Environmental/Occupational Epidemiology Research

ENV_OCC

Overview

Research in environmental/occupational epidemiology requires an interdisciplinary approach. To gain this perspective, students cross-train through coursework, research, and other enrichment activities in ENVR/OCCUP EPID as well as through those offered by other EPID programs areas (for example, Cancer, CVD, Infectious Diseases, Reproductive/Perinatal/Pediatric), or departments outside of EPID (e.g., Geography, Environmental Sciences & Engineering, Toxicology and other departments within Public Health and Medicine).

Learning Objectives

The overall objectives of the program in Environmental and Occupational Epidemiology are to provide an interdisciplinary education that offers the students a solid foundation in environmental and occupational health, with practicum experiences to enhance applied learning, and high-quality research experiences. The learning objectives for the environmental and occupational program area are the same as those for the Department of Epidemiology as a whole with the following additions.

Upon satisfactory completion, students in the program should be able to:

  • Apply the competencies laid out in the Epidemiology Department’s overall learning objectives to the solution of problems in one of more of the program subspecialty areas;
  • Enumerate and discuss important health problems, with their descriptive epidemiology and determinants, for one or more of the program subspecialty areas of environmental/ occupational epidemiology;
  • Identify key surveillance systems and other sources of data relevant to the problem;
  • Discuss study design and measurement issues particular to the subspeciality area;
  • Appreciate key concepts from such related disciplines as environmental sciences, toxicology, and biostatistics;
  • Collaborate with experts in the preceding fields to conduct epidemiologic research;
  • Appreciate the uses of epidemiologic research in identifying hazardous agents, evaluating environmental injustice, and in setting health and safety standards; and
  • Communicate epidemiologic concepts, methods, and findings to community groups, labor unions, health professionals, government agencies, and employers.

In addition, students specializing in occupational or environmental epidemiology who satisfactorily complete the PhD should be able to:

  • Understand the principles of exposure assessment and collaborate with specialists from the relevant fields to assess exposure for epidemiologic research;
  • Analyze and interpret exposure data in epidemiologic studies.

Courses

Curriculum and Coursework

Because of the diversity of the subject matter, students and advisors work in consultation to develop individualized programs of study to meet students’ personal objectives. Students will typically specialize in one of the two areas of environmental or occupational epidemiology, but the areas may intersect; for example, the same chemical agent may be present in both workplaces and the ambient environment.


Coursework

Required

Environmental Epidemiology (EPID 785) and Advanced Environmental Epid (EPID 700b)

Recommended:

  • Community-Driven Epidemiology and Environmental Justice (EPID 786),
  • Integrating Biomarkers in Population-Based Research (EPID 690),
  • Occupational Epidemiology (EPID 780),
  • GIS in Public Health (GEOG 541),
  • Interdisciplinary Approaches in Occupational Health (PUBH 785),
  • Advanced Functions of Temporal GIS (ENVR 468),
  • Global Climate Change (ENVR 575),
  • Environmental Exposure Assessment (ENVR 640),
  • Molecular/Biochemical Toxicology (TOXC 442).

Seminars

Students are also encouraged to attend the Environmental/Occupational Epidemiology seminar series within our program area (held on Fridays from 2 to 3  pm). Students may also choose to take advantage of other seminar series of interest in the department as well as at local government agencies. See additional information, below.

Research

Students are strongly encouraged to become involved in research early in their studies. This involvement not only facilitates the student’s intellectual growth as an epidemiologist, but teaches practical skills of data collection, data analysis, and research conduct. Opportunities for research in environmental/occupational epidemiology are available within the Department and the School of Public Health, as well as through other campus or local government agencies, such as the EPA and NIEHS.

Journal Club

The ENVR/OCCUP journal club is peer-led (with faculty participation) held on Mondays from 2:30 to 3:30 pm. See additional information, below.


Program Faculty

Christy AveryDr. Christy Avery, Assistant Professor: air pollution-CVD outcomes, gene*environment interactions, methods.

Julie DanielsDr. Julie Daniels, Associate Professor: flame retardants, persistent organic pollutants, pesticides, metals, and nutrition in relation to perinatal and pediatric outcomes, specifically neurodevelopment and growth.

Tania DesrosiersDr. Tania Desrosiers , Research Assistant Professor: employment and occupational exposures during pregnancy; environmental exposures; perinatal/pediatric outcomes.

Jessie EdwardsDr. Jessie Edwards , Research Assistant Professor: measurement error; exposure mixtures; occupational exposures.

Michael EmchDr. Michael Emch, Professor (& Chair of Geography): medical geography/spatial epidemiology, geographic information systems (GIS), satellite remote sensing, spatial modeling techniques, environmental modeling, and social network analysis to examine risk factors for infectious diseases.

Larry EngelDr. Larry Engel, Associate Professor: environmental/occupational exposures; pesticides; persistent organic pollutants; petroleum-related exposures; cancer; molecular epidemiology.

Stephanie EngelDr. Stephanie Engel, Associate Professor: environmental pediatric and perinatal epidemiology; child development/maternal/reproductive health; endocrine disruptors, pesticides, molecular epidemiology.

Marilie GammonDr. Marilie Gammon, Professor ( ENVR/OCCUP EPID program leader): environmental/nutritional exposures; cancer; biomarkers, environmental sampling, geographic modeling; molecular epidemiology.

Alexander KeilDr. Alexander Keil , Research Assistant Professor: bias in occupational studies; effects of long term ambient exposures; occupational exposures; radiation; arsenic .

Steve MarshallDr. Stephen Marshall, Professor: occupational injury; survival analysis.

Kari NorthDr. Kari North, Professor: genetic epidemiology; interactions with active/passive tobacco smoke.

Andrew OlshanDr. Andrew Olshan, Professor (& Chair of Epidemiology): environmental/occupational exposures; perinatal/pediatric/reproductive outcomes, cancer; molecular epidemiology; racial disparities.

Charles PooleDr. Charles Poole, Associate Professor: EMF; pesticides; cancer; perinatal/reproductive outcomes; exposure measurement; and other methodologic issues.

David RichardsonDr. David Richardson, Associate Professor: radiation; occupational exposures; cancer, risk modeling.

Shabbar RanapurwalaDr. Shabbar Ranapurwala, Research Assistant Professor: occupational injury and violence; epidemiologic methods.

Melissa TroesterDr. Melissa Troester, Associate Professor: biomarkers of exposure and response; molecular profiling; molecular epidemiology; cancer.

Eric WhitselDr. Eric Whitsel, Res Associate Professor: air/noise pollution; epigenetics; CVD; GIS; exposure measurement.

Karin B YeattsDr. Karin Yeatts, Research Assistant Professor: air pollution; asthma.


Research resources: for potential research projects, collaborators/mentors, and potential student support


NIH-supported Training Programs:

Environmental Biostatistics, Environmental Epidemiology and Environmental Health;
Occupational Epidemiology;
Reproductive and Perinatal Epidemiology; and
Cancer Prevention and Control


Research Studies: Select environmental/occupational-related epidemiology studies at UNC

Adult Cancer Outcomes

Multiple Adult Outcomes

Pediatric/Perinatal/Reproductive Outcomes

Carolina Breast Cancer Study (CBCS) + the AMBER Consortium;
Carolina Head & Neck Study (CHANCE);
Genes, Environment and Melanoma Study (GEM);
Long Island Breast Cancer Study Project (LBCSP)

Atherosclerosis Risk in Communities (ARIC) Study;
Community Health Effects of Industrial Hog Operations;
Gulf Long-Term Follow-up Study of Deepwater Horizon oil spill clean-up workers (GuLF STUDY);
Nuclear Worker Cohorts at Oak Ridge, Hanford, Savannah River and Los Alamos;
Rural Air Pollutants and Children’s Health Study

