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Results for “Surrogate variables analysis”

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PubMed1998

Sex as a variable can be a surrogate for some working conditions: factors associated with sickness absence.

More than twice as many workdays are lost to illness than for personal or family reasons. We examine possible workplace determinants of sickness absence among French workers in the food processing industry. These workers are exposed to a variety of environmental and organizational constraints: cold, uncomfortable postures, assembly-line work, and irregular schedules. In 1987-1988, a medical examination and questionnaire were administered to 558 men and 790 women as part of a study of 17 poultry slaughterhouses and 6 canning factories. Women's and men's working conditions were very different, and their sickness absences for musculoskeletal and respiratory illnesses were related to some of their specific working conditions: cold exposure, ill-adapted work stations, and problems with their supervisors and co-workers. If male and female workers were combined into a single analysis that adjusted for sex, many of the associations operant for a single sex could no longer be seen.

Absenteeism↗

PubMed1992

Heated dorsal hand vein sampling for metabolic studies: a reappraisal.

The purpose of the current study was to determine the accuracy of a given heated dorsal hand vein (HDHV) measurement in predicting a simultaneous arterial measurement and to validate this technique for use in stable isotope studies. Twenty catheterizations of the femoral artery, femoral vein, and a dorsal hand vein were performed in 13 healthy male subjects. Simultaneous blood samples were obtained from all three sites during primed continuous infusions of L-[1-13C]leucine (Leu) and L-[ring-2H5]phenylalanine (Phe) in the postabsorptive state, with or without intravenous glucose infusion. Relationships were examined by linear regression analysis, with 95% prediction intervals for femoral arterial values determined using the HDHV-derived values as independent variable. Glucose concentrations and isotopic enrichments of ketoisocaproate (KIC), Leu, and Phe were similar in HDHV- and arterial-derived blood, with slopes between 0.9414 and 1.0008, intercepts not different from zero, and r2 values of 0.7613 or greater (P < 0.05). Intercepts for KIC, Leu, and Phe concentrations all were different from zero (P < 0.05), and slopes ranged between 0.7560 and 0.8625. For each analysis the HDHV sample correlated better with the femoral arterial sample than with the femoral venous sample. These data support the use of HDHV sampling as a surrogate for direct arterial sampling but document significant limitations in the technique.

Adult↗

PubMed2000

Exposure to environmental tobacco smoke and the risk of lung cancer: a meta-analysis.

A meta-analysis was carried out to calculate a pooled estimate of relative risk of lung cancer following exposure to environmental tobacco smoke (ETS) and to determine whether there was any heterogeneity in the pooled estimates according to selected characteristics of the studies. A total of 35 case-control and five cohort studies providing quantitative estimates of the association between lung cancer and exposure to ETS published between January 1981 and March 1999 were identified. Using fixed- and random-effects models, we calculated pooled estimates of relative risk for exposure to ETS from subjects' parents (during childhood), spouses, and coworkers. As well, we investigated whether the pooled estimates of relative risk varied by study location, degree of control of potential confounding variables, proportion of cases confirmed histologically, proportion of surrogate respondents, nonresponse rates, and year of publication. The relative risk of lung cancer among non smoking women ever exposed to ETS from their husbands' smoking was 1.20 (95% confidence interval (CI): 1.12-1.29). The pooled relative risk was 1.19 (95% CI: 1.10-1.29) for case-control studies and 1.29 (95% CI: 1.04-1.62) for cohort studies. In various subgroup and meta-regression analyses, we found no statistically significant differences by selected characteristics of the studies. In addition, we found that the risk of lung cancer increased consistently with increasing levels of exposure. The 11 studies reporting relative risks among male non smokers yielded a pooled relative risk of 1.48 (95% CI: 1.13-1.92) for ever exposed to ETS, and the relative risk of lung cancer for ever being exposed to ETS at work was a 1.16 (95% CI: 1.05-1.28). These results are consistent with the hypothesis that exposure to ETS increases the risk of lung cancer. While there may be alternative explanations to the data, it is more likely that the observed association is not an artifact and that ETS causes lung cancer in non smokers.

Adult↗

PubMed1998

A nonparametric approach to a survival study with surrogate endpoints.

