Publications by authors named "Dalsu Baris"

86 Publications

Occupational insecticide exposure and risk of non-Hodgkin lymphoma: A pooled case-control study from the InterLymph Consortium.

Int J Cancer 2021 Nov 29;149(10):1768-1786. Epub 2021 Jul 29.

Division of Population Health, Centre for Occupational and Environmental Health, University of Manchester, Manchester, UK.

Evidence for the human health effects of pesticides is needed to inform risk assessment. We studied the relationship between occupational insecticide use and risk of non-Hodgkin lymphoma (NHL) by pooling data from nine case-control studies participating in the InterLymph Consortium, including 7909 cases and 8644 controls from North America, the European Union and Australia. Insecticide use was coded using self-report or expert assessment, for insecticide groups (eg, organophosphates, pyrethroids) and active ingredients (eg, malathion, permethrin). Associations with insecticides were estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CI) for all NHL and NHL subtypes, with adjustment for study site, demographic factors and use of other pesticides. Occupational insecticide use, overall, was not associated with risk of NHL. Use of organophosphate insecticides was associated with increased risk of all NHL and the subtype follicular lymphoma, and an association was found with diazinon, in particular (ever use: OR = 2.05, 95%CI: 1.24-3.37). The carbamate insecticide, carbaryl, was associated with risk of all NHL, and the strongest associations were found with T-cell NHL for ever-use (OR = 2.44, 95%CI: 1.13-5.28) and longer duration (>8 years vs never: OR = 2.90, 95%CI: 1.02-8.25). There was no association of NHL with other broad groups of insecticides, including organochlorines and pyrethroids, and some inverse associations were estimated in relation to historical DDT use. Our findings contribute to the totality of evidence available to help inform risk decisions by public health and regulatory agencies of importance given continued, widespread use of organophosphate and carbamate insecticides.
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http://dx.doi.org/10.1002/ijc.33740DOI Listing
November 2021

Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors.

Clin Cancer Res 2021 Jul 13;27(13):3725-3733. Epub 2021 Apr 13.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Purpose: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.

Experimental Design: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.

Results: Non-silent mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater Signature mutations compared with former ( = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with Signature mutations and APOBEC-Signature13 mutations among current ( = 0.005) and former smokers ( = 0.0004), respectively.

Conclusions: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254772PMC
July 2021

Bladder cancer risk associated with family history of cancer.

Int J Cancer 2021 06 5;148(12):2915-2923. Epub 2021 Mar 5.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Twin studies suggest a familial aggregation of bladder cancer, but elements of this increased familial risk of bladder cancer are not well understood. To characterize familial risk of bladder cancer, we examined the relationship between family history of bladder and other types of cancer among first-degree relatives and risk of bladder cancer in 1193 bladder cancer cases and 1418 controls in a large population-based case-control study. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between family history of bladder cancer (defined as at least one first-degree family member with bladder cancer or a cancer of any other site). We also evaluated cancer aggregation of specific sites in family members. Participants with a first-degree relative with bladder cancer had nearly double the risk of bladder cancer (OR = 1.8, 95% CI 1.2-2.9) as those without a family history of bladder cancer. Risk was increased for having a sibling with bladder cancer (OR = 2.6, 95% CI 1.3-5.3) compared to no siblings with cancer. Bladder cancer risk was elevated when participants reported a first-degree relative with a history of female genital cancer (OR = 1.5, 95% CI 1.1-2.1), melanoma (OR = 1.9, 95% CI 1.02-3.6), and tobacco-associated cancer (OR = 1.3, 95% CI 1.06-1.6). These findings add to evidence of a familial predisposition to bladder cancer. Clarification of the aggregation of bladder cancer in families and with other cancer sites will be of interest as many loci and common polymorphisms related to bladder cancer have yet to be identified in large genomic studies.
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http://dx.doi.org/10.1002/ijc.33486DOI Listing
June 2021

Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes.

Environ Int 2020 02 18;135:105346. Epub 2019 Dec 18.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. Electronic address:

Background: The International Agency for Research on Cancer (IARC) classifies diesel engine exhaust as carcinogenic to humans based on sufficient evidence for lung cancer. IARC noted, however, an increased risk of bladder cancer (based on limited evidence).

Objective: To evaluate the association between quantitative, lifetime occupational diesel exhaust exposure and risk of urothelial cell carcinoma of the bladder (UBC) overall and according to pathological subtypes.

Methods: Data from personal interviews with 1944 UBC cases, as well as formalin-fixed paraffin-embedded tumor tissue blocks, and 2135 controls were pooled from two case-control studies conducted in the U.S. and Spain. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary surrogate for diesel exhaust. Unconditional logistic regression and two-stage polytomous logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors.

Results: Exposure to cumulative REC was associated with an increased risk of UBC; workers with cumulative REC >396 μg/m-years had an OR of 1.61 (95% CI, 1.08-2.40). At this level of cumulative exposure, similar results were observed in the U.S. and Spain, OR = 1.75 (95% CI, 0.97-3.15) and OR = 1.54 (95% CI, 0.89-2.68), respectively. In lagged analysis, we also observed a consistent increased risk among workers with cumulative REC >396 μg/m-years (range of ORs = 1.52-1.93) for all lag intervals evaluated (5-40 years). When we accounted for tumor subtypes defined by stage and grade, a significant association between diesel exhaust exposure and UBC was apparent (global test for association p = 0.0019).

Conclusions: Combining data from two large epidemiologic studies, our results provide further evidence that diesel exhaust exposure increases the risk of UBC.
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http://dx.doi.org/10.1016/j.envint.2019.105346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237313PMC
February 2020

Ingested Nitrate and Nitrite and Bladder Cancer in Northern New England.