National Birth Defects Prevention Study;
Mount Sinai Children’s Environmental Health Center Birth Cohort;
NC Autism and Developmental Disabilities Monitoring Project;
Prenatal Environmental Exposures and ADHD in the Norwegian Mother and Child Cohort (MOBA);
Study tExplore Early Development, Pregnancy Infection and Nutrition Pediatric Study (PIN);
Breast Cancer and the Environment Research Program (BCERP)


Collaborators: Other environmental/occupational-related UNC Departments, Centers and Triangle Institutions with whom our students/faculty collaborate

UNC Centers/Institutes

UNC Departments

Other NC Institutions with active collaborations with UNC ENVR/OCCUP EPID faculty/students

Carolina Institute for Developmental Disabilities;
Carolina Population Center;
Center of Environmental Medicine, Asthma, and Lung Biology;
Center for Environmental Health and Susceptibility;
Institute of the Environment;
Lineberger Comprehensive Cancer Center

Environmental Science & Engineering;
Geography;
Toxicology;
Biostatistics, and
Other departments in Public Health, Medicine, and Arts & Sciences

Environmental Health Science Cluster at NC State University, Raleigh;
Environmental Protection Agency (EPA), Chapel Hill & Research Triangle Park (RTP);
National Institute of Environmental Health Sciences (NIEHS), RTP;
Nicholas School of the Environment at Duke University, Durham


Additional Information

Environmental/Occupational Additional Information
Environmental and Occupational Epidemiology The Environmental/Occupational Epidemiology Program prepares students to apply the perspective, theory, and methods of epidemiology to practical and scientific problems related to the relationship of human health to the environment and the workplace. The subject matter embraced by this program is extraordinarily broad, potentially including a wide range of health outcomes and exposures, but usually focusing on the traditionally defined realms of exposures to physical and chemical pollutants in the workplace and in ambient air, water and soil.Methodological research is also an important activity in the program. Faculty interested in environmental and occupational causes of cancer, for example, are applying advanced laboratory-based techniques to study gene-environment interactions. Methods for the assessment of exposure, including both statistical methodologies and measurement techniques ranging from biological markers to traditional environmental monitoring, are another important area of methodological research for several faculty members, and others are involved with such areas as quantitative risk assessment, meta-analysis, statistical modeling, and the use of geographic information systems (GIS).This program is designed primarily for students interested in pursuing research careers in academics, government and/or private institutions who will complete the PhD, but individuals with appropriate backgrounds may also pursue the MPH with a concentration in this area.

The primary goal of the Environmental/Occupational Epidemiology Program is to develop new knowledge relevant to the etiology, diagnosis, prognosis, and prevention of health outcomes associated with environmental and occupational exposures using an interdisciplinary epidemiologic approach. The faculty have developed an extensive research program in searching for, and in mitigating, environmental/occupational-related causes of cancer, reproductive outcomes, CVD, and asthma, for example. Recent research activities, with a particular focus on collaborations between program faculty and with epidemiology students interested in environmental/occupational epidemiology, are outlined below.

Various research centers across campus also serve as significant resources for our program faculty and students. The UNC-affiliated centers with which program faculty are associated are the following:

Examples of recent facultly publications:

Christy Avery, Stephanie Engel & Andrew Olshan
Harmon QE* (*UNC PhD student in epidemiology), Engel SM, Olshan AF, Moran T, Stuebe AM, Luo J, Wu MC, Avery CL. Association of polymorphisms in natural killer cell-related genes with preterm birth. Am J Epidemiol. 2013 Oct 15;178(8):1208-18.
Inflammation is implicated in preterm birth, but genetic studies of inflammatory genes have yielded inconsistent results. Maternal DNA from 1,646 participants in the Pregnancy, Infection, and Nutrition Cohort, enrolled in Orange and Wake counties, North Carolina (1995-2005), were genotyped for 432 tag single-nucleotide polymorphisms (SNPs) in 30 candidate genes. Gene-level and SNP associations were modeled within strata of genetic ancestry. Six genes were associated with preterm birth among European Americans: interleukin 12A (IL12A); colony-stimulating factor 2 (CSF2); interferon ? receptor 2 (IFNGR2); killer cell immunoglobulin-like receptor, three domain, long cytoplasmic tail, 2 (KIR3DL2); interleukin 4 (IL4); and interleukin 13 (IL13). Of these, relatively strong single-SNP associations were seen in IFNGR2 and KIR3DL2. Among the 4 genes related to natural killer cell function, 2 (IL12A and CSF2) were consistently associated with reduced risk of prematurity for both European and African Americans. SNPs tagging a locus control region for IL4 and IL13 were associated with an increased risk of spontaneous preterm birth for European Americans (rs3091307; risk ratio = 1.9; 95% confidence interval: 1.4, 2.5). Although gene-level associations were detected only in European Americans, single-SNP associations among European and African Americans were often similar in direction, though estimated with less precision among African Americans. In conclusion, we identified novel associations between variants in the natural killer cell immune pathway and prematurity in this biracial US population.

Christy Avery, Charles Poole & Eric Whitsel
Avery CL, Mills KT, Williams R, McGraw KA, Poole C, Smith RL, Whitsel EA. Estimating error in using residential outdoor PM2.5 concentrations as proxies for personal exposures: a meta-analysis. Environ Health Perspect. 2010 May;118(5):673-8.
BACKGROUND: Studies examining the health effects of particulate matter <or= 2.5 microm in aerodynamic diameter (PM2.5) commonly use ambient PM2.5 concentrations measured at distal monitoring sites as proxies for personal exposure and assume spatial homogeneity of ambient PM2.5. An alternative proxy-the residential outdoor PM2.5 concentration measured adjacent to participant homes-has few advantages under this assumption. OBJECTIVES: We systematically reviewed the correlation between residential outdoor PM2.5 and personal PM2.5 (-rj) as a means of comparing the magnitude and sources of measurement error associated with their use as exposure surrogates. METHODS: We searched seven electronic reference databases for studies of the within-participant residential outdoor-personal PM2.5 correlation. RESULTS: The search identified 567 candidate studies, nine of which were abstracted in duplicate, that were published between 1996 and 2008. They represented 329 nonsmoking participants 6-93 years of age in eight U.S. cities, among whom -rj was estimated (median, 0.53; range, 0.25-0.79) based on a median of seven residential outdoor-personal PM2.5 pairs per participant. We found modest evidence of publication bias (symmetric funnel plot; pBegg = 0.4; pEgger = 0.2); however, we identified evidence of heterogeneity (Cochran’s Q-test p = 0.05). Of the 20 characteristics examined, earlier study midpoints, eastern longitudes, older mean age, higher outdoor temperatures, and lower personal-residential outdoor PM2.5 differences were associated with increased within-participant residential outdoor-personal PM2.5 correlations. CONCLUSIONS: These findings were similar to those from a contemporaneous meta-analysis that examined ambient-personal PM2.5 correlations (rj = median, 0.54; range, 0.09-0.83). Collectively, the meta-analyses suggest that residential outdoor-personal and ambient-personal PM2.5 correlations merit greater consideration when evaluating the potential for bias in studies of PM2.5-mediated health effects.

Julie Daniels
Keil AP* (*UNC MSPH/PhD student in epidemiology), Daniels JL, Hertz-Picciotto I. Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Environ Health. 2014 Jan 23;13(1):3.
BACKGROUND: The environmental contribution to autism spectrum disorders (ASD) is largely unknown, but household pesticides are receiving increased attention. We examined associations between ASD and maternally-reported use of imidacloprid, a common flea and tick treatment for pets. METHODS: Bayesian logistic models were used to estimate the association between ASD and imidacloprid and to correct for potential differential exposure misclassification due to recall in a case control study of ASD. RESULTS: Our analytic dataset included complete information for 262 typically developing controls and 407 children with ASD. Compared with exposure among controls, the odds of prenatal imidacloprid exposure among children with ASD were slightly higher, with an odds ratio (OR) of 1.3 (95% Credible Interval [CrI] 0.78, 2.2). A susceptibility window analysis yielded higher ORs for exposures during pregnancy than for early life exposures, whereas limiting to frequent users of imidacloprid, the OR increased to 2.0 (95% CI 1.0, 3.9). CONCLUSIONS: Within plausible estimates of sensitivity and specificity, the association could result from exposure misclassification alone. The association between imidacloprid exposure and ASD warrants further investigation, and this work highlights the need for validation studies regarding prenatal exposures in ASD.

