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1.  A Prospective Study of Vitamin and Mineral Supplement Use and the Risk of Upper Gastrointestinal Cancers 
PLoS ONE  2014;9(2):e88774.
We examined the association of use of multivitamins or single vitamin/mineral supplements with risk of four upper gastrointestinal cancers in the NIH-AARP Diet and Health Study cohort with 11 years of follow-up. After exclusions, 490,593 persons were included in our analytic cohort and 1780 upper gastrointestinal cancers were accrued. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox models with adjustment for potential confounders. We observed no significant associations between multivitamin use and risk for the four cancer outcomes in crude or adjusted models. Among individual vitamin or mineral supplements, use of iron supplements was associated with significantly lower risk of esophageal adenocarcinoma (HR = 0.68, 95% CI = 0.49 to 0.94) and a significantly increased risk of gastric noncardia adenocarcinoma (HR = 1.59, 95% CI = 1.24 to 2.05). For gastric noncardia adenocarcinoma, we saw associations with zinc use (HR = 1.28, 95% CI = 1.01 to 1.62) and vitamin C use (HR = 0.79 95% CI = 0.65 to 0.96). Calcium use, some of which was reported as antacids and used to treat reflux disease, was associated with higher risk of esophageal adenocarcinoma (HR = 1.27, 95% CI = 1.06 to 1.52) and gastric cardia adenocarcinoma (HR = 1.27, 95% CI = 1.03 to 1.56) cancers. We saw no evidence that multivitamin use was associated with reduced risk of four highly fatal upper gastrointestinal cancers, but there were some differences in risk with reported use of individual supplements.
doi:10.1371/journal.pone.0088774
PMCID: PMC3928299  PMID: 24558423
2.  Association of dietary fat intakes with risk of esophageal and gastric cancer in the NIH-AARP Diet and Health study 
The aim of this study was to investigate whether intakes of total fat and fat subtypes were associated with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastric cardia or gastric non-cardia adenocarcinoma. From 1995–1996, dietary intake data was reported by 494,978 participants of the NIH-AARP cohort. 630 EAC, 215 ESCC, 454 gastric cardia and 501 gastric non-cardia adenocarcinomas accrued to the cohort. Cox proportional hazards regression was used to examine the association between the dietary fat intakes, whilst adjusting for potential confounders. Though apparent associations were observed in energy-adjusted models, multivariate adjustment attenuated results to null (e.g. EAC energy adjusted hazard ratio (HR) and 95% confidence interval (95%CI) 1.66 (1.27–2.18) P for trend <0.01; EAC multivariate adjusted HR (95%CI) 1.17 (0.84–1.64) P for trend=0.58). Similar patterns were also observed for fat subtypes (e.g. EAC saturated fat, energy adjusted HR (95%CI) 1.79 (1.37–2.33) P for trend <0.01; EAC saturated fat, multivariate adjusted HR (95%CI) 1.27 (0.91–1.78) P for trend=0.28). However, in multivariate models an inverse association for polyunsaturated fat (continuous) was seen for EAC in subjects with a body mass index (BMI) in the normal range (18.5–<25 kg/m2) (HR (95%CI) 0.76 (0.63–0.92)), that was not present in overweight subjects (HR (95%CI) 1.04 (0.96–1.14)), or in unstratified analysis (HR (95%CI) 0.97 (0.90–1.05)). P for interaction=0.02. Overall, we found null associations between the dietary fat intakes with esophageal or gastric cancer risk; though a protective effect of polyunsaturated fat intake was seen for EAC in subjects with a normal BMI.
doi:10.1002/ijc.27366
PMCID: PMC3346853  PMID: 22116732
cohort; dietary fat; esophageal neoplasms; stomach neoplasms; prospective
3.  Intake of Fruits and Vegetables and Risk of Pancreatic Cancer in a Pooled Analysis of 14 Cohort Studies 
American Journal of Epidemiology  2012;176(5):373-386.
