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1.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
PMCID: PMC4287989  PMID: 25569183
2.  Calibrating a population-based job-exposure matrix using inspection measurements to estimate historical occupational exposure to lead for a population-based cohort in Shanghai, China 
The epidemiologic evidence for the carcinogenicity of lead is inconsistent and requires improved exposure assessment to estimate risk. We evaluated historical occupational lead exposure for a population-based cohort of women (n=74,942) by calibrating a job-exposure matrix (JEM) with lead fume (n=20,084) and lead dust (n=5,383) measurements collected over four decades in Shanghai, China. Using mixed-effect models, we calibrated intensity JEM ratings to the measurements using fixed-effects terms for year and JEM rating. We developed job/industry-specific estimates from the random-effects terms for job and industry. The model estimates were applied to subjects’ jobs when the JEM probability rating was high for either job or industry; remaining jobs were considered unexposed. The models predicted that exposure increased monotonically with JEM intensity rating and decreased 20–50-fold over time. The cumulative calibrated JEM estimates and job/industry-specific estimates were highly correlated (Pearson correlation=0.79–0.84). Overall, 5% of the person-years and 8% of the women were exposed to lead fume; 2% of the person-years and 4% of the women were exposed to lead dust. The most common lead-exposed jobs were manufacturing electronic equipment. These historical lead estimates should enhance our ability to detect associations between lead exposure and cancer risk in future epidemiologic analyses.
PMCID: PMC3508334  PMID: 22910004
lead; cancer; exposure assessment; occupational exposure; job exposure matrix; mixed-effects model
5.  The population-based Occupational and Environmental Health Prospective Cohort Study (AMIGO) in the Netherlands 
BMJ Open  2014;4(11):e005858.
Occupational and environmental exposures remain important modifiable risk factors of public health. Existing cohort studies are often limited by the level of detail of data collected on these factors and health. It is also often assumed that the more healthy group is over-represented in cohort studies, which is of concern for their external validity. In this cohort profile, we describe how we set up the population-based Occupational and Environmental Health Cohort Study (AMIGO) to longitudinally study occupational and environmental determinants of diseases and well-being from a multidisciplinary and life course point of view. Reviewed by the Medical Ethics Research Committee of the University Medical Center Utrecht (protocol 10-268/C). All cohort members participate voluntarily and gave informed consent prior to their inclusion.
14 829 adult cohort members (16% of those invited) consented and filled in the online baseline questionnaire. Determinants include chemical, biological, physical (eg, electromagnetic fields), and psychosocial factors. Priority health outcomes include cancer, neurological, cardiovascular and respiratory diseases and non-specific symptoms. Owing to the recruitment strategy via general practitioners of an established network, we also collect longitudinal data registered in their electronic medical records including symptoms, diagnosis and treatments. Besides the advantage of health outcomes that cannot be easily captured longitudinally by other means, this created a unique opportunity to assess health-related participation bias by comparing general practitioner-registered prevalence rates in the cohort and its source population.
Findings to date
We found no indications of such a systematic bias. The major assets of the AMIGO approach are its detailed occupational and environmental determinants in combination with the longitudinal health data registered in general practice besides linkage to cancer and mortality registries and self-reported health.
Future plans
We are now in the phase of prospective follow-up, with the aim of continuing this for as long as possible (20+ years), pending future funding. Findings will be disseminated through scientific conferences and peer-reviewed journals, and through newsletters and the project website to participants, stakeholders and the wider public.
PMCID: PMC4248092  PMID: 25428630
6.  Welding and Lung Cancer in a Pooled Analysis of Case-Control Studies 
American Journal of Epidemiology  2013;178(10):1513-1525.
Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer.
PMCID: PMC3888276  PMID: 24052544
case-control studies; lung cancer; occupational exposure; welding
7.  Combustion-derived nanoparticle exposure and household solid fuel use in Xuanwei and Fuyuan, China 
Combustion-derived nanoparticles (CDNPs) have not been readably measurable until recently. We conducted a pilot study to determine CDNP levels during solid fuel burning. The aggregate surface area of CDNP (μm2/cm3) was monitored continuously in 15 Chinese homes using varying fuel types (i.e. bituminous coal, anthracite coal, wood) and stove types (i.e. portable stoves, stoves with chimneys, firepits). Information on fuel burning activities was collected and PM2.5 levels were measured. Substantial exposure differences were observed during solid fuel burning (mean: 228.1 μm2/cm3) compared to times without combustion (mean: 14.0 μm2/cm3). The observed levels during burning were reduced by about four-fold in homes with a chimney (mean: 92.1 μm2/cm3; n = 9), and effects were present for all fuel types. Each home’s CDNP measurement was only moderately correlated with the respective PM2.5 measurements (r2 = 0.43; p = 0.11). Our results indicate that household coal and wood burning contributes to indoor nanoparticle levels, which are not fully reflected in PM2.5 measurements.