Taylor KW* (*UNC PhD student in epidemiology), Hoffman K, Thayer KA, Daniels JL. Polyfluoroalkyl chemicals and menopause among women 20-65 years of age (NHANES). Environ Health Perspect. 2014 Feb;122(2):145-50.
BACKGROUND: Polyfluoroalkyl chemicals (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) have been associated with early menopause. However, previous cross-sectional studies have lacked adequate data to investigate possible reverse causality (i.e., higher serum concentrations due to decreased excretion after menopause). OBJECTIVES: We investigated the association between PFOS, PFOA, perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) and age at natural menopause among women 20-65 years of age in NHANES (National Health and Nutrition Examination Survey).Methods: We used proportional hazard models to estimate hazard ratios (HRs) for the onset of natural menopause as a function of age and serum PFC levels, and to investigate reverse causation by estimating associations between PFC levels and the rate of hysterectomy. We also used multivariable linear regression to determine whether time since menopause predicted serum PFC levels. RESULTS: After adjusting for age at survey, race/ethnicity, education, ever smoking, and parity, women with higher levels of PFCs had earlier menopause than did women with the lowest PFC levels. We observed a monotonic association with PFHxS: The HR was 1.42 (95% CI: 1.08, 1.87) for serum concentrations in tertile 2 versus tertile 1, and 1.70 (95% CI: 1.36, 2.12) for tertile 3 versus tertile 1. We also found evidence of reverse causation: PFCs were positively associated with rate of hysterectomy, and time since natural menopause was positively associated with serum PFCs.
CONCLUSIONS: Our ?ndings suggest a positive association between PFCs and menopause; however, at least part of the association may be due to reverse causation. Regardless of underlying cause, women appear to have higher PFC concentrations after menopause.

Michael Emch
Wu J, Yunus M, Streatfield PK, Emch M. Association of climate variability and childhood diarrhoeal disease in rural Bangladesh, 2000-2006. Epidemiol Infect. 2013 Oct 30:1-10. [Epub ahead of print] SUMMARY This study examined the effects of meteorological factors, particularly, extreme weather events, on the prevalence of childhood diarrhoeal disease in Matlab, Bangladesh. Logistic regression models were used to examine impacts of temperature, rainfall and the extreme weather factors (the number of hot days and days with heavy rainfall) on childhood diarrhoea from 2000 to 2006 at the bari (cluster of dwellings) level. The results showed that the increases in the number of hot days and days with heavy rainfall were associated with an increase in daily diarrhoea cases by 0o8-3o8% and 1-6o2%, respectively. The results from multivariable stepwise models showed that the extreme weather factors were still positively associated with childhood diarrhoea, while the associations for average temperature and rainfall could be negative after other variables were controlled. The findings showed that not only the intensity, but also the frequency of extreme weather events had significant effects on childhood diarrhoea.

Winston JJ, Escamilla V, Perez-Heydrich C, Carrel M, Yunus M, Streatfield PK, Emch M. Protective benefits of deep tube wells against childhood diarrhea in Matlab, Bangladesh. Am J Public Health. 2013 Jul;103(7):1287-91.
OBJECTIVES: We investigated whether deep tube wells installed to provide arsenic-free groundwater in rural Bangladesh have the added benefit of reducing childhood diarrheal disease incidence. METHODS: We recorded cases of diarrhea in children younger than 5 years in 142 villages of Matlab, Bangladesh, during monthly community health surveys in 2005 and 2006. We surveyed the location and depth of 12,018 tube wells and integrated these data with diarrhea data and other data in a geographic information system. We fit a longitudinal logistic regression model to measure the relationship between childhood diarrhea and deep tube well use. We controlled for maternal education, family wealth, year, and distance to a deep tube well. RESULTS: Household clusters assumed to be using deep tube wells were 48.7% (95% confidence interval = 27.8%, 63.5%) less likely to have a case of childhood diarrhea than were other household clusters. CONCLUSIONS: Increased access to deep tube wells may provide dual benefits to vulnerable populations in Matlab, Bangladesh, by reducing the risk of childhood diarrheal disease and decreasing exposure to naturally occurring arsenic in groundwater.

Larry Engel
Engel LS, Satagopan J, Sima CS, Orlow I, Mujumdar U, Coble J, Roy P, Yoo S, Sandler DP, Alavanja MC. Sun exposure, vitamin D receptor genetic variants, and risk of breast cancer in the Agricultural Health Study. Environ Health Perspect. 2014 Feb;122(2):165-71.
BACKGROUND: Epidemiologic evidence suggests a negative relation between sunlight exposure and breast cancer risk. The hypothesized mechanism is sunlight-induced cutaneous synthesis of vitamin D. OBJECTIVES: Our goal was to examine sun exposure and its interaction with vitamin D receptor (VDR) gene variants on breast cancer risk. METHODS: We examined sun exposure and breast cancer incidence among 31,021 private pesticide applicators’ wives, including 578 cases, enrolled in the prospective Agricultural Health Study cohort and followed 8.6 years on average. We estimated interactions between sun exposure, VDR variants, and breast cancer in a nested case-control study comprising 293 cases and 586 matched controls. Information on sun exposure was obtained by questionnaire at cohort enrollment. Relative risks were estimated using Cox proportional hazards regression for the cohort data and conditional logistic regression for the nested case-control data. RESULTS: We observed a small decrease in breast cancer risk in association with usual sun exposure of ? 1 hr/day (versus < 1 hr/day) 10 years before the start of follow-up among all participants [hazard ratio (HR) = 0.8; 95% CI: 0.6, 1.0]. The association appeared to be slightly stronger in relation to estrogen receptor-positive tumors (HR = 0.7; 95% CI: 0.5, 0.9) than estrogen receptor-negative tumors (HR = 1.1; 95% CI: 0.6, 2.1). The HR for joint exposure ? 1 hr/day of sunlight and one VDR haplotype was less than expected given negative HRs for each individual exposure (interaction p-value = 0.07). CONCLUSION: Our results suggest that sun exposure may be associated with reduced risk of breast cancer, but we did not find clear evidence of modification by VDR variants. Larger studies are warranted, particularly among populations in whom low levels of usual sun exposure can be more precisely characterized.

Larry Engel & Stephanie Engel
Engel LS, Buckley JP* (*UNC PhD student in epidemiology), Yang G, Liao LM, Satagopan J, Calafat AM, Matthews CE, Cai Q, Ji BT, Cai H, Engel SM, Wolff MS, Rothman N, Zheng W, Xiang YB, Shu XO, Gao YT, Chow WH. Predictors and Variability of Repeat Measurements of Urinary Phenols and Parabens in a Cohort of Shanghai Women and Men.  Environ Health Perspect. 2014 Mar 21. [Epub ahead of print] BACKGROUND: Exposure to certain phenols is ubiquitous due to their use in many consumer and personal care products. However, predictors of exposure have not been well characterized in most populations. OBJECTIVES: To identify predictors of exposure and assess reproducibility of phenol concentrations across serial spot urine samples among Chinese adults. METHODS: We measured 2,4-dichlorophenol, 2,5-dichlorophenol, butyl paraben, methyl paraben, propyl paraben, benzophenone-3, bisphenol A, and triclosan in urine collected during 1997-2006 among 50 participants of the Shanghai Women’s Health Study cohort and during 2002-2006 among 50 participants of the Shanghai Men’s Health Study cohort. We investigated predictors of concentrations using the Satterthwaite t-test and assessed reproducibility among serial samples using intraclass correlation coefficients (ICC) and Spearman correlation coefficients (SCC). RESULTS: Creatinine-corrected phenol concentrations were generally higher among women than men. Participants who took medicine in the past 24 hours had higher concentrations of propyl paraben. Cigarette smoking was associated with lower concentrations of propyl and methyl parabens among men. Bottled water consumption was associated with higher bisphenol A, 2,4-dichlorophenol, and 2,5-dichlorophenol concentrations among women. Among men, reproducibility across serial samples was moderate for 2,4-dichlorophenol and 2,5-dichlorophenol (ICC=0.54-0.60, SCC=0.43-0.56), but lower for other analytes (ICC=0.20-0.29). Reproducibility among women was low (ICC=0.13-0.39), but increased when restricted to morning-only urine samples. CONCLUSIONS: Among these 100 Shanghai residents, urinary phenol concentrations varied by sex, smoking, and consumption of bottled water. Our results suggest that a single urine sample may be adequate for ranking exposure to the precursors of 2,4-dichlorophenol and 2,5-dichlorophenol among men and, under certain circumstances, among women.