Epidemiology 2020 01;31(1):136-144

From the Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Background: N-nitroso compounds are hypothesized human bladder carcinogens. We investigated ingestion of N-nitroso compound precursors nitrate and nitrite from drinking water and diet and bladder cancer in the New England Bladder Cancer Study.

Methods: Using historical nitrate measurements for public water supplies and measured and modeled values for private wells, as well as self-reported water intake, we estimated average nitrate concentrations (mg/L NO3-N) and average daily nitrate intake (mg/d) from 1970 to diagnosis/reference date (987 cases and 1,180 controls). We estimated overall and source-specific dietary nitrate and nitrite intakes using a food frequency questionnaire (1,037 cases and 1,225 controls). We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). We evaluated interactions with factors that may affect N-nitroso compound formation (i.e., red meat, vitamin C, smoking), and with water intake.

Results: Average drinking water nitrate concentration above the 95th percentile (>2.07 mg/L) compared with the lowest quartile (≤0.21 mg/L) was associated with bladder cancer (OR = 1.5, 95% CI = 0.97, 2.3; P trend = 0.01); the association was similar for average daily drinking water nitrate intake. We observed positive associations for dietary nitrate and nitrite intakes from processed meat (highest versus lowest quintile OR for nitrate = 1.4, 95% CI = 1.0, 2.0; P trend = 0.04; OR for nitrite = 1.5, 95% CI = 1.0, 2.1; P trend = 0.04, respectively), but not other dietary sources. We observed positive interactions between drinking water nitrate and red meat (P-interaction 0.05) and processed red meat (0.07).

Conclusions: Our results suggest the importance of both drinking water and dietary nitrate sources as risk factors for bladder cancer.
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http://dx.doi.org/10.1097/EDE.0000000000001112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927574PMC
January 2020

Validity of retrospective occupational exposure estimates of lead and manganese in a case-control study.

Occup Environ Med 2019 09 15;76(9):680-687. Epub 2019 Jul 15.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Objectives: The validity of surrogate measures of retrospective occupational exposure in population-based epidemiological studies has rarely been evaluated. Using toenail samples as bioindicators of exposure, we assessed whether work tasks and expert assessments of occupational metal exposure obtained from personal interviews were associated with lead and manganese concentrations.

Methods: We selected 609 controls from a case-control study of bladder cancer in New England who had held a job for ≥1 year 8-24 months prior to toenail collection. We evaluated associations between toenail metal concentrations and five tasks extracted from occupational questionnaires (grinding, painting, soldering, welding, working near engines) using linear regression models. For 139 subjects, we also evaluated associations between the toenail concentrations and exposure estimates from three experts.

Results: We observed a 1.9-fold increase (95% CI 1.4 to 2.5) in toenail lead concentrations with painting and 1.4-fold increase (95% CI 1.1 to 1.7) in manganese concentrations with working around engines and handling fuel. We observed significant trends with increasing frequency of both activities. For lead, significant trends were observed with the ratings from all three experts. Their average ratings showed the strongest association, with subjects rated as possibly or probably exposed to lead having concentrations that were 2.0 and 2.5 times higher, respectively, than in unexposed subjects (p <0.001). Expert estimates were only weakly associated with manganese toenail concentrations.

Conclusions: Our findings support the ability of experts to identify broad contrasts in previous occupational exposure to lead. The stronger associations with task frequency and expert assessments support using refined exposure characterisation whenever possible.
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http://dx.doi.org/10.1136/oemed-2019-105744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767614PMC
September 2019

Pooled study of occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma.

Occup Environ Med 2018 11 18;75(11):798-806. Epub 2018 Aug 18.

Department of Public Health and Clinical Molecular Medicine, University of Cagliari, Cagliari, Italy.

Objectives: To investigate the association between occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma (MM) in a large, consortium-based study.

Methods: We pooled data on 2854 cases and 10 743 controls from nine studies participating in the InterLymph consortium. Occupational exposures to benzene, toluene and xylene were assigned by a job-exposure matrix, coupled with 'correction' of exposure probability by self-reported or expert-assessed exposure from the individual studies. Cumulative intensity was calculated as the job-specific exposure intensity multiplied by job duration, summed across jobs. Associations were estimated using logistic regression, with inclusion of covariates for study matching factors and other potential confounders. We repeated our main analysis using random-effects meta-analysis to evaluate heterogeneity of effect.

Results: Benzene, toluene and xylene were each associated with MM. For the three solvents, the highest quartile of high-probability cumulative intensity exposure (vs unexposed) was associated with 42% to 63% increased risks of MM. Associations with toluene and xylene exposures were fairly consistent and robust to sensitivity analyses. The estimated effect for benzene was moderately heterogeneous between the studies. Each solvent's association with MM was stronger for exposure occurring within 20 years of diagnosis than with exposure lagged by more than 20 years.

Conclusions: Our study adds important evidence for a role of aromatic hydrocarbon solvents in causation of MM. The difficulty in disentangling individual compounds in this group and a lack of data on potential carcinogenicity of toluene and xylene, in widespread current use, underscore a need for further epidemiological evaluation.
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http://dx.doi.org/10.1136/oemed-2018-105154DOI Listing
November 2018

Potential effect modifiers of the arsenic-bladder cancer risk relationship.

