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.

SourceResearch connectionFrom yearThrough year

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

At least 379 records · Page 21Linked to original sources

PubMed2005

Quality assessment of oral anticoagulation in Belgium, as practiced by a group of general practitioners.

OBJECTIVE: In Belgium oral anticoagulation therapy is mainly supervised by general practitioners (GPs). This study aims to evaluate the quality of management of oral anticoagulation by Belgian GPs and to verify the relation between time in range and a set of potentially influencing co-variables. METHODS: In a retrospective cross-sectional study, involving 66 GP-practices, the INR-values obtained over a 6-month period were analysed. All INR-values were determined by a single clinical laboratory and additional medical information was provided by the GPs. Linear mixed models have been used to model the patient-specific percentage INR in target as a function of different co-variables. RESULTS: 737 patients were included in the study. Patients who underwent a surgical intervention with an interruption of the anticoagulation during the study were excluded. Patients were only included after the initial starting-up period. 5890 INR-values were obtained. A total of 92,566 days of therapy was evaluated. 50% of the day values were within 0.5 INR-units from target (and 66% within 0.75 INR-units from target). In a multiple regression model, a significant relation between the percentage of time in range and the target INR (2.5 or 3.5) and the gender of the patient was shown. The incidence rate for major bleeding was 5.5/100 patient years (and 3.5/100 patient years for thrombo-embolic events). CONCLUSION: The quality of management of oral anticoagulation by the GPs in Belgium is suboptimal. It is unknown whether interventions such as guidelines, feedback, point-of-care monitoring and computer-assisted anticoagulation monitoring could improve the results.

Aged↗

PubMed2004

Evaluation of a larval development assay (DrenchRite) for the detection of anthelmintic resistance in cyathostomin nematodes of horses.

A larval development assay (LDA, DrenchRite) was evaluated to determine the effectiveness of this method in detecting anthelmintic resistance in cyathostomin nematodes of horses. A total of 15 horse farms from Georgia and South Carolina (USA) and Population S ponies from the University of Kentucky (USA) were included in this study. Nematode eggs were extracted from pooled fecal samples and placed into the wells of a DrenchRite plate for testing against thiabendazole (TBZ), levamisole (LEV) and 2 ivermectin (IVM) analogs (IVM-1, IVM-2). After a 7-day incubation larvae in each well were counted and data were analyzed by logistic regression. Resistance status of each farm for different drugs was determined in a separate study using a fecal egg count reduction test. LDA were performed on the 15 farms once, however, the Population S cyathostomins were assayed on 3 separate occasions to estimate the consistency of results between assays. Mean TBZ LC50 for oxibendazole resistant, suspected resistant and sensitive farms were 0.2015, 0.1625, and 0.1355 microM, respectively. For LEV, mean LC50 for PYR resistant, suspected resistant and sensitive farms were 1.590, 1.8018 and 1.4219 microM, respectively. All 15 farms had worms susceptible to IVM; mean LC50 for IVM-1 and for IVM-2 were 7.5727 and 87.9718 nM, respectively. A linear mixed model was fitted to the data to determine the relationship between LC50 and LC95 and resistance status for each farm. No meaningful relations were found. Consistency of assays varied between drugs, being best for TBZ and worst for LEV and IVM-1. All farms in this study had benzimidazole-resistant nematodes; therefore usefulness of DrenchRite for discriminating susceptibility versus resistance to this drug class could not be accurately assessed. Moreover, since all farms tested were sensitive to IVM and resistance to this drug class has not yet been reported in cyathostomins, it is not possible to assess accurately the usefulness of DrenchRite LDA for detecting IVM resistance at this time. Assay results for LEV suggest that LEV in a LDA does not yield data that is useful in estimating PYR efficacy in vivo. Based on results for PYR/LEV, the current high prevalence of benzimidazole resistance, no known cases of IVM resistance, and the sometimes extreme variation in results seen in many of the assays, DrenchRite LDA cannot be considered a useful tool for the diagnosis of resistance in cyathostomins of horses at present.

Animals↗

PubMed1997

Assessing infections at multiple levels of aggregation.