Fruit and vegetable intake may protect against pancreatic cancer, since fruits and vegetables are rich in potentially cancer-preventive nutrients. Most case-control studies have found inverse associations between fruit and vegetable intake and pancreatic cancer risk, although bias due to reporting error cannot be ruled out. In most prospective studies, inverse associations have been weaker and imprecise because of small numbers of cases. The authors examined fruit and vegetable intake in relation to pancreatic cancer risk in a pooled analysis of 14 prospective studies from North America, Europe, and Australia (study periods between 1980 and 2005). Relative risks and 2-sided 95% confidence intervals were estimated separately for the 14 studies using the Cox proportional hazards model and were then pooled using a random-effects model. Of 862,584 men and women followed for 7−20 years, 2,212 developed pancreatic cancer. The pooled multivariate relative risks of pancreatic cancer per 100-g/day increase in intake were 1.01 (95% confidence interval (CI): 0.99, 1.03) for total fruits and vegetables, 1.01 (95% CI: 0.99, 1.03) for total fruits, and 1.02 (95% CI: 0.99, 1.06) for total vegetables. Associations were similar for men and women separately and across studies. These results suggest that fruit and vegetable intake during adulthood is not associated with a reduced pancreatic cancer risk.
doi:10.1093/aje/kws027
PMCID: PMC3499118  PMID: 22875754
diet; fruit; pancreatic neoplasms; prospective studies; vegetables
4.  Differences between food group reports of low energy reporters and non-low energy reporters on a food frequency questionnaire 
Background
Low-energy reporters (LERs) and non-LERs differ with respect to a number of characteristics, including self-reported intake of foods. Limited data exists investigating food intake differences with LERs identified using doubly labeled water (DLW).
Objective
In the Observing Protein and Energy Nutrition Study (September, 1999-March, 2000), differences were examined between food group reports of LERs and non-LERs on a food frequency questionnaire (FFQ) (n=440).
Design
LERs were identified using DLW. LERs' (n=220) and non-LERs' (n=220) reports of 43 food groups on the FFQ were examined in three ways: whether they reported consuming a food group (yes/no), how frequently they reported consuming it (times/day), and the reported portion size (small, medium, or large). Analyses were adjusted for total energy expenditure from DLW.
Results
LERs compared to non-LERs were less likely to report consumption for one food group among women (soft drinks/regular) and no food groups among men. Reported mean daily frequency of consumption was lower in LERs compared to non-LERs for 23 food groups among women and 24 food groups among men (18 food groups were similar in men and women). Additionally, reported mean portion sizes were smaller for LERs compared to non-LERs for 6 food groups among women and 5 food groups among men (3 food groups were similar in men and women). Results varied minimally by sex and body mass index (BMI).
Conclusions
LERs as compared to non-LERs were more likely to differ regarding their reported frequency of consumption of food groups than their reported consumption (yes/no) of the food groups or the food groups' reported portion sizes. Results did not vary greatly by sex or BMI. It still remains to be known whether improvement in questionnaire design or additional tools or methods would lead to a decrease in differential reporting due to LER status on an FFQ.
doi:10.1016/j.jada.2009.04.004
PMCID: PMC3721508  PMID: 19559136
energy underreporting; dietary assessment; food frequency questionnaire; foods
5.  Coffee intake and breast cancer risk in the NIH-AARP Diet and Health Cohort Study 
There are several biologic mechanisms whereby coffee might reduce breast cancer risk. Caffeine and caffeic acid, major coffee constituents, have been shown to suppress mammary tumor formation in animal models and to inhibit DNA methylation in human breast cancer cells, respectively. Coffee may also reduce risk through decreasing inflammation and influencing estrogen metabolism. However, epidemiologic studies have been inconsistent and few studies have examined the association by estrogen and progesterone receptor (ER/PR) status. We evaluated coffee intake for its effect on incident breast cancer in the NIH-AARP Diet and Health Study cohort, which included 198,404 women aged 50–71 with no history of cancer, who in 1995–1996 completed a questionnaire capturing usual coffee intake over the past year. State cancer registry and mortality index linkage identified 9,915 primary incident breast carcinomas through December 2006; available information on hormone receptor status identified 2,051 ER+/PR+ and 453 ER−/PR− cancers. In multivariate proportional hazards models, coffee intake was not associated with breast cancer risk (p-value for trend=0.38) (relative risk=0.98, 95% confidence interval: 0.91–1.07, for ≥ 4 cups per day as compared to women who never drank coffee), and results did not vary by body mass index or history of benign breast biopsy (p-value for interaction >0.10). We found no evidence of a relationship with either caffeinated or decaffeinated coffee. Null findings persisted for risk of both hormone receptor positive and negative breast cancers. These findings from a large prospective cohort do not support a role of coffee intake in breast carcinogenesis.