Int J Cancer 2018 12 29;143(11):2640-2646. Epub 2018 Sep 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

Populations exposed to arsenic in drinking water have an increased bladder cancer risk and evidence suggests that several factors may modify arsenic metabolism, influencing disease risk. We evaluated whether the association between cumulative lifetime arsenic exposure from drinking water and bladder cancer risk was modified by factors that may impact arsenic metabolism in a population-based case-control study of 1,213 cases and 1,418 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between cumulative arsenic intake and bladder cancer stratified by age, sex, smoking status, body mass index (BMI), alcohol consumption and folate intake. P-values for interaction were computed using a likelihood ratio test. We observed no statistically significant multiplicative interactions although some variations in associations were notable across risk factors, particularly for smoking and BMI. Among former smokers and current smokers, those with the highest cumulative arsenic intake had elevated risks of bladder cancer (OR = 1.4, 95% CI: 0.96-2.0 and OR = 1.6, 95% CI: 0.91-3.0, respectively; while the OR among never smokers was 1.1, 95% CI: 0.6-1.9, p-interaction = 0.49). Among those classified as normal or overweight based on usual adult BMI, the highest level of cumulative arsenic intake was associated with elevated risks of bladder cancer (OR = 1.3, 95% CI: 0.89-2.0 and OR = 1.6, 95% CI: 1.1-2.4, respectively), while risk was not elevated among those who were obese (OR = 0.9, 95% CI: 0.4-1.8) (p-interaction = 0.14). Our study provides some limited evidence of modifying roles of age, sex, smoking, BMI, folate and alcohol on arsenic-related bladder cancer risk that requires confirmation in other, larger studies.
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http://dx.doi.org/10.1002/ijc.31720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235710PMC
December 2018

Bladder Cancer and Water Disinfection By-product Exposures through Multiple Routes: A Population-Based Case-Control Study (New England, USA).

Environ Health Perspect 2017 06 21;125(6):067010. Epub 2017 Jun 21.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Bethesda, Maryland, USA

Background: Ingestion of disinfection byproducts has been associated with bladder cancer in multiple studies. Although associations with other routes of exposure have been suggested, epidemiologic evidence is limited.

Objectives: We evaluated the relationship between bladder cancer and total, chlorinated, and brominated trihalomethanes (THMs) through various exposure routes.

Methods: In a population-based case–control study in New England (=(1,213) cases; =(1,418) controls), we estimated lifetime exposure to THMs from ingestion, showering/bathing, and hours of swimming pool use. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression adjusted for confounders.

Results: Adjusted ORs for bladder cancer comparing participants with exposure above the 95th percentile with those in the lowest quartile of exposure (based on the distribution in controls) were statistically significant for average daily intake mg/d of total THMs [OR=1.53 (95% CI: 1.01, 2.32), -trend=0.16] and brominated THMs [OR=1.98 (95% CI: 1.19, 3.29), p-trend=0.03]. For cumulative intake mg, the OR at the 95th percentile of total THMs was 1.45 (95% CI: 0.95, 2.2), -trend=0.13; the ORs at the 95th percentile for chlorinated and brominated THMs were 1.77 (95% CI: 1.05, 2,.99), -trend=0.07 and 1.78 (95% CI: 1.05, 3.00), -trend=0.02, respectively. The OR in the highest category of showering/bathing for brominated THMs was 1.43 (95% CI: 0.80, 2.42), -trend=0.10. We found no evidence of an association for bladder cancer and hours of swimming pool use.

Conclusions: We observed a modest association between ingestion of water with higher THMs (>95th percentile vs.<25th percentile) and bladder cancer. Brominated THMs have been a particular concern based on toxicologic evidence, and our suggestive findings for multiple metrics require further study in a population with higher levels of these exposures. Data from this population do not support an association between swimming pool use and bladder cancer. https://doi.org/10.1289/EHP89.
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http://dx.doi.org/10.1289/EHP89DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743617PMC
June 2017

Young Adult and Usual Adult Body Mass Index and Multiple Myeloma Risk: A Pooled Analysis in the International Multiple Myeloma Consortium (IMMC).

Cancer Epidemiol Biomarkers Prev 2017 06 21;26(6):876-885. Epub 2017 Feb 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Rockville, Maryland.

Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case-control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI. We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls. In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04-1.14; = 0.007]. We observed significant heterogeneity by study design ( = 0.04), noting the BMI-multiple myeloma association only for population-based studies ( = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m; OR, 1.2; 95% CI, 1.1-1.3; = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI ( <0.0001); we noted statistically significant associations with multiple myeloma for persons overweight (25-<30 kg/m) or obese (30+ kg/m) in both younger and usual adulthood (vs. individuals consistently <25 kg/m), but not for those overweight or obese at only one time period. BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood. These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0762-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457306PMC
June 2017

Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic.

J Natl Cancer Inst 2016 09 2;108(9). Epub 2016 May 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD (DB [formerly], LEBF, JSC, MHW, NR, LEM, CS [formerly], RNH, JFF, DTS); Geisel School of Medicine at Dartmouth, Hanover, NH (RW, AS, MRK); Maine Cancer Registry, Augusta, ME (MS, CC [formerly]); US Geological Survey, Pembroke, NH (JA), Reston, VA (GR); Colorado State University, Fort Collins, CO (JN); Dartmouth College, Hanover, NH (BJ); Information Management Services, Calverton, MD (AT); New Hampshire State Cancer Registry, Concord, NH (GMH); New Hampshire State Occupational Surveillance Program, Concord, NH (KRA); Vermont Department of Health, Burlington, VT (RM, AJ).

Background: Bladder cancer mortality rates have been elevated in northern New England for at least five decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than the United States overall. We explored reasons for this excess, focusing on arsenic in drinking water from private wells, which are particularly prevalent in the region.

Methods: In a population-based case-control study in these three states, 1213 bladder cancer case patients and 1418 control subjects provided information on suspected risk factors. Log transformed arsenic concentrations were estimated by linear regression based on measurements in water samples from current and past homes. All statistical tests were two-sided.