The patterns of sero-prevalence of antibodies to four infectious diseases, representing a broad range of pathogens (bacteria: brucellosis; mycoplasma: contagious bovine pleuropneumonia; viruses: infectious bovine rhinotracheitis; protozoa: trypanosomosis) were investigated at three levels of organization (farm, area and district). Three contrasting districts in Kenya were compared: an arid and pastoral area (Samburu); a tropical highland area (Kiambu), and a tropical coastal area (Kilifi). Cattle in three districts were selected by two-stage cluster sampling between August 1991 and 1992. Schall's algorithm, a generalized linear mixed model suitable for multi-level analysis, was compared to ordinary logistic regression (OLR), which ignores clustering of responses; generalized estimating equations (GEE) or Jacknife, to account for clustering at the farm level; SAS VARCOMP, which provides normal-theory random-effects models. Schall's algorithm provided similar estimates to GEE (regression effects) and Jackknife (standard errors) for farm-level clustered data. Extending Schall's procedure for additional district and area-within-district random effects usually provided additional information. In general, models that included only a farm-level random effect consistently provided larger estimates of farms' variance components than did models with additional district and area random effects. The four type diseases exhibited various amounts of clustering. Brucellosis had moderate farm clustering plus some area and district clustering. Contagious bovine pleuropneumonia had only a small amount of clustering, mostly by area. Infectious bovine rhinotracheitis exhibited a large amount of clustering, primarily at the farm level. Trypanosomiasis antibody prevalence varied by district, area and farm. We believe that patterns of disease clustering identified by multi-level analysis can be used to better target high-risk units for disease control and guide research to understand disease transmission factors.

Algorithms↗

PubMed2005

Characterization of Staphylococcus aureus isolated from chronically infected dairy goats.

A herd of 88 Alpine goats in Northern Italy was monitored for a complete lactation. Milk samples were taken from each udder half during 8 monthly visits. Goats (n = 28) with > or =2 consecutive positive tests for Staphylococcus aureus in the same udder half were identified as chronically infected, and all of those had > or =4 positive tests of the 8 samples. Goats with no infections in either udder half during any visit were considered healthy (n = 26). Linear mixed models were used to examine the relationship between chronic infection by S. aureus and SCC and production traits. The bacteria isolated from one sample from each infected goat were genotyped on the basis of polymorphism in several genes and evaluated for the presence of genes encoding for enterotoxins. The bacteria isolated from each animal were also subject to a test for beta-lactamase production and to minimum inhibitory concentration tests for 11 antimicrobial agents. As expected, SCC (log2) was significantly higher in infected goats than in healthy goats (7.55 vs. 5.50). Also, mean log SCC from infected udder halves (8.02) was greater than that in uninfected udder halves from the same goats (6.44). No significant differences were observed in milk yield or for fat and protein percentages between infected and healthy goats. No genetic variability was observed among the bacteria isolated, suggesting that all were from the same strain, although isolates did vary in susceptibility to various antimicrobial agents. All S. aureus isolates were negative for the beta-lactamase production test. The most effective drugs when tested in vitro were benzylpenicillin, amoxicillin plus clavulanic acid, cloxacillin, and cephalosporins.

Animals↗

PubMed2005

Effect of recall rate on earlier screen detection of breast cancers based on the Dutch performance indicators.

BACKGROUND: The recall rate (i.e., the rate at which mammographically screened women are recalled for additional assessment) in the Dutch breast screening program (0.89% in 2000 for subsequent examinations) is the lowest worldwide, with possible consequences including higher rates of late-detected (i.e., "missed") interval and screen-detected cancers. To estimate the effect of changes in recall rate on earlier detection of cancers, we carried out a blinded review of interval and screen-detected cancers in the Dutch screening program. METHODS: A total of 495 sets of screen-negative mammograms (prediagnostic mammogram and the immediate previous mammogram) were collected from women participating in the biennial Dutch screening program. Of these, 250 were from control subjects, and 245 were from women who were subsequently diagnosed with breast cancer (123 interval and 122 screen-detected cancers). These mammograms were read by 15 radiologists who specialize in screening mammography and were blinded to outcome. Mean detection sensitivities for different false-positive rates were calculated using a linear mixed model. These results were used to calculate the effect of recall rate adjustment on earlier detection of cancers and numbers of false-positives. RESULTS: Increasing the recall rate to 2.0% would increase the detection rate from 4.20 per thousand to 4.52 per thousand due to the earlier detection of interval cancers. Moreover, 0.54 per thousand of the screen-detected cancers would be detected 2 years earlier (late screen-detected cancers). At recall rates of 3.0% and 4.0% the detection rate would increase to 4.58 per thousand and 4.63 per thousand, respectively, and 0.64 per thousand and 0.72 per thousand, respectively, of the screen-detected cancers would be detected 2 years earlier. For each 1.0% incremental increase in recall rate above 5.0%, the detection rate would increase by approximately 0.03 per thousand, with positive predictive values decreasing to below 10%. CONCLUSION: Breast cancer can be detected earlier by lowering the threshold for recall, especially for recall rates of 1%-4%. With further recall rate increases, cancer detection levels off with a disproportionate increase of false-positive rates.