A nonparametric estimator for the joint distribution of a survival time and surrogate response time, which may occur earlier during follow-up, is presented. In the absence of the surrogate response variable, the estimator reduces to the Kaplan Meier nonparametric estimator for the survival time alone. The estimator derived in this paper is done so in a particular novel way using an exchangeable process (reinforced random walks) to model individual observations. The methodology introduced in the paper is readily extended to modelling multiple state processes.

Humans↗

PubMed2002

Race, socioeconomic status, and breast carcinoma in the U.S: what have we learned from clinical studies.

BACKGROUND: Whether African-American women have biologically more aggressive breast carcinoma compared with white women and whether race acts as a significant independent prognostic factor for survival have not been determined. Alternatively, race merely may be a surrogate for socioeconomic status (SES). METHODS: A literature review was performed of clinical trials and retrospective studies in the U.S. that compared survival between white women and black women with breast carcinoma after adjustment for known prognostic factors (patient age, disease stage, lymph node status, and estrogen receptor status) to assess the impact of race and SES. RESULTS: Single institutional and clinical studies suggest that, when black patients are treated appropriately and other prognostic variables are controlled, their survival is similar to the survival of white patients. Twelve retrospective studies and 1 analysis of a clinical trial included SES and race as variables for survival. Only three of those studies revealed race as a significant prognostic factor for survival after adjusting for SES. CONCLUSIONS: SES replaces race as a predictor of worse outcome after women are diagnosed with breast carcinoma in many studies. However, black women present with more advanced disease that appear more aggressive biologically, and they present at a younger age compared with white women. Further research should be conducted concerning the precise elements of SES that account for the incidence of breast carcinoma, age at diagnosis, hormone receptor status, and survival to devise better strategies to improve outcome.

Black or African American↗

PubMed2005

Lower extremity strength plays only a small role in determining the maximum recoverable lean angle in older adults.

BACKGROUND: The purpose of this study was to determine the extent to which measures of lower extremity strength and power contribute to the ability of older men and women to restore postural equilibrium using a single-step recovery following a large postural disturbance. METHODS: The postural disturbance, which has been used as a surrogate for forward-directed falls, involved a sudden release from a forward-leaning angle. The ability to recover using a single step was evaluated as the maximum recoverable lean angle for 56 healthy older women and men. Maximum voluntary isometric and isokinetic strength was measured for ankle plantarflexion and dorsiflexion, knee flexion and extension, and hip flexion and extension. Discriminant analysis was used to determine the strength measures that best classified participants as members of the highest (n = 14) or lowest (n = 14) quartiles of maximum recoverable lean angle. Those variables were subsequently entered into a regression analysis to characterize the relationship between strength and maximum recoverable lean angle for the entire participant sample. RESULTS: Maximum isokinetic dorsiflexion strength at 90 degrees /s satisfied the criteria of the stepwise discriminant analysis, and correctly classified 82.1% of the participants in the highest or lowest quartiles of maximum recoverable lean angle. The multiple regression procedure, performed on all participants (n = 56) revealed a significant quadratic relationship between maximum isokinetic dorsiflexion strength at 90 degrees /s and maximum recoverable lean angle (R2 = 0.295; p <.001). CONCLUSIONS: Lower extremity strength makes a small, but significant contribution to maximum recoverable lean angle. However, because 70% of the shared variability remained unaccounted for, it is suggested that other performance factors, such as coordination, may be of greater importance to performance of this time-critical motor task.

Accidental Falls↗

PubMedDate not supplied

Postprostatectomy salvage radiation therapy for prostate cancer: impact of pathological and biochemical variables and prostate fossa biopsy.

