinity)), its maximum concentration in plasma (C(max)), and total clearance (CL/F). Healthy subjects (n = 24), enrolled in a bioequivalence study, received 20 mg PO of the prodrug prednisone as reference and test tablets, and plasma prednisolone concentrations (n = 576) were measured by a validated HPLC assay. A linear regression analysis of AUC(0-infinity), C(max), CL/F, and log(CL/F) against the plasma prednisolone concentrations for the reference formulation was carried out to develop LSS models to estimate these parameters. The LSS models were validated on the test formulation data sets and on simulated sets generated by the software ADAPT II. LSS models based on a single [1.5 hours for C(max) and 7 hours for AUC(0-infinity), CL/F, and log(CL/F)] plasma sample, accurately estimated (R2 = 0.84-0.97, mean bias < 1%; mean precision < 10%) these pharmacokinetic parameters. Validation tests indicated that the most informative single-point LSS models developed for the reference formulation provide precise estimates (R(2) > 0.83; mean bias < 3%; mean precision < 10%) of the corresponding pharmacokinetic parameters for the test formulation. LSS models based on the two most informative sampling points (1.5 and 7 hours) were required for accurate estimates (R(2) > 0.87; mean bias < 6%; mean precision < 8%) of prednisolone's C(max), AUC(0-infinity), CL/F, and log(CL/F) for the simulated data sets. Finally, bioequivalence assessment of the prednisone formulations, based on LSS-derived AUC(0-infinity) and C(max) values provided results identical to those obtained using the original values for these parameters. One- and 2-point LSS models provided accurate estimates of prednisolone's C(max), AUC(0-infinity), and CL/F, following single oral doses of prednisone, and allowed correct assessment of bioequivalence between two prednisone formulations.

Adolescent↗

[Population pharmacokinetic model for gentamycin and its predictive value].

AIM: To construct a population pharmacokinetic model to describe gentamycin concentrations in serum in newborn infants and to validate the predictive ability of this model. METHODS: Data used in this study were obtained from 30 neonates with 80 serum samples. A one-compartment open model was used to describe the kinetics of gentamycin after intravenous infusion. Following Sheiner's idea of population pharmacokinetics, a programs to estimate population parameter and individual parameter of gentamycin was made. The target function minimality was obtained from Monte Carlo algorithm. The predictive ability of the developed model was evaluated by computing precision and accuracy of serum concentration predicted using the parameter estimates. RESULTS: Fitted population pharmacokinetic parameters (mean +/- standard deviation) were as follows: Ke: 0.220 +/- 0.022 h-1, Vd: 0.51 +/- 0.06 L.kg-1, Cl: 112 +/- 10 mL.h-1.kg-1. For the population analysis sample and the predictive sample, predicted and observed concentrations were all close with correlation coefficient 0.920 and 0.946, respectively. Mean prediction error (ME) and root mean squared error (RMSE) were 0.001 mg.L-1 and 0.84 mg.L-1 for the predictive sample, respectively. CONCLUSION: Observed gentamycin serum concentrations were explained very well by this model. We propose the use of this population pharmacokinetic model to optimize gentamycin clinical therapies in our institution and others with similar patient population characteristics.

Anti-Bacterial Agents↗

Study of accuracy of commonly used fetal parameters for estimation of gestational age.

Estimation of the gestational age by sonographic measurements of fetal parameters is usually done by measuring mean sac diameter (MSD), Crown-rump length (CRL), biparietal diameter (BPD), head circumference (HC), femoral length (FL) and abdominal circumference (AC) depending on the trimester of pregnancy. This is a prospective study to see the correlation of different fetal parameters in estimating the gestational age. A total of 71 normal women were taken and ultrasonogram was done to take MSD and CRL in 1st trimester and BPD, HC, FL and AC in 2nd and 3rd trimester. Gestational age was calculated by MSD using Rempen normogram and Hadlock normograms were used for the rest of fetal parameters. Gestational age by LMP was also calculated at the same time. Correlation of different fetal parameters in estimating gestational age in different trimesters was done by Pearson correlation. Pearson correlation showed that the CRL was the best fetal parameter (correlation coefficient of 0.909) in the first trimester. The correlation of MSD and average gestational age by MSD and CRL was with correlation coefficients of 0.778 and 0.888 respectively. Thus the averaging of gestational age in 1st trimester decreases the accuracy in the gestational age estimation. Correlation of gestational age by BPD, HC, FL and AC and their average in 2nd trimester showed that the best correlation was by AC and the least correlation by BPD in this study. It is in contrary to other studies which could be due to chance finding or bias because of prospective study. Pearson correlation calculated in 3rd trimester showed HC and FL were better parameters than BPD and AC. Average gestational age by simple averaging of BPD, HC, FL and AC gives more accurate estimation of gestational age in both 2nd and 3rd trimester.

