Context Bisphenol A (BPA) is widely used in epoxy resins lining food and beverage containers. Evidence of effects in animals has generated concern over low-level chronic exposures in humans.Objective To examine associations between urinary BPA concentrations and adult health status.Design, Setting, and Participants Cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States, using data from the National Health and Nutrition Examination Survey 2003-2004. Participants were 1455 adults aged 18 through 74 years with measured urinary BPA and urine creatinine concentrations. Regression models were adjusted for age, sex, race/ ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration. The sample provided 80% power to detect unadjusted odds ratios (ORs) of 1.4 for diagnoses of 5% prevalence per 1-SD change in BPA concentration, or standardized regression coefficients of 0.075 for liver enzyme concentrations, at a significance level of PϽ.05. Main Outcome MeasuresChronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes. ResultsHigher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P=.001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; PϽ.001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes ␥-glutamyltransferase (OR per

Objective To determine whether, and to what extent, physical activity interventions affect the overall activity levels of children.Design Systematic review and meta-analysis.Data sources Electronic databases (Embase, Medline, PsycINFO, SPORTDiscus) and reference lists of included studies and of relevant review articles.Study selection Design: randomised controlled trials or controlled clinical trials (cluster and individual) published in peer reviewed journals. Intervention: incorporated a component designed to increase the physical activity of children/adolescents and was at least four weeks in duration. Outcomes: measured whole day physical activity objectively with accelerometers either before or immediately after the end of the intervention period. Data analysisIntervention effects (standardised mean differences) were calculated for total physical activity, time spent in moderate or vigorous physical activity, or both for each study and pooled using a weighted random effects model. Meta-regression explored the heterogeneity of intervention effects in relation to study participants, design, intervention type, and methodological quality.Results Thirty studies (involving 14 326 participants; 6153 with accelerometer measured physical activity) met the inclusion criteria and all were eligible for meta-analysis/meta-regression. The pooled intervention effect across all studies was small to negligible for total physical activity (standardised mean difference 0.12, 95% confidence interval 0.04 to 0.20; P<0.01) and small for moderate or vigorous activity (0.16, 0.08 to 0.24; P<0.001). Meta-regression indicated that the pooled intervention effect did not differ significantly between any of the subgroups (for example, for total physical activity, standardised mean differences were 0.07 for age <10 years and 0.16 for ≥10 years, P=0.19; 0.07 for body mass index across the entire range and 0.22 for exclusively overweight/obese children, P=0.07; 0.12 for study duration ≤6 months and 0.09 for >6 months, P=0.71; 0.15 for home/family based intervention and 0.10 for school based intervention, P=0.53; and 0.09 for higher quality studies and 0.14 for lower quality studies, P=0.52). ConclusionsThis review provides strong evidence that physical activity interventions have had only a small effect (approximately 4 minutes more walking or running per day) on children's overall activity levels. This finding may explain, in part, why such interventions have had limited success in reducing the body mass index or body fat of children. IntroductionPhysical activity is associated with many health benefits, 1-3 but most children fail to meet national recommendations. [4][5][6] Prevention of obesity in particular is thought to be one of the benefits to being more active, and accordingly most interventions aimed at reducing childhood obesity incorporate a physical activity component. Observational studies consistently show that greater activity is associated (r~−0.2) with lower body mass index and girth, 7-11 yet physical activity int...

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10−57), CCL4L1 (p = 3.9×10−21), IL18 (p = 6.8×10−13), LPA (p = 4.4×10−10), GGT1 (p = 1.5×10−7), SHBG (p = 3.1×10−7), CRP (p = 6.4×10−6) and IL1RN (p = 7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

Credit scoring is the term used to describe formal statistical methods used for classifying applicants for credit into`good' and`bad' risk classes. Such methods have become increasingly important with the dramatic growth in consumer credit in recent years. A wide range of statistical methods has been applied, though the literature available to the public is limited for reasons of commercial con®dentiality. Particular problems arising in the credit scoring context are examined and the statistical methods which have been applied are reviewed.