PURPOSE: A subgroup of prostate cancer patients who have experienced biochemical relapse after radical retropubic prostatectomy (RRP) can benefit from radiation therapy to the prostate fossa. These patients demonstrate biochemical relapse secondary to local failure in the absence of distant failure. In order to define this subgroup, we investigated the impact of pathological and biochemical variables and pre-radiation therapy biopsy of the prostate fossa on biochemical disease-free survival (bNED) and initial prostate-specific antigen response. METHODS: Sixty-two patients with localized prostate cancer who had biochemical relapse after RRP were treated with post-RRP radiation therapy localized to the prostate fossa (median dose, 6120 cGy) and were subsequently followed up for a median time of 47 months. Cox regression analyses and Kaplan-Meier estimates for bNED were used to identify prognostic variables. The Fisher's exact test was used to test the interaction of initial prostate-specific antigen response with identified prognostic variables. RESULTS: Cox regression analysis of bNED as a function of pathological and biochemical parameters showed that only Gleason's score was a significant predictor of bNED. On univariate analysis, seminal vesicle involvement was also found to be a significant predictor. Prostate fossa biopsy result was not significantly related to bNED. Because of the overall high rates of biochemical failure, we wished to identify a high-risk subgroup that did not have local relapse as a component of biochemical relapse after RRP. We assessed initial biochemical response following radiation therapy as a surrogate for local relapse. A complete biochemical response was observed in 50% of patients, and a partial biochemical response was observed in an additional 34%, yielding an overall biochemical response rate of 84%. When stratified by Gleason's score, seminal vesicle, pre-radiation therapy prostate-specific antigen, and biopsy result, response rates greater than 50% were seen for all subgroups. CONCLUSIONS: Gleason's score and seminal vesicle involvement predicted bNED after post-RRP radiation therapy in our cohort. Overall biochemical response rates were high in all subgroups, suggesting that all subgroups demonstrated a high likelihood of residual local disease as a component of failure. Pre-radiation therapy biopsy was predictive of neither bNED nor overall biochemical response.

Adenocarcinoma↗

PubMed2006

Prolactin deficiency is independently associated with reduced insulin-like growth factor I status in severely growth hormone-deficient adults.

BACKGROUND: In adult life, considerable overlap in IGF-I status exists between normal and severely GH-deficient (GHD) subjects defined by conventional dynamic testing of GH secretion. IGF-I is not therefore widely viewed as a reliable diagnostic marker for GHD. Recognized factors influencing serum IGF-I level in GHD include age, gender, timing of onset of GHD, and exogenous estrogen therapy, but these do not fully explain GH/IGF-I discordance in severe GHD. The primary structures of prolactin and GH are closely related. Effects of hypoprolactinemia are not well described in humans, but laboratory studies suggest a role for prolactin in hepatic IGF-I release, possibly through a signal transducer and activator of transcription 5 (STAT5) pathway. The purpose of this study was to evaluate a potential contribution of prolactin to IGF-I status in severely GHD adults. PATIENTS AND METHODS: Using multiple regression analysis techniques, contributions of the following variables to age-adjusted IGF-I sd scores were evaluated in 162 (85 female) GHD adults: gender, timing of onset of GHD, presence or absence of prolactin deficiency, body mass index, number of additional pituitary deficits, and underlying pathology. RESULTS: Childhood onset GHD (P < 0.0001) and presence of prolactin deficiency (P < 0.0001) were independently associated with reduced IGF-I status. The contributions of these parameters to IGF-I sd scores were -2.55 and -2.67, respectively. Gender (P = 0.06), body mass index (P = 0.99), number of additional pituitary deficits (P = 0.64), and underlying pathology (P = 0.06) did not significantly influence IGF-I status. CONCLUSIONS: Prolactin deficiency is independently associated with reduced IGF-I status in hypopituitary adults. It is possible that prolactin deficiency is a surrogate for the degree of severity of GHD, implying a GHD paradigm undetected by conventional GH provocative tests; alternatively, it remains plausible that circulating prolactin contributes to IGF-I release in the absence of GH, possibly through a signal transducer and activator of transcription 5 (STAT5) pathway.

Adolescent↗

PubMed2006

Associations between white matter lesions, cerebrovascular risk factors, and low CSF Abeta42.

