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PubMed2005

Application of a population-based severity scoring system to individual patients results in frequent misclassification.

INTRODUCTION: APACHE II (AP2) was developed to allow a systematic examination of intensive care unit outcomes in a risk adjusted manner. AP2 has been widely adopted in clinical trials to assure broad consistency amongst different groups. Although errors in calculating the true AP2 score may not be reducible below 15%, the self-canceling effect of random errors reduces the importance of such errors when applied to large populations. It has been suggested that a threshold AP2 score be used in clinical decision making for individual patients. This study reports the AP2 scoring errors of researchers involved in a large sepsis trial and models the consequences of such an error rate for individual severe sepsis patients. METHODS: Fifty-six researchers with explicit training in data abstraction and completion of the AP2 score received scenarios consisting of composites of real patient histories. Descriptive statistics were calculated for each scenario. The standard deviations were calculated compared with an adjudicated score. Intraclass correlations for inter-observer reliability were performed using Shrout-Fleiss methodology. Theoretical distribution curves were calculated for a broad range of AP2 scores using standard deviations of 6, 9 and 12. For each curve, the misclassification rate was determined using an AP2 score cut-off of >or=25. The percentage of misclassifications for each true AP2 score was then applied to the corresponding AP2 score obtained from the PROGRESS severe sepsis registry. RESULTS: The error rate for the total AP2 score was 86% (individual variables were in the range 10% to 87%). Intraclass correlation for the inter-observer reliability was 0.51. Of the patients from the PROGRESS registry. 50% had AP2 scores in the range 17 to 28. Within this interquartile range, 70% to 85% of all misclassified patients would reside. CONCLUSION: It is more likely that an individual patient will be scored incorrectly than correctly. The data obtained from the scenarios indicated that as the true AP2 score approached an arbitrary cut-off point of 25, the observed misclassification rate increased. Integrating our study of AP2 score errors with the published literature leads us to conclude that the AP2 is an inappropriate sole tool for resource allocation decisions for individual patients.

APACHE↗

PubMed1998

Microsatellites reveal heterosis in red deer.

The fitness consequences of inbreeding and outbreeding are poorly understood in natural populations. We explore two microsatellite-based variables, individual heterozygosity (likely to correlate with recent inbreeding) and a new individual-specific internal distance measure, mean d2 (focusing on events deeper in the pedigree), in relation to two measures of fitness expressed early in life, birth weight and neonatal survival, in 670 red deer calves (Cervus elaphus) born on the Isle of Rum between 1982 and 1996. For comparison, we also analyse inbreeding coefficients derived from pedigrees in which paternity was inferred by molecular methods. Only 14 out of 231 calves (6.1%) had non-zero inbreeding coefficients, and neither inbreeding coefficient nor individual heterozygosity was consistently related to birth weight or neonatal survival. However, mean d2 was consistently related to both fitness measures. Low mean d2 was associated with low birth weight, especially following cold Aprils, in which foetal growth is reduced. Low mean d2 was also associated with low neonatal survival, but this effect was probably mediated by birth weight because fitting birth weight to the neonatal survival model displaced mean d2 as an explanatory variable. We conclude that in the deer population fitness measures expressed early in life do not show evidence of inbreeding depression, but they do show evidence of heterosis, possibly as a result of population mixing. We also demonstrate the practical problems of estimating inbreeding via pedigrees compared with a direct marker-based estimate of individual heterozygosity. We suggest that, together, individual heterozygosity and mean d2, estimated using microsatellites, are useful tools for exploring inbreeding and outbreeding in natural population.

Age Factors↗

PubMed1988

Plasma melatonin levels in patients suffering from colorectal carcinoma.

Plasma melatonin was determined in samples of patients with colorectal carcinoma and in controls using an iodinated radioimmunoassay. Both groups showed large individual variability in absolute melatonin levels. However, during the night, melatonin concentration in cancer patients was significantly lower than in controls.

Aged↗

PubMed2006

Self-selected exercise intensity during household/garden activities and walking in 55 to 65-year-old females.