Anthropometry↗

"Other patients are really in need of medical attention"--the quality of health services for rape survivors in South Africa.

OBJECTIVE: To investigate in the South African public health sector where the best services for rape survivors were provided, who provided them, what the providers' attitudes were towards women who had been raped and whether there were problems in delivering care for rape survivors. METHODS: A cross-sectional study of facilities was carried out. Two district hospitals, a regional hospital and a tertiary hospital (where available) were randomly sampled in each of the nine provinces in South Africa. At each hospital, senior staff identified two doctors and two nurses who regularly provided care for women who had been raped. These doctors and nurses were interviewed using a questionnaire with both open-ended and closed questions. We interviewed 124 providers in 31 hospitals. A checklist that indicated what facilities were available for rape survivors was also completed for each hospital. FINDINGS: A total of 32.6% of health workers in hospitals did not consider rape to be a serious medical condition. The mean number of rape survivors seen in the previous six months at each hospital was 27.9 (range = 9.3-46.5). A total of 30.3% of providers had received training in caring for rape survivors. More than three-quarters of regional hospitals (76.9%) had a private exam room designated for use in caring for rape survivors. Multiple regression analysis of practitioner factors associated with better quality of clinical care found these to be a practitioner being older than 40 years (parameter estimate = 2.4; 95% confidence interval (CI) = 0.7-5), having cared for a higher number of rape survivors before (parameter estimate = 0.02; 95% CI = 0.001-0.03), working in a facility that had a clinical management protocol for caring for rape survivors (parameter estimate = 2; 95% CI = 0.12-3.94), having worked for less time in the facility (parameter estimate = -0.2; 95% CI = -0.3 to -0.04) and perceiving rape to be a serious medical problem (parameter estimate = 2.8; 95% CI = 1.9-3.8). CONCLUSION: There are many weaknesses in services for rape survivors in South Africa. Our findings suggest that care can be improved by disseminating clinical management guidelines and ensuring that care is provided by motivated providers who are designated to care for survivors.

Adult↗

Estimating the parameters of the operational model of pharmacological agonism.

The aim of this work is practical. We show that the parameters of the widely used operational model of pharmacological agonism are difficult to estimate from single dose-response curves. The parameters can be estimated using pairs of dose-response curves (usually treatment and control) sharing some parameters. Confidence bands for the estimators are developed. In the case of multiple dose-response curve pairs one can employ a non-linear mixed effects model to allow for inter-individual variation. The point estimates and the confidence intervals thus obtained are similar to the more naive construction based on mean and standard errors of parameter estimates. To test for difference of certain parameters between treatment and control we employ a permutation test and Wald's test.

Animals↗

Survival estimates and sample size: what can we conclude?

Attempts to understand aging processes often involve life-span measurements from which a survival curve is constructed and model parameters estimated. The parameter estimates are then compared, and conclusions concerning the underlying biological processes are subsequently deduced, based upon the magnitude of the parameter differences. In this article we discuss the role of sample size and sample fluctuation on the parameter estimates and the profound effect that these factors may play in our arrival at meaningful biological conclusions. We then extend this discussion to examine one methodology that can help select sample sizes for specific parametric survival models.

Aging↗

The use of generalized estimating equations in the analysis of motor vehicle crash data.

The purpose of this study was to determine if it is necessary to use generalized estimating equations (GEEs) in the analysis of seat belt effectiveness in preventing injuries in motor vehicle crashes. The 1992 Utah crash dataset was used, excluding crash participants where seat belt use was not appropriate (n=93,633). The model used in the 1996 Report to Congress [Report to congress on benefits of safety belts and motorcycle helmets, based on data from the Crash Outcome Data Evaluation System (CODES). National Center for Statistics and Analysis, NHTSA, Washington, DC, February 1996] was analyzed for all occupants with logistic regression, one level of nesting (occupants within crashes), and two levels of nesting (occupants within vehicles within crashes) to compare the use of GEEs with logistic regression. When using one level of nesting compared to logistic regression, 13 of 16 variance estimates changed more than 10%, and eight of 16 parameter estimates changed more than 10%. In addition, three of the independent variables changed from significant to insignificant (alpha=0.05). With the use of two levels of nesting, two of 16 variance estimates and three of 16 parameter estimates changed more than 10% from the variance and parameter estimates in one level of nesting. One of the independent variables changed from insignificant to significant (alpha=0.05) in the two levels of nesting model; therefore, only two of the independent variables changed from significant to insignificant when the logistic regression model was compared to the two levels of nesting model. The odds ratio of seat belt effectiveness in preventing injuries was 12% lower when a one-level nested model was used. Based on these results, we stress the need to use a nested model and GEEs when analyzing motor vehicle crash data.