PMCID: PMC4231791  PMID: 22639822
coal; biomass; wood; stove; nanoparticle; respiratory
8.  Lung Cancer Risk Among Hairdressers: A Pooled Analysis of Case-Control Studies Conducted Between 1985 and 2010 
American Journal of Epidemiology  2013;178(9):1355-1365.
Increased lung cancer risks among hairdressers were observed in large registry-based cohort studies from Scandinavia, but these studies could not adjust for smoking. Our objective was to evaluate the lung cancer risk among hairdressers while adjusting for smoking and other confounders in a pooled database of 16 case-control studies conducted in Europe, Canada, China, and New Zealand between 1985 and 2010 (the Pooled Analysis of Case-Control Studies on the Joint Effects of Occupational Carcinogens in the Development of Lung Cancer). Lifetime occupational and smoking information was collected through interviews with 19,369 cases of lung cancer and 23,674 matched population or hospital controls. Overall, 170 cases and 167 controls had ever worked as hairdresser or barber. The odds ratios for lung cancer in women were 1.65 (95% confidence interval (CI): 1.16, 2.35) without adjustment for smoking and 1.12 (95% CI: 0.75, 1.68) with adjustment for smoking; however, women employed before 1954 also experienced an increased lung cancer risk after adjustment for smoking (odds ratio = 2.66, 95% CI: 1.09, 6.47). The odds ratios in male hairdressers/barbers were generally not elevated, except for an increased odds ratio for adenocarcinoma in long-term barbers (odds ratio = 2.20, 95% CI: 1.02, 4.77). Our results suggest that the increased lung cancer risks among hairdressers are due to their smoking behavior; single elevated risk estimates should be interpreted with caution and need replication in other studies.
PMCID: PMC3813309  PMID: 24068200
case-control studies; hair bleaching agents; hair color; lung neoplasms; occupational exposure
9.  Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning 
Respiratory medicine  2013;107(11):10.1016/j.rmed.2013.08.018.
Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.
PMCID: PMC3848251  PMID: 24055406
EGFR; KRAS; lung cancer; never smoking; China; driver mutations; tumor tissue
10.  Using GPS-derived speed patterns for recognition of transport modes in adults 
Identification of active or sedentary modes of transport is of relevance for studies assessing physical activity or addressing exposure assessment. We assessed in a proof-of-principle study if speed as logged by GPSs could be used to identify modes of transport (walking, bicycling, and motorized transport: car, bus or train).
12 persons commuting to work walking, bicycling or with motorized transport carried GPSs for two commutes and recorded their mode of transport. We evaluated seven speed metrics: mean, 95th percentile of speed, standard deviation of the mean, rate-of-change, standardized-rate-of-change, acceleration and deceleration. We assessed which speed metric would best identify the transport mode using discriminant analyses. We applied cross validation and calculated agreement (Cohen’s Kappa) between actual and derived modes of transport.
Mode of transport was reliably classified whenever a person used a mode of transport for longer than one minute. Best results were observed when using the 95th percentile of speed, acceleration and deceleration (kappa 0.73). When we combined all motorized traffic into one category, kappa increased to 0.95.
GPS-measured speed enable the identification of modes of transport. Given the current low costs of GPS devices and the built-in capacity of GPS tracking in most smartphones, the use of such devices in large epidemiological studies may facilitate the assessment of physical activity related to transport modes, or improve exposure assessment using automated travel mode detection.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-072X-13-40) contains supplementary material, which is available to authorized users.
PMCID: PMC4320483  PMID: 25304171
Physical activity; Active transport; Motorized; Bike; Walk; Discriminant analysis
11.  Household air pollution and lung cancer in China: a review of studies in Xuanwei 
Chinese Journal of Cancer  2014;33(10):471-475.
