Jonathan Pollak

Association between exposure to low to moderate arsenic levels and incident cardiovascular disease. A prospective cohort study.

BACKGROUND Long-term exposure to high levels of arsenic is associated with increased risk for cardiovascular disease, whereas risk from long-term exposure to low to moderate arsenic levels (< 100μg/L in drinking water) is unclear. OBJECTIVE To evaluate the association between long-term exposure to low to moderate arsenic levels and incident cardiovascular disease. DESIGN Prospective cohort study. SETTING The Strong Heart Study baseline visit between 1989 and 1991, with follow-up through 2008. PATIENTS 3575 American Indian men and women aged 45 to 74 years living in Arizona, Oklahoma, and North and South Dakota. MEASUREMENTS The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of long-term arsenic exposure. Outcomes were incident fatal and nonfatal cardiovascular disease. RESULTS A total of 1184 participants developed fatal and nonfatal cardiovascular disease. When the highest and lowest quartiles of arsenic concentrations (> 15.7 vs. < 5.8 μg/g creatinine) were compared,the hazard ratios for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for sociodemographic factors, smoking, body mass index, and lipid levels were 1.65 (95%CI, 1.20 to 2.27; P for trend < 0.001), 1.71 (CI, 1.19 to 2.44; P for trend < 0.001), and 3.03 (CI, 1.08 to 8.50; P for trend = 0.061),respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (CI,1.09 to 1.59; P for trend = 0.002), 1.30 (CI, 1.04 to 1.62; P for trend = 0.006), and 1.47 (CI, 0.97 to 2.21; P for trend = 0.032).These associations varied by study region and were attenuated after further adjustment for diabetes, hypertension, and kidney disease measures. LIMITATION Direct measurement of individual arsenic levels in drinking water was unavailable. CONCLUSION Long-term exposure to low to moderate arsenic levels was associated with cardiovascular disease incidence and mortality.

Incidence and associated premorbid diagnoses of patients with chronic rhinosinusitis

BACKGROUND Chronic rhinosinusitis (CRS) is a prevalent condition with underexplored risk factors. OBJECTIVES We sought to determine CRS incidence and evaluate associations with a range of premorbid medical conditions for chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) using real-world clinical practice data. METHODS Electronic health records data from 446,480 Geisinger Clinic primary care patients were used for a retrospective longitudinal cohort study for data from 2001-2010. By using logistic regression, newly diagnosed CRS cases between 2007 and 2009 were compared with frequency-matched control subjects on premorbid factors in the immediate (0-6 months), intermediate (7-24 months), and entire observed timeframes before diagnosis. RESULTS The average incidence of CRS was 83 ± 13 CRSwNP cases per 100,000 person-years and 1048 ± 78 CRSsNP cases per 100,000 person-years. Between 2007 and 2009, 595 patients with incident CRSwNP and 7523 patients with incident CRSsNP were identified and compared with 8118 control subjects. Compared with control subjects and patients with CRSsNP, patients with CRSwNP were older and more likely to be male. Before diagnosis, patients with CRS had a higher prevalence of acute rhinosinusitis, allergic rhinitis, chronic rhinitis, asthma, gastroesophageal reflux disease, adenotonsillitis, sleep apnea, anxiety, and headaches (all P < .001). Patients with CRSsNP had a higher premorbid prevalence of infections of the upper and lower airway, skin/soft tissue, and urinary tract (all P < .001). In the immediate and intermediate timeframes analyzed, patients with CRS had more outpatient encounters and antibiotic prescriptions (P < .001), but guideline-recommended diagnostic testing was performed in a minority of cases. CONCLUSIONS Patients who are given a diagnosis of CRS have a higher premorbid prevalence of anxiety, headaches, gastroesophageal reflux disease, sleep apnea, and infections of the respiratory system and some nonrespiratory sites, which results in higher antibiotic, corticosteroid, and health care use. The use of guideline-recommended diagnostic testing for confirmation of CRS remains poor.

Arsenic species and selected metals in human urine: validation of HPLC/ICPMS and ICPMS procedures for a long-term population-based epidemiological study

Exposure to high inorganic arsenic concentrations in drinking water has been related to detrimental health effects, including cancers and possibly cardiovascular disease, in many epidemiological studies. Recent studies suggest that arsenic might elicit some of its toxic effects also at lower concentrations. The Strong Heart Study, a large epidemiological study of cardiovascular disease in American Indian communities, collected urine samples and performed medical examinations on 4,549 participants over a 10-year period beginning in 1989. We used anion-exchange HPLC/ICPMS to determine concentrations of arsenic species (methylarsonate, dimethylarsinate and arsenate) in 5,095 urine samples from the Strong Heart Study. We repeated the chromatography on a portion of the urine sample that had been oxidised, by addition of H(2)O(2), to provide additional information on the presence of As(III) species and thio-arsenicals, and by difference, of arsenobetaine and other non-retained cations. Total concentrations for As, Cd, Mo, Pb, Sb, Se, U, W, and Zn were also determined in the urine samples by ICPMS. The dataset will be used to evaluate the relationships between the concentrations of urinary arsenic species and selected metals with various cardiometabolic health endpoints. We present and discuss the analytical protocol put in place to produce this large and valuable dataset.

Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and Other Exposures in Human Blood DNA Samples

Background: The association between human blood DNA global methylation and global hydroxymethylation has not been evaluated in population-based studies. No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals. Objective: We evaluated the association between global DNA methylation and global DNA hydroxymethylation in 48 Strong Heart Study participants for which selected metals had been measured in urine at baseline and DNA was available from 1989–1991 (visit 1) and 1998–1999 (visit 3). Methods: We measured the percentage of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in samples using capture and detection antibodies followed by colorimetric quantification. We explored the association of participant characteristics (i.e., age, adiposity, smoking, and metal exposure) with both global DNA methylation and global DNA hydroxymethylation. Results: The Spearman’s correlation coefficient for 5-mC and 5-hmC levels was 0.32 (p = 0.03) at visit 1 and 0.54 (p < 0.001) at visit 3. Trends for both epigenetic modifications were consistent across potential determinants. In cross-sectional analyses, the odds ratios of methylated and hydroxymethylated DNA were 1.56 (95% CI: 0.95, 2.57) and 1.76 (95% CI: 1.07, 2.88), respectively, for the comparison of participants above and below the median percentage of dimethylarsinate. The corresponding odds ratios were 1.64 (95% CI: 1.02, 2.65) and 1.16 (95% CI: 0.70, 1.94), respectively, for the comparison of participants above and below the median cadmium level. Arsenic exposure and metabolism were consistently associated with both epigenetic markers in cross-sectional and prospective analyses. The positive correlation of 5-mC and 5-hmC levels was confirmed in an independent study population. Conclusions: Our findings support that both epigenetic measures are related at the population level. The consistent trends in the associations between these two epigenetic modifications and the characteristics evaluated, especially arsenic exposure and metabolism, suggest the need for understanding which of the two measures is a better biomarker for environmental epigenetic effects in future large-scale epidemiologic studies. Citation: Tellez-Plaza M, Tang WY, Shang Y, Umans JG, Francesconi KA, Goessler W, Ledesma M, Leon M, Laclaustra M, Pollak J, Guallar E, Cole SA, Fallin MD, Navas-Acien A. 2014. Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. Environ Health Perspect 122:946–954; http://dx.doi.org/10.1289/ehp.1306674

Unconventional natural gas development and birth outcomes in Pennsylvania, USA

Background: Unconventional natural gas development has expanded rapidly. In Pennsylvania, the number of producing wells increased from 0 in 2005 to 3,689 in 2013. Few publications have focused on unconventional natural gas development and birth outcomes. Methods: We performed a retrospective cohort study using electronic health record data on 9,384 mothers linked to 10,946 neonates in the Geisinger Health System from January 2009 to January 2013. We estimated cumulative exposure to unconventional natural gas development activity with an inverse-distance squared model that incorporated distance to the mother’s home; dates and durations of well pad development, drilling, and hydraulic fracturing; and production volume during the pregnancy. We used multilevel linear and logistic regression models to examine associations between activity index quartile and term birth weight, preterm birth, low 5-minute Apgar score and small size for gestational age birth, while controlling for potential confounding variables. Results: In adjusted models, there was an association between unconventional natural gas development activity and preterm birth that increased across quartiles, with a fourth quartile odds ratio of 1.4 (95% confidence interval = 1.0, 1.9). There were no associations of activity with Apgar score, small for gestational age birth, or term birth weight (after adjustment for year). In a posthoc analysis, there was an association with physician-recorded high-risk pregnancy identified from the problem list (fourth vs. first quartile, 1.3 [95% confidence interval = 1.1, 1.7]). Conclusion: Prenatal residential exposure to unconventional natural gas development activity was associated with two pregnancy outcomes, adding to evidence that unconventional natural gas development may impact health. See Video Abstract at http://links.lww.com/EDE/B14.

Body mass index and the built and social environments in children and adolescents using electronic health records.

BACKGROUND No prior studies in children have evaluated how age may modify relationships of the built and social environments with BMI, nor evaluated the range of scales and contexts over which places may influence health. PURPOSE To systematically evaluate associations of 33 environmental measures in three domains (land use, physical activity, and social environments) with BMI in children and adolescents in five geographies. METHODS A cross-sectional, multilevel analysis was completed in 2009-2010 of electronic health record data (2001-2008) from 47,769 children aged 5-18 years residing in a 31-county region of Pennsylvania. Associations of environmental measures with BMI were evaluated using 0.5-mile network buffers; census tracts; minor civil divisions (i.e., townships, boroughs, cities); a mixed definition of place (townships, boroughs, and census tracts in cities); and counties, overall and by age strata. RESULTS Among all children, lower levels of community socioeconomic deprivation and greater diversity of physical activity establishments were associated with lower BMI. Associations of environmental measures differed by age, depending on scale and context. For example, higher population density was associated with lower BMI in older children; this effect was strongest in the larger geographies. Similarly, a lower level of county sprawl was associated with lower BMI in older children. CONCLUSIONS Associations differed by age and definition of place, suggesting that the benefits of environmental intervention may not be uniform across the childhood age range. The study demonstrated the utility of using electronic patient information for large-scale, population-based epidemiologic research, a research area of growing interest and investment in the U.S.

