William Henley

Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults.

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 P < .05. MAIN OUTCOME MEASURES Chronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes. RESULTS Higher 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; P < .001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes gamma-glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14-1.46; P < .001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18-1.85; P = .002). CONCLUSION Higher BPA exposure, reflected in higher urinary concentrations of BPA, may be associated with avoidable morbidity in the community-dwelling adult population.

Association of Urinary Bisphenol A Concentration with Heart Disease: Evidence from NHANES 2003/06

Background Bisphenol 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 Findings A 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. Conclusions Higher 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.

Effectiveness of intervention on physical activity of children: systematic review and meta-analysis of controlled trials with objectively measured outcomes (EarlyBird 54)

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 analysis Intervention 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). Conclusions This 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.

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

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.

Association between Serum Perfluorooctanoic Acid (PFOA) and Thyroid Disease in the U.S. National Health and Nutrition Examination Survey

Background Perfluorooctanoic 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. Objectives We estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population. Methods Analyses 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. Results The 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. Conclusions Higher 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.

A k-nearest-neighbour classifier for assessing consumer credit risk

SUMMARY The last 30 years have seen the development of credit scoring techniques for assessing the creditworthiness of consumer loan applicants. Traditional credit scoring methodology has involved the use of techniques such as discriminant analysis, linear or logistic regression, linear programming and decision trees. In this paper we look at the application of the k-nearest-neighbour (k-NN) method, a standard technique in pattern recognition and nonparametric statistics, to the credit scoring problem. We propose an adjusted version of the Euclidean distance metric which attempts to incorporate knowledge of class separation contained in the data. Our k-NN methodology is applied to a real data set and we discuss the selection of optimal values of the parameters k and D included in the method. To assess the potential of the method we make comparisons with linear and logistic regression and decision trees and graphs. We end by discussing a practical implementation of the proposed k-NN classifier.

Vitamin D and the risk of dementia and Alzheimer disease

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/Alzheimers 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.

Urinary Bisphenol A Concentration and Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women

Background— The endocrine-disrupting chemical bisphenol A (BPA) is widely used in food and beverage packaging. Higher urinary BPA concentrations were cross-sectionally associated with heart disease in National Health and Nutrition Examination Survey (NHANES) 2003–2004 and NHANES 2005–2006, independent of traditional risk factors. Methods and Results— We included 758 incident coronary artery disease (CAD) cases and 861 controls followed for 10.8 years from the European Prospective Investigation of Cancer–Norfolk UK. Respondents aged 40 to 74 years and free of CAD, stroke, or diabetes mellitus provided baseline spot urine samples. Urinary BPA concentrations (median value, 1.3 ng/mL) were low. Per-SD (4.56 ng/mL) increases in urinary BPA concentration were associated with incident CAD in age-, sex-, and urinary creatinine–adjusted models (n=1919; odds ratio=1.13; 95% confidence interval, 1.02–1.24; P=0.017). With CAD risk factor adjustment (including education, occupational social class, body mass index category, systolic blood pressure, lipid concentrations, and exercise), the estimate was similar but narrowly missed 2-sided significance (n=1744; odds ratio=1.11; 95% confidence interval, 1.00–1.23; P=0.058). Sensitivity analyses with the fully adjusted model, excluding those with early CAD (<3-year follow-up), body mass index >30, or abnormal renal function or with additional adjustment for vitamin C, C-reactive protein, or alcohol consumption, all produced similar estimates, and all showed associations at P⩽0.05. Conclusions— Associations between higher BPA exposure (reflected in higher urinary concentrations) and incident CAD during >10 years of follow-up showed trends similar to previously reported cross-sectional findings in the more highly exposed NHANES respondents. Further work is needed to accurately estimate the prospective exposure-response curve and to establish the underlying mechanisms.

Fatness leads to inactivity, but inactivity does not lead to fatness: a longitudinal study in children (EarlyBird 45)

Objective To establish in children whether inactivity is the cause of fatness or fatness the cause of inactivity. Design A non-intervention prospective cohort study examining children annually from 7 to 10 years. Baseline versus change to follow-up associations were used to examine the direction of causality. Setting Plymouth, England. Participants 202 children (53% boys, 25% overweight/obese) recruited from 40 Plymouth primary schools as part of the EarlyBird study. Main outcome measures Physical activity (PA) was measured using Actigraph accelerometers. The children wore the accelerometers for 7 consecutive days at each annual time point. Two components of PA were analysed: the total volume of PA and the time spent at moderate and vigorous intensities. Body fat per cent (BF%) was measured annually by dual energy x ray absorptiometry. Results BF% was predictive of changes in PA over the following 3 years, but PA levels were not predictive of subsequent changes in BF% over the same follow-up period. Accordingly, a 10% higher BF% at age 7 years predicted a relative decrease in daily moderate and vigorous intensities of 4 min from age 7 to 10 years (r=−0.17, p=0.02), yet more PA at 7 years did not predict a relative decrease in BF% between 7 and 10 years (r=−0.01, p=0.8). Conclusions Physical inactivity appears to be the result of fatness rather than its cause. This reverse causality may explain why attempts to tackle childhood obesity by promoting PA have been largely unsuccessful.

Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing.

Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in‐vivo RNA in a large‐scale transcriptomic microarray study (subjects aged 30–104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n = 458), following‐up findings in a replication set (n = 240). We confirmed expression of key results by real‐time PCR. Of 16 571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age‐related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age‐associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P < 0.002, false discovery rate (FDR) q < 0.05]. This is supported by our observation of age‐associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging.