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Supplementary Table S1. Cohorts Participating in the Liver Cancer Pooling Project with Information on Aspirin Use. Supplementary Table S2. Assessment of aspirin and ibuprofen use, Liver Cancer Pooling Project. Supplemental Table S3. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex, Cigarette Use, Alcohol Consumption, and Ibuprofen Use, Liver Cancer Pooling Project. Supplemental Table S4. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Confirmed or Suspected Hepatocellular Carcinoma, Liver Cancer Pooling Project.

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57–0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42–0.98) but not women (HR, 1.34; 95% CI, 0.89–2.01; Pinteraction = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. Cancer Prev Res; 8(12); 1156–62. ©2015 AACR.

Background: Observational and experimental studies suggest that vitamin D may influence breast cancer etiology. Most known effects of vitamin D are mediated via the vitamin D receptor (VDR). Few polymorphisms in the VDR gene have been well studied in relation to breast cancer risk and results have been inconsistent.Methods: We investigated VDR polymorphisms and haplotypes in relation to breast cancer risk by genotyping 26 single nucleotide polymorphisms (SNP) that (i) had known/suspected impact on VDR function, (ii) were tagging SNPs for the three VDR haplotype blocks among whites, or (iii) were previously associated with breast cancer risk. We estimated odds ratios (OR) and 95% confidence intervals (CI) in relation to breast cancer risk among 270 incident cases and 554 matched controls within the Agricultural Health Study cohort.Results: In individual SNP analyses, homozygous carriers of the minor allele for rs2544038 had significantly increased breast cancer risk (OR = 1.5; 95% CI: 1.0–2.5) and homozygous carriers of the minor allele for rs11168287 had significantly decreased risk (OR = 0.6; 95% CI: 0.4–1.0). Carriers of the minor allele for rs2239181 exhibited marginally significant association with risk (OR = 1.4; 95% CI: 0.9–2.0). Haplotype analyses revealed three haplotype groups (blocks “A,” “B,” and “C”). Haplotype GTCATTTCCTA in block B was significantly associated with reduced risk (OR = 0.5; 95% CI: 0.3–0.9).Conclusions: These results suggest that variation in VDR may be associated with breast cancer risk.Impact: Our findings may help guide future research needed to define the role of vitamin D in breast cancer prevention. Cancer Epidemiol Biomarkers Prev; 21(10); 1856–67. ©2012 AACR.

Supplemental Table 1. Prevalence of tobacco use by gender; Supplemental Table 2. Cigarette Smoking Characteristics among exclusive cigarette and dual tobacco users

Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee–HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.Methods: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression.Results: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53–0.99; Ptrend cups/day = Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26–0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63–1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50–1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55–1.54). There was no association between coffee consumption and ICC.Conclusions: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC.Impact: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Cancer Epidemiol Biomarkers Prev; 24(9); 1398–406. ©2015 AACR.

PDF file, 86K, Primer sequences used in the genotyping by mass spectrometry (Supplementary tables S1 and S2 referred to in the manuscript text).

figure legends for supp. figures 1, 2, and 3

Descriptive table or cohorts and results from sensitivity analyses

Background: Cigarettes are well known to cause cancer, but less is known about the risks of other tobacco products and use of more than one product.Methods: We examined cancer incidence in relation to exclusive use of six tobacco products [cigarettes, other combustibles (pipe, cigar, cigarillo), and smokeless tobacco (chewing tobacco, snuff)] in the Agricultural Health Study. We also examined the added cancer risks associated with use of cigarettes and other tobacco products.Results: In our study population of 84,015, ever use of smokeless tobacco was higher than the general United States population, whereas cigarette use was lower and other combustible product use was about the same. The strongest associations for exclusive ever use were for lung cancer [cigarettes HR = 15.48; 95% confidence interval (CI), 11.95–20.06; other combustible tobacco HR = 3.44; 95% CI, 1.53–7.71; smokeless tobacco HR = 2.21; 95% CI, 1.11–4.42]. Compared with exclusive cigarette smokers, cigarette smokers who additionally ever-used another combustible product had higher risks of smoking-related cancers (HR = 1.16; 95% CI, 1.04–1.30), especially among those who smoked cigarettes for more than 15 years.Conclusions and Impact: Cigarette smokers who additionally ever used smokeless tobacco had cancer risks similar to exclusive cigarette smokers. Users of cigarettes and other combustible tobacco may have higher risks of certain cancers than exclusive cigarette users. Cancer Epidemiol Biomarkers Prev; 26(5); 769–78. ©2016 AACR.

