Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “linear mixed model”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 829 records · Page 46Linked to original sources
PubMed2002

Relative therapeutic index between inhaled formoterol and salbutamol in asthma patients.

A double-blind, randomized crossover study in 28 asthmatic patients assessed the relative therapeutic index for inhaled formoterol and salbutamol. Pre-drug administration FEV1 (mean 2.08 l) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutamol. Patients inhaled single doses of formoterol (Oxis) (4.5,18 and 54 microg, delivered doses) via Turbuhaler, salbutamol (Ventolin) (200 and 1800 microg) via pressurized metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. Relative local (maximum FEV1) and systemic (minimum S-K+) dose potencies, and their ratio, the relative therapeutic index, were estimated using a non-linear mixed effect model. The drug effects were well tolerated and dose dependent. A log-linear approximation was used to describe the bronchodilatory effect, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index between formoterol 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to be 2.5 in favour of formoterol; this trend was not statistically significant.

Adult↗
PubMed2026

Estimating the heritability of longitudinal rate-of-change: genetic insights into PSA velocity in prostate cancer-free individuals.

Serum prostate-specific antigen (PSA) is widely used for prostate cancer screening. While the genetics of PSA levels have been studied to enhance screening accuracy, the genetic basis of PSA velocity, the rate of PSA change over time, remains unclear. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a large, randomized study with longitudinal PSA data (15,260 cancer-free males, averaging 5.34 samples per subject) and genome-wide genotype data, provides a unique opportunity to estimate PSA velocity heritability. We developed a mixed model to jointly estimate the heritability of PSA levels at age 54 and PSA velocity. To accommodate the large dataset, we implemented 2 efficient computational approaches: a partitioning and meta-analysis strategy using average information restricted maximum likelihood (AI-REML) and a fast restricted Haseman-Elston (REHE) regression method. Simulations showed that both methods yield unbiased estimates of both heritability metrics, with AI-REML providing smaller variability in the estimation of velocity heritability than REHE. Applying AI-REML to PLCO data, we estimated heritability at 0.32 (s.e. = 0.07) for baseline PSA and 0.45 (s.e. = 0.18) for PSA velocity. These findings reveal a substantial genetic contribution to PSA velocity, supporting future genome-wide studies to identify variants affecting PSA dynamics and improve PSA-based screening.

Humans↗
PubMed1998

Analysis of clustered data in receiver operating characteristic studies.

Clustered data is not simply correlated data, but has its own unique aspects. In this paper, various methods for correlated receiver operating characteristic (ROC) curve data that have been extended specifically to clustered data are reviewed. For those methods that have not yet been extended, suggestions for their application to clustered ROC studies are provided. Various methods with respect to their ability to meet either of two objectives of the analysis of clustered ROC data are compared to consider a variety of ROC indices and their accessibility to researchers. The available statistical methods for clustered data vary in the range of indices that can be considered and in their accessibility to researchers. Parametric models permit all indices to be considered but, owing to computational complexity, are the least accessible of available methods. Nonparametric methods are much more accessible, but only permit estimation and inference about ROC curve area. The jackknife method is the most accessible and permits any index to be considered. Future development of methods for clustered ROC studies should consider the continuation ratio model, which will permit the application of widely available software for the analysis of mixed generalized linear models. Another area of development should be in the adoption of bootstrapping methods to clustered ROC data.

Bayes Theorem↗
PubMed2006

Time spent outdoors at midday and children's body mass index.

OBJECTIVES: We investigated whether the Kidskin sun protection intervention increased children's body mass index by reducing the time spent outdoors at midday. METHODS: The Kidskin sun protection intervention involved 1614 Australian school children assigned to 1 of 3 groups: a control group, a moderate-intervention group, or a high-intervention group. Schools in the control group received the standard health curriculum and schools in the intervention groups received a multicomponent intervention. Outcomes included time spent outdoors and nevus development (a marker of melanoma risk). Height and weight were measured at 3 time points. Body mass index was transformed into age- and gender-specific z scores; z scores at each age were modeled simultaneously. Time spent outdoors at ages 10 and 12 years was analyzed using a linear mixed effects modeling. RESULTS: The proportion of children who were overweight or obese increased with age. The moderate-intervention and control groups had a minimal increase in z score over time, and the z score for the high-intervention group decreased over time. There were no differences among groups with respect to total time outdoors at any age. CONCLUSIONS: It is possible to reduce the time children spend outdoors when ultraviolet radiation is high without producing an unfavorable effect on the children's body mass index.