Stephanie Engel & Andrew Olshan
Engel SM, Joubert BR, Wu MC, Olshan AF, Håberg SE, Ueland PM, Nystad W, Nilsen RM, Vollset SE, Peddada SD, London SJ. Neonatal genome-wide methylation patterns in relation to birth weight in the Norwegian Mother and Child Cohort. Am J Epidemiol. 2014 Apr 1;179(7):834-42.
Although epigenetic regulation plays a critical role in embryonic development, few studies have examined the relationship of epigenome-wide methylation with fetal growth. Using the Infinium HumanMethylation450 BeadChip (Illumina, Inc., San Diego, California) in a substudy of 1,046 infants from the Norwegian Mother and Child Cohort Study (MoBa) enrolled between 1999 and 2008, we examined epigenome-wide cord blood DNA methylation in relation to birth weight. In multivariable-adjusted robust linear regression models, we identified differential methylation at 19 cytosine-guanine dinucleotides (CpGs) associated with either decreased (AT-rich interactive domain 5B (MRF1-like) (ARID5B), 2 CpGs) or increased (x-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3), 4 CpGs) birth weight. ARID5B knockout mice have less adipose tissue and significantly lower weight in the postnatal period. XRCC3 plays a key role in the maintenance of chromosome stability and the repair of DNA damage. Although there are fewer data on the other implicated genes, many of these genes have been shown to have roles in developmental processes. This constitutes the largest and most robust study of birth weight using an epigenome-wide methylation platform and offers potential insights into epigenetic mechanisms of fetal growth.

Stephanie Engel & David Richardson
Starling AP* (*UNC PhD student in epidemiology), Engel SM, Richardson DB, Baird DD, Haug LS, Stuebe AM, Klungsøyr K, Harmon Q, Becher G, Thomsen C, Sabaredzovic A, Eggesbø M, Hoppin JA, Travlos GS, Wilson RE, Trogstad LI, Magnus P, Longnecker MP. Perfluoroalkyl substances during pregnancy and validated preeclampsia among nulliparous women in the Norwegian Mother and Child Cohort Study. Am J Epidemiol. 2014 Apr 1;179(7):824-33.
Perfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants, and human exposure to these substances may be related to preeclampsia, a common pregnancy complication. Previous studies have found serum concentrations of PFAS to be positively associated with pregnancy-induced hypertension and preeclampsia in a population with high levels of exposure to perfluorooctanoate. Whether this association exists among pregnant women with background levels of PFAS exposure is unknown. Using data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health, we carried out a study of nulliparous pregnant women enrolled in 2003-2007 (466 cases, 510 noncases) to estimate associations between PFAS concentrations and an independently validated diagnosis of preeclampsia. We measured levels of 9 PFAS in maternal plasma extracted midpregnancy; statistical analyses were restricted to 7 PFAS that were quantifiable in more than 50% of samples. In proportional hazards models adjusted for maternal age, prepregnancy body mass index (weight (kg)/height (m)(2)), educational level, and smoking status, we observed no strongly positive associations between PFAS levels and preeclampsia. We found an inverse association between preeclampsia and the highest quartile of perfluoroundecanoic acid concentration relative to the lowest quartile (hazard ratio = 0.55, 95% confidence interval: 0.38, 0.81). Overall, our findings do not support an increased risk of preeclampsia among nulliparous Norwegian women with background levels of PFAS exposure.

Marilie Gammon
White AJ* (*UNC MSPH/PhD student in epidemiology), Teitelbaum SL, Wolff MS, Stellman SD, Neugut AI, Gammon MD. Exposure to fogger trucks and breast cancer incidence in the Long Island Breast Cancer Study Project: a case-control study. Environ Health. 2013 Mar 15;12-24.
BACKGROUND: Few studies have supported an association between breast cancer and DDT, usually assessed with biomarkers that cannot discern timing of exposure, or differentiate between the accumulation of chronic low-dose versus acute high-dose exposures in the past. Previous studies suggest that an association may be evident only among women exposed to DDT during biologically susceptible windows, or among those diagnosed with estrogen receptor/progesterone receptor-positive (ER+PR+) breast cancer subtypes. Self-reported acute exposure to a fogger truck, which sprayed DDT prior to 1972, was hypothesized to increase the risk of breast cancer, particularly among women exposed at a young age or diagnosed with ER+PR+ breast cancer. METHODS: We examined these possibilities in the Long Island Breast Cancer Study Project (LIBCSP) (1,508 cases, 1,556 controls), which included exposure assessment by structured questionnaire and serum samples collected between 1996-1998, using adjusted logistic and polytomous regression to estimate ORs and 95% CIs. RESULTS: Women with ER+PR+ breast cancer had a 44% increased odds of ever seeing a pre-1972 fogger truck compared to other subtypes (OR?=?1.44; 95% CI 1.08-1.93). However, there was little variation in the observed increase in breast cancer risk when considering all women who reported seeing a pre-1972 fogger truck at their residence (OR?=?1.16; 95% CI 0.98, 1.37), or during hypothesized susceptible windows. Self-reported acute exposure was not correlated with serum concentrations, a biomarker of long-term exposure. CONCLUSIONS: These findings support the hypothesis that seeing a fogger truck, a proxy measure for acute DDT exposure, may be associated with ER+PR+ tumors, the most commonly diagnosed breast cancer subtype among American women.

Marilie Gammon & David Richardson
Smith GS* (*UNC MSPH/PhD student in epidemiology), Schoenbach VJ, Richardson DB, Gammon MD. Particulate air pollution and susceptibility to the development of pulmonary tuberculosis disease in North Carolina: an ecological study. Int J Environ Health Res. 2014 Apr;24(2):103-12.
Although Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis (PTB), environmental factors may influence disease progression. Ecologic studies conducted in countries outside the USA with high levels of air pollution and PTB have suggested a link between active disease and ambient air pollution. The present investigation is the first to examine the ambient air pollution-PTB association in a country, where air pollution levels are comparatively lower. We used Poisson regression models to examine the association of outdoor air pollutants, PM10 and PM2.5 with rates of PTB in North Carolina residents during 1993-2007. Results suggest a potential association between long-term exposure to particulate matter (PM) and PTB disease. In view of the high levels of air pollution and high rates of PTB worldwide, a potential association between ambient air pollution and tuberculosis warrants further study.