Breast Neoplasms↗

PubMed2005

Myo-inositol, glucose and zinc concentrations determined in the preconceptional period, during and after pregnancy.

OBJECTIVE: To determine the blood concentrations of myo-inositol, glucose and zinc before, during and after normal pregnancy. STUDY DESIGN: Preconceptionally, at 6, 10, 20, 30 and 37 weeks amenorrhea, and 6 weeks after delivery, blood samples of 18 nulliparae and 19 multiparae were obtained and concentrations of serum inositol and glucose, and red blood cell zinc were determined. The data were analyzed using a linear mixed model. RESULTS: The preconceptional mean (S.E.M.) inositol concentration of 21.7 (1.03) micromol/L was comparable to the concentrations at 6 and 37 weeks amenorrhea, 22.2 (1.03) micromol/L, and 19.9 (1.10) micromol/L, respectively. However, the inositol concentrations at 10 and 20 weeks amenorrhea and post partum were significantly lower than the preconceptional inositol concentration, p<0.05. The preconceptional mean (S.E.M.) glucose concentration of 3.9 (1.03) mmol/L was comparable to the concentration at 6 and 10 weeks amenorrhea, 3.9 (1.04) mmol/L and 3.8 (1.04) mmol/L respectively. Also at 20, 30 and 37 weeks amenorrhea and after delivery the glucose concentration was significantly lower than the preconceptional glucose concentration, p<0.05. Preconceptional red blood cell zinc concentrations were comparable to concentrations at 6, 10 and 20 weeks amenorrhea. At 30 and 37 weeks amenorrhea and post partum the zinc concentrations were significantly higher than in the preconceptional period (p<0.01). CONCLUSION: The concentrations of inositol, glucose and zinc significantly change during pregnancy. However, the preconceptional blood concentrations reflect the concentrations determined in the first pregnancy trimester rather well, which is important information to be used in future studies into the role of inositol, glucose and zinc in reproductive disorders.

Adult↗

PubMed2004

Identification of differentially expressed genes in individual bovine preimplantation embryos produced by nuclear transfer: improper reprogramming of genes required for development.

Using an interwoven-loop experimental design in conjunction with highly conservative linear mixed model methodology using estimated variance components, 18 genes differentially expressed between nuclear transfer (NT)- and in vitro fertilization (IVF)-produced embryos were identified. The set is comprised of three intermediate-filament protein genes (cytokeratin 8, cytokeratin 19, and vimentin), three metabolic genes (phosphoribosyl pyrophosphate synthetase 1, mitochondrial acetoacetyl-coenzyme A thiolase, and alpha-glucosidase), two lysosomal-related genes (prosaposin and lysosomal-associated membrane protein 2), and a gene associated with stress responses (heat shock protein 27) along with major histocompatibility complex class I, nidogen 2, a putative transport protein, heterogeneous nuclear ribonuclear protein K, mitochondrial 16S rRNA, and ES1 (a zebrafish orthologue of unknown function). The three remaining genes are novel. To our knowledge, this is the first report comparing individual embryos produced by NT and IVF using cDNA microarray technology for any species, and it uses a rigorous experimental design that emphasizes statistical significance to identify differentially expressed genes between NT and IVF embryos in cattle.

Animals↗

PubMed2007

Tympanic temperature measurements: are they reliable in the critically ill? A clinical study of measures of agreement.