Accidents, Traffic↗

Approaches to fitting age-period-cohort models with unequal intervals.

Age-period-cohort models have provided useful insights into the analysis of time trends for disease rates, in spite of the well known identifiability problem. Unique parameter estimates that avoid arbitrary constraints are provided by estimable functions of the parameter estimates. For data that are generated using equal interval widths for age and period, the identifiability issue may be expressed in terms of the age, period and cohort slopes. However, when the interval widths are not the same for age and period, additional identifiability problems arise. These may be represented in terms of macro-trends, which have the identical identifiability problem seen in the equal interval case, and micro-trends, which are the source of the additional problems. A framework for testing estimability is presented, and a variety of potentially interesting functions of the parameters considered. Unlike the equal interval case, drift is not estimable for unequal intervals, but local drift may be. In addition, the available functions for forecasting are much more restrictive in the latter case. This estimability problem induces cyclical patterns in the estimates of trend as is demonstrated using data on leukaemia in Connecticut males, but this can be avoided through the use of smoothing splines. These methods of are illustrated for three-year period and five-year age intervals using data on lung cancer mortality in Californian women.

Adult↗

Evidence of circadian rhythm in low-density lipoprotein apoB catabolism and its impact on the estimation of kinetic parameters.

BACKGROUND: Compartmental models with constant parameters are commonly used in kinetic analysis of low-density lipoproteins (LDLs). Recent studies in animals have demonstrated the existence of circadian rhythms (CRs) in cholesterol synthesis and LDL catabolism. In this study, we investigated the possible existence of a CR in the fractional catabolic rate (FCR) of LDL apoB in man. MATERIALS AND METHODS: Radioactivity data from 45 turnover studies using 125I-labelled LDL apoB were analysed. In a preliminary analysis the pattern of radioactivity decay was investigated. Kinetic analysis was performed by using one- and two-compartment models with constant parameters (steady-state, SS, analysis). Parameters were estimated by the use of the whole data set, which included frequent sampling during the first day of the turnover study, or the once-a-day data, taken at 08.00 h. The selection of once-a-day data allowed elimination of the impact of a CR on parameter evaluation. Furthermore, non-steady-state (NSS) analysis was performed in which the FCR of LDL apoB was calculated as a function of time. In one additional subject, the FCR of LDL apoB was calculated separately for the day and the night using the urine-to-plasma (U/P) radioactivity ratio. RESULTS: The presence of a CR in LDL apoB catabolism, with higher FCR values during the day than during the morning, was demonstrated by the NSS analysis and confirmed by LDL apoB calculation from the U/P ratio. The SS analysis with the whole and the once-a-day data sets resulted in similar average FCR of apoB values (0.329 +/- 0.076 and 0.321 +/- 0.071 respectively) when the two-compartment model was used. Thus, a CR appeared to have little impact on the average FCR of apoB estimation. However, frequent sampling used in the hope of improving parameter estimation accuracy actually resulted in deterioration of the intercompartmental parameter estimators. CONCLUSION: The fractional catabolic rate of LDL apoB exhibited a circadian rhythm with higher FCR values during the day than during the morning. The presence of a CR had, however, a limited impact on the overall FCR of apoB values.

Apolipoproteins B↗

Some methodological problems in estimating radiobiological parameters from clinical data. Alpha/beta ratios and electron RBE for cutaneous reactions in patients treated with postmastectomy radiotherapy.

A number of biological, dosimetric, and statistical problems encountered in the determination of alpha/beta ratios and the relative biological efficiency (RBE) of high energy electrons are discussed. The analysis is based on isoeffect dose determination from logit analysis of dose-response data. Monte Carlo simulations of the logit analysis show that the estimated isoeffect dose may be treated as a normally distributed random variable. Under this assumption, formulae for the standard error of the derived radiobiological parameters are presented. The importance of specifying not only parameter estimates but also their confidence limits is emphasized. As a practical example, the dose-response relationships for severe erythema and subcutaneous fibrosis are discussed in two series of patients treated with postmastectomy irradiation with electrons and photons in two fractionation schedules. Because of a different dose per fraction in the electron and photon fields, a determination of RBE requires a fraction size correction. This is performed using the alpha/beta formalism. The present analysis suggests a high energy electron RBE for severe erythema of 0.93 (95% confidence limits 0.89 and 0.96) and for subcutaneous fibrosis of 0.84 (95% confidence limits 0.77 and 0.92).