Body Mass Index↗
PubMed1994

Variance components testing in the longitudinal mixed effects model.

This article discusses the asymptotic behavior of likelihood ratio tests for nonzero variance components in the longitudinal mixed effects linear model described by Laird and Ware (1982, Biometrics 38, 963-974). Our discussion of the large-sample behavior of likelihood ratio tests for nonzero variance components is based on the results for nonstandard testing situations by Self and Liang (1987, Journal of the American Statistical Association 82, 605-610).

Age Factors↗
PubMed2003

Analysis of gene x environment interactions in sibships using mixed models.

BACKGROUND: Gene x environment models are widely used to assess genetic and environmental risks and their association with a phenotype of interest for many complex diseases. Mixed generalized linear models were used to assess gene x environment interactions with respect to systolic blood pressure on sibships adjusting for repeated measures and hierarchical nesting structures. A data set containing 410 sibships from the Framingham Heart Study offspring cohort (part of the Genetic Analysis Workshop 13 data) was used for all analyses. Three mixed gene x environment models, all adjusting for repeated measurement and varying levels of nesting, were compared for precision of estimates: 1) all sibships with adjustment for two levels of nesting (sibs within sibships and sibs within pedigrees), 2) all sibships with adjustment for one level of nesting (sibs within sibships), and 3) 100 data sets containing random draws of one sibship per extended pedigree adjusting for one level of nesting. RESULTS: The main effects were: gender, baseline age, body mass index (BMI), hypertensive treatment, cigarettes per day, grams of alcohol per day, and marker GATA48G07A. The interaction fixed effects were: baseline age by gender, baseline age by cigarettes per day, baseline age by hypertensive treatment, baseline age by BMI, hypertensive treatment by BMI, and baseline age by marker GATA48G07A. The estimates for all three nesting techniques were not widely discrepant, but precision of estimates and determination of significant effects did change with the change in adjustment for nesting. CONCLUSION: Our results show the importance of the adjustment for all levels of hierarchical nesting of sibs in the presence of repeated measures.

Adult Children↗
PubMed1999

Comparison of different methods to evaluate population dose-response and relative potency: importance of interoccasion variability.

Different mixed-effects models were compared to evaluate the population dose-response and relative potency of two albuterol inhalers. Bronchodilator response was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-effects (Emax) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50 and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose-response and relative potency, there are important differences in the assumptions made by each method.

Administration, Inhalation↗
PubMed2005

Evidence of a major gene from Bayesian segregation analyses of liability to osteochondral diseases in pigs.

Bayesian segregation analyses were used to investigate the mode of inheritance of osteochondral lesions (osteochondrosis, OC) in pigs. Data consisted of 1163 animals with OC and their pedigrees included 2891 animals. Mixed-inheritance threshold models (MITM) and several variants of MITM, in conjunction with Markov chain Monte Carlo methods, were developed for the analysis of these (categorical) data. Results showed major genes with significant and substantially higher variances (range 1.384-37.81), compared to the polygenic variance (sigmau2). Consequently, heritabilities for a mixed inheritance (range 0.65-0.90) were much higher than the heritabilities from the polygenes. Disease allele frequencies range was 0.38-0.88. Additional analyses estimating the transmission probabilities of the major gene showed clear evidence for Mendelian segregation of a major gene affecting osteochondrosis. The variants, MITM with informative prior on sigmau2, showed significant improvement in marginal distributions and accuracy of parameters. MITM with a "reduced polygenic model" for parameterization of polygenic effects avoided convergence problems and poor mixing encountered in an "individual polygenic model." In all cases, "shrinkage estimators" for fixed effects avoided unidentifiability for these parameters. The mixed-inheritance linear model (MILM) was also applied to all OC lesions and compared with the MITM. This is the first study to report evidence of major genes for osteochondral lesions in pigs; these results may also form a basis for underpinning the genetic inheritance of this disease in other animals as well as in humans.

Animals↗
PubMed2002

A Bayesian approach to parameter estimation in HIV dynamical models.

In the context of a mathematical model describing HIV infection, we discuss a Bayesian modelling approach to a non-linear random effects estimation problem. The model and the data exhibit a number of features that make the use of an ordinary non-linear mixed effects model intractable: (i) the data are from two compartments fitted simultaneously against the implicit numerical solution of a system of ordinary differential equations; (ii) data from one compartment are subject to censoring; (iii) random effects for one variable are assumed to be from a beta distribution. We show how the Bayesian framework can be exploited by incorporating prior knowledge on some of the parameters, and by combining the posterior distributions of the parameters to obtain estimates of quantities of interest that follow from the postulated model.