OBJECTIVE: Accurate measurement of temperature is vital in the intensive care setting. A prospective trial was performed to compare the accuracy of tympanic, urinary, and axillary temperatures with that of pulmonary artery (PA) core temperature measurements. DESIGN: A total of 110 patients were enrolled in a prospective observational cohort study. SETTING: Multidisciplinary intensive care unit of a university teaching hospital. PATIENTS: The cohort was (mean +/- sd) 65 +/- 16 yrs of age, Acute Physiology and Chronic Health Evaluation (APACHE) II score was 25 +/- 9, 58% of the patients were men, and 76% were mechanically ventilated. The accuracy of tympanic (averaged over both ears), axillary (averaged over both sides), and urinary temperatures was referenced (as mean difference, Delta degrees centigrade) to PA temperatures as standard in 6,703 recordings. Lin concordance correlation (pc) and Bland-Altman 95% limits of agreement (degrees centigrade) described the relationship between paired measurements. Regression analysis (linear mixed model) assessed covariate confounding with respect to temperature modes and reliability formulated as an intraclass correlation coefficient. MEASUREMENTS AND MAIN RESULTS: Concordance of PA temperatures with tympanic, urinary, and axillary was 0.77, 0.92, and 0.83, respectively. Compared with PA temperatures, Delta (limits of agreement) were 0.36 degrees C (-0.56 degrees C, 1.28 degrees C), -0.05 degrees C (-0.69 degrees C, 0.59 degrees C), and 0.30 degrees C (-0.42 degrees C, 1.01 degrees C) for tympanic, urinary, and axillary temperatures, respectively. Temperature measurement mode effect, estimated via regression analysis, was consistent with concordance and Delta (PA vs. urinary, p = .98). Patient age (p = .03), sedation score (p = .0001), and dialysis (p = .0001) had modest negative relations with temperature; quadratic relationships were identified with adrenaline and dobutamine. No interactions with particular temperature modes were identified (p > or = .12 for all comparisons) and no relationship was identified with either mean arterial pressure or APACHE II score (p > or = .64). The average temperature mode intraclass correlation coefficient for test-retest reliability was 0.72. CONCLUSION: Agreement of tympanic with pulmonary temperature was inferior to that of urinary temperature, which, on overall assessment, seemed more likely to reflect PA core temperature.

APACHE↗

PubMed2006

Airway inflammation in Michigan pleasure horses: prevalence and risk factors.

REASONS FOR PERFORMING STUDY: Although subclinical airway inflammation is thought to be common in horses, there is little information on its prevalence and none on risk factors. OBJECTIVE: To determine the prevalence and risk factors for an increased number of inflammatory cells and for mucus accumulation in the trachea of pleasure horses. METHODS: Horses (n = 266) in stables (n = 21) in Michigan were examined endoscopically, once in winter and once in summer 2004. Visible tracheal mucoid secretions were graded 0-5 and inflammatory cell numbers counted in a tracheal lavage sample. Information collected about each horse included age, gender, presence of cough, percent time indoors and source of roughage. The repeated measures were analysed by generalised estimating equations and linear mixed models. RESULTS: Horses eating hay, especially from round bales, had the most neutrophils, whereas horses feeding from pasture had the fewest. Being female and being outdoors in winter were associated with increased numbers of inflammatory cells. Older horses had fewer macrophages than young horses. More than 70% of horses had >20% neutrophils in tracheal lavage. Twenty percent of horses had a mucus accumulation score >1; 17% had both a mucus score >1 and >20% neutrophils. The significant risk factors for mucus accumulation >1 were age >15 years, feeding on hay as compared to pasture, and being outdoors for more than 80% time in winter. Even though mucus accumulation score >1 was a risk factor for cough, only half of such horses coughed. Cough and mucus accumulation were associated with increased number of neutrophils. CONCLUSIONS: In comparison to pasture feeding, hay feeding, particularly from round bales, was associated with an increased number of neutrophils in the airway. Being outdoors in winter was associated with increased numbers of inflammatory cells and with mucus accumulation. Because 70% of horses have >20% neutrophils, this value should not be used as the sole indicator of airway inflammation. POTENTIAL RELEVANCE: The study reinforces the importance of hay feeding and older age as risk factors for inflammatory airway disease. Horses that do not have 'heaves' may be best kept indoors when winters are cold.

Age Factors↗

PubMed2026

Genome-wide association studies for feed efficiency, production and feeding behavior traits in Canadian purebred Duroc pigs.

This study aimed to identify potential genetic variants and candidate genes associated with feed efficiency (FE), production, and feeding behavior traits in Canadian purebred Duroc pigs. Genome-wide association studies (GWAS) were conducted using 8,861 individuals and an imputed Affymetrix PigGen Canada 50K panel v2.0 using a linear mixed model (LMM) and a Bayesian B model. This analysis used an adjusted P-value threshold (ranging from 6.6 × 10-5 to 1.3 × 10-4) using a false-discovery rate to determine significance. The number of significant SNPs identified for each trait was as follows: average daily gain (ADG, 48), daily feed intake (DFI, 85), feed conversion ratio (FCR, 101), residual feed intake (RFI, 37), residual gain (RG, 64), residual intake and gain (RIG, 55), backfat thickness (BF, 100), loin depth (LD, 6), Kleiber's ratio (KR, 0), total time spent eating per day (TPD, 7), and number of visits to the feeder per day (NVD, 6). Several traits (BF, DFI, FCR, RFI, RG, and RIG) showed strong overlapping signals on chromosomes 7 and 10 with 24 shared significant SNPs, indicating potential shared genetic mechanisms. These traits also had 71 overlapping candidate genes, such as PACSIN1, PTCH1, ADIPOR1, and ITPR3, associated with glucose, lipid, and cholesterol metabolism. Well-known candidate genes in literature associated with growth and fatness such as MC4R and CDH20 were also identified to be associated with ADG, BF, FCR, and DFI in this study. Gene ontology enrichment analysis revealed that a set of the candidate genes were involved in the gonadotropin-releasing hormone (GnRH) and the platelet-derived growth factor (PDGF) signaling pathways. Overall, this study contributed to understanding the genetic architecture and provided a biological foundation for improving FE, production, and feeding behavior traits in Canadian Duroc pigs, facilitating the selection of more efficient pigs.

Sus scrofa↗

PubMed2006

Density effects on life-history traits in a wild population of the great tit Parus major: analyses of long-term data with GIS techniques.

1. Population density often has strong effects on the population dynamics and reproductive processes of territorial animals. However, most estimates of density-dependent effects use the number of breeding pairs per unit area in a given season and look for correlations across seasons, a technique that assigns the same density score to each breeding pair, irrespective of local spatial variation. 2. In this study, we employed GIS techniques to estimate individual breeding densities for great tits breeding in Wytham Woods UK, between 1965 and 1996. We then used linear mixed modelling to analyse the effect of density on reproductive processes. 3. The areas of Thiessen polygons formed around occupied nestboxes were used to approximate territory size (necessarily inverse of breeding density). There were significant, independent and positive relationships between clutch size, fledging mass and the number of offspring recruited to the population, and territory size (all P < 0.001), but no effect of territory size on lay-date or egg mass. 4. Thiessen polygons are contiguous and cover all of the available area. Therefore, at low nest densities territory polygons were excessively oversized. Using a novel procedure to address this limitation, territory sizes were systematically capped through a range of maxima, with the greatest effect in the models when territories were capped at 0.9-2.3 ha. This figure approximates to the maximum effective territory size in our population and is in close agreement with several field-based studies. This capping refinement also revealed a significant negative relationship between lay-date and territory size capped at 0.9 ha (P < 0.001). 5. These density-dependent effects were also detected when analyses were restricted to changes within individual females, suggesting that density effects do not merely result from either increased proportions of low-quality individuals, or increased occupation of poor sites, when population density is high. 6. Overall, these results suggest that, in the current population, great tits with territories smaller than c. 2 ha independently lay smaller and later clutches, have lighter fledglings, and recruit fewer offspring to the breeding population. These analyses thus suggest a pervasive and causal role of local population density in explaining individual reproductive processes.

Animals↗

PubMed2003

Simulation study of teat score in first-parity Gelbvieh cows: parameter estimation.