Over half of the world's population is exposed to household air pollution from the burning of solid fuels at home. Household air pollution from solid fuel use is a leading risk factor for global disease and remains a major public health problem, especially in low- and mid-income countries. This is a particularly serious problem in China, where many people in rural areas still use coal for household heating and cooking. This review focuses on several decades of research carried out in Xuanwei County, Yunnan Province, where household coal use is a major source of household air pollution and where studies have linked household air pollution exposure to high rates of lung cancer. We conducted a series of case-control and cohort studies in Xuanwei to characterize the lung cancer risk in this population and the factors associated with it. We found lung cancer risk to vary substantially between different coal types, with a higher risk associated with smoky (i.e., bituminous) coal use compared to smokeless (i.e., anthracite) coal use. The installation of a chimney in homes resulted in a substantial reduction in lung cancer incidence and mortality. Overall, our research underscores the need among existing coal users to improve ventilation, use the least toxic fuel, and eventually move toward the use of cleaner fuels, such as gas and electricity.
PMCID: PMC4198749  PMID: 25223911
Coal; household air pollution; lung cancer
12.  The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk 
The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case–control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10–24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.
PMCID: PMC4172002  PMID: 25295243
children; adolescents; brain tumors; ELF–EMF; mobile phones; RF-EMF
13.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
PMCID: PMC4169232  PMID: 23143601
15.  Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure 
PLoS ONE  2014;9(5):e91828.
Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.
PMCID: PMC4006721  PMID: 24786086
16.  A Case-Control Study of the Protective Effect of Alcohol, Coffee, and Cigarette Consumption on Parkinson Disease Risk: Time-Since-Cessation Modifies the Effect of Tobacco Smoking 
PLoS ONE  2014;9(4):e95297.
The aim of this study was to investigate the possible reduced risk of Parkinson Disease (PD) due to coffee, alcohol, and/or cigarette consumption. In addition, we explored the potential effect modification by intensity, duration and time-since-cessation of smoking on the association between cumulative pack-years of cigarette smoking (total smoking) and PD risk. Data of a hospital based case-control study was used including 444 PD patients, diagnosed between 2006 and 2011, and 876 matched controls from 5 hospitals in the Netherlands. A novel modeling method was applied to derive unbiased estimates of the potential modifying effects of smoking intensity, duration, and time-since-cessation by conditioning on total exposure. We observed no reduced risk of PD by alcohol consumption and only a weak inverse association between coffee consumption and PD risk. However, a strong inverse association of total smoking with PD risk was observed (OR = 0.27 (95%CI: 0.18–0.42) for never smokers versus highest quartile of tobacco use). The observed protective effect of total smoking was significantly modified by time-since-cessation with a diminishing protective effect after cessation of smoking. No effect modification by intensity or duration of smoking was observed indicating that both intensity and duration have an equal contribution to the reduced PD risk. Understanding the dynamics of the protective effect of smoking on PD risk aids in understanding PD etiology and may contribute to strategies for prevention and treatment.
PMCID: PMC4005732  PMID: 24788751
17.  Inside the black box: starting to uncover the underlying decision rules used in one-by-one expert assessment of occupational exposure in case-control studies 
Evaluating occupational exposures in population-based case-control studies often requires exposure assessors to review each study participants' reported occupational information job-by-job to derive exposure estimates. Although such assessments likely have underlying decision rules, they usually lack transparency, are time-consuming and have uncertain reliability and validity. We aimed to identify the underlying rules to enable documentation, review, and future use of these expert-based exposure decisions.
Classification and regression trees (CART, predictions from a single tree) and random forests (predictions from many trees) were used to identify the underlying rules from the questionnaire responses and an expert's exposure assignments for occupational diesel exhaust exposure for several metrics: binary exposure probability and ordinal exposure probability, intensity, and frequency. Data were split into training (n=10,488 jobs), testing (n=2,247), and validation (n=2,248) data sets.
The CART and random forest models' predictions agreed with 92–94% of the expert's binary probability assignments. For ordinal probability, intensity, and frequency metrics, the two models extracted decision rules more successfully for unexposed and highly exposed jobs (86–90% and 57–85%, respectively) than for low or medium exposed jobs (7–71%).
CART and random forest models extracted decision rules and accurately predicted an expert's exposure decisions for the majority of jobs and identified questionnaire response patterns that would require further expert review if the rules were applied to other jobs in the same or different study. This approach makes the exposure assessment process in case-control studies more transparent and creates a mechanism to efficiently replicate exposure decisions in future studies.
PMCID: PMC3975600  PMID: 23155187
diesel exhaust; classification; data mining; occupational exposure
18.  Alterations in serum immunoglobulin levels in workers occupationally exposed to trichloroethylene 
Carcinogenesis  2012;34(4):799-802.
Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n = 80) and unexposed controls (n = 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P = 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL.
PMCID: PMC3616671  PMID: 23276795
19.  Assessing Exposure and Health Consequences of Chemicals in Drinking Water: Current State of Knowledge and Research Needs 
Environmental Health Perspectives  2014;122(3):213-221.