Bayes Theorem↗
PubMed2005

A linear mixed-effects calibration in qualifying experiments.

In many applications, controls are used to monitor the process or experiment and to assess whether the process is in control or the experiment is valid. In this case, the traditional fixed-effects calibration is usually not adequate, but a mixed-effects model is appropriate. In this article, a linear mixed-effects calibration model is considered to qualify an experiment. Two estimating methods for the controls based on maximum likelihood and restricted maximum likelihood are proposed. The bias and mean squared error performances are studied by simulation. Five different methods to construct confidence intervals for the controls are compared. A dataset is used to demonstrate the advantages of the mixed-effects model.

Calibration↗
PubMed2002

Assessment of a relative therapeutic index between inhaled formoterol and salbuterol in asthma patients.

OBJECTIVE: To quantify the relation between local and systemic magnitudes of effects of inhaled formoterol and salbutamol. METHODS: Twenty-eight stable asthmatic patients completed this double-blind, randomised crossover study. Pre-drug administration FEV1 (mean 2.08 L) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutanmol. Patients inhaled three single doses of formoterol fumarate dihydrate (Oxis) (delivered doses of 4.5, 18 and 54 microg) via Turbuhaler, two single doses of salbutamol (200 and 1800 microg) via a pressurised metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. A classic sigmoid model of log-dose response was used to discriminate pharmacologically between formoterol and salbutamol. Relative local (maximum FEV1) and systemic (minimum S-KC) dose potencies, and their ratio, the relative therapeutic index, were estimated using an on-linear mixed effect model. RESULTS: The drug effects were well tolerated and dose dependent The bronchodilating effect was on a part of the dose response curve that could be well approximated by a log-linear function, the serum potassium suppressing effect sometimes was not (the lowest doses differed only marginally from placebo). Thus, a log-linear approximation was used to describe bronchodilation, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index was estimated to be 2.5 (95%confidence interval: 0.9-6.5). CONCLUSIONS: The mean relative therapeutic index between formoterol (Oxis) 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to 2.5 in favour of formoterol; this trend was not statistically significant.

Adolescent↗
PubMed2004

pO2 and regional blood flow in a rabbit model of limb ischemia.

Oxygen tension (pO2) in muscles and regional blood flow were measured in a rabbit model of limb ischemia. pO2 was measured repetitively by EPR oximetry with EMS char in four different muscle groups in the same animals. Blood flow in the same muscles at several time points was measured using microspheres. A linear mixed effects model was developed to analyze the data on pO2 and blood flow. The results suggest that while under normal conditions pO2 in muscles does not depend significantly on blood flow, immediately after arterial occlusion pO2 correlates linearly with blood flow. Within two weeks of occlusion the pO2 is recovered to 45% of baseline. This study demonstrates, for the first time, the applicability of EPR oximetry in animals larger than rodents.

Algorithms↗
PubMed1992

Methods of segregation analysis for animal breeding data: parameter estimates.

Three approximations to the combined model likelihood (including variation due to both polygenes and a major gene) used in segregation analysis were compared in their ability to estimate the parameters describing the model. Paternal half-sib data simulated under four different combined models were used. In general, when a combined model provides the best explanation of the data the parameter estimates from all three approximations investigated are, on average, in good agreement with the values simulated. The use of Hermite integration to replace the integration in the combined model likelihood provided the parameter estimates closest to those stimulated. The other two approximations, based on extensions of linear mixed-model theory, gave estimates further from the expected values, however, these latter two methods can estimate transmitting abilities for the sires directly from the analyses. The three approximations are similar in their ability to genotype sires at the major locus. On average, with the models studied here, about 65 per cent of sires can be successfully genotyped.

Alleles↗
PubMed1996

Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone.

1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children (< or = 15 years) and patients aged > 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

Acute Disease↗
PubMed1999

Visit-driven endpoints in randomized HIV/AIDS clinical trials: impact of missing data on treatment difference measured on summary statistics.