Teat scores from 9,598 first-parity Gelbvieh cows were used to investigate the adequacy of grouping approaches to decrease score misclassifications or inconsistencies as well as to simplify the data collection process. The procedure was tested using simulated data and then validated using teat score records of Gelbvieh cattle. First-parity cows were considered to be 4 yr of age or younger at first calving, did not have multiple records within 280 d, and were at least 50% Gelbvieh. Producers scored cows within 24 h of parturition. Teat score, a subjective measure of teat size, ranged from 0 (very large) to 50 (very small). A linear mixed model that included herd-year, month of calving, and age at calving as systematic effects; regression on the percentage of Gelbvieh; and additive breeding values (BV) and residual as random effects was used to generate the data. Simulated data were analyzed using one of three scoring methods: all values (S50), 10 classes (S10), and five classes (S5). The 10 classes were formed by subdividing every five scores into a single class starting at score zero. Similarly, the five classes were formed by combining every 10 scores into one class. The average Pearson correlations, based on five replicates, between the true and estimated BV (systematic effects) were 0.36 (0.85), 0.35 (0.89), and 0.32 (0.87) using S50, S10, and S5, respectively. Average correlations between estimated BV (systematic effects) were 0.97 (0.95), 0.89 (0.92), and 0.92 (0.97) based on S50 and S10, S50 and S5, and S10 and S5, respectively. Field data were used to validate the simulation procedure. The field data were categorized into 10 classes (F10) and five classes (F5) as described for the simulated data. Pearson correlations between estimated BV (systematic effects) were 0.99 (0.93), 0.93 (0.88), and 0.93 (0.96), based on F50 with F10, F50 with F5, and F10 with F5, respectively. The extremely high correlations between predicted BV based on S50, S10, S5, F50, F10, with F5 suggest that a simplified score classification method could be adopted without compromising the expected genetic progress for the trait under consideration. Furthermore, the difference in corresponding Pearson correlations across the field and simulated data might suggest the presence of some inconsistencies or misclassifications of the actual scoring system.

Animals↗

PubMed2002

Postponed development of disability in elderly runners: a 13-year longitudinal study.

BACKGROUND: The magnitude and duration of the benefit of running and other aerobic exercise on disability and mortality in elderly persons are not well understood. We sought to quantify the benefits of aerobic exercise, including running, on disability and mortality in elderly persons and to examine whether morbidity can be compressed into later years of life by regular exercise. METHODS: A 13-year prospective cohort study of 370 members of a runners' club for persons aged 50 and older and 249 control subjects initially aged 50 to 72 years (mean, 59 years), with annual ascertainment of the Health Assessment Questionnaire disability score, noting any deaths and their causes. Linear mixed models were used to compute postponement in disability, and survival analysis was conducted to determine the time to and causes of death. RESULTS: Significantly (P<.001) lower disability levels in runners' club members vs controls and in ever runners vs never runners were sustained for at least 13 years. Reaching a Health Assessment Questionnaire disability level of 0.075 was postponed by 8.7 (95% confidence interval [CI], 5.5-13.7) years in runners' club members vs controls. Running club membership and participation in other aerobic exercise protected against mortality (rate ratio, 0.36 [95% CI, 0.20-0.65] and 0.88 [95% CI, 0.77-0.99], respectively), while male sex and smoking were detrimental (rate ratio, 2.4 [95% CI, 1.4-4.2] and 2.2 [95% CI, 1.1-4.6], respectively). Controls had a 3.3 times higher rate of death than runners' club members, with higher death rates in every disease category. Accelerated rates of disability and mortality were still not seen in the runners' club members; true compression of morbidity was not yet observable through an average age of 72 years. CONCLUSION: Running and other aerobic exercise in elderly persons protect against disability and early mortality, and are associated with prolongation of a disability-free life.

Age Factors↗

PubMed2005

Influence of patients' requests for direct-to-consumer advertised antidepressants: a randomized controlled trial.