doi:10.1002/ijc.26372
PMCID: PMC3290744  PMID: 22020403
breast neoplasms; coffee; caffeine; cohort studies; epidemiology
6.  A Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses following Colonoscopic Polypectomy 
Gastroenterology  2008;136(3):832-841.
Background & Aims
Limited data exist regarding the actual risk of developing advanced adenomas and cancer following polypectomy or the factors that determine risk.
Methods
We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously-resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with development of advanced colorectal neoplasms during surveillance.
Results
During a median follow-up of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; SE=2.2) and those with an adenoma 20 mm in size or greater (19.3%; SE=1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P <0.0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI] 1.19–1.65) were significantly associated with increased risk of metachronous advanced neoplasia, as were the number and size of prior adenomas (P <0.0001 for trend), the presence of villous features (OR, 1.28; 95% CI 1.07–1.52), and proximal location (OR, 1.68; 95% CI 1.43–1.98). High-grade dysplasia was not independently associated with metachronous advanced neoplasia after adjustment for other adenoma characteristics.
Conclusions
Occurrence of advanced colorectal neoplasia is common following polypectomy. Factors that are most strongly associated with risk of advanced neoplasia are patient age and the number and size of prior adenomas.
doi:10.1053/j.gastro.2008.12.007
PMCID: PMC3685417  PMID: 19171141
7.  Dietary Lignan and Proanthocyanidin Consumption and Colorectal Adenoma Recurrence in the Polyp Prevention Trial 
Lignans and proanthocyanidins are plant polyphenols that have shown protective properties against colorectal neoplasms in some human studies. Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to prospectively evaluate the association between lignan and proanthocyanidin intake, estimated from databases linked to a food frequency questionnaire, and adenoma recurrence in 1,859 participants of the Polyp Prevention Trial. Overall, individual or total lignans or proanthocyanidins were not associated with colorectal adenoma recurrence. However, in sex-specific analyses, total lignan intake was positively associated with any adenoma recurrence in women (highest versus lowest lignan intake quartile OR = 2.07, 95% CI: 1.22-3.52, P trend = 0.004) but not in men (P interaction = 0.04). To conclude, dietary lignan and proanthocyanidin consumption was not generally related to colorectal adenoma recurrence; however, high lignan intake may increase the risk of adenoma recurrence in women.
doi:10.1002/ijc.26184
PMCID: PMC3235262  PMID: 21618513
cancer prevention; colorectal adenoma; colorectal cancer; lignans; proanthocyanidins
8.  Health status, neighborhood socioeconomic context and premature mortality in the United States: The NIH-AARP Diet and Health Study 
American journal of public health  2011;102(4):680-688.
Objectives
This study examined whether the risk of premature mortality associated with living in socioeconomically deprived neighborhoods varies according to health status of individuals, accounting for individual-level socioeconomic and health-risk factors.
Methods
566,402 community-dwelling adults (50–71 years of age) in six US states and two metropolitan areas participated in the ongoing prospective NIH-AARP Diet and Health Study, which began in 1995. This analysis included 565,679 eligible subjects. Data were obtained on dietary, lifestyle, self-rated health status, and medical history on baseline mailed questionnaires. Participants were linked to 2000 census data for an index of census-tract socioeconomic deprivation. The main outcome was all-cause mortality ascertained through 2006.
Results
In adjusted survival analyses of persons in good-to-excellent health at baseline, risk of mortality increased with increasing levels of census-tract socioeconomic deprivation. In comparison, neighborhood socioeconomic mortality disparities among persons in fair-to-poor health were not statistically significant after adjustment for demographic characteristics, educational achievement, lifestyle factors and medical conditions of participants.