In randomized HIV/AIDS clinical trials, CD4 lymphocyte counts and plasma HIV-1 RNA measurements are often used as endpoints. The comparison between treatment groups is mainly based on a summary measure of outcome, so-called summary statistic. Such analyses are often complicated by missing data occurring as drop-outs. For the most currently used summary statistics in these trials, we examined the impact of missing data occurring as drop-outs on test size, in order to help choosing between these statistics. A simulation of missing-data patterns was performed, using HIV-1 plasma RNA measurements as the main endpoint, to compare the effect of three plausible informative patterns, depending on treatment group, and on baseline or current plasma viral load, on eight different summary statistics. Missing data resulted in test sizes over the nominal value for the area under the curve minus baseline, the least-squares slope, the slope estimated with use of a mixed effects linear model, assuming a linear trend over the entire study, the difference between baseline and nadir, and the difference between baseline and week 24. The difference between baseline and week 8 was an acceptable summary with respect to the test size, but did not reflect accurately the durability of the effect of treatment. Two criteria appeared as the best summary statistics: the slope estimated by a mixed effects model, with a change of slope after two weeks of treatment, and to a lesser degree, the area under the curve after carrying forward the last observation.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Optimal sampling theory and population modelling: application to determination of the influence of the microgravity environment on drug distribution and elimination.

Newer mathematical techniques such as optimal sampling theory and NON-linear Mixed Effects Modelling (NONMEM) allow the determination of pharmacokinetics and pharmacodynamics in populations of individuals previously believed to be "too ill" or "too difficult to study." Optimal sampling determines the most information-rich times to sample the system, allowing robust parameter estimates to be determined from the minimal number of samples. NONMEM, by taking the population as the unit of analysis, allows even fragmentary patient data sets to contribute to population parameter estimates. Obviously, the microgravity environment presents extreme logistical difficulties to the performance of traditional pharmacokinetic and pharmacodynamic studies. Examples of the validation of these techniques are presented, which indicates their likely utility in the important task of determining the influence of the microgravity environment on drug distribution and elimination, even accounting for the limitations of support which will be faced in this circumstance.

Bayes Theorem↗
PubMed2006

Population modelling to describe pharmacokinetics of amiodarone in rats: relevance of plasma protein and tissue depot binding.

The objective of this paper was to characterize the disposition phase of AM in rats, after different high doses and modalities of i.v. administration. Three fitting programs, WINNONLIN, ADAPT II and NONMEM were employed. The two-stage fitting methods led to different results, none of which can adequately explain amiodarone's behaviour, although a great amount of data per subject is available. The non-linear mixed effect modelling approach allows satisfactory estimation of population pharmacokinetic parameters, and their respective variability. The best model to define the AM pharmacokinetic profile is a two-compartment model, with saturable and dynamic plasma protein binding and linear tissular depot dynamic binding. These results indicate that peripheral tissues act as depots, causing an important fall in AM plasma levels in the first moment after dosing. Later, the return of the drug from these depots causes a slow increase in serum concentration whenever the dose is reduced.

Amiodarone↗
PubMed1995

A population pharmacokinetic study of alminoprofen penetration into synovial fluid.

The pharmacokinetics of alminoprofen in plasma and synovial fluid (SF) at steady state (300 mg t.i.d.) was studied in 45 patients with knee effusion. Plasma and SF samples, one each per patient, were obtained. Six groups were made according to the time of sampling after ingestion of the 13th dose: 1 h (n = 7), 2 h (n = 7), 4 h (n = 7), 6 h (n = 10), 8 h (n = 6), 12 h (n = 8). A three-compartment model was used to describe alminoprofen kinetics in plasma and SF, with two parameterizations, a 'classical' and a 'physiological' one. The non-linear mixed effect model approach was used to estimate the mean and variance of the pharmacokinetic parameters. The mean +/- SE of the estimates (coefficient of variation of interindividual variability as a percentage) were volume of distribution, 11.0 +/- 1.711 (12%); elimination rate constant, 0.236 +/- 0.025 h-1 (18%); absorption rate constant 2.80 +/- 0.31 h-1 (464%), clearance of influx into SF, 0.29 +/- 0.14 mL min-1; clearance of efflux into plasma, 0.56 +/- 0.25 mL min-1. These two clearances were not significantly different, which indicates that passive diffusion occurs in both directions. The mean +/- SD alminoprofen concentration versus time curve in plasma and SF at steady state was simulated and showed that the mean +/- SD maximal concentration in SF was 8.1 +/- 6.3 mg L-1 and was obtained 4 h after dose administration.

Absorption↗