CONTEXT: Direct-to-consumer (DTC) advertising of prescription drugs in the United States is both ubiquitous and controversial. Critics charge that it leads to overprescribing, while proponents counter that it helps avert underuse of effective treatments, especially for conditions that are poorly recognized or stigmatized. OBJECTIVE: To ascertain the effects of patients' DTC-related requests on physicians' initial treatment decisions in patients with depressive symptoms. DESIGN: Randomized trial using standardized patients (SPs). Six SP roles were created by crossing 2 conditions (major depression or adjustment disorder with depressed mood) with 3 request types (brand-specific, general, or none). SETTING: Offices of primary care physicians in Sacramento, Calif; San Francisco, Calif; and Rochester, NY, between May 2003 and May 2004. PARTICIPANTS: One hundred fifty-two family physicians and general internists recruited from solo and group practices and health maintenance organizations; cooperation rates ranged from 53% to 61%. INTERVENTIONS: The SPs were randomly assigned to make 298 unannounced visits, with assignments constrained so physicians saw 1 SP with major depression and 1 with adjustment disorder. The SPs made a brand-specific drug request, a general drug request, or no request (control condition) in approximately one third of visits. MAIN OUTCOME MEASURES: Data on prescribing, mental health referral, and primary care follow-up obtained from SP written reports, visit audiorecordings, chart review, and analysis of written prescriptions and drug samples. The effects of request type on prescribing were evaluated using contingency tables and confirmed in generalized linear mixed models that accounted for clustering and adjusted for site, physician, and visit characteristics. RESULTS: Standardized patient role fidelity was excellent, and the suspicion rate that physicians had seen an SP was 13%. In major depression, rates of antidepressant prescribing were 53%, 76%, and 31% for SPs making brand-specific, general, and no requests, respectively (P<.001). In adjustment disorder, antidepressant prescribing rates were 55%, 39%, and 10%, respectively (P<.001). The results were confirmed in multivariate models. Minimally acceptable initial care (any combination of an antidepressant, mental health referral, or follow-up within 2 weeks) was offered to 98% of SPs in the major depression role making a general request, 90% of those making a brand-specific request, and 56% of those making no request (P<.001). CONCLUSIONS: Patients' requests have a profound effect on physician prescribing in major depression and adjustment disorder. Direct-to-consumer advertising may have competing effects on quality, potentially both averting underuse and promoting overuse.

Adjustment Disorders↗

PubMed2006

An educational intervention to improve physician reporting of adverse drug reactions: a cluster-randomized controlled trial.

CONTEXT: Data on the adverse effects of newly marketed drugs are limited. Voluntary reporting is an important part of postmarketing surveillance but is underused by physicians. OBJECTIVE: To evaluate the effectiveness of educational outreach visits for improving adverse drug reaction (ADR) reporting by physicians. DESIGN, SETTING, AND PARTICIPANTS: A cluster-randomized controlled trial covering all National Health System physicians in the north of Portugal, with intervention in March 2004 through July 2004, and 13 to 16 months of follow-up. A total of 1388 physicians were assigned in 4 spatial clusters to the intervention group, and 5063 were assigned in 11 clusters to the control group. INTERVENTION: One-hour educational outreach visits tailored to training needs identified in a previous study. MAIN OUTCOME MEASURES: Change in total number of reported ADRs and number of serious, high-causality, unexpected, and new-drug-related ADRs, using generalized linear mixed models adjusted for baseline ADR reporting, age, specialty, and work setting. RESULTS: At baseline, ADR reporting rates (per 1000 physician-years) did not differ significantly between the intervention groups and the control groups in reporting ADRs overall (7.6 vs 11.3), nor did they differ significantly by category: serious, 4.3 vs 6.0; high-causality, 5.4 vs 7.6; unexpected, 1.6 vs 3.5; and new-drug-related ADRs, 3.7 vs 3.8. (P>.05 for all comparisons). The control group had no significant increase in ADR reports during follow-up. The adjusted increase in ADR reporting rates attributable to intervention was 90.19 for total ADRs (95% confidence interval [CI], 54.51-125.87; relative risk [RR], 10.23; 95% CI, 3.81-27.51), 30.16 for serious ADRs (95% CI, 18.84-41.47; RR, 6.32; 95% CI, 2.09-19.16), 64.90 for high-causality ADRs (95% CI, 38.38-91.42; RR, 8.75; 95% CI, 3.05-25.07), 28.04 for unexpected ADRs (95% CI, 16.25-39.83; RR, 30.21; 95% CI, 4.54-200.84), and 42.17 for new-drug-related ADRs (95% CI, 21.58-62.76; RR, 8.05; 95% CI, 2.10 -30.83). The greatest difference occurred during the first 4 months after intervention, but differences remained statistically significant for 12 months. CONCLUSION: A targeted outreach program may improve high-quality reporting of ADRs among physicians.