This study determined whether some of the more vigorous household and garden tasks (sweeping, window cleaning, vacuuming and lawn mowing) were performed at a moderate intensity (3-6 METs or metabolic equivalents) by a representative sample of 50, 55 to 65-year-old women (X +/- SD; 59.3 +/- 3.1 years, 161.5 +/- 5.2 cm, 69.4 +/- 12.4 kg, 38.4 +/- 7.3% BF). Data collection was conducted in a standardised laboratory environment and in the subjects' homes. Energy expenditure during self-perceived moderate paced walking around a quadrangle was also used as a marker of exercise intensity. Energy expenditure measured via indirect calorimetry was also predicted from: HR, CSA accelerometer counts, Quetelet's index and the Borg rating of perceived exertion. Ninety-six percent of the subjects walked at an intensity of >or= 3.0 METs. Except for vacuuming in the laboratory (X = 2.9 METs; P = 0.19), the intensity of each of the other activities was significantly (P or= 3.0 METs when the four household/garden activities were performed in the subjects' homes. These activities therefore have the potential to contribute to the 30 min day(-1) of moderate intensity physical activity required to confer health benefits but there was much inter-individual variability in the intensity at which these tasks were performed. Random intercept regression analyses yielded prediction equations with 95% confidence intervals of +/- 0.80 and +/- 0.84 METs for the laboratory and home based equations, respectively. Considering the means for the five activities ranged from 2.9 to 5.5 METs, these 95% confidence intervals lack predictive precision at the individual level. Nevertheless, the laboratory and home-based equations predicted with correct classification rates of 89 and 90%, respectively, whether energy expenditure was < 3.0 or >or= 3.0 METs.

Activities of Daily Living↗

PubMed1993

Initial performance, learning and observer variability for hyperacuity tasks.

Psychophysically-experienced and -inexperienced human observers were tested on 34 different non-stereo and 49 stereo hyperacuity stimuli. Performance reached hyperacuity levels within the first five trials for the non-stereo stimuli. For stereoacuity tasks the results were very different. Even extremely experienced observers with very low thresholds for certain stereo tasks required considerable practice to achieve their best performance for slightly different stereo tasks. Performance on both types of tasks showed considerable observer variability. These results suggest that adults do not synthesize new visual modules for hyperacuity tasks early in the visual pathway on a task-driven basis. We also interpret these results to suggest that there can be many equally general models of hyperacuity performance that show only the qualitative general trends of a "standard" observer. Incorporating individual variability might provide sufficient constraints on such models to provide clues about physiological mechanisms.

Depth Perception↗

PubMed2006

Behaviour of human heterochromatic regions during the synapsis of homologous chromosomes.

BACKGROUND: Alterations of synapsis can disturb or arrest meiosis and result in infertility. Synaptic abnormalities are frequently observed in infertile patients but also in fertile men. METHODS: The subtelomere-specific multiplex fluorescence in-situ hybridization (stM-FISH) has been applied in combination with immunofluorescence to identify all synaptonemal complexes (SCs) and to analyse those presenting synaptic anomalies in fertile and infertile men. RESULTS: SCs with heterochromatin blocks other than centromere (noncentromeric heterochromatin) presented a higher frequency of gaps (SC discontinuities) and splits (unsynapsed SC regions) at pachytene, the incidences for 9qh, 1qh, 15p and 21p being the highest ones. Inter-individual variability in the incidence of synaptic anomalies in these regions has been observed. In addition, synaptic anomalies in other SC regions are more frequent in infertile cases than in controls. Clear association of the SC15 and SC21 to the XY pair has been seen. CONCLUSION: Noncentromeric heterochromatic regions are the last to synapse. The inter-individual variation observed in the incidence of gaps and splits in these regions may be explained by the heteromorphism of these regions in the general population. The presence of synaptic anomalies in other SC regions may indicate nuclei with a severely affected synapsis. Noncentromeric heterochromatic regions might play a role in the association of autosomal SC15 and SC21 with the XY pair.

Centromere↗

PubMed2001

Is perioperative plasma aprotinin concentration more predictable and constant after a weight-related dose regimen?