Results: Bladder cancer risk increased with increasing water intake (Ptrend = .003). This trend was statistically significant among participants with a history of private well use (Ptrend = .01). Among private well users, this trend was apparent if well water was derived exclusively from shallow dug wells (which are vulnerable to contamination from manmade sources, Ptrend = .002) but not if well water was supplied only by deeper drilled wells (Ptrend = .48). If dug wells were used pre-1960, when arsenical pesticides were widely used in the region, heavier water consumers (>2.2 L/day) had double the risk of light users (<1.1 L/day, Ptrend = .01). Among all participants, cumulative arsenic exposure from all water sources, lagged 40 years, yielded a positive risk gradient (Ptrend = .004); among the highest-exposed participants (97.5th percentile), risk was twice that of the lowest-exposure quartile (odds ratio = 2.24, 95% confidence interval = 1.29 to 3.89).

Conclusions: Our findings support an association between low-to-moderate levels of arsenic in drinking water and bladder cancer risk in New England. In addition, historical consumption of water from private wells, particularly dug wells in an era when arsenical pesticides were widely used, was associated with increased bladder cancer risk and may have contributed to the New England excess.
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http://dx.doi.org/10.1093/jnci/djw099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939854PMC
September 2016

Computer-based coding of free-text job descriptions to efficiently identify occupations in epidemiological studies.

Occup Environ Med 2016 Jun 21;73(6):417-24. Epub 2016 Apr 21.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Background: Mapping job titles to standardised occupation classification (SOC) codes is an important step in identifying occupational risk factors in epidemiological studies. Because manual coding is time-consuming and has moderate reliability, we developed an algorithm called SOCcer (Standardized Occupation Coding for Computer-assisted Epidemiologic Research) to assign SOC-2010 codes based on free-text job description components.

Methods: Job title and task-based classifiers were developed by comparing job descriptions to multiple sources linking job and task descriptions to SOC codes. An industry-based classifier was developed based on the SOC prevalence within an industry. These classifiers were used in a logistic model trained using 14 983 jobs with expert-assigned SOC codes to obtain empirical weights for an algorithm that scored each SOC/job description. We assigned the highest scoring SOC code to each job. SOCcer was validated in 2 occupational data sources by comparing SOC codes obtained from SOCcer to expert assigned SOC codes and lead exposure estimates obtained by linking SOC codes to a job-exposure matrix.

Results: For 11 991 case-control study jobs, SOCcer-assigned codes agreed with 44.5% and 76.3% of manually assigned codes at the 6-digit and 2-digit level, respectively. Agreement increased with the score, providing a mechanism to identify assignments needing review. Good agreement was observed between lead estimates based on SOCcer and manual SOC assignments (κ 0.6-0.8). Poorer performance was observed for inspection job descriptions, which included abbreviations and worksite-specific terminology.

Conclusions: Although some manual coding will remain necessary, using SOCcer may improve the efficiency of incorporating occupation into large-scale epidemiological studies.
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http://dx.doi.org/10.1136/oemed-2015-103152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871757PMC
June 2016

Low Levels of Circulating Adiponectin Are Associated with Multiple Myeloma Risk in Overweight and Obese Individuals.

Cancer Res 2016 04 26;76(7):1935-41. Epub 2016 Feb 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

The association between obesity and multiple myeloma risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate multiple myeloma risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 multiple myeloma cases and 1,246 individually matched controls from seven cohorts participating in the Multiple Myeloma Cohort Consortium. Analysis of circulating analyte levels measured by ELISA revealed that higher total adiponectin levels were associated with reduced multiple myeloma risk overall [highest quartile vs. lowest: OR, 0.64; 95% confidence interval (CI) 0.47-0.85; Ptrend = 0.001]. This association was apparent among cases diagnosed six or more years after blood collection (OR, 0.60; 95% CI, 0.40-0.90; Ptrend = 0.004) and was similar in magnitude for men and women (OR, 0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR, 0.41; 95% CI, 0.26-0.65) or obese (OR, 0.41; 95% CI, 0.17-0.98) but not among those with normal weight (OR, 1.20; 95% CI, 0.73-2.00; overweight/obese vs. normal weight, Pinteraction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against multiple myeloma development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. Cancer Res; 76(7); 1935-41. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878138PMC
April 2016

Combining Decision Rules from Classification Tree Models and Expert Assessment to Estimate Occupational Exposure to Diesel Exhaust for a Case-Control Study.

Ann Occup Hyg 2016 May 4;60(4):467-78. Epub 2016 Jan 4.

1.Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 208952, USA;

Objectives: To efficiently and reproducibly assess occupational diesel exhaust exposure in a Spanish case-control study, we examined the utility of applying decision rules that had been extracted from expert estimates and questionnaire response patterns using classification tree (CT) models from a similar US study.

Methods: First, previously extracted CT decision rules were used to obtain initial ordinal (0-3) estimates of the probability, intensity, and frequency of occupational exposure to diesel exhaust for the 10 182 jobs reported in a Spanish case-control study of bladder cancer. Second, two experts reviewed the CT estimates for 350 jobs randomly selected from strata based on each CT rule's agreement with the expert ratings in the original study [agreement rate, from 0 (no agreement) to 1 (perfect agreement)]. Their agreement with each other and with the CT estimates was calculated using weighted kappa (κ w) and guided our choice of jobs for subsequent expert review. Third, an expert review comprised all jobs with lower confidence (low-to-moderate agreement rates or discordant assignments, n = 931) and a subset of jobs with a moderate to high CT probability rating and with moderately high agreement rates (n = 511). Logistic regression was used to examine the likelihood that an expert provided a different estimate than the CT estimate based on the CT rule agreement rates, the CT ordinal rating, and the availability of a module with diesel-related questions.