Breast Neoplasms↗

Satisfaction with end-of-life care for nursing home residents with advanced dementia.

OBJECTIVES: To identify factors associated with satisfaction with care for healthcare proxies (HCPs) of nursing home (NH) residents with advanced dementia. DESIGN: Cross-sectional study. SETTING: Thirteen NHs in Boston. PARTICIPANTS: One hundred forty-eight NH residents aged 65 and older with advanced dementia and their formally designated HCPs. MASUREMENTS: The dependent variable was HCPs' score on the Satisfaction With Care at the End of Life in Dementia (SWC-EOLD) scale (range 10-40; higher scores indicate greater satisfaction). Resident characteristics analyzed as independent variables were demographic information, functional and cognitive status, comfort, tube feeding, and advance care planning. HCP characteristics were demographic information, health status, mood, advance care planning, and communication. Multivariate stepwise linear regression was used to identify factors independently associated with higher SWC-EOLD score. RESULTS: The mean ages+/-standard deviation of the 148 residents and HCPs were 85.0+/-8.1 and 59.1+/-11.7, respectively. The mean SWC-EOLD score was 31.0+/-4.2. After multivariate adjustment, variables independently associated with greater satisfaction were more than 15 minutes discussing advance directives with a care provider at the time of NH admission (parameter estimate=2.39, 95% confidence interval (CI)=1.16-3.61, P<.001), greater resident comfort (parameter estimate=0.10, 95% CI=0.02-0.17, P=.01), care in a specialized dementia unit (parameter estimate=1.48, 95% CI=0.25-2.71, P=.02), and no feeding tube (parameter estimate=2.87, 95% CI=0.46-5.25, P=.02). CONCLUSION: Better communication, greater resident comfort, no tube feeding, and care in a specialized dementia unit are modifiable factors that may improve satisfaction with care in advanced dementia.

Adult↗

[Creation of a dynamic digital phantom and its application to a kinetic analysis].

A dynamic digital brain phantom was created from the MRI to evaluate visually the relationship between the noise and the error in the parameter estimates in the PET kinetic analysis. This phantom incorporates the noise level depending on administration dose, camera efficiency and the data acquisition schedule. We simulated a serial dynamic scan with 18F-FDG or 11C-flumazenil, assuming 2-tissue 3-parameter model and 1-tissue 2-parameter model, respectively, and the sampling schedule was determined according to the clinical examination. The noise in the tissue time activity curve in FDG had a peak in the first minute and decreased thereafter, whereas the noise increased gradually in the flumazenil study after the initial peak due to radioactivity decay. We examined the relationship between the noise level and the error in the parameter estimates. Both mean absolute differences between true and estimated values and standard deviation became large, and the quality of the parametric images became poor with increasing noise level. This simulation was compared with human tissue time activity curves and parametric images, which were obtained with 100 MBq administration dose in FDG study and 430 MBq in flumazenil study. We inferred that the noise level in the human study was 10-20% in FDG, and 20-40% in flumazenil, and the error in the estimated parameter of K-complex in FDG study was about 20%, that of DV in flumazenil study was 2%.

Brain↗

The effect of ignoring individual heterogeneity in Weibull log-normal sire frailty models.

The objective of this study was, by means of simulation, to quantify the effect of ignoring individual heterogeneity in Weibull sire frailty models on parameter estimates and to address the consequences for genetic inferences. Three simulation studies were evaluated, which included 3 levels of individual heterogeneity combined with 4 levels of censoring (0, 25, 50, or 75%). Data were simulated according to balanced half-sib designs using Weibull log-normal animal frailty models with a normally distributed residual effect on the log-frailty scale. The 12 data sets were analyzed with 2 models: the sire model, equivalent to the animal model used to generate the data (complete sire model), and a corresponding model in which individual heterogeneity in log-frailty was neglected (incomplete sire model). Parameter estimates were obtained from a Bayesian analysis using Gibbs sampling, and also from the software Survival Kit for the incomplete sire model. For the incomplete sire model, the Monte Carlo and Survival Kit parameter estimates were similar. This study established that when unobserved individual heterogeneity was ignored, the parameter estimates that included sire effects were biased toward zero by an amount that depended in magnitude on the level of censoring and the size of the ignored individual heterogeneity. Despite the biased parameter estimates, the ranking of sires, measured by the rank correlations between true and estimated sire effects, was unaffected. In comparison, parameter estimates obtained using complete sire models were consistent with the true values used to simulate the data. Thus, in this study, several issues of concern were demonstrated for the incomplete sire model.