UNLABELLED: To determine whether a weight-related dose had advantages over a fixed, large-dose regimen, we measured plasma concentrations of aprotinin by using an enzyme-linked immunosorbent assay method at set time points in 30 patients having heart surgery with cardiopulmonary bypass. A weight-related dose comprising a preincision bolus injection of 40,000 kallikrein-inhibiting units (KIU)/kg (5.6 mg/kg) with the same amount given in the oxygenator prime was compared with a large-dose regimen of 2 x 10(6) KIU (280 mg) preincision bolus and addition to prime, together with an infusion of 500,000 KIU/h (70 mg/h). Peak plasma concentration in the Weight-Related group was less variable than with the fixed-dose regimen. Forty percent of patients allocated to the fixed-dose regimen had an aprotinin concentration of more than 400 KIU/mL, compared with none in the Weight-Related group; this suggests a relative overdosing in the early surgical period in the Fixed-Dose group. There was great individual variability between patients in the time-concentration curves for aprotinin, with no difference between the two regimens. The weight-related dose regimen benefited by not requiring an intraoperative infusion while achieving the same plasma concentrations of aprotinin. IMPLICATIONS: Peak plasma concentrations of aprotinin were less variable with a weight-related dose schedule. This has implications for safety with regard to control of anticoagulation and cost in patients with small body mass. Plasma concentrations varied greatly with time between patients. This observation has implications for determining an optimal dose on the basis of aprotinin's currently known mechanisms of action.

Adult↗

PubMed1985

Factors affecting the decline of ventilatory function in chronic bronchitis.

Ninety six middle aged male patients with chronic bronchitis with relatively well preserved ventilatory function who were resident in Queensland, New South Wales, or Victoria took part in a prospective study to determine the relationship of various factors to the rate of decline of the FEV1. Thirty of the subjects withdrew, leaving 66 to be followed for four to six years. The mean rate of decline of the FEV1 was 58.6 (SD 51.4) ml/year. The subjects' ventilatory responses to bronchodilator and to methacholine (measures of bronchial lability) were significantly related to each other and to sputum eosinophilia. With a linear model for the data on 57 patients who had methacholine and skin tests the rate of decline of the FEV1 was found, after adjustment had been made for other variables, to be significantly related to State of residence, current smoking, response to bronchodilator, age, and occupational exposure to dust. Response to bronchodilator was interchangeable with response to methacholine. With the five variables in the model none of the following factors was related to the rate of decline of the FEV1:FEV1 on entry, FEV1% predicted normal, FEV1/VC%, skin test reaction, occupation on entry, history of sinusitis and rhinitis, and height. When data from all 66 subjects were introduced into the model, in addition to the five significant individual variables (FEV1/VC% X response to bronchodilator) was significantly related to the rate of decline of the FEV1. Of these prognostic indices, response to bronchodilator was independent of the initial FEV1, FEV/VC%, and FEV1% predicted. The difference between States, which was not explained by differences due to sampling or withdrawal of subjects, was due to a low rate of decline in Queensland.

Age Factors↗

PubMedDate not supplied

[Congenital pyloric hyperthrophy. Factors associated with its frequency].

With the idea of clearing out several variables individually found associated with a greater incidence of congenital pyloric stenosis in the same group of children, 298 clinical histories in infants complaining of this deviation were reviewed. Information was obtained as to sex, birth number, blood group and the month these children with stenosis were born. The distribution of frequencies in each one of these variables was compared to that in 309 children surgically operated from peritonitis. The results showed a greater incidence of congenital pyloric stenosis in males than in females; also, the disease appeared more frequently in first-borns. Patients with type A blood group were less prone to present the anomaly. The birth month showed no statistical difference. The findings stress the importance shown by the genetic component of this disease.

Blood Group Antigens↗

PubMed2000

[Microabluminuria in arterial hypertension. Measurement, variables, interpretation, recommendations].

Permanent hypertension is frequently associated with increased glomerular permeability to albumin at an early stage, indicating renal involvement and endothelial dysfunction. The definition of microalbuminuria is an urinary albumin excretion of 30-300 mg/24 hrs, confirmed on two occasions over a 3 month period. It may also be expressed in microgram/min, m/l or mg/mmol of creatinine. Radio-immunological, immunonephelometric methods and Elisa are specific and the most sensitive methods of measurement. There is a large intra-individual variability (25-60%) making it essential to repeat measurements always by the same technique. The prevalence of microalbuminuria is 5-8% in the general population and 6-24% in hypertensive patients. When present, it is a marker of increased cardiovascular risk. Clinical recommendations suggest adaptation of urinary collection according to the context: screening, diagnosis or clinical research. It is always necessary to start by dip-stick detection of proteinuria, haematuria or urinary infection. Clinical research requires repeated measurement of 24 hour microalbuminuria, sometimes divided into two periods of day and night, often associated with ambulatory blood pressure recordings and renal function tests. Studies of the effects of anti-hypertensive drugs on microalbuminuria could provide better evaluation. In conclusion, measurement of microalbuminuria remains a tool of clinical research allowing an assessment of cardiovascular and renal risk of hypertensive patients.