Results: Agreement between estimates made by two experts and between estimates made by each of the experts and the CT estimates was very high for jobs with estimates that were determined by rules with high CT agreement rates (κ w: 0.81-0.90). For jobs with estimates based on rules with lower agreement rates, moderate agreement was observed between the two experts (κ w: 0.42-0.67) and poor-to-moderate agreement was observed between the experts and the CT estimates (κ w: 0.09-0.57). In total, the expert review of 1442 jobs changed 156 probability estimates, 128 intensity estimates, and 614 frequency estimates. The expert was more likely to provide a different estimate when the CT rule agreement rate was <0.8, when the CT ordinal ratings were low to moderate, or when a module with diesel questions was available.

Conclusions: Our reliability assessment provided important insight into where to prioritize additional expert review; as a result, only 14% of the jobs underwent expert review, substantially reducing the exposure assessment burden. Overall, we found that we could efficiently, reproducibly, and reliably apply CT decision rules from one study to assess exposure in another study.
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http://dx.doi.org/10.1093/annhyg/mev095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850897PMC
May 2016

Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry.

Hum Mol Genet 2016 Mar 4;25(6):1203-14. Epub 2016 Jan 4.

Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD, USA.

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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http://dx.doi.org/10.1093/hmg/ddv492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817084PMC
March 2016

A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium.

Cancer Epidemiol Biomarkers Prev 2016 Jan 13;25(1):217-21. Epub 2015 Oct 13.

Unit of Infections and Cancer, Cancer Epidemiology Research Programme, IDIBELL, Catalan Institute of Oncology, Barcelona, Spain. Department of Medicine, University of Barcelona, Barcelona, Spain. CIBER Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain.

Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations.

Methods: We conducted a pooled analysis of seven case-control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses.

Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68-1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80-1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37-1.15, I(2) = 76.0%, Pheterogeneity = 0.01).

Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis.

Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-0953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745255PMC
January 2016

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

J Natl Cancer Inst 2015 Dec 12;107(12):djv279. Epub 2015 Oct 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (JNS, OP, SIB, QL, CCA, LTA, JDF, MTL, LM, SAS, PRT, KAM, PR, DA, DB, BAB, AB, LBr, WHC, CCC, JSC, JFFJr, NDF, LEBF, MGC, AMG, RNH, NH, WH, PDI, BTJ, CK, CMK, LML, MSL, LEM, LPO, RSSS, WeiT, MT, CWa, SW, NW, KY, PH, LMM, NEC, NR, DTS, SJC, NC); Information Management Services, Silver Spring, MD (WAW, CG); Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD (MY, ZW, LBu, AH, CLi); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (IDV, KAB, BMB, CoC, MCB, CF, EG, SL, JP, MSt, DJH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (IDV, OA, KAB, CoC, MCB, EG, RSK, SL, JP, HDS, MSt, DTr, DJH, PK); Ontario Health Study, Toronto, Ontario, Canada (MPP); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (HOA, EWe); Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (AA, MF); UCL Cancer Institute, London, UK (MFA, AMF, DH); Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK (MFA, AMF, DH, RT); Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (SJA, JS, YLW, XCZ); Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden (UA, RH, BSM); Division of Urologic Surgery, Washington University School of Medicine, Saint Louis, MO (GAJr, RGIII); Litwin Centre for Cancer Genetics, University of Toronto, Ontario, Canada (ILA, NG, JSW); Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (ILA, SG, NG, JSW); Hematology Unit, Ospedale Oncologico di Riferimento Regionale A. Businco, Cagliari, Italy (EA); Department of Medicin

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.

Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.

Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.

Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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http://dx.doi.org/10.1093/jnci/djv279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806328PMC
December 2015

Risk of multiple myeloma in a case-spouse study.

Leuk Lymphoma 2016 16;57(6):1450-9. Epub 2015 Nov 16.

b International Myeloma Foundation , Hollywood , CA , USA ;

This study examined lifestyle, occupation, medical history and medication use with multiple myeloma risk in a case-spouse study (481 patients, 351 spouses). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using logistic regression. Compared to spouse controls, cases were more likely to have a family history of multiple myeloma (OR = 2.8, 95% CI = 1.2-6.4) and smoked cigarettes (OR = 1.7, 95% CI = 1.2-2.5), but less likely to have consumed alcohol (OR = 0.6, 95% CI = 0.4-0.9). Nurse/health practitioners (OR = 2.8, 95% CI = 1.3-6.2) and production workers (OR = 3.7, 95% CI = 1.0-13.7) had significantly increased risks; and some occupations linked to diesel exhaust had elevated, but non-significant, risks. History of herpes simplex (OR = 1.7, 95% CI = 1.2-2.4), shingles (OR = 1.7, 95% CI = 1.1-2.7), sexually transmitted diseases (OR = 2.0, 95% CI = 1.0-3.7) and medication allergies (OR = 1.7, 95% CI = 1.2-2.4) were associated with higher risks. Use of angiotensin-converting enzyme inhibitors, anti-convulsants, antidepressants, statins and diuretics were associated with reduced risks. The results are consistent with previous population-based studies and support the utility of patient databanks and spouse controls as a resource in epidemiologic research.
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http://dx.doi.org/10.3109/10428194.2015.1094693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497084PMC
January 2017

Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms.

J Natl Cancer Inst 2015 Nov 14;107(11). Epub 2015 Sep 14.