Results from individual participant meta-analysis of WC. Footnote to Supplementary Figure 2. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

Supplementary Table S1: Cohorts participating in analysis of coffee variables, Liver Cancer Pooling Project. Supplementary Table S2: Assessment of coffee consumption, Liver Cancer Pooling Project. Supplementary Table S3: Characteristics of participants in the Liver Cancer Pooling Project by coffee drinking. Supplementary Table S4: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Intrahepatic Cholangiocarcinoma Incidence by Sex, Smoking Status, Body Mass Index, and Diabetes, Liver Cancer Pooling Project. Supplementary Table S5: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content; Sensitivity Analysis Excluding WHI and Jointly Modeling Caffeine Content and Drinking Intensity, Liver Cancer Pooling Project. Supplementary Table S6: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Suspected Hepatocellular Carcinoma Incidence by Caffeine Content, Liver Cancer Pooling Project. Supplementary Table S7: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S8: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S9: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Table S10: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Figure S1: Meta-influence Graph of the Influence of Individuals Studies for Associations between Coffee Consumption versus No Consumption and Hepatocellular Carcinoma, Liver Cancer Pooling Project.

Results from individual participant meta-analysis of diabetes. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

Results from individual participant meta-analysis of BMI. Multivariable models include age, sex, study, alcohol, smoking, and race.

Background: Because of unique exposures, studies among farmers may yield insights into the relationship between allergies and non-Hodgkin lymphoid (NHL) neoplasms. We evaluated farm characteristics, allergic symptoms and conditions, and risk of NHL including specific subtypes in the Agricultural Health Study, a prospective cohort of farmers and spouses from North Carolina and Iowa.Methods: We identified 710 incident cases of NHL (including chronic lymphocytic leukemia and multiple myeloma) among 82,370 participants with baseline data on crop and animal exposures, including 454 cases among 52,850 participants with baseline data on recent allergy symptoms (rhinitis) and living on a farm during childhood. HR and 95% confidence intervals (CI) were calculated using multivariable-adjusted proportional hazards models.Results: We observed reduced risks of NHL among farmers and spouses with rhinitis at baseline (HR, 0.63; 95% CI, 0.51–0.79), related to growing soybeans (HR, 0.80; 95% CI, 0.67–0.96), and among farmers who handled stored grains or hay (HR, 0.66; 95% CI, 0.52–0.82). Growing up on a farm was associated with increased NHL risk (HR, 1.51; 95% CI, 1.15–1.98). Results did not differ significantly by NHL subtype.Conclusions: Both the reduced risk of NHL among those with allergy symptoms and specific farm exposures in adulthood, and the increased risk among those who grew up on a farm suggest that the host immune response to agricultural allergens may influence NHL development.Impact: This prospective study is, to our knowledge, the first to investigate the relationship between allergy symptoms and NHL risk in farmers; confirmation of these findings in other farming populations is warranted. Cancer Epidemiol Biomarkers Prev; 24(3); 587–94. ©2015 AACR.

Epidemiological studies are increasingly collecting buccal cells and other sources of DNA for genetic analysis. However, high refusal rates raise concerns about possible selection bias. This study examines the subject characteristics associated with refusal or failure to provide a buccal cell sample. Subjects were male farmers in the Agricultural Health Study, which is being conducted in Iowa and North Carolina. As part of a 5-year follow-up, cohort members were contacted by telephone and asked to participate in a telephone interview and to consent to providing a buccal cell sample using a kit that was mailed to them. Demographic, lifestyle, disease, and occupational characteristics were compared between consenters who returned a sample ("compliers"), nonconsenters ("refusers"), and consenters who failed to return a sample ("noncompliers"). Compliers (n = 8794), refusers (n = 3178), and noncompliers (n = 3008) were quite similar, although compliers tended to be slightly older. Although some significant differences between these groups were observed, the magnitude of these differences was generally small, usually no more than a few percentage points. In conclusion, this study found little difference between male farmers who agreed to provide buccal cell samples versus those who either refused to provide a sample or who agreed but failed to return the sample. Observed differences were typically small and would be unlikely to compromise etiologic associations identified in such a prospective study. In short, there appears to be little selection bias in the Agricultural Health Study buccal cell collection process, further supporting the use of such mailed collection kits in epidemiological research.