Steve Marshall & Charlie Poole
Vladutiu CJ* (*UNC doctoral student in epidemiology), Marshall SW, Poole C, Casteel C, Menard MK, Weiss HB. Adverse pregnancy outcomes following motor vehicle crashes. Am J Prev Med. 2013 Nov;45(5):629-36.
BACKGROUND: Motor vehicle crashes are a leading cause of serious trauma during pregnancy, but little is known about their relationships with pregnancy outcomes. PURPOSE: To estimate the association between motor vehicle crashes and adverse pregnancy outcomes. METHODS: A retrospective cohort study of 878,546 pregnant women, aged 16-46 years, who delivered a singleton infant in North Carolina from 2001 to 2008. Pregnant drivers in crashes were identified by probabilistic linkage of vital records and crash reports. Poisson regression modeled the association among crashes, vehicle safety features, and adverse pregnancy outcomes. Analyses were conducted in 2012. RESULTS: In 2001-2008, 2.9% of pregnant North Carolina women were drivers in one or more crashes. After a single crash, compared to not being in a crash, pregnant drivers had slightly elevated rates of preterm birth (adjusted rate ratio [aRR]=1.23, 95% CI=1.19, 1.28); placental abruption (aRR=1.34, 95% CI=1.15, 1.56); and premature rupture of the membranes (PROM; aRR=1.32, 95% CI=1.21, 1.43). Following a second or subsequent crash, pregnant drivers had more highly elevated rates of preterm birth (aRR=1.54, 95% CI=1.24, 1.90); stillbirth (aRR=4.82, 95% CI=2.85, 8.14); placental abruption (aRR=2.97, 95% CI=1.60, 5.53); and PROM (aRR=1.95, 95% CI=1.27, 2.99). Stillbirth rates were elevated following crashes involving unbelted pregnant drivers (aRR=2.77, 95% CI=1.22, 6.28) compared to belted pregnant drivers. CONCLUSIONS: Crashes while driving during pregnancy were associated with elevated rates of adverse pregnancy outcomes, and multiple crashes were associated with even higher rates of adverse pregnancy outcomes. Crashes were especially harmful if drivers were unbelted.

Steve Marshall & Steve Wing
Heaney CD, Sams E, Dufour AP, Brenner KP, Haugland RA, Chern E, Wing S, Marshall S, Love DC, Serre M, Noble R, Wade TJ. Fecal indicators in sand, sand contact, and risk of enteric illness among beachgoers. Epidemiology. 2012 Jan;23(1):95-106.
BACKGROUND: Beach sand can harbor fecal indicator organisms and pathogens, but enteric illness risk associated with sand contact remains unclear. METHODS: In 2007, visitors at 2 recreational marine beaches were asked on the day of their visit about sand contact. Ten to 12 days later, participants answered questions about health symptoms since the visit. F+ coliphage, Enterococcus, Bacteroidales, fecal Bacteroides, and Clostridium spp. in wet sand were measured using culture and molecular methods. RESULTS: We analyzed 144 wet sand samples and completed 4999 interviews. Adjusted odds ratios (aORs) were computed, comparing those in the highest tertile of fecal indicator exposure with those who reported no sand contact. Among those digging in sand compared with those not digging in sand, a molecular measure of Enterococcus spp. (calibrator cell equivalents/g) in sand was positively associated with gastrointestinal (GI) illness (aOR = 2.0 [95% confidence interval (CI) = 1.2-3.2]) and diarrhea (2.4 [1.4-4.2]). Among those buried in sand, point estimates were greater for GI illness (3.3 [1.3-7.9]) and diarrhea (4.9 [1.8-13]). Positive associations were also observed for culture-based Enterococcus (colony-forming units/g) with GI illness (aOR digging = 1.7 [1.1-2.7]) and diarrhea (2.1 [1.3-3.4]). Associations were not found among nonswimmers with sand exposure.
CONCLUSIONS: We observed a positive relationship between sand-contact activities and enteric illness as a function of concentrations of fecal microbial pollution in beach sand.

Andrew Olshan
Wyss A* (*UNC PhD student in epidemiology), Hashibe M, Chuang SC, Lee YC, Zhang ZF, Yu GP, Winn DM, Wei Q, Talamini R, Szeszenia-Dabrowska N, Sturgis EM, Smith E, Shangina O, Schwartz SM, Schantz S, Rudnai P, Purdue MP, Eluf-Neto J, Muscat J, Morgenstern H, Michaluart P Jr, Menezes A, Matos E, Mates IN, Lissowska J, Levi F, Lazarus P, La Vecchia C, Koifman S, Herrero R, Hayes RB, Franceschi S, Wünsch-Filho V, Fernandez L, Fabianova E, Daudt AW, Dal Maso L, Curado MP, Chen C, Castellsague X, de Carvalho MB, Cadoni G, Boccia S, Brennan P, Boffetta P, Olshan AF. Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Am J Epidemiol. 2013 Sep 1;178(5):679-90. Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ? 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.

Andrew Olshan, Julie Daniels & David Richardson
Stingone JA* (*UNC PhD student in epidemiology), Luben TJ, Daniels JL, Fuentes M, Richardson DB, Aylsworth AS, Herring AH, Anderka M, Botto L, Correa A, Gilboa SM, Langlois PH, Mosley B, Shaw GM, Siffel C, Olshan AF; National Birth Defects Prevention Study. Maternal Exposure to Criteria Air Pollutants and Congenital Heart Defects in Offspring: Results from the National Birth Defects Prevention Study. Environ Health Perspect. 2014 Apr 11. [Epub ahead of print] BACKGROUND: Epidemiologic literature suggests exposure to air pollutants is associated with fetal development. OBJECTIVES: To investigate maternal exposures to air pollutants during weeks two through eight of pregnancy and congenital heart defects. METHODS: Mothers from the National Birth Defects Prevention Study, a nine-state case-control study, were assigned one-week and seven-week averages of daily maximum concentrations of carbon monoxide, nitrogen dioxide, ozone, and sulfur dioxide and 24-hour measurements of fine and coarse particulate matter using the closest air monitor within 50 km to their residence during early pregnancy. Depending upon the pollutant, a maximum of 4632 live-birth controls and 3328 live-birth, fetal-death or electively terminated cases had exposure data. Hierarchical regression models, adjusted for maternal demographics, tobacco and alcohol use, were constructed. Principal component analysis was used to assess these relationships in a multipollutant context. RESULTS: Positive associations were observed between exposure to nitrogen dioxide and coarctation of the aorta and pulmonary valve stenosis. Exposure to fine particulate matter was positively associated with hypoplastic left heart syndrome but inversely associated with atrial septal defects. Examining individual exposure-weeks suggested associations between pollutants and defects that were not observed using the seven-week average. Associations between left ventricular outflow tract obstructions and nitrogen dioxide and hypoplastic left heart syndrome and particulate matter were supported by findings from the multipollutant analyses, although estimates were attenuated at the highest exposure levels. CONCLUSIONS: Utilizing daily maximum pollutant levels and exploring individual exposure-weeks revealed some positive associations between certain pollutants and defects and suggested potential windows of susceptibility during pregnancy.

Charles Poole & Julie Daniels
Rappazzo KM* (*UNC PhD student in epidemiology), Daniels JL, Messer LC, Poole C, Lobdell DT3. Exposure to Fine Particulate Matter during Pregnancy and Risk of Preterm Birth among Women in New Jersey, Ohio, and Pennsylvania, 2000-2005. Environ Health Perspect. 2014 May 30. [Epub ahead of print] BACKGROUND: Particulate matter < 2.5 micrometers in aerodynamic diameter (PM2.5) has been variably associated with preterm birth (PTB). OBJECTIVE: We classified preterm births into four categories (20-27, 28-31, 32-34, and 35-36 weeks completed gestation) and estimated risk differences (RD) for each category in association with a 1-µg/m3 increase in PM2.5 exposure during each week of gestation. METHODS:
We assembled a cohort of singleton pregnancies that completed at least 20 weeks of gestation during 2000-2005 using live birth certificate data from three states (Pennsylvania, Ohio, and New Jersey) (n = 1,940,213; 8% PTB). We estimated mean PM2.5 exposures for each week of gestation from monitor-corrected Community Multi-Scale Air Quality modeling data. RDs were estimated using modified Poisson linear regression, adjusted for maternal race/ethnicity, marital status, education, age, and ozone. RESULTS:
RD estimates varied by exposure window and outcome period. Average PM2.5 exposure during the fourth week of gestation was positively associated with all PTB outcomes, though magnitude varied by PTB category (e.g., for a 1-µg/m3 increase, RD = 11.8 (95% CI: -6, 29.2); RD = 46 (95% CI: 23.2, 68.9); RD = 61.1 (95% CI: 22.6, 99.7); and RD = 28.5 (95% CI: -39, 95.7) for preterm births during 20-27, 28-31, 32-34, and 35-36 weeks, respectively). Exposures during the week of birth and the two weeks before birth also were positively associated with all PTB categories. Exposures beginning around the time of implantation and near birth appeared to be more strongly associated with PTB than exposures during other time periods. Because particulate matter exposure is ubiquitous, evidence of effects of PM2.5 exposure on PTB, even if small in magnitudes, is cause for concern.