Division of Cancer Epidemiology and Genetics (JDF, SK, JSC, MGC, MCF, DB, PS, LEM, LPO, ARB, AP, JFFJr, SJC, NC, NR, DTS), Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research (KY, JYC, SMH), and Cancer and Inflammation Program (MLN), National Cancer Institute, Bethesda, MD; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh UK (JDF); CIBERESP, CIBER Epidemiologia y Salud Publica, Madrid, Spain (MK, AT, JL); Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain (MK); Municipal Institute of Medical Research (IMIM-Hospital del Mar), Barcelona, Spain (MK); Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK (MGC); Spanish National Cancer Research Centre (CNIO), Madrid, Spain (FXR, NM); Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain (FXR, CS); Maine Cancer Registry, Augusta, ME (MS); Vermont Cancer Registry, Burlington, VT (AJ); Geisel School of Medicine at Dartmouth, Hanover, NH (MRK, AS); New Hampshire Department of Health and Human Services, Concord, NH (KRA); Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc. (formerly SAIC-Frederick, Inc.), Frederick National Laboratory for Cancer Research, Frederick, MD (PL); Molecular Epidemiology Group, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Asturias, Spain (AT); Hospital Ramón y Cajal, Elche, Madrid, Spain (AC); Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain (RGC).

Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism (P interaction ≤ .001), rs11892031 (UGT1A, P interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 (TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis.
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http://dx.doi.org/10.1093/jnci/djv223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675099PMC
November 2015

Is the inverse association between selenium and bladder cancer due to confounding by smoking?

Am J Epidemiol 2015 Apr 15;181(7):488-95. Epub 2015 Mar 15.

Selenium has been linked to a reduced risk of bladder cancer in some studies. Smoking, a well-established risk factor for bladder cancer, has been associated with lower selenium levels in the body. We investigated the selenium-bladder cancer association in subjects from Maine, New Hampshire, and Vermont in the New England Bladder Cancer Case-Control Study. At interview (2001-2005), participants provided information on a variety of factors, including a comprehensive smoking history, and submitted toenail samples, from which we measured selenium levels. We estimated odds ratios and 95% confidence intervals among 1,058 cases and 1,271 controls using logistic regression. After controlling for smoking, we saw no evidence of an association between selenium levels and bladder cancer (for fourth quartile vs. first quartile, odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.77, 1.25). When results were restricted to regular smokers, there appeared to be an inverse association (OR = 0.76, 95% CI: 0.58, 0.99); however, when pack-years of smoking were considered, this association was attenuated (OR = 0.91, 95% CI: 0.68, 1.20), indicating potential confounding by smoking. Despite some reports of an inverse association between selenium and bladder cancer overall, our results, combined with an in-depth evaluation of other studies, suggested that confounding from smoking intensity or duration could explain this association. Our study highlights the need to carefully evaluate the confounding association of smoking in the selenium-bladder cancer association.
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http://dx.doi.org/10.1093/aje/kwu324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447815PMC
April 2015

Exposure-response relationships for select cancer and non-cancer health outcomes in a cohort of U.S. firefighters from San Francisco, Chicago and Philadelphia (1950-2009).

Occup Environ Med 2015 Oct 11;72(10):699-706. Epub 2015 Feb 11.

Division of Surveillance, Hazard Evaluations, and Field Studies, National Institute for Occupational Safety and Health, Cincinnati, Ohio, USA.

Objectives: To examine exposure-response relationships between surrogates of firefighting exposure and select outcomes among previously studied US career firefighters.

Methods: Eight cancer and four non-cancer outcomes were examined using conditional logistic regression. Incidence density sampling was used to match each case to 200 controls on attained age. Days accrued in firefighting assignments (exposed-days), run totals (fire-runs) and run times (fire-hours) were used as exposure surrogates. HRs comparing 75th and 25th centiles of lagged cumulative exposures were calculated using loglinear, linear, log-quadratic, power and restricted cubic spline general relative risk models. Piecewise constant models were used to examine risk differences by time since exposure, age at exposure and calendar period.

Results: Among 19,309 male firefighters eligible for the study, there were 1333 cancer deaths and 2609 cancer incidence cases. Significant positive associations between fire-hours and lung cancer mortality and incidence were evident. A similar relation between leukaemia mortality and fire-runs was also found. The lung cancer associations were nearly linear in cumulative exposure, while the association with leukaemia mortality was attenuated at higher exposure levels and greater for recent exposures. Significant negative associations were evident for the exposure surrogates and colorectal and prostate cancers, suggesting a healthy worker survivor effect possibly enhanced by medical screening.

Conclusions: Lung cancer and leukaemia mortality risks were modestly increasing with firefighter exposures. These findings add to evidence of a causal association between firefighting and cancer. Nevertheless, small effects merit cautious interpretation. We plan to continue to follow the occurrence of disease and injury in this cohort.
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http://dx.doi.org/10.1136/oemed-2014-102671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558385PMC
October 2015

A pooled analysis of cigarette smoking and risk of multiple myeloma from the international multiple myeloma consortium.

Cancer Epidemiol Biomarkers Prev 2015 Mar 23;24(3):631-4. Epub 2014 Dec 23.

Information Management Services, Inc., Silver Spring, Maryland.

Background: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association, we conducted a pooled analysis of nine case-control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates.

Methods: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (OR) and 95% confidence intervals (CI) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center.

Results: Neither ever smokers (OR, 0.95; 95% CI, 0.87-1.05), current smokers (OR, 0.82; 95% CI, 0.73-0.93), nor former smokers (OR, 1.03; 95% CI, 0.92-1.14) had increased risks of multiple myeloma compared with never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups.

Conclusion: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma.