Adult↗

PubMed2026

Neurometabolites and Antipsychotic Response in Psychosis: A Mega-Analysis.

IMPORTANCE: Revealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets. OBJECTIVE: To examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis. DATA SOURCES: Web of Science was searched for studies published between January 1, 1980, and November 1, 2025. Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data. STUDY SELECTION: Eighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability. DATA EXTRACTION AND SYNTHESIS: Individual participant data were analyzed using linear mixed models with study as a random effect. Subgroup analyses examined prospective designs and treatment-resistant samples. Published group means and standard deviations were extracted for meta-analyses. MAIN OUTCOMES AND MEASURES: Group differences in glutamate, glutamate plus glutamine, choline, myo-inositol, N-acetylaspartate, γ-aminobutyric acid, and glutathione in the medial frontal cortex, dorsolateral prefrontal cortex, thalamus, and basal ganglia. RESULTS: The mega-analysis included 1189 participants from 18 studies; of these, 476 were treatment nonresponders (mean [SD] age, 33.0 [12.5] years; 340 male), 427 were treatment responders (mean [SD] age, 30.3 [11.5] years; 299 male), and 286 were healthy control individuals (mean [SD] age, 31.0 [12.5] years; 170 male). Compared with the antipsychotic response group, nonresponders showed elevations in medial frontal glutamate (Glass Δ = 0.21; P = .02), glutamate plus glutamine (Glass Δ = 0.29; P = .002), choline (Glass Δ = 0.22; P = .03), and myo-inositol (Glass Δ = 0.35; P = .001); similar elevations were observed relative to control individuals. Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Δ = 0.41; P = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Δ = 0.64; P = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response. CONCLUSIONS AND RELEVANCE: These findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway-associated interventions for psychosis and schizophrenia.

Humans↗

PubMed1999

Classifying individuals based on predictors of random effects. Multicenter AIDS Cohort Study.

Often one wishes to describe individuals according to whether their average exposure over a period of time is above or below some meaningful threshold. In this article, we treat predictors of random effects as diagnostic tools to aid in such classification, given that the true unobservable mean exposure for each of a set of individuals is defined according to a mixed linear model. Viewing candidate predictors in this light engenders the consideration of a unique set of performance criteria, and invites the use of nomenclature commonly used by epidemiologists and decision analysts to evaluate diagnostic techniques. We describe these criteria analytically and graphically under a random effects analysis of variance model, with the expressed goal of classifying subjects with regard to their true mean. Given knowledge of the model parameters, we compare typical predictors and illustrate the fact that completely new alternatives can arise depending on the particular set of criteria emphasized. We include a brief simulation study in which we also compare prediction methods according to various classification criteria, after incorporating estimates of the unknown model parameters. We provide two examples using data from participants in the Multicenter AIDS Cohort Study. In the first example, we seek to classify HIV seronegative individuals based on their mean diastolic blood pressure. In the second, via a natural extension to a randomized regression model, we classify HIV seropositive individuals according to their CD4+ slope over time.

Analysis of Variance↗

PubMed2000

A practical approach for evaluating population and individual bioequivalence.

Pharmacokinetic measurements provided by subjects to each of two formulations of a drug have a joint distribution that can be characterized by parameters reflecting scale and correlation as well as location. The bioavailability of the formulations can be expressed in terms of the means of the marginal distributions, their means and variances, or the marginal means and variances and the joint correlation. These expressions correspond, respectively, to 'average', 'population', and 'individual' bioequivalence when the joint distribution of the measurements is bivariate normal. Current proposals for assessing the degree of bioequivalence of two formulations are based on statistics that are composites of variance components and squares of expected mean differences from a mixed linear model. There are technical and practical issues associated with these proposals, particularly that they require more complicated designs than the familiar 2x2 cross-over. This paper describes an alternative approach that can be applied with standard 2x2 cross-over designs, and that provides evaluations of population and individual bioequivalence that should be adequate for all practical clinical purposes. The approach is based on easily computed correlation and regression coefficients whose statistical properties under normality are well known and for which non-parametric and robust alternatives exist when normality cannot be assumed. The approach yields conclusions consistent with those obtained by the current proposals when applied to data sets supplied by the FDA. In the cases where the conclusions do not match, the new approach appears to be more consistent with the data.

Area Under Curve↗