Albuminuria↗

PubMed2000

Differential effect of knee extension isometric training on the different muscles of the quadriceps femoris in humans.

This study determined the effects of a short period of knee isometric training on the quadriceps muscles accessible to surface electromyography (EMG). For this purpose, a training (n = 9) and a control (n = 7) group were tested on five identical occasions at 1 week intervals during 4 weeks. The training group exercised three times a week by making isometric knee extensions at 80% of the maximal voluntary contraction (MVC). During the test sessions, maximal and submaximal torque and associated activations of the rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM) muscles were analysed. As a result of training, differences between MVC values of the two groups were highly significant (P<0.001), whereas only RF-EMG showed significant differences (P<0.05). The VL and VM did not present any significant changes in maximal activation. The EMG torque relationships were analysed individually before and after the training period. For the control subjects, EMG-torque relationships did not present significant changes while for the training group, these relationships showed a significant increase in RF, VL, and VM maximal activation in 6, 6 and 4 subjects, respectively, and a significant decrease in 1, 2 and 5 subjects, respectively. In almost all cases, a significant downward shift of the relationship was observed. This study confirmed that the parts of the quadriceps muscle tested present different adaptation capacities and demonstrate inter-individual variability in the strategies used to enhance muscle strength. In conclusion, to analyse the neural effects resulting from training in a large and compartmentalized muscle like the quadriceps femoris, it is desirable to take into account each muscle independently. Moreover, we suggest that overall results obtained from the experiment population should be completed by an analysis on individuals.

Adult↗

PubMed1989

Early rearrangements of genes encoding murine immunoglobulin kappa chains, unlike genes encoding heavy chains, use variable gene segments dispersed throughout the locus.

Immunoglobulin heavy-chain variable region (TH) gene segments located closest to the joining (JH) gene segments are preferentially rearranged during ontogeny, indicating that chromosomal position influences the frequency of rearrangement. In addition, certain VH gene segments are repeatedly rearranged, suggesting that the DNA sequence or structure surrounding these segments may increase the probability of rearrangement. To determine whether there is similar based rearrangement of kappa variable (V kappa) gene segments, 25 rearrangements were sequenced from murine fetal and neonatal B-cell hybridomas and from subclones of a pre-B cell line that rearranged V kappa genes during in vitro culture. Four gene segments were isolated twice and one gene segment was isolated three times, suggesting that the process that targets individual variable gene segments for repeated rearrangement operates on both the VH and V kappa loci. Based on a current map of the V kappa locus, the rearranged gene segments belong to nine families that are dispersed throughout the locus. Thus, in these cell types, V kappa rearrangements use germ-line gene segments located across the entire locus, whereas the corresponding VH rearrangements use gene segments proximal to the JH gene segments. Heterogeneity of V kappa rearrangements would add diversity to the biased pool of VH rearrangements, producing a broad repertoire of antibodies early in development.

Amino Acid Sequence↗

PubMed2005

Host determinants of antiretroviral drug activity.

PURPOSE OF REVIEW: As physicians are confronted with a diversity of adverse events and variability in response to medication among patients, this review will focus on the available evidence regarding the impact of genetic variation on drug response. Specifically, variation in drug metabolizing enzymes such as the cytochrome P450s, drug transporters and human leucocyte antigen (for idiosyncratic drug reactions). The potential role of pharmacogenetics in the management of HIV-1 infected individuals and drug discovery will be discussed. RECENT FINDINGS: Wide inter-individual variability of antiretroviral therapy efficacy and toxicity in HIV-infected patients has been extensively reported in the literature. Since treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host as well as drug-drug interactions, antiretroviral drug therapy represents a significant challenge. Despite this inherent complexity, considerable recent advances have led to a greater understanding of interactions between genetic and host factors that influence the efficacy and toxicity of these agents. SUMMARY: The goal of pharmacogenetics in antiretroviral therapy is to outline differences within a given population that influence drug efficacy and toxicity. Although to date, despite the numerous studies available in the literature, conclusions on how the analysis of the relationship between single nucleotide polymorphisms and drug efficacy may not always be clinically useful. Further studies are warranted to clarify the role of pharmacogenetics and antiretroviral drug management.