Impact: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. Cancer Epidemiol Biomarkers Prev; 24(3); 631-4. ©2014 AACR.
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http://dx.doi.org/10.1158/1055-9965.EPI-14-1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355157PMC
March 2015

Using hierarchical cluster models to systematically identify groups of jobs with similar occupational questionnaire response patterns to assist rule-based expert exposure assessment in population-based studies.

Ann Occup Hyg 2015 May 3;59(4):455-66. Epub 2014 Dec 3.

11.Biostatistics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Objectives: Rule-based expert exposure assessment based on questionnaire response patterns in population-based studies improves the transparency of the decisions. The number of unique response patterns, however, can be nearly equal to the number of jobs. An expert may reduce the number of patterns that need assessment using expert opinion, but each expert may identify different patterns of responses that identify an exposure scenario. Here, hierarchical clustering methods are proposed as a systematic data reduction step to reproducibly identify similar questionnaire response patterns prior to obtaining expert estimates. As a proof-of-concept, we used hierarchical clustering methods to identify groups of jobs (clusters) with similar responses to diesel exhaust-related questions and then evaluated whether the jobs within a cluster had similar (previously assessed) estimates of occupational diesel exhaust exposure.

Methods: Using the New England Bladder Cancer Study as a case study, we applied hierarchical cluster models to the diesel-related variables extracted from the occupational history and job- and industry-specific questionnaires (modules). Cluster models were separately developed for two subsets: (i) 5395 jobs with ≥1 variable extracted from the occupational history indicating a potential diesel exposure scenario, but without a module with diesel-related questions; and (ii) 5929 jobs with both occupational history and module responses to diesel-relevant questions. For each subset, we varied the numbers of clusters extracted from the cluster tree developed for each model from 100 to 1000 groups of jobs. Using previously made estimates of the probability (ordinal), intensity (µg m(-3) respirable elemental carbon), and frequency (hours per week) of occupational exposure to diesel exhaust, we examined the similarity of the exposure estimates for jobs within the same cluster in two ways. First, the clusters' homogeneity (defined as >75% with the same estimate) was examined compared to a dichotomized probability estimate (<5 versus ≥5%; <50 versus ≥50%). Second, for the ordinal probability metric and continuous intensity and frequency metrics, we calculated the intraclass correlation coefficients (ICCs) between each job's estimate and the mean estimate for all jobs within the cluster.

Results: Within-cluster homogeneity increased when more clusters were used. For example, ≥80% of the clusters were homogeneous when 500 clusters were used. Similarly, ICCs were generally above 0.7 when ≥200 clusters were used, indicating minimal within-cluster variability. The most within-cluster variability was observed for the frequency metric (ICCs from 0.4 to 0.8). We estimated that using an expert to assign exposure at the cluster-level assignment and then to review each job in non-homogeneous clusters would require ~2000 decisions per expert, in contrast to evaluating 4255 unique questionnaire patterns or 14983 individual jobs.

Conclusions: This proof-of-concept shows that using cluster models as a data reduction step to identify jobs with similar response patterns prior to obtaining expert ratings has the potential to aid rule-based assessment by systematically reducing the number of exposure decisions needed. While promising, additional research is needed to quantify the actual reduction in exposure decisions and the resulting homogeneity of exposure estimates within clusters for an exposure assessment effort that obtains cluster-level expert assessments as part of the assessment process.
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http://dx.doi.org/10.1093/annhyg/meu101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385262PMC
May 2015

Comparison of ordinal and nominal classification trees to predict ordinal expert-based occupational exposure estimates in a case-control study.

Ann Occup Hyg 2015 Apr 27;59(3):324-35. Epub 2014 Nov 27.

5.Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, MSC 9776, Bethesda, MD 20892, USA.

Objectives: To evaluate occupational exposures in case-control studies, exposure assessors typically review each job individually to assign exposure estimates. This process lacks transparency and does not provide a mechanism for recreating the decision rules in other studies. In our previous work, nominal (unordered categorical) classification trees (CTs) generally successfully predicted expert-assessed ordinal exposure estimates (i.e. none, low, medium, high) derived from occupational questionnaire responses, but room for improvement remained. Our objective was to determine if using recently developed ordinal CTs would improve the performance of nominal trees in predicting ordinal occupational diesel exhaust exposure estimates in a case-control study.

Methods: We used one nominal and four ordinal CT methods to predict expert-assessed probability, intensity, and frequency estimates of occupational diesel exhaust exposure (each categorized as none, low, medium, or high) derived from questionnaire responses for the 14983 jobs in the New England Bladder Cancer Study. To replicate the common use of a single tree, we applied each method to a single sample of 70% of the jobs, using 15% to test and 15% to validate each method. To characterize variability in performance, we conducted a resampling analysis that repeated the sample draws 100 times. We evaluated agreement between the tree predictions and expert estimates using Somers' d, which measures differences in terms of ordinal association between predicted and observed scores and can be interpreted similarly to a correlation coefficient.

Results: From the resampling analysis, compared with the nominal tree, an ordinal CT method that used a quadratic misclassification function and controlled tree size based on total misclassification cost had a slightly better predictive performance that was statistically significant for the frequency metric (Somers' d: nominal tree = 0.61; ordinal tree = 0.63) and similar performance for the probability (nominal = 0.65; ordinal = 0.66) and intensity (nominal = 0.65; ordinal = 0.65) metrics. The best ordinal CT predicted fewer cases of large disagreement with the expert assessments (i.e. no exposure predicted for a job with high exposure and vice versa) compared with the nominal tree across all of the exposure metrics. For example, the percent of jobs with expert-assigned high intensity of exposure that the model predicted as no exposure was 29% for the nominal tree and 22% for the best ordinal tree.