OBJECTIVE: To analyze a putative relationship between white matter lesions (WMLs), risk factors for WMLs, and Alzheimer disease (AD) as measured with the surrogate marker CSF Abeta42. METHODS: The authors analyzed effects of acquired risk factors for cerebrovascular disease and WMLs on AD as measured with an intermediate marker, CSF Abeta42. A total of 127 consecutive patients with subjective memory impairment (mean age 66 years; 57 women) investigated at a university-based memory clinic had brain MRI scans. WMLs were rated on a 12-point scale with a semiquantitative procedure. They used path analysis with established and possible risk factors for WMLs and for reduced CSF Abeta42 (age, hypertension, hyperhomocysteinemia, hypercholesterolemia, APOE-epsilon4) as variables. RESULTS: The WML score was 1.5 points higher (p < 0.05) in hypertensive than in nonhypertensive patients and 1.9 points higher (p < 0.05) in patients with hyperhomocysteinemia than in those with normal homocysteine levels. Hypercholesterolemia increased the probability of low CSF Abeta42 levels by 0.2 (p < 0.05). For each point increase in WML score, the probability of low CSF Abeta42 levels increased by 0.03 (p < 0.05). APOE-epsilon4 was associated with reduced CSF Abeta42 (p < 0.01). CONCLUSION: Both hypercholesterolemia and white matter lesions may contribute to low CSF Abeta42 by independent mechanisms.

Adult↗

PubMed2002

Clustering of thrombotic factors with insulin resistance in South Asian patients with ischaemic stroke.

We aimed to investigate significant correlations of insulin resistance with thrombotic factors in South Asians with stroke. Correlations of Homeostasis Model Assessment (HOMA)(as a surrogate of insulin resistance) were analysed with 6 thrombotic factors in 140 South Asian patients with a history of confirmed (by computerised tomography) ischaemic stroke. Age and sex adjusted HOMA was correlated to waist-hip ratio (r = 0.38, p = 0.0001), triglycerides (r = 0.22, p = 0.03), systolic blood pressure (r = 0.21, p = 0.04), tissue plasminogen activator (t-PA) (r = 0.22, p = 0.04); plasminogen activator inhibitor 1(PAI-1) (r = 0.26, p = 0.02); fibrinogen (r = 0.25, p = 0.02); and factor VII antigen (r = 0.21, p = 0.06). On regression analysis, with HOMA as dependent variable and significant correlates as independent variables in the model, HOMA was independently associated with PAI-1 antigen. There is extensive clustering of metabolic and thrombotic factors with insulin resistance in South Asian patients with ischaemic stroke, which may contribute to high prevalence of vascular disease in this population.

Adult↗

PubMed2004

Impact of left ventricular diastolic function on exercise capacity in patients with chronic mitral regurgitation: an exercise echocardiography study.

BACKGROUND: Mitral regurgitation (MR) is known as one of the most frequent causes of heart failure and sudden death. In spite of increasing prevalence of MR, there have been no available data on cardiac determinants of exercise capacity in patients with chronic MR. HYPOTHESIS: This study aimed to investigate cardiac determinants of exercise capacity in patients with chronic MR. METHODS: We consecutively enrolled 32 patients (11 men, mean age: 44 +/- 14 years) who had greater than moderate MR with normal left ventricular (LV) systolic function (LV ejection fraction >50%). Conventional echocardiographic indices and parameters measured by Doppler tissue imaging at septal side of mitral annulus were obtained before exercise. Mitral regurgitation fraction, forward stroke volume, pulmonary venous flow velocities, and systolic pulmonary artery pressure (sPAP) were also obtained with standard methods. RESULTS: Left ventricular ejection fraction was 61 +/- 6% and MR fraction was 48 +/- 13%. All patients finished a symptom-limited treadmill exercise test with a peak heart rate of >85% of predicted maximum heart rate. Mean exercise time was 9.95 +/- 2.17 min, corresponding to 11 +/- 2 metabolic equivalents. Among pre-exercise echocardiographic variables, only early diastolic mitral annulus velocity (E') and pulmonary venous reversal flow velocity (PVa) showed a significant correlation with exercise time (r = 0.44, p = 0.011, and r = -0.40, p = 0.040, respectively), which persisted after multivariate analysis (p = 0.011 and 0.038, respectively). Other parameters such as systolic mitral annulus velocity, resting and postexercise sPAP, forward stroke volume, LV size, LV ejection fraction, left atrial size, and regurgitant fraction showed no significant correlation. CONCLUSIONS: Left ventricular diastolic function is an important determinant of exercise capacity in patients with chronic MR. Both E' and PVa, accepted surrogate estimates for LV diastolic function, may be useful for identifying patients with chronic MR and with poor exercise capacity.