Kalkbrenner AE* (*UNC PhD student in epidemiology), Daniels JL, Chen JC, Poole C, Emch M, Morrissey J. Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8. Epidemiology. 2010 Sep;21(5):631-41.
BACKGROUND: Hazardous air pollutants are plausible candidate exposures for autism spectrum disorders. They have been explored in recent studies for their role in the development of these disorders. METHODS:
We used a prevalent case-control design to screen perinatal exposure to 35 hazardous air pollutants for further investigation in autism etiology. We included 383 children with autism spectrum disorders and, as controls, 2,829 children with speech and language impairment. All participants were identified from the records-based surveillance of 8-year-old children conducted by the Autism and Developmental Disabilities Monitoring Network in North Carolina (for children born in 1994 and 1996) and West Virginia (born in 1992 and 1994). Exposures to ambient concentrations of metal, particulate, and volatile organic air pollutants in the census tract of the child’s birth residence were assigned from the 1996 National Air Toxics Assessment annual-average model. We estimated odds ratios (ORs) for autism spectrum disorders and corresponding 95% confidence intervals (CIs), comparing across the 20th and 80th percentiles of log-transformed hazardous air pollutant concentration among the selected controls, using semi-Bayes logistic models and adjusting for sampling variables (surveillance year and state), a priori demographic confounders from the birth certificate and census, and covarying air pollutants. RESULTS: We estimated many near-null ORs, including those for metals, established human neurodevelopmental toxicants, and several pollutants that were elevated in a similar study in California. Hazardous air pollutants with more precise and elevated OR estimates included methylene chloride, 1.4 (95% CI = 0.7-2.5), quinoline, 1.4 (1.0-2.2), and styrene, 1.8 (1.0-3.1). CONCLUSIONS: Our screening design was limited by exposure misclassification of air pollutants and the use of an alternate developmental disorder as the control group, both of which may have biased results toward the null. Despite these limitations, methylene chloride, quinoline, and styrene emerged (based on this analysis and prior epidemiologic evidence) as candidates that warrant further investigation for a possible role in autism etiology.

David Richardson
Naimi AI* (*UNC PhD student in epidemiology), Cole SR, Hudgens MG, Richardson DB. Estimating the effect of cumulative occupational asbestos exposure on time to lung cancer mortality: using structural nested failure-time models to account for healthy-worker survivor bias. Epidemiology. 2014 Mar;25(2):246-54.
BACKGROUND: Previous estimates of the effect of occupational asbestos on lung cancer mortality have been obtained by using methods that are subject to the healthy-worker survivor bias. G-estimation of a structural nested model provides consistent exposure effect estimates under this bias. METHODS: We estimated the effect of cumulative asbestos exposure on lung cancer mortality in a cohort comprising 2564 textile factory workers who were followed from January 1940 to December 2001. RESULTS: At entry, median age was 23 years, with 42% of the cohort being women and 20% nonwhite. During the follow-up period, 15% of person-years were classified as occurring while employed and 13% as occupationally exposed to asbestos. For a 100 fiber-year/ml increase in cumulative asbestos, a Weibull model adjusting for sex, race, birth year, baseline exposure, and age at study entry yielded a survival time ratio of 0.88 (95% confidence interval = 0.83 to 0.93). Further adjustment for work status yielded no practical change. The corresponding survival time ratio obtained using g-estimation of a structural nested model was 0.57 (0.33 to 0.96). CONCLUSIONS: Accounting for the healthy-worker survivor bias resulted in a 35% stronger effect estimate. However, this estimate was considerably less precise. When healthy-worker survivor bias is suspected, methods that account for it should be used.

David Richardson & Andrew Olshan
Edwards JK* (*UNC PhD student in epidemiology), Cole SR, Chu H, Olshan AF, Richardson DB. Accounting for outcome misclassification in estimates of the effect of occupational asbestos exposure on lung cancer death. Am J Epidemiol. 2014 Mar 1;179(5):641-7.
In studies of the health effects of asbestos, lung cancer death is subject to misclassification. We used modified maximum likelihood to explore the effects of outcome misclassification on the rate ratio of lung cancer death per 100 fiber-years per milliliter of cumulative asbestos exposure in a cohort study of textile workers in Charleston, South Carolina, followed from 1940 to 2001. The standard covariate-adjusted estimate of the rate ratio was 1.94 (95% confidence interval: 1.55, 2.44), and modified maximum likelihood produced similar results when we assumed that the specificity of outcome classification was 0.98. With sensitivity assumed to be 0.80 and specificity assumed to be 0.95, estimated rate ratios were further from the null and less precise (rate ratio = 2.17; 95% confidence interval: 1.59, 2.98). In the present context, standard estimates for the effect of asbestos on lung cancer death were similar to estimates accounting for the limited misclassification. However, sensitivity analysis using modified maximum likelihood was needed to verify the robustness of standard estimates, and this approach will provide unbiased estimates in settings with more misclassification.

Melissa Troester
Sun X* (*UNC PhD student in epidemiology), Casbas-Hernandez P*(*UNC MPH student in epidemiology), Bigelow C, Makowski L, Joseph Jerry D, Smith Schneider S, Troester MA. Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat. 2012 Feb;131(3):1003-12.
Activation of inflammatory pathways is one plausible mechanism underlying the association between obesity and increased breast cancer risk. However, macrophage infiltration and local biomarkers of inflammation in breast adipose tissue have seldom been studied in association with obesity. Gene expression profiles of normal breast tissue from reduction mammoplasty patients were evaluated by whole genome microarrays to identify patterns associated with obesity status (normal-weight, body mass index (BMI) <25; overweight, BMI 25-29.9; obese, BMI ?30). The presence of macrophage-enriched inflammatory loci with immunopositivity for CD68 protein was evaluated by immunohistochemistry (IHC). After adjusting for confounding by age, 760 genes were differentially expressed (203 up and 557 down; FDR = 0.026) between normal-weight and obese women. Gene ontology analysis suggested significant enrichment for pathways involving IL-6, IL-8, CCR5 signaling in macrophages and RXR? and PPAR? activation, consistent with a pro-inflammatory state and suggestive of macrophage infiltration. Gene set enrichment analysis also demonstrated that the genomic signatures of monocytes and macrophages were over-represented in the obese group with FDR of 0.08 and 0.13, respectively. Increased macrophage infiltration was confirmed by IHC, which showed that the breast adipose tissue of obese women had higher average macrophage counts (mean = 8.96 vs. 3.56 in normal-weight women) and inflammatory foci counts (mean = 4.91 vs. 2.67 in normal-weight women). Obesity is associated with local inflammation and macrophage infiltration in normal human breast adipose tissues. Given the role of macrophages in carcinogenesis, these findings have important implications for breast cancer etiology and progression.