Conclusion
Neighborhood socioeconomic inequalities lead to large disparities in risk of premature mortality among healthy US adults, but not for persons who were already in poor health.
doi:10.2105/AJPH.2011.300158
PMCID: PMC3489366  PMID: 21852636
9.  Body fat distribution, weight change during adulthood, and thyroid cancer risk in the NIH-AARP Diet and Health Study 
Body mass index (BMI) has been positively associated with thyroid cancer risk in several studies, but the underlying mechanisms remain unclear. We examined the associations for waist and hip circumference and weight change during adulthood with thyroid cancer risk among 125,347 men and 72,363 women in the NIH-AARP Diet and Health Study who completed a second mailed questionnaire in 1996–97. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated separately by sex and adjusted for race/ethnicity, education, and smoking status. During follow-up (median=10.1 years), 106 men and 105 women were diagnosed with a first primary thyroid cancer, as identified through linkage to state cancer registries. Having a large waist circumference (above the clinical cutpoint for normal: >102 cm in men and >88 cm in women) was associated with increased risk in both men (HR=1.79, 95% CI: 1.21–2.63) and women (HR=1.54, 95% CI: 1.05–2.26). Having both a large waist and BMI in the obese range (≥30 kg/m2) approximately doubled the risk of thyroid cancer (HR in men=2.13, 95% CI: 1.18–3.85; HR in women=1.91, 95% CI: 1.31–3.25) compared to having a normal waist circumference/normal BMI (18.5–24.9 kg/m2). We also observed a positive association for weight gain between ages 18–35 in men (gained ≥10.0 kg versus lost/gained <5 kg, HR=1.49, 95% CI: 0.93–2.39, P-trend=0.03), but the association was less pronounced in women. No clear association for weight gain in later life was observed. These results support a potential role for hormonal and metabolic parameters common to central adiposity in thyroid carcinogenesis.
doi:10.1002/ijc.26161
PMCID: PMC3242922  PMID: 21544808
thyroid cancer; anthropometry; obesity; prospective study
10.  Pre-diagnostic Total and High Density Lipoprotein Cholesterol and Risk of Cancer 
Background
Circulating total cholesterol has been inversely associated with cancer risk; however, the role of reverse causation and the associations for high density lipoprotein (HDL) cholesterol have not been fully characterized. We examined the relationship between serum total and HDL cholesterol and risk of overall and site-specific cancers among 29,093 men in the ATBC Study cohort.
Methods
Fasting serum total and HDL cholesterol were assayed at baseline, and 7,545 incident cancers were identified during up to 18 years of follow-up. Multivariable proportional hazards models were conducted to estimate relative risks.
Results
Higher serum total cholesterol concentration was associated with decreased risk of cancer overall (RR for comparing high versus low quintile=0.85, 95%CI=0.79–0.91; P trend < 0.001; >276.7 versus <203.9 mg/dL), and the inverse association was particularly evident for cancers of the lung and liver. These associations were no longer significant, however, when cases diagnosed during the first nine years of follow-up were excluded. Greater HDL cholesterol was also associated with decreased risk of cancer (RR for high versus low quintile=0.89, 95%CI=0.83–0.97; P trend=0.01; >55.3 versus <36.2 mg/dL). The inverse association of HDL cholesterol was evident for cancers of lung, prostate, liver, and the hematopoietic system, and the associations of HDL cholesterol with liver and lung cancers remained after excluding cases diagnosed within 12 years of study entry.
Conclusion
Our findings suggest that prior observations regarding serum total cholesterol and cancer are largely explained by reverse causation. Although chance and reverse causation may explain some of the inverse HDL associations, we cannot rule out some etiologic role for this lipid fraction.
doi:10.1158/1055-9965.EPI-08-1248
PMCID: PMC3534759  PMID: 19887581
serum; cholesterol; high density lipoprotein cholesterol; cancer; risk; prospective; cohort
11.  Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study 
Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50–71 years at the time of the baseline questionnaire in 1995–1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01–1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05–1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies.
doi:10.1097/CEJ.0b013e328347622f
PMCID: PMC3394850  PMID: 21934624
epithelial; nitrate and nitrite; ovarian cancer
12.  Folate Intake and Risk of Pancreatic Cancer: Pooled Analysis of Prospective Cohort Studies 
Background
Epidemiological studies evaluating the association between folate intake and risk of pancreatic cancer have produced inconsistent results. The statistical power to examine this association has been limited in previous studies partly because of small sample size and limited range of folate intake in some studies.