Animals↗

The impact of nonnormality on full information maximum-likelihood estimation for structural equation models with missing data.

A Monte Carlo simulation examined full information maximum-likelihood estimation (FIML) in structural equation models with nonnormal indicator variables. The impacts of 4 independent variables were examined (missing data algorithm, missing data rate, sample size, and distribution shape) on 4 outcome measures (parameter estimate bias, parameter estimate efficiency, standard error coverage, and model rejection rates). Across missing completely at random and missing at random patterns, FIML parameter estimates involved less bias and were generally more efficient than those of ad hoc missing data techniques. However, similar to complete-data maximum-likelihood estimation in structural equation modeling, standard errors were negatively biased and model rejection rates were inflated. Simulation results suggest that recently developed correctives for missing data (e.g., rescaled statistics and the bootstrap) can mitigate problems that stem from nonnormal data.

Data Collection↗

Estimating kinetic parameters for single channels with simulation. A general method that resolves the missed event problem and accounts for noise.

Analysis of currents recorded from single channels is complicated by the limited time resolution (filtering) of the data which can prevent the detection of brief intervals. Although a number of approaches have been used to correct for the undetected intervals (missed events) when identifying kinetic models and estimating parameters, none of them provide a general method which takes into account the true effects of noise and limited time resolution. This paper presents such a method. The approach is to use simulated single-channel currents to incorporate the true effects of filtering and noise on missed events and interval durations. The simulated currents are then analyzed in a manner identical to that used to analyze the experimental currents. An iterative search process using likelihood comparison of two-dimensional dwell-time distributions obtained from the simulated and experimental single-channel currents then allows the most likely rate constants to be determined. The large errors and false solutions that can result from the more typically applied assumptions of no noise and an absolute dead time (idealized filtering) are excluded by the iterative simulation method, and the correlation information contained in the two-dimensional distributions should increase the ability to distinguish among different gating mechanisms. The iterative simulation method is generally applicable to channels which typically open to a single conductance level. For these channels the method places no restrictions on the proposed gating mechanism or the form of the predicted dwell-time distributions.

Ion Channel Gating↗

On the modeling and interpretation of oxygen uptake kinetics from ramp work rate tests.

Ramp work rate tests have been used to estimate aerobic parameters in exercise stress testing. Previous studies have suggested an assumption of a linear dynamic system for O2 uptake kinetics. The implication is that model parameters estimated from ramp tests should be similar to those estimated from other dynamic tests. In nine healthy subjects, we found that model parameters used to characterize O2 consumption ramp data were not consistent with those used to characterize step data, when the comparison was made on a subject-to-subject basis. Furthermore the ramp data model parameter values were highly dependent (P less than 0.0001) on the ramp slope. A linear dynamic system interpretation of the ramp data model does not appear to be appropriate, suggesting that caution is needed in the interpretation of ramp data aerobic parameters. The data may be better described by nonlinear or higher order function. Ramp exercise testing is not suitable for assessing dynamic control properties of the cardiorespiratory response to exercise.

Adolescent↗

Bias and efficiency in family-based gene-characterization studies: conditional, prospective, retrospective, and joint likelihoods.

We revisit the usual conditional likelihood for stratum-matched case-control studies and consider three alternatives that may be more appropriate for family-based gene-characterization studies: First, the prospective likelihood, that is, Pr(D/G,A second, the retrospective likelihood, Pr(G/D); and third, the ascertainment-corrected joint likelihood, Pr(D,G/A). These likelihoods provide unbiased estimators of genetic relative risk parameters, as well as population allele frequencies and baseline risks. The parameter estimates based on the retrospective likelihood remain unbiased even when the ascertainment scheme cannot be modeled, as long as ascertainment only depends on families' phenotypes. Despite the need to estimate additional parameters, the prospective, retrospective, and joint likelihoods can lead to considerable gains in efficiency, relative to the conditional likelihood, when estimating genetic relative risk. This is true if baseline risks and allele frequencies can be assumed to be homogeneous. In the presence of heterogeneity, however, the parameter estimates assuming homogeneity can be seriously biased. We discuss the extent of this problem and present a mixed models approach for providing consistent parameter estimates when baseline risks and allele frequencies are heterogeneous. The efficiency gains of the mixed-model prospective, retrospective, and joint likelihoods relative to the efficiency of conditional likelihood are small in the situations presented here.

Alleles↗