Melissa Troester & Andrew Olshan
Razzaghi H* (*UNC PhD student in epidemiology), Troester MA, Gierach GL, Olshan AF, Yankaskas BC, Millikan RC. Association between mammographic density and basal-like and luminal A breast cancer subtypes. Breast Cancer Res. 2013;15(5):R76.
INTRODUCTION: Mammographic density is a strong risk factor for breast cancer overall, but few studies have examined the association between mammographic density and specific subtypes of breast cancer, especially aggressive basal-like breast cancers. Because basal-like breast cancers are less frequently screen-detected, it is important to understand how mammographic density relates to risk of basal-like breast cancer. METHODS: We estimated associations between mammographic density and breast cancer risk according to breast cancer subtype. Cases and controls were participants in the Carolina Breast Cancer Study (CBCS) who also had mammograms recorded in the Carolina Mammography Registry (CMR). A total of 491 cases had mammograms within five years prior to and one year after diagnosis and 528 controls had screening or diagnostic mammograms close to the dates of selection into CBCS. Mammographic density was reported to the CMR using Breast Imaging Reporting and Data System categories. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 1 and 2 (HER1 and HER2), and cytokeratin 5/6 (CK5/6) were assessed by immunohistochemistry and dichotomized as positive or negative, with ER+ and/or PR+, and HER2- tumors classified as luminal A and ER-, PR-, HER2-, HER1+ and/or CK5/6+ tumors classified as basal-like breast cancer. Triple negative tumors were defined as negative for ER, PR and HER2. Of the 491 cases 175 were missing information on subtypes; the remaining cases included 181 luminal A, 17 luminal B, 48 basal-like, 29 ER-/PR-/HER2+, and 41 unclassified subtypes. Odds ratios comparing each subtype to all controls and case-case odds ratios comparing mammographic density distributions in basal-like to luminal A breast cancers were estimated using logistic regression. RESULTS: Mammographic density was associated with increased risk of both luminal A and basal-like breast cancers, although estimates were imprecise. The magnitude of the odds ratio associated with mammographic density was not substantially different between basal-like and luminal A cancers in case-control analyses and case-case analyses (case-case OR = 1.08 (95% confidence interval: 0.30, 3.84)). CONCLUSIONS: These results suggest that risk estimates associated with mammographic density are not distinct for separate breast cancer subtypes (basal-like/triple negative vs. luminal A breast cancers). Studies with a larger number of basal-like breast cancers are needed to confirm our findings.

Eric Whitsel & Christy Avery
Napier MD* (*UNC PhD student in epidemiology), on behalf of the MOPMAP Investigators. A trans-ethnic, genome-wide association study of ventricular and supraventricular ectopy. Am J Epidemiol 2014; In press.
Rationale: Although ventricular and supraventricular ectopy (VE; SVE) are common forms of arrhythmia, their infrequent and intermittent manifestation in the general population limits ability to characterize their genetic underpinnings. Objective: To identify genetic variants associated with ectopy in the Atherosclerosis Risk in Communities (ARIC) study and Women’s Health Initiative (WHI) clinical trials. Methods: We conducted cohort-, race/ethnicity-, and sex-stratified longitudinal analyses of electrocardiographically identified SVE and VE across 9 ARIC and WHI subpopulations (n=26,549). In each, we used generalized estimating equations to estimate associations with ~2.5 million genotyped and imputed single nucleotide polymorphisms (SNPs) while adjusting for ancestral admixture and multiple comparisons. We then used inverse variance-weighted, fixed-effects meta-analysis (METAL) and a Bayesian alternative allowing for ancestral heterogeneity (MANTRA) to combine stratum-specific estimates of SNP dosage-ectopy associations. Results: For both VE and SVE, we identified 2 novel loci with a log10Bayes’ Factor (BF) ? 6 and posterior probability of heterogeneity < 0.5. One SVE locus was replicated in independent samples (rs4885575; log10BF=6.2; p=2.79 x 10-8; OR 1.14, 95% CI 1.04, 1.26). Conclusions: The results provide evidence of a genetic basis for ectopy in black, white and Hispanic populations while illustrating the value of ancestral diversity, longitudinal data, and alternative meta-analytic methods for discovering trans-ethnically important risk variants in studies of uncommon traits.

Eric Whitsel, Christy Avery & Charles Poole
Holliday KM* (*UNC PhD student in epidemiology), Avery CL, Poole C, McGraw K, Williams R, Liao D, Smith RL, Whitsel EA. Estimating personal exposures from ambient air pollution measures: using meta-analysis to assess measurement error . Epidemiology 2014;25(1):35-43.
BACKGROUND: Although ambient concentrations of particulate matter ?10 ?m (PM10) are often used as proxies for total personal exposure, correlation (r) between ambient and personal PM10 concentrations varies. Factors underlying this variation and its effect on health outcome-PM exposure relationships remain poorly understood. METHODS: We conducted a random-effects meta-analysis to estimate effects of study, participant, and environmental factors on r; used the estimates to impute personal exposure from ambient PM10 concentrations among 4,012 nonsmoking, participants with diabetes in the Women’s Health Initiative clinical trial; and then estimated the associations of ambient and imputed personal PM10 concentrations with electrocardiographic measures, such as heart rate variability. RESULTS: We identified 15 studies (in years 1990-2009) of 342 participants in five countries. The median r was 0.46 (range = 0.13 to 0.72). There was little evidence of funnel plot asymmetry but substantial heterogeneity of r, which increased 0.05 (95% confidence interval = 0.01 to 0.09) per 10 µg/m increase in mean ambient PM10 concentration. Substituting imputed personal exposure for ambient PM10 concentrations shifted mean percent changes in electrocardiographic measures per 10 µg/m increase in exposure away from the null and decreased their precision, for example, -2.0% (-4.6% to 0.7%) versus -7.9% (-15.9% to 0.9%), for the standard deviation of normal-to-normal RR interval duration. CONCLUSIONS: Analogous distributions and heterogeneity of r in extant meta-analyses of ambient and personal PM2.5 concentrations suggest that observed shifts in mean percent change and decreases in precision may be generalizable across particle size.

Steve Wing
Rinsky JL* (*UNC PhD student in epidemiology), Nadimpalli M, Wing S, Hall D, Baron D, Price LB, Larsen J, Stegger M, Stewart J, Heaney CD. Livestock-associated methicillin and multidrug resistant Staphylococcus aureus is present among industrial, not antibiotic-free livestock operation workers in North Carolina. PLoS One. 2013 Jul 2;8(7):e67641.
OBJECTIVES: Administration of antibiotics to food animals may select for drug-resistant pathogens of clinical significance, such as methicillin-resistant Staphylococcus aureus (MRSA). In the United States, studies have examined prevalence of MRSA carriage among individuals exposed to livestock, but prevalence of multidrug-resistant S. aureus (MDRSA) carriage and the association with livestock raised with versus without antibiotic selective pressure remains unclear. We aimed to examine prevalence, antibiotic susceptibility, and molecular characteristics of S. aureus among industrial livestock operation (ILO) and antibiotic-free livestock operation (AFLO) workers and household members in North Carolina. METHODS: Participants in this cross-sectional study were interviewed and provided a nasal swab for S. aureus analysis. Resulting S. aureus isolates were assessed for antibiotic susceptibility, multi-locus sequence type, and absence of the scn gene (a marker of livestock association). RESULTS: Among 99 ILO and 105 AFLO participants, S. aureus nasal carriage prevalence was 41% and 40%, respectively. Among ILO and AFLO S. aureus carriers, MRSA was detected in 7% (3/41) and 7% (3/42), respectively. Thirty seven percent of 41 ILO versus 19% of 42 AFLO S. aureus-positive participants carried MDRSA. S. aureus clonal complex (CC) 398 was observed only among workers and predominated among ILO (13/34) compared with AFLO (1/35) S. aureus-positive workers. Only ILO workers carried scn-negative MRSA CC398 (2/34) and scn-negative MDRSA CC398 (6/34), and all of these isolates were tetracycline resistant. CONCLUSIONS: Despite similar S. aureus and MRSA prevalence among ILO and AFLO-exposed individuals, livestock-associated MRSA and MDRSA (tetracycline-resistant, CC398, scn-negative) were only present among ILO-exposed individuals. These findings support growing concern about antibiotics use and confinement in livestock production, raising questions about the potential for occupational exposure to an opportunistic and drug-resistant pathogen, which in other settings including hospitals and the community is of broad public health importance.