Methods
We analyzed primary data from 14 prospective cohort studies that included 319 716 men and 542 948 women to assess the association between folate intake and risk of pancreatic cancer. Folate intake was assessed through a validated food-frequency questionnaire at baseline in each study. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random effects model. All statistical tests were two-sided.
Results
During 7–20 years of follow-up across studies, 2195 pancreatic cancers were identified. No association was observed between folate intake and risk of pancreatic cancer in men and women (highest vs lowest quintile: dietary folate intake, pooled multivariable RR = 1.06, 95% CI = 0.90 to 1.25, Ptrend = .47; total folate intake [dietary folate and supplemental folic acid], pooled multivariable RR = 0.96, 95% CI = 0.80 to 1.16, Ptrend = .90). No between-study heterogeneity was observed (for dietary folate, Pheterogeneity = .15; for total folate, Pheterogeneity = .22).
Conclusion
Folate intake was not associated with overall risk of pancreatic cancer in this large pooled analysis.
doi:10.1093/jnci/djr431
PMCID: PMC3243674  PMID: 22034634
13.  Dietary fiber intake and mortality in the NIH-AARP Diet and Health Study 
Archives of internal medicine  2011;171(12):1061-1068.
Background
Dietary fiber has been hypothesized to lower risk of coronary heart disease, diabetes, and some cancers. However, little is known of the effect of dietary fiber on total death and cause-specific deaths.
Methods
We examined dietary fiber intake in relation to total mortality and death from specific causes in the NIH-AARP Diet and Health Study, a prospective cohort study. Diet was assessed using a food frequency questionnaire at baseline. Cause of death was identified using the National Death Index Plus. Cox proportional hazard models were used to estimate relative risks (RRs) and two-sided 95% confidence intervals (CI).
Results
During an average of 9 years of follow-up, we identified 20,126 deaths in men and 11,330 deaths in women. Dietary fiber intake was associated with significantly lowered risk of total death in both men and women (multivariate RR comparing the highest vs. the lowest quintile =0.78, 95% CI:0.73–0.82, p-trend, <0.001 in men; 0.78. 95% CI:0.73–0.85, p-trend, <0.001 in women). Dietary fiber intake also lowered risk of death from cardiovascular, infectious, and respiratory diseases by 24%–56% in men and 34%–59% in women. Inverse association between dietary fiber intake and cancer death was observed in men, but not in women. Dietary fiber from grains, but not from other sources, was significantly inversely related to total and cause-specific death in both men and women.
Conclusions
Dietary fiber may reduce the risk of death from cardiovascular, infectious and respiratory diseases. Making fiber-rich food choices more often may provide significant health benefits.
doi:10.1001/archinternmed.2011.18
PMCID: PMC3513325  PMID: 21321288
14.  Prospective Study of Dietary Fiber, Whole Grain Foods, and Small Intestinal Cancer 
Gastroenterology  2008;135(4):1163-1167.
Background & Aims
Although a number of epidemiologic studies have found dietary fiber and whole grains to be inversely associated with colorectal cancer incidence, studies of dietary and other risk factors for small intestinal cancer have been sparse and all of a case-control design. We conducted a prospective cohort study to determine the relationship between intake of dietary fiber/whole grains and the incidence of small intestinal cancer.
Methods
We analyzed dietary data collected in 1995 and 1996 from 293,703 men and 198,618 women in the NIH-AARP Diet and Health Study. We used multivariate Cox proportional hazards models to estimate relative risk (RR) and two-sided 95% confidence intervals (CIs) for quintiles of dietary fiber and whole grain intake.