BackgroundBisphenol A (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years.Methodology and FindingsA cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18–74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant.ConclusionsHigher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.

Background Research using data-driven cluster analysis has proposed five subgroups of diabetes with differences in diabetes progression and risk of complications. We aimed to compare the clinical utility of this subgroup-based approach for predicting patient outcomes with an alternative strategy of developing models for each outcome using simple patient characteristics. Methods We identified five clusters in the ADOPT trial (n=4351) using the same data-driven cluster analysis as reported by Ahlqvist and colleagues. Differences between clusters in glycaemic and renal progression were investigated and contrasted with stratification using simple continuous clinical features (age at diagnosis for glycaemic progression and baseline renal function for renal progression). We compared the effectiveness of a strategy of selecting glucose-lowering therapy using clusters with one combining simple clinical features (sex, BMI, age at diagnosis, baseline HbA 1c) in an independent trial cohort (RECORD [n=4447]). Findings Clusters identified in trial data were similar to those described in the original study by Ahlqvist and colleagues. Clusters showed differences in glycaemic progression, but a model using age at diagnosis alone explained a similar amount of variation in progression. We found differences in incidence of chronic kidney disease between clusters; however, estimated glomerular filtration rate at baseline was a better predictor of time to chronic kidney disease. Clusters differed in glycaemic response, with a particular benefit for thiazolidinediones in patients in the severe insulin-resistant diabetes cluster and for sulfonylureas in patients in the mild age-related diabetes cluster. However, simple clinical features outperformed clusters to select therapy for individual patients. Interpretation The proposed data-driven clusters differ in diabetes progression and treatment response, but models that are based on simple continuous clinical features are more useful to stratify patients. This finding suggests that precision medicine in type 2 diabetes is likely to have most clinical utility if it is based on an approach of using specific phenotypic measures to predict specific outcomes, rather than assigning patients to subgroups.

Objective:To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.Methods:One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population–based Cardiovascular Health Study between 1992–1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992–1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.Results:During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23–4.13) and 1.53 (95% CI: 1.06–2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02–4.83) and 1.69 (95% CI: 1.06–2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.Conclusion:Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.

BackgroundPerfluorooctanoic acid (PFOA, also known as C8) and perfluorooctane sulfonate (PFOS) are stable compounds with many industrial and consumer uses. Their persistence in the environment plus toxicity in animal models has raised concern over low-level chronic exposure effects on human health.ObjectivesWe estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population.MethodsAnalyses of PFOA/PFOS versus disease status in the National Health and Nutrition Examination Survey (NHANES) for 1999–2000, 2003–2004, and 2005–2006 included 3,974 adults with measured concentrations for perfluorinated chemicals. Regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and alcohol intake.ResultsThe NHANES-weighted prevalence of reporting any thyroid disease was 16.18% (n = 292) in women and 3.06% (n = 69) in men; prevalence of current thyroid disease with related medication was 9.89% (n = 163) in women and 1.88% (n = 46) in men. In fully adjusted logistic models, women with PFOA ≥ 5.7 ng/mL [fourth (highest) population quartile] were more likely to report current treated thyroid disease [odds ratio (OR) = 2.24; 95% confidence interval (CI), 1.38–3.65; p = 0.002] compared with PFOA ≤ 4.0 ng/mL (quartiles 1 and 2); we found a near significant similar trend in men (OR = 2.12; 95% CI, 0.93–4.82; p = 0.073). For PFOS, in men we found a similar association for those with PFOS ≥ 36.8 ng/mL (quartile 4) versus ≤ 25.5 ng/mL (quartiles 1 and 2: OR for treated disease = 2.68; 95% CI, 1.03–6.98; p = 0.043); in women this association was not significant.ConclusionsHigher concentrations of serum PFOA and PFOS are associated with current thyroid disease in the U.S. general adult population. More work is needed to establish the mechanisms involved and to exclude confounding and pharmacokinetic explanations.