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Linear Mixed Effects Model (linear + mixed_effects_model)
Selected AbstractsUrinary biomarker profiling in transitional cell carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 11 2006Nicholas P. Munro Abstract Urinary biomarkers or profiles that allow noninvasive detection of recurrent transitional cell carcinoma (TCC) of the bladder are urgently needed. We obtained duplicate proteomic (SELDI) profiles from 227 subjects (118 TCC, 77 healthy controls and 32 controls with benign urological conditions) and used linear mixed effects models to identify peaks that are differentially expressed between TCC and controls and within TCC subgroups. A Random Forest classifier was trained on 130 profiles to develop an algorithm to predict the presence of TCC in a randomly selected initial test set (n = 54) and an independent validation set (n = 43) several months later. Twenty two peaks were differentially expressed between all TCC and controls (p < 10,7). However potential confounding effects of age, sex and analytical run were identified. In an age-matched sub-set, 23 peaks were differentially expressed between TCC and combined benign and healthy controls at the 0.005 significance level. Using the Random Forest classifier, TCC was predicted with 71.7% sensitivity and 62.5% specificity in the initial set and with 78.3% sensitivity and 65.0% specificity in the validation set after 6 months, compared with controls. Several peaks of importance were also identified in the linear mixed effects model. We conclude that SELDI profiling of urine samples can identify patients with TCC with comparable sensitivities and specificities to current tumor marker tests. This is the first time that reproducibility has been demonstrated on an independent test set analyzed several months later. Identification of the relevant peaks may facilitate multiplex marker assay development for detection of recurrent disease. © 2006 Wiley-Liss, Inc. [source] 31Phosphorus magnetic resonance spectroscopy study of tissue specific changes in high energy phosphates before and after sertraline treatment of geriatric depressionINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 8 2009Brent P. Forester Abstract Introduction We investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12-week treatment trial of sertraline. Methods Thirteen older adults, age ,55, with Major Depressive Disorder (HAMD17 score of ,18) were recruited along with ten age-matched controls. The depression subjects had a pre- and post-treatment 4T 31P-MRS scan using a three-dimensional chemical shift imaging sequence. The extracted brain images were segmented into white matter (WM), gray matter (GM) and CSF. A linear mixed effects model analyzed the effects of pre-treatment and post-treatment depression on phosphorus metabolite concentration estimates (including calculated pH and Mg++). Results Total tissue beta-NTP (,8%, t(18.66),=,3.50; p,=,0.0024) and total tissue total NTP (,6%, t(17.41),=,2.68; p,=,0.0156) were lower in subjects with geriatric depression compared with healthy controls. Total tissue levels of total-NTP changed significantly with treatment (,2%, t(14.84),=,,2.47; p,=,0.0259). Total NTP was reduced in the WM, but not the GM, in the pre-treatment depression group (t(51.65),=,4.02; p,=,0.0002). Intracellular pH was higher in the GM of subjects with pre-treatment depression (t(1133.84),=,,2.10; p,=,0.0353) and decreased to approximate control levels after treatment (t(648.86),=,,2.53; p,=,0.0115). Discussion These findings demonstrate bioenergetic changes including tissue specific differences in 31P-MRS metabolites in geriatric depression. Decreased white matter total NTP may reflect alterations in white matter function. Copyright © 2009 John Wiley & Sons, Ltd. [source] Is a School-Based Physical Activity Intervention Effective for Increasing Tibial Bone Strength in Boys and Girls?,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2007Heather M Macdonald Abstract This 16-month randomized, controlled school-based study compared change in tibial bone strength between 281 boys and girls participating in a daily program of physical activity (Action Schools! BC) and 129 same-sex controls. The simple, pragmatic intervention increased distal tibia bone strength in prepubertal boys; it had no effect in early pubertal boys or pre or early pubertal girls. Introduction: Numerous school-based exercise interventions have proven effective for enhancing BMC, but none have used pQCT to evaluate the effects of increased loading on bone strength during growth. Thus, our aim was to determine whether a daily program of physical activity, Action Schools! BC (AS! BC) would improve tibial bone strength in boys and girls who were pre- (Tanner stage 1) or early pubertal (Tanner stage 2 or 3) at baseline. Materials and Methods: Ten schools were randomized to intervention (INT, 7 schools) or control (CON, 3 schools). The bone-loading component of AS! BC included a daily jumping program (Bounce at the Bell) plus 15 minutes/day of classroom physical activity in addition to regular physical education. We used pQCT to compare 16-month change in bone strength index (BSI, mg2/mm4) at the distal tibia (8% site) and polar strength strain index (SSIp, mm3) at the tibial midshaft (50% site) in 281 boys and girls participating in AS! BC and 129 same-sex controls. We used a linear mixed effects model to analyze our data. Results: Children were 10.2 ± 0.6 years at baseline. Intervention boys tended to have a greater increase in BSI (+774.6 mg2/mm4; 95% CI: 672.7, 876.4) than CON boys (+650.9 mg2/mm4; 95% CI: 496.4, 805.4), but the difference was only significant in prepubertal boys (p = 0.03 for group × maturity interaction). Intervention boys also tended to have a greater increase in SSIp (+198.6 mm3; 95% CI: 182.9, 214.3) than CON boys (+177.1 mm3; 95% CI: 153.5, 200.7). Change in BSI and SSIp was similar between CON and INT girls. Conclusions: Our findings suggest that a simple, pragmatic program of daily activity enhances bone strength at the distal tibia in prepubertal boys. The precise exercise prescription needed to elicit a similar response in more mature boys or in girls might be best addressed in a dose,response trial. [source] Asymptotic bias in the linear mixed effects model under non-ignorable missing data mechanismsJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES B (STATISTICAL METHODOLOGY), Issue 1 2005Chandan Saha Summary., In longitudinal studies, missingness of data is often an unavoidable problem. Estimators from the linear mixed effects model assume that missing data are missing at random. However, estimators are biased when this assumption is not met. In the paper, theoretical results for the asymptotic bias are established under non-ignorable drop-out, drop-in and other missing data patterns. The asymptotic bias is large when the drop-out subjects have only one or no observation, especially for slope-related parameters of the linear mixed effects model. In the drop-in case, intercept-related parameter estimators show substantial asymptotic bias when subjects enter late in the study. Eight other missing data patterns are considered and these produce asymptotic biases of a variety of magnitudes. [source] Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3ABRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Sandrine Turpault WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform-selective probe drugs have been reported to investigate drug,drug interactions in vivo. , This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP-based drug interactions. WHAT THIS STUDY ADDS , This study describes a new cocktail containing five probe drugs that has never been published. , This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails. AIMS To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone. METHODS This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William's design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg,1 midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed Cmax, AUClast and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte Cmax, AUClast and AUC. RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25. CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug,drug interactions in vivo. [source] | ||||||||||