Results
165 individuals developed small intestinal cancers through 2003. Dietary fiber/whole grain intake was generally associated with a lower risk of small intestinal cancer. The multivariate RR (95% CIs; 5th vs. 1st. intake quintile) were 0.79 (0.43–1.44) (p-trend, 0.41) for total dietary fiber, 0.51 (0.29–0.89) (p-trend, 0.01) for fiber from grains, and 0.59 (0.33–1.05) (p-trend=0.06) for whole-grain foods.
Conclusions
Intake of fiber from grains and whole-grain foods was inversely associated with small intestinal cancer incidence; the RR values were consistent with those of the same dietary factors for large bowel cancer in this cohort. In conjunction with the anatomic and physiologic commonalities of the large and small bowel, as well as the mutually increased risks for second cancer for both organs, grain fiber and whole grain foods appear to protect against lower gastrointestinal cancers.
doi:10.1053/j.gastro.2008.07.015
PMCID: PMC3513331  PMID: 18727930
dietary fiber; whole grain; small intestinal cancer; cohort study
15.  Fatherhood and the risk of cardiovascular mortality in the NIH-AARP Diet and Health Study 
Human Reproduction (Oxford, England)  2011;26(12):3479-3485.
Background
Fertility potential and reproductive fitness may reflect a man's future health, given that over one-third of the male human genome is involved in reproduction. We sought to determine if offspring number predicts cardiovascular death in the US men.
Methods
Using data from the NIH-AARP Diet and Health Study, 137 903 men (aged 50–71) without prior cardiovascular disease were followed-up for an average of 10.2 years. International Classification of Diseases, ninth edition, codes were used to establish the cause of death, and multivariable Cox proportional hazards modeling was used to estimate the association between offspring number and cardiovascular death while accounting for sociodemographic and lifestyle characteristics.
Results
Almost all (92%) participants had fathered at least one child and 50% had three or more offspring. A total of 3082 men died of cardiovascular causes during follow-up for an age-adjusted incidence rate of 2.70 per 1000 person-years. Compared with fathers, after adjusting for sociodemographic and lifestyle factors, childless men had a 17% [hazard ratio (HR): 1.17; 95% confidence interval (CI): 1.03–1.32] increased risk of death from cardiovascular disease contracted in the study period, and this elevated risk appeared to extend also to men with only one child. In comparison with fathers of five or more children, adjusted relative hazards for cardiovascular mortality of this sort were 1.06 (95% CI: 0.92–1.22) for four children, 1.02 (0.90–1.16) for three children, 1.02 (0.90–1.16) for two children, 1.11 (0.95–1.30) for one child and 1.21 (1.03–1.41) for no children.
Conclusions
Married men who have no children have a higher risk of dying from cardiovascular disease contracted after the age of 50 than men with two or more children.
doi:10.1093/humrep/der305
PMCID: PMC3212876  PMID: 21946940
infertility; male infertility; epidemiology
16.  Using Regression Calibration Equations That Combine Self-Reported Intake and Biomarker Measures to Obtain Unbiased Estimates and More Powerful Tests of Dietary Associations 
American Journal of Epidemiology  2011;174(11):1238-1245.
The authors describe a statistical method of combining self-reports and biomarkers that, with adequate control for confounding, will provide nearly unbiased estimates of diet-disease associations and a valid test of the null hypothesis of no association. The method is based on regression calibration. In cases in which the diet-disease association is mediated by the biomarker, the association needs to be estimated as the total dietary effect in a mediation model. However, the hypothesis of no association is best tested through a marginal model that includes as the exposure the regression calibration-estimated intake but not the biomarker. The authors illustrate the method with data from the Carotenoids and Age-Related Eye Disease Study (2001--2004) and show that inclusion of the biomarker in the regression calibration-estimated intake increases the statistical power. This development sheds light on previous analyses of diet-disease associations reported in the literature.
doi:10.1093/aje/kwr248
PMCID: PMC3224252  PMID: 22047826
bias (epidemiology); carotenoids; cataract; lutein; measurement error; sample size
17.  Socioeconomic deprivation impact on meat intake and mortality: NIH-AARP Diet and Health Study 
Cancer causes & control : CCC  2011;22(12):1699-1707.