Anti-HIV Agents↗

PubMed1992

Interindividual variabilities in haloperidol interconversion and the reduced haloperidol/haloperidol ratio.

Metabolism of haloperidol in humans includes N-dealkylation to inactive metabolites and reduction to reduced haloperidol; reduced haloperidol is also oxidized back to haloperidol. A single 0.5 mg/kg (0.00133 mmol/kg) oral dose of haloperidol and reduced haloperidol was administered to seven Chinese schizophrenics in a randomized crossover manner separated by a 2-week interval. The clearance values for the different metabolic pathways of haloperidol and reduced haloperidol were determined. There were differences up to 10-fold in both oxidation and reduction capacities. There were also interindividual variabilities in the elimination of reduced haloperidol (0.37 +/- 0.20 L/hr/kg) and the N-dealkylation pathway (0.74 +/- 0.36 L/hr/kg). Four weeks after the single-dose study, the same patients also received haloperidol (10 mg) twice daily for 4 weeks. The reduced haloperidol to haloperidol concentration ratio (0.40 +/- 0.16) after the 4-week therapy is related to individual variabilities in the interconversion process and the N-dealkylation pathway of haloperidol.

Adult↗

PubMed1977

Physiological and morphological factors associated with successful fencing performance.

The relation between fencing success during a season of intercollegiate competition and various physiological and morphological variables were determined in 14 fencers. Bivariate and multiple regression analysis was used to determine the extent to which the independent variables, individually and collectively, accounted for the variance in two measures of fencing success. The fencing scores correlated significantly with VE max, Vo2 max, the 2 km run, and weight, while there was no significant correlation between the fencing scores and submaximal heart rate at 6 mph, and 1 min steptest score, or other morphological measurements. Cardiorespiratory fitness variables of Vo2 max and VE max accounted for the greatest variance in each of the two fencing scores (57.7 and 58.1%, respectively). Although morphological factors play a role in fencing success, their influence is small when physiological factors are accounted for. Future energy-cost studies are suggested to determine the physiological basis for the relationship between cardiorespiratory fitness and fencing success.

Adipose Tissue↗

PubMed2005

Population pharmacokinetics of tacrolimus in full liver transplant patients: modelling of the post-operative clearance.

OBJECTIVE: To investigate the population pharmacokinetics of tacrolimus in an adult liver transplant cohort using routine drug monitoring data and to identify patient characteristics that influence pharmacokinetic parameters. METHODS: Tacrolimus pharmacokinetics was studied in 37 adult patients using a population approach performed with NONMEM. RESULTS: A one-compartment open model with linear absorption and elimination adequately described the data. The apparent clearance (CL) was approximately zero in the immediate post-operative days (PODs) and then rapidly increased as a function of POD to reach a plateau. This was modelled as a sigmoid relationship with the characteristic parameters CL(max) (plateau), TCL(50) (time to obtain 50% of the plateau) and gamma (coefficient of sigmoidicity). This clearance model was thought to describe the hepatic function regeneration after transplantation. Typical population estimates (percentage inter-individual variability) of CL(max), TCL50, and gamma and apparent distribution volumes (V) were 36 l/h (43%), 6.3 days (33%), and 4.9 l and 1870 l (49%), respectively. The CL(max) was negatively related to plasma albumin, and TCL50 was positively related to aspartate amino transferase (ASAT). Bayesian estimations performed at different POD times indicated that acceptable precisions in individual pharmacokinetic predictions could be obtained after the 15th POD. CONCLUSION: Tacrolimus clearance modelling showed that there was a large variation in individual CL estimates up to the 15th day post-surgery. After this period, the mean error resulting from the Bayesian estimation was strongly decreased and this estimation method could be applicable and should limit tacrolimus monitoring.