Background: Safe drinking water is essential for well-being. Although microbiological contamination remains the largest cause of water-related morbidity and mortality globally, chemicals in water supplies may also cause disease, and evidence of the human health consequences is limited or lacking for many of them.
Objectives: We aimed to summarize the state of knowledge, identify gaps in understanding, and provide recommendations for epidemiological research relating to chemicals occurring in drinking water.
Discussion: Assessing exposure and the health consequences of chemicals in drinking water is challenging. Exposures are typically at low concentrations, measurements in water are frequently insufficient, chemicals are present in mixtures, exposure periods are usually long, multiple exposure routes may be involved, and valid biomarkers reflecting the relevant exposure period are scarce. In addition, the magnitude of the relative risks tends to be small.
Conclusions: Research should include well-designed epidemiological studies covering regions with contrasting contaminant levels and sufficient sample size; comprehensive evaluation of contaminant occurrence in combination with bioassays integrating the effect of complex mixtures; sufficient numbers of measurements in water to evaluate geographical and temporal variability; detailed information on personal habits resulting in exposure (e.g., ingestion, showering, swimming, diet); collection of biological samples to measure relevant biomarkers; and advanced statistical models to estimate exposure and relative risks, considering methods to address measurement error. Last, the incorporation of molecular markers of early biological effects and genetic susceptibility is essential to understand the mechanisms of action. There is a particular knowledge gap and need to evaluate human exposure and the risks of a wide range of emerging contaminants.
Citation: Villanueva CM, Kogevinas M, Cordier S, Templeton MR, Vermeulen R, Nuckols JR, Nieuwenhuijsen MJ, Levallois P. 2014. Assessing exposure and health consequences of chemicals in drinking water: current state of knowledge and research needs. Environ Health Perspect 122:213–221;
PMCID: PMC3948022  PMID: 24380896
20.  Lifetime Occupational Exposure to Dusts, Gases and Fumes Is Associated with Bronchitis Symptoms and Higher Diffusion Capacity in COPD Patients 
PLoS ONE  2014;9(2):e88426.
Occupational exposure to dusts, gases and fumes has been associated with reduced FEV1 and sputum production in COPD patients. The effect of occupational exposure on other characteristics of COPD, especially those reflecting emphysema, has not been studied in these patients.
We studied 338 patients hospitalized for a first exacerbation of COPD in 9 Spanish hospitals, obtaining full occupational history in a face-to-face interview; job codes were linked to a job exposure matrix for semi-quantitative estimation of exposure to mineral/biological dust, and gases/fumes for each job held. Patients underwent spirometry, diffusing capacity testing and analysis of gases in stable conditions. Quality of life, dyspnea and chronic bronchitis symptoms were determined with a questionnaire interview. A high- resolution CT scan was available in 133 patients.
94% of the patients included were men, with a mean age of 68(8.5) years and a mean FEV1% predicted 52 (16). High exposure to gases or fumes was associated with chronic bronchitis, and exposure to mineral dust and gases/fumes was associated with higher scores for symptom perception in the St. George’s questionnaire. No occupational agent was associated with a lower FEV1. High exposure to all occupational agents was associated with better lung diffusion capacity, in long-term quitters. In the subgroup with CT data, patients with emphysema had 18% lower DLCO compared to those without emphysema.
In our cohort of COPD patients, high exposure to gases or fumes was associated with chronic bronchitis, and high exposure to all occupational agents was consistently associated with better diffusion capacity in long-term quitters.
PMCID: PMC3916435  PMID: 24516659
21.  Occupational exposure to formaldehyde and alterations in lymphocyte subsets 
Formaldehyde is used in many occupational settings, most notably in manufacturing, health care, and embalming. Formaldehyde has been classified as a human carcinogen, but its mechanism of action remains uncertain.
We carried out a cross-sectional study of 43 formaldehyde exposed-workers and 51 unexposed age and sex-matched controls in Guangdong, China to study formaldehyde’s early biologic effects. To follow-up our previous report that the total lymphocyte count was decreased in formaldehyde-exposed workers compared to controls, we evaluated each major lymphocyte subset (i.e., CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and B cells) and T cell lymphocyte subset (CD4+ naïve and memory T cells, CD8+ naïve and memory T cells, and regulatory T cells). Linear regression of each subset was used to test for differences between exposed workers and controls, adjusting for potential confounders.