Conclusions: The overall agreements were similar across CT models; however, the use of ordinal models reduced the magnitude of the discrepancy when disagreements occurred. As the best performing model can vary by situation, researchers should consider evaluating multiple CT methods to maximize the predictive performance within their data.
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http://dx.doi.org/10.1093/annhyg/meu098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365762PMC
April 2015

The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease.

Cancer Res 2014 Oct;74(20):5808-18

Ramón y Cajal Hospital, Madrid, Spain.

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-1531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203382PMC
October 2014

Estimation of the probability of exposure to machining fluids in a population-based case-control study.

J Occup Environ Hyg 2014 ;11(11):757-70

a Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda , Maryland.

We describe an approach for estimating the probability that study subjects were exposed to metalworking fluids (MWFs) in a population-based case-control study of bladder cancer. Study subject reports on the frequency of machining and use of specific MWFs (straight, soluble, and synthetic/semi-synthetic) were used to estimate exposure probability when available. Those reports also were used to develop estimates for job groups, which were then applied to jobs without MWF reports. Estimates using both cases and controls and controls only were developed. The prevalence of machining varied substantially across job groups (0.1->0.9%), with the greatest percentage of jobs that machined being reported by machinists and tool and die workers. Reports of straight and soluble MWF use were fairly consistent across job groups (generally 50-70%). Synthetic MWF use was lower (13-45%). There was little difference in reports by cases and controls vs. controls only. Approximately, 1% of the entire study population was assessed as definitely exposed to straight or soluble fluids in contrast to 0.2% definitely exposed to synthetic/semi-synthetics. A comparison between the reported use of the MWFs and U.S. production levels found high correlations (r generally >0.7). Overall, the method described here is likely to have provided a systematic and reliable ranking that better reflects the variability of exposure to three types of MWFs than approaches applied in the past. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resources: a list of keywords in the occupational histories that were used to link study subjects to the metalworking fluids (MWFs) modules; recommendations from the literature on selection of MWFs based on type of machining operation, the metal being machined and decade; popular additives to MWFs; the number and proportion of controls who reported various MWF responses by job group; the number and proportion of controls assigned to the MWF types by job group and exposure category; and the distribution of cases and controls assigned various levels of probability by MWF type.].
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http://dx.doi.org/10.1080/15459624.2014.918984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359797PMC
June 2015

A case-control study of occupational exposure to metalworking fluids and bladder cancer risk among men.

Occup Environ Med 2014 Oct 20;71(10):667-74. Epub 2014 Jun 20.

Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Objectives: Metalworking has been associated with an excess risk of bladder cancer in over 20 studies. Metalworking fluids (MWFs) are suspected as the responsible exposure, but epidemiological data are limited. We investigated this association among men in the New England Bladder Cancer Study using state-of-the-art, quantitative exposure assessment methods.

Methods: Cases (n=895) and population controls (n=1031) provided occupational histories during personal interviews. For selected jobs, exposure-oriented modules were administered to collect information on use of three MWF types: (1) straight (mineral oil, additives), (2) soluble (mineral oil, water, additives) and (3) synthetic (water, organics, additives) or semisynthetic (hybrid of soluble and synthetic). We computed ORs and 95% CIs relating bladder cancer risk to a variety of exposure metrics, adjusting for smoking and other factors. Non-metalworkers who had held jobs with possible exposure to mineral oil were analysed separately.

Results: Bladder cancer risk was elevated among men who reported using straight MWFs (OR=1.7, 95% CI 1.1 to 2.8); risk increased monotonically with increasing cumulative exposure (p=0.041). Use of soluble MWFs was associated with a 50% increased risk (95% CI 0.96 to 2.5). ORs were non-significantly elevated for synthetic/semisynthetic MWFs based on a small number of exposed men. Non-metalworkers holding jobs with possible exposure to mineral oil had a 40% increased risk (95% CI 1.1 to 1.8).

Conclusions: Exposure to straight MWFs was associated with a significantly increased bladder cancer risk, as was employment in non-metalworking jobs with possible exposure to mineral oil. These findings strengthen prior evidence for mineral oil as a bladder carcinogen.
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http://dx.doi.org/10.1136/oemed-2013-102056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690539PMC
October 2014

Developing estimates of frequency and intensity of exposure to three types of metalworking fluids in a population-based case-control study of bladder cancer.

Am J Ind Med 2014 Aug;57(8):915-27

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Rockville, Maryland.

Background: A systematic, transparent, and data-driven approach was developed to estimate frequency and intensity of exposure to straight, soluble, and synthetic/semi-synthetic metalworking fluids (MWFs) within a case-control study of bladder cancer in New England.

Methods: We assessed frequency using individual-level information from job-specific questionnaires wherever possible, then derived and applied job group-level patterns to likely exposed jobs with less information. Intensity estimates were calculated using a statistical model developed from measurements and determinants extracted from the published literature.

Results: For jobs with probabilities of exposure≥0.5, median frequencies were 8-10 hr/week, depending on MWF type. Median intensities for these jobs were 2.5, 2.1, and 1.0 mg/m3 for soluble, straight, and synthetic/semi-synthetic MWFs, respectively.

Conclusions: Compared to case-by-case assessment, these data-driven decision rules are transparent and reproducible and may result in less biased estimates. These rules can also aid future exposure assessments of MWFs in population-based studies.
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http://dx.doi.org/10.1002/ajim.22328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112469PMC
August 2014

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.

Hum Mol Genet 2014 Dec 15;23(24):6616-33. Epub 2014 Jul 15.

Department of Preventive Medicine, Biostatistics Division, Keck School of Medicine and.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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http://dx.doi.org/10.1093/hmg/ddu363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240198PMC
December 2014
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