Bayes Theorem↗

PubMed1997

Determination of urinary metabolites of polycyclic aromatic hydrocarbons (PAH) for the risk assessment of PAH-exposed workers.

A method for the simultaneous determination of urinary phenanthrene, fluoranthene, pyrene, chrysene and benzo[a]pyrene metabolites has been developed for individual risk assessment at polycyclic aromatic hydrocarbon (PAH)-burdened workplaces. The concentration of urinary metabolites as a measure for individual PAH exposure takes account not only of PAH masses resorbed by the respiratory tract but also those incorporated percutaneously. The method allows the determination of 25 different components with a low margin of error; the individual metabolite profiles thereby allow conclusions on the individual characteristics of PAH-oxidizing enzymes (monooxygenases). The coefficients of variation are lower than 10%. After enzymatic treatment of the urine with glucuronidase and arylsulfatase one part of the benzene or toluene extract is treated with diazomethane to convert phenols into methylethers, while another part is used to convert dihydrodiols into phenols. After further purification the metabolites are determined by means of a combination of gas chromatography and mass spectrometry. The PAH exposure of cock plant workers during several consecutive days resulted in fairly constant individual urinary metabolite profiles which, however, exhibited significant inter-individual variability. This held true also for Wistar rats exposed to tar pitch aerosol on 5 days during a period of 10 days. It was also demonstrated that in the case of coke plant workers there is a correlation between inhaled PAH and metabolites excreted. Mass relationships between inhaled PAH and metabolites excreted were found to differ from one individual to another.

Administration, Inhalation↗

PubMed2003

Population pharmacokinetics of platinum after nedaplatin administration and model validation in adult patients.

AIMS: The pharmacokinetics of unbound platinum after administration of an anticancer drug nedaplatin, cis-diammineglycolateplatinum were examined using population analysis. The relevant covariates and the extent of inter- and intra-individual variability were evaluated. METHODS: In order to clarify the pharmacokinetic profile of nedaplatin, unbound platinum concentrations (789 points) in plasma after intravenous infusion of nedaplatin were obtained from 183 courses for 141 patients. Plasma concentration data were analysed by nonlinear mixed effect modelling using NONMEM to evaluate the population mean parameters and variances for inter- and intra-individual random effects. The final population model was validated by parameter sensitivity analysis using objective function mapping, the bootstrap resampling and a data-splitting technique, i.e. the Jackknife method, and the predictive performance of the final model was evaluated. RESULTS: A two-compartment pharmacokinetic model with zero-order input and first order elimination described the current data well. The significant covariates were creatinine clearance (CLcr) for clearance of platinum (CL) [population mean [95% confidence interval (CI)] CL (l h(-1)) = 4.47 (3.27, 5.67) + 0.0738 (0.0581, 0.0896) x CLcr (CLcr: ml min(-1))] and body weight (BW: kg) for volume of distribution of platinum (Vc) [Vc (l) = 12.0 (7.5, 16.5) + 0.163 (0.081, 0.246) x BW]. Inter-individual variations (CV%, 95% CI) for CL and Vc were 25.5% (20.7, 29.6) and 21.4% (17.0, 24.1), respectively, and intra-individual variation (CV%, 95% CI) was 12.6% (10.5, 14.4). The effects of pretreatment with nedaplatin or other platinum agents on clearance and volume of distribution were also tested, but no significant effect was found. The relationship between the observed and predicted unbound platinum concentration by empirical Bayesian prediction showed good correlation with no bias, suggesting that the final model explains well the observed data in the patients. The mean prediction error and root mean square prediction error (95% CI) were - 0.0164 micro g ml(-1) (- 0.4379, 0.4051) and 0.2155 micro g ml(-1) (not calculable, 0.6523), respectively. The values of mean, standard error and 95% CI for objective function mapping, the bootstrap resampling, the Jackknife estimates and the final model coincided well. CONCLUSIONS: A population pharmacokinetic model was developed for unbound platinum after intravenous infusion of nedaplatin. Only creatinine clearance was found to be a significant covariate of clearance, and BW was found to be a significant covariate of volume of distribution. These population pharmacokinetic estimates are useful for setting initial dosing of nedaplatin using its population mean and can also be used for setting appropriate dosage regimens using empirical Bayesian forecasting.

Adult↗