Total NK cell and T cell counts were about 24% (p=0.037) and 16% (p=0.0042) lower, respectively, among exposed workers. Among certain T cell subsets, decreased counts among exposed workers were observed for CD8+ T cells (p=0.026), CD8+ effector memory T cells (p=0.018), and regulatory T cells (CD4+FoxP3+: p=0.04; CD25+FoxP3+: p=0.008).
Formaldehyde exposed-workers experienced decreased counts of NK cells, regulatory T cells, and CD8+ effector memory T cells; however, due to the small sample size these findings need to be confirmed in larger studies.
PMCID: PMC3493854  PMID: 22767408
formaldehyde; NK cell; B cell; T cell; T cell subset
23.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
PMCID: PMC3729927  PMID: 23770605
24.  Exposure-Response Estimates for Diesel Engine Exhaust and Lung Cancer Mortality Based on Data from Three Occupational Cohorts 
Environmental Health Perspectives  2013;122(2):172-177.
Background: Diesel engine exhaust (DEE) has recently been classified as a known human carcinogen.
Objective: We derived a meta-exposure–response curve (ERC) for DEE and lung cancer mortality and estimated lifetime excess risks (ELRs) of lung cancer mortality based on assumed occupational and environmental exposure scenarios.
Methods: We conducted a meta-regression of lung cancer mortality and cumulative exposure to elemental carbon (EC), a proxy measure of DEE, based on relative risk (RR) estimates reported by three large occupational cohort studies (including two studies of workers in the trucking industry and one study of miners). Based on the derived risk function, we calculated ELRs for several lifetime occupational and environmental exposure scenarios and also calculated the fractions of annual lung cancer deaths attributable to DEE.
Results: We estimated a lnRR of 0.00098 (95% CI: 0.00055, 0.0014) for lung cancer mortality with each 1-μg/m3-year increase in cumulative EC based on a linear meta-regression model. Corresponding lnRRs for the individual studies ranged from 0.00061 to 0.0012. Estimated numbers of excess lung cancer deaths through 80 years of age for lifetime occupational exposures of 1, 10, and 25 μg/m3 EC were 17, 200, and 689 per 10,000, respectively. For lifetime environmental exposure to 0.8 μg/m3 EC, we estimated 21 excess lung cancer deaths per 10,000. Based on broad assumptions regarding past occupational and environmental exposures, we estimated that approximately 6% of annual lung cancer deaths may be due to DEE exposure.
Conclusions: Combined data from three U.S. occupational cohort studies suggest that DEE at levels common in the workplace and in outdoor air appear to pose substantial excess lifetime risks of lung cancer, above the usually acceptable limits in the United States and Europe, which are generally set at 1/1,000 and 1/100,000 based on lifetime exposure for the occupational and general population, respectively.
Citation: Vermeulen R, Silverman DT, Garshick E, Vlaanderen J, Portengen L, Steenland K. 2014. Exposure-response estimates for diesel engine exhaust and lung cancer mortality based on data from three occupational cohorts. Environ Health Perspect 122:172–177;
PMCID: PMC3915263  PMID: 24273233
25.  The Nightingale study: rationale, study design and baseline characteristics of a prospective cohort study on shift work and breast cancer risk among nurses 
BMC Cancer  2014;14:47.
Evidence for the carcinogenicity of shift work in humans is limited because of significant heterogeneity of the results, thus more in-depth research in needed. The Nightingale Study is a nationwide prospective cohort study on occupational exposures and risks of chronic diseases among female nurses and focuses on the potential association between shift work and risk of breast cancer. The study design, methods, and baseline characteristics of the cohort are described.
The source population for the cohort comprised 18 to 65 year old women who were registered as having completed training to be a nurse in the nationwide register for healthcare professionals in the Netherlands. Eligible women were invited to complete a web-based questionnaire including full job history, a detailed section on all domains of shift work (shift system, cumulative exposure, and shift intensity) and potential confounding factors, and an informed consent form for linkage with national (disease) registries. Women were also asked to donate toenail clippings as a source of DNA for genetic analyses. Between October 6, 2011 and February 1, 2012, 31% of the 192,931 women who were invited to participate completed the questionnaire, yielding a sample size of 59,947 cohort members. The mean age of the participants was 46.9 year (standard deviation 11.0 years). Toenail clippings were provided by 23,439 participants (39%).
Results from the Nightingale Study will contribute to the scientific evidence of potential shift work-related health risks among nurses and will help develop preventive measures and policy aimed at reducing these risks.
PMCID: PMC3946235  PMID: 24475944
Shift work; Night work; Occupational exposures; Breast cancer; Chronic disease; Nurses

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