Adult↗

PubMed1999

Correlations between indices of heart rate variability in healthy children and children with congenital heart disease.

Heart rate variability, as determined from 24-hour Holter recordings, represents a noninvasive parameter for studying the autonomic control of the heart. It decreases with certain disease states characterized by autonomic dysfunction such as congestive heart failure. No study in healthy or cardiac children has been performed to determine the correlations between and within time and frequency domain indices of heart rate variability. We examined five time domain (SDNN, SDNNi, SDANNi, rMSSD and pNN50) and five frequency domain measures (ULF, VLF, LF, HF and balance LF/HF) in 200 healthy children and 200 children with congenital heart disease, aged 3 days to 14 years. All measures were significantly correlated with each other. However, the strength of correlation varied greatly. Our data show that variables strongly dependent on vagal tone (rMSSD, pNN50 and HF) were highly correlated (r value > 0.90), as well as SDNN and SDANNi. We conclude that certain time and frequency domain indices correlate so strongly with each other that they can act as surrogates for each other.

Adolescent↗

PubMed2006

Can severity be predicted by treatment variables in rheumatoid arthritis administrative data bases?

OBJECTIVE: Administrative data bases provide rapid access to data regarding treatment and morbidity of rheumatoid arthritis (RA). A serious limitation of administrative data bases is the lack of information regarding RA severity, as in the case of lymphoma, where RA severity may contribute to the cause of the adverse outcome. We examined whether treatment variables could predict RA severity. METHODS: We studied 7541 patients with RA who were participating in a longitudinal study of RA outcomes. Disease severity was determined by the Patient Activity Scale (PAS), which represents on a 0 to 10 scale the mean of 0-10 standardized values of pain (by visual analog scale), patient global severity, and the Health Assessment Questionnaire. We tested the ability of disease modifying antirheumatic drugs (DMARD) and biologic treatment variables and the lifetime number of these treatments to predict severity status. The receiver-operating characteristic (ROC) area under the curve (AUC) was used to describe the association between severity and treatment variables. RESULTS: There was little difference in PAS scores between various treatments and treatment groups, including scores of the 18.3% of patients receiving no DMARD or biologic therapy. The ROC AUC to distinguish PAS scores above and below the median was 0.64 (60.5% correctly classified) and was 0.70 (67.2% correctly classified) in distinguishing first compared to fourth quartiles PAS scores. CONCLUSION: Treatment variables do not accurately or usefully identify severity status. As a corollary, there is little difference in severity between patients receiving different treatment regimens, and actual measures of severity rather than treatment surrogates are required to assess RA severity.

Aged↗

PubMed2005

Interlaboratory comparison of red-cell ATP, 2,3-diphosphoglycerate and haemolysis measurements.

BACKGROUND AND OBJECTIVES: Red blood cell (RBC) storage systems are licensed based on their ability to prevent haemolysis and maintain RBC 24-h in vivo recovery. Preclinical testing includes measurement of RBC ATP as a surrogate for recovery, 2,3-diphosphoglycerate (DPG) as a surrogate for oxygen affinity, and free haemoglobin, which is indicative of red cell lysis. The reproducibility of RBC ATP, DPG and haemolysis measurements between centres was investigated. MATERIALS AND METHODS: Five, 4-day-old leucoreduced AS-1 RBC units were pooled, aliquotted and shipped on ice to 14 laboratories in the USA and European Union (EU). Each laboratory was to sample the bag twice on day 7 and measure RBC ATP, DPG, haemoglobin and haemolysis levels in triplicate on each sample. The variability of results was assessed by using coefficients of variation (CV) and analysis of variance. RESULTS: Measurements were highly reproducible at the individual sites. Between sites, the CV was 16% for ATP, 35% for DPG, 2% for total haemoglobin and 54% for haemolysis. For ATP and total haemoglobin, 94 and 80% of the variance in measurements was contributed by differences between sites, and more than 80% of the variance for DPG and haemolysis measurements came from markedly discordant results from three sites and one site, respectively. In descending order, mathematical errors, unvalidated analytical methods, a lack of shared standards and fluid handling errors contributed to the variability in measurements from different sites. CONCLUSIONS: While the methods used by laboratories engaged in RBC storage system clinical trials demonstrated good precision, differences in results between laboratories may hinder comparative analysis. Efforts to improve performance should focus on developing robust methods, especially for measuring RBC ATP.