Attention deficit disorder, stimulant use, and childhood body mass index trajectory.

BACKGROUND: Childhood attention-deficit/hyperactivity disorder (ADHD) has been associated with childhood and adult obesity, and stimulant use with delayed childhood growth, but the independent influences are unclear. No longitudinal studies have examined associations of ADHD diagnosis and stimulant use on BMI trajectories throughout childhood and adolescence. METHODS: We used longitudinal electronic health record data from the Geisinger Health System on 163 820 children ages 3 to 18 years in Pennsylvania. Random effects linear regression models were used to model BMI trajectories with increasing age in relation to ADHD diagnosis, age at first stimulant use, and stimulant use duration, while controlling for confounding variables. RESULTS: Mean (SD) age at first BMI was 8.9 (5.0) years, and children provided a mean (SD) of 3.2 (2.4) annual BMI measurements. On average, BMI trajectories showed a curvilinear relation with age. There were consistent associations of unmedicated ADHD with higher BMIs during childhood compared with those without ADHD or stimulants. Younger age at first stimulant use and longer duration of stimulant use were each associated with slower BMI growth earlier in childhood but a more rapid rebound to higher BMIs in late adolescence. CONCLUSIONS: The study provides the first longitudinal evidence that ADHD during childhood not treated with stimulants was associated with higher childhood BMIs. In contrast, ADHD treated with stimulants was associated with slower early BMI growth but a rebound later in adolescence to levels above children without a history of ADHD or stimulant use. The findings have important clinical and neurobiological implications.

A population-based study of the epidemiology and clinical features of methicillin-resistant Staphylococcus aureus infection in Pennsylvania, 2001-2010.

No U.S. general population-based study has characterized the epidemiology and risk factors, including skin and soft tissue infection (SSTI), for healthcare-associated (HA) and community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA). We estimated the incidence of HA- and CA-MRSA and SSTI over a 9-year period using electronic health record data from the Geisinger Clinic in Pennsylvania. MRSA cases were frequency-matched to SSTI cases and controls in a nested case-control analysis. Logistic regression was used to assess risk factors, while accounting for antibiotic administration. We identified 1713 incident CA- and 1506 HA-MRSA cases and 78 216 SSTI cases. On average, from 2005 to 2009, the annual incidence of CA-MRSA increased by 34%, HA-MRSA by 7%, and SSTI by 4%. Age, season, community socioeconomic deprivation, obesity, smoking, previous SSTI, and antibiotic administration were identified as independent risk factors for CA-MRSA.

Antibiotic use and childhood body mass index trajectory

Background/Objectives:Antibiotics are commonly prescribed for children. Use of antibiotics early in life has been linked to weight gain but there are no large-scale, population-based, longitudinal studies of the full age range among mainly healthy children.Subjects/Methods:We used electronic health record data on 163 820 children aged 3–18 years and mixed effects linear regression to model associations of antibiotic orders with growth curve trajectories of annual body mass index (BMI) controlling for confounders. Models evaluated three kinds of antibiotic associations—reversible (time-varying indicator for an order in year before each BMI), persistent (time-varying cumulative orders up to BMIj) and progressive (cumulative orders up to prior BMI (BMIj-1))—and whether these varied by age.Results:Among 142 824 children under care in the prior year, a reversible association was observed and this short-term BMI gain was modified by age (P<0.001); effect size peaked in mid-teen years. A persistent association was observed and this association was stronger with increasing age (P<0.001). The addition of the progressive association among children with at least three BMIs (n=79 752) revealed that higher cumulative orders were associated with progressive weight gain; this did not vary by age. Among children with an antibiotic order in the prior year and at least seven lifetime orders, antibiotics (all classes combined) were associated with an average weight gain of approximately 1.4 kg at age 15 years. When antibiotic classes were evaluated separately, the largest weight gain at 15 years was associated with macrolide use.Conclusions:We found evidence of reversible, persistent and progressive effects of antibiotic use on BMI trajectories, with different effects by age, among mainly healthy children. The results suggest that antibiotic use may influence weight gain throughout childhood and not just during the earliest years as has been the primary focus of most prior studies.

Community socioeconomic deprivation and obesity trajectories in children using electronic health records

Longitudinal studies of the role of community context in childhood obesity are lacking. The objective of this study was to examine associations of community socio economic deprivation (CSD) with trajectories of change in body mass index (BMI) in childhood and adolescence.