Steve Wing & David Richardson
Hamra G* (*UNC PhD student in epidemiology), Richardson D, Maclehose R, Wing S. Integrating informative priors from experimental research with Bayesian methods: an example from radiation epidemiology. Epidemiology. 2013 Jan;24(1):90-5.
Informative priors can be a useful tool for epidemiologists to handle problems of sparse data in regression modeling. It is sometimes the case that an investigator is studying a population exposed to two agents, X and Y, where Y is the agent of primary interest. Previous research may suggest that the exposures have different effects on the health outcome of interest, one being more harmful than the other. Such information may be derived from epidemiologic analyses; however, in the case where such evidence is unavailable, knowledge can be drawn from toxicologic studies or other experimental research. Unfortunately, using toxicologic findings to develop informative priors in epidemiologic analyses requires strong assumptions, with no established method for its utilization. We present a method to help bridge the gap between animal and cellular studies and epidemiologic research by specification of an order-constrained prior. We illustrate this approach using an example from radiation epidemiology.

Karin Yeatts
Weir CH, Yeatts KB, Sarnat JA, Vizuete W, Salo PM, Jaramillo R, Cohn RD, Chu H, Zeldin DC, London SJ. Nitrogen dioxide and allergic sensitization in the 2005-2006 National Health and Nutrition Examination Survey. Respir Med. 2013 Nov;107(11):1763-72.
BACKGROUND: Allergic sensitization is a risk factor for asthma and allergic diseases. The relationship between ambient air pollution and allergic sensitization is unclear. OBJECTIVE: To investigate the relationship between ambient air pollution and allergic sensitization in a nationally representative sample of the US population. METHODS: We linked annual average concentrations of nitrogen dioxide (NO2), particulate matter ?10 ?m (PM10), particulate matter ?2.5 ?m (PM2.5), and summer concentrations of ozone (O3), to allergen-specific immunoglobulin E (IgE) data for participants in the 2005-2006 National Health and Nutrition Examination Survey (NHANES). In addition to the monitor-based air pollution estimates, we used the Community Multiscale Air Quality (CMAQ) model to increase the representation of rural participants in our sample. Logistic regression with population-based sampling weights was used to calculate adjusted prevalence odds ratios per 10 ppb increase in O3 and NO2, per 10 ?g/m(3) increase in PM10, and per 5 ?g/m(3) increase in PM2.5 adjusting for race, gender, age, socioeconomic status, smoking, and urban/rural status. RESULTS: Using CMAQ data, increased levels of NO2 were associated with positive IgE to any (OR 1.15, 95% CI 1.04, 1.27), inhalant (OR 1.17, 95% CI 1.02, 1.33), and indoor (OR 1.16, 95% CI 1.03, 1.31) allergens. Higher PM2.5 levels were associated with positivity to indoor allergen-specific IgE (OR 1.24, 95% CI 1.13, 1.36). Effect estimates were similar using monitored data. CONCLUSIONS: Increased ambient NO2 was consistently associated with increased prevalence of allergic sensitization.

Cohen R, Sexton KG, Yeatts KB. Hazard assessment of United Arab Emirates (UAE) incense smoke . Sci Total Environ. 2013 Aug 1;458-460:176-86.
Incense burning inside the home, a common practice in Arabian Gulf countries, has been recognized as a potentially modifiable source of indoor air pollution. To better understand potential adverse effects of incense burning in exposed individuals, we conducted a hazard assessment of incense smoke exposure. The goals of this study were first to characterize the particles and gases emitted from Arabian incense over time when burned, and secondly to examine in vitro human lung cells responses to incense smoke. Two types of incense (from the United Arab Emirates) were burned in a specially designed indoor environmental chamber (22 m(3)) to simulate the smoke concentration in a typical living room and the chamber air was analyzed. Both particulate (PM) concentrations and sizes were measured, as were gases carbon monoxide (CO), sulfur dioxide (SO2), oxides of nitrogen (NOx), formaldehyde (HCHO), and carbonyls. During the burn, peak concentrations were recorded for PM (1.42 mg/m(3)), CO (122 pm), NOx (0.3 ppm), and HCHO (85 ppb) along with pentanal (71.9 ?g/m(3)), glyoxal (84.8 ?g/m(3)), and several other carbonyls. Particle sizes ranged from 20 to 300 nm with count median diameters ranging from 65 to 92 nm depending on time post burn-out. PM, CO, and NOx time-weighted averages exceeded current government regulation values and emissions seen previously from environmental tobacco smoke. Charcoal emissions were the main contributor to both the high CO and NOx concentrations. A significant cell inflammatory response was observed in response to smoke components formed from incense burning. Our hazard evaluation suggests that incense burning contributes to indoor air pollution and could be harmful to human health.

Karin Yeatts & Steve Wing
Heaney CD, Wing S, Wilson SM, Campbell RL, Caldwell D, Hopkins B, O’Shea S, Yeatts K. Public infrastructure disparities and the microbiological and chemical safety of drinking and surface water supplies in a community bordering a landfill. J Environ Health. 2013 Jun;75(10):24-36.
The historically African-American Rogers-Eubanks community straddles unincorporated boundaries of two municipalities in Orange County, North Carolina, and predates a regional landfill sited along its border in 1972. Community members from the Rogers-Eubanks Neighborhood Association (RENA), concerned about deterioration of private wells and septic systems and a lack of public drinking water and sewer services, implemented a community-driven research partnership with university scientists and community-based organizations to investigate water and sewer infrastructure disparities and the safety of drinking and surface water supplies. RENA drafted memoranda of agreement with partners and trained community monitors to collect data (inventory households, map water and sewer infrastructure, administer household water and sewer infrastructure surveys, and collect drinking and surface water samples). Respondents to the surveys reported pervasive signs of well vulnerability (100%) and septic system failure (68%). Each 100-m increase in distance from the landfill was associated with a 600 most probable number/100 mL decrease in enterococci concentrations in surface water (95% confidence interval = -1106, -93). Pervasive private household water and sewer infrastructure failures and poor water quality were identified in this community bordering a regional landfill, providing evidence of a need for improved water and sanitation services.

Training Grants

Dr. Marilie Gammon directs the Environmental Epidemiology Training Program for the Department of Epidemiology, which is funded by the National Institute of Environmental Health Sciences as a multi-disciplinary training grant to Dr. Amy Herring in the Department of Biostatistics. The Training Program in Environmental Epidemiology offers 6 predoctoral and 3 postdoctoral positions that provide funds to be applied trainee stipends, tuition remission, health insurance, and some travel costs. Application for Training Grant positions is competitive.

Dr. David Richardson directs the Occupational Epidemiology Program for the Department of Epidemiology, which is funded Epidemiology graduate students can also compete for a predoctoral position on the occupational epidemiology training grant, funded by OSHA. Two training grant positions in occupational epidemiology are available. The program is directed by Dr. David Richardson in epidemiology.

Graduate Student Research Assistantships

Research assistantships (RAs) offer students an opportunity to gain research-related experience, develop close working relationships with faculty, and sometimes earn co-authorship on peer-reviewed publications. Information on the type of assistantships available and how to locate them is available from Student Services. A small number of RA positions are typically available in the Environmental/Occupational program. Students interested in an assistantship should submit an application form (available from Student Services), and should discuss this interest with their advisors.

External Funding

Students in the Environmental/Occupational Epidemiology training program are sometimes able to secure funding through sources that external to the university. Below is a list of a number of the external sources from which students have received financial support.

National Institute for Environmental Health Sciences Predoctoral Fellowships
Minority Predoctoral Fellowships
National Cancer Institute Summer Intern Program (DCEG)

 

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