2,3-Diphosphoglycerate↗

PubMed1999

No evidence of chaos in the heart rate variability of normal and cardiac transplant human subjects.

INTRODUCTION: The variability observed in the heart rate may reflect fundamental aspects of cardiac activity. It has been under discussion whether heart rate variability (HRV) is due to noise or chaos, which is irregular behavior occurring in deterministic nonlinear systems. METHODS AND RESULTS: Using chaos analysis techniques, we analyzed HRV of five normal and five human cardiac transplant subjects at rest. HRV is studied using the beat-to-beat RR interval time series extracted from the ECG. The cardiac transplant subjects exhibited a much smaller HRV than the normal subjects because of heart denervation. We present the map and correlation dimension estimation for the RR time series. To test for nonlinear correlations in the dynamics, we built surrogate time series that have the same power spectra as the experimental time series, but also have randomized phases. The experimental and the surrogate data were compared using the correlation integral. No correlation dimension was found for the RR time series of either the normal or the cardiac transplant subjects. Nevertheless, nonlinear correlations were detected in the HRV of the normal subjects but not in HRV of the cardiac transplant subjects. For the latter, no significant changes were observed in the correlation integral as a function of time after transplantation. CONCLUSION: We found no evidence of low-dimensional chaos in the HRV of normal and cardiac transplant subjects. However, some nonlinear correlations were detected in the HRV of the normal subjects, which may be associated with autonomic nervous system influence.

Electrophysiology↗

PubMed1995

Group sequential comparison of changes: ad-hoc versus more exact method.

There are many clinical trials in which we are interested in comparing changes in responses between two treatment groups sequentially. Investigators might assume a simple linear model, take the average of the ordinary least square estimators of slope within each treatment group, and use the standardized difference between these two averages as the test statistic at each interim analysis. Ad-hoc construction of the boundary values for interim analysis might be based on group sequential methods which assume that the interim test statistics have independent increments even though it may not be true when a response variable is measured repeatedly over time for each subject. This ad-hoc method is very simple and appealing, and thus has been used in a clinical trial setting. Lee and DeMets (1991, Journal of the American Statistical Association 86, 757-762) have proposed a more exact group sequential method for comparing rates of change. Under the assumption that the response follows the linear mixed effects model, they have derived the asymptotic joint distribution of the sequentially computed statistics. Construction of group sequential boundaries is based on this distribution theory. By simulation studies, we first study the robustness of the more exact method to violations of the typical assumptions. In addition, we compare the ad-hoc method with the more exact method and examine how well these two methods work for various situations. The relationship between two different information times, Fisher information and a surrogate information, are also discussed from the simulation studies.

Analysis of Variance↗

PubMed2004

Impact of inter-individual differences in drug metabolism and pharmacokinetics on safety evaluation.

Safety evaluation aims to assess the dose-response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is 'without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 10(0.5) (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment.

Administration, Oral↗

PubMed2001

How closely correlated are molecular and quantitative measures of genetic variation? A meta-analysis.

The ability of populations to undergo adaptive evolution depends on the presence of quantitative genetic variation for ecologically important traits. Although molecular measures are widely used as surrogates for quantitative genetic variation, there is controversy about the strength of the relationship between the two. To resolve this issue, we carried out a meta-analysis based on 71 datasets. The mean correlation between molecular and quantitative measures of genetic variation was weak (r = 0.217). Furthermore, there was no significant relationship between the two measures for life-history traits (r = -0.11) or for the quantitative measure generally considered as the best indicator of adaptive potential, heritability (r = -0.08). Consequently, molecular measures of genetic diversity have only a very limited ability to predict quantitative genetic variability. When information about a population's short-term evolutionary potential or estimates of local adaptation and population divergence are required, quantitative genetic variation should be measured directly.

Animals↗