Objective
Previous studies have not examined potential interactions between meat intake and characteristics of the local environment on the risk of mortality. This study examined the impact of area socioeconomic deprivation on the association between meat intake and all-cause and cause-specific mortality after accounting for individual-level risk factors.
Methods
In the prospective NIH-AARP Diet and Health Study, we analyzed data from adults, ages 50–71 years at baseline (1995–1996). Individual-level dietary intake and health risk information was linked to the demographic and socioeconomic context of participants’ local environment based on census tract data. Deaths (n=33,831) were identified through December 2005. Multilevel Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for quintiles of area deprivation scores.
Results
Associations of red and processed meats with mortality were consistent across deprivation quintiles. Men residing in least-deprived neighborhoods had a stronger protective effect for white meat consumption. No differences by deprivation index were observed for women.
Conclusion
Red and processed meat intake increases mortality risk regardless of level of deprivation within a given neighborhood suggesting biological mechanisms rather than neighborhood contextual factors may underlie these meat-mortality associations. The effect of white meat intake on cancer mortality was modified by area deprivation among men.
doi:10.1007/s10552-011-9846-0
PMCID: PMC3405542  PMID: 21971817
meat consumption; mortality; census; socioeconomic; clustered survival data
18.  Reproductive and Hormonal Factors and Lung Cancer Risk in the NIH-AARP Diet and Health Study Cohort 
Background
Lung cancer exhibits unique patterns among women, including high adenocarcinoma rates among non-smokers. Inconsistent findings regarding hormonal factors on risk may reflect incomplete control for confounding, misclassification of exposures, or insufficient attention to variation by histology.
Methods
Among 185,017 women, ages 50–71 years, recruited during 1995–1996 for the NIH-AARP Diet and Health Study, we identified 3,512 incident lung cancers (including 276 in never smokers) in follow-up through December 2006. Multivariable Cox proportional hazards models estimated relative risks (RRs) and 95% confidence intervals (CIs) for self-reported hormonally-related risk factors.
Results
After adjustment for smoking and other confounders, subjects with late menarche were at reduced risk, with the association specific for adenocarcinomas (RR=0.72 for menarche 15+ vs. <11, p for trend<0.01). Subjects with early ages at ovarian cessation (either from natural menopause or bilateral oophorectomy) were at an increased risk for adenocarcinomas and squamous cell tumors, but the associations were strongest for smokers, suggesting either residual confounding or an enhanced effect of menopausally-related factors among subjects with decreased endogenous estrogens. In contrast, we saw no relationships of risk with either parity, age at first birth, or exogenous hormone use.
Conclusions
Elevated levels of hormones may adversely affect lung function early in life, while assisting with cellular and immunologic responses later in life. Additional attention towards the role of hormonal factors may further our understanding of lung carcinogenesis.
Impact
Our findings provide some support for a role of hormonal factors in the etiology of lung cancer, although the mechanisms appear complicated.
doi:10.1158/1055-9965.EPI-10-1325
PMCID: PMC3507989  PMID: 21467241
lung cancer; hormonal factors; menopause; risk; histology
19.  Physical activity and head and neck cancer risk 
Cancer causes & control : CCC  2008;19(10):1391-1399.
Objective
To investigate the relation of physical activity to head and neck cancer.
Methods
We prospectively examined the association between physical activity and head and neck cancer in 487,732 men and women who, at baseline in 1995–1996, were 50–71 years old and free of cancer and emphysema. Follow-up occurred through December 31, 2003.
Results
During follow-up, 1,249 participants developed head and neck cancer, of which 42.0%, 18.9%, and 32.5% were located in the oral cavity, pharynx, and larynx, respectively. In analyses adjusted for age and gender, the relative risks (RR) of head and neck cancer for increasing frequency of physical activity (0, < 1, 1–2, 3–4, and ≥ 5 times per week) were 1.0 (reference), 0.76, 0.66, 0.57, and 0.62 (95%-CI=0.52–0.74), respectively (p for trend<0.001). After multivariate adjustment including smoking, the relation was attenuated and became statistically non-significant (RR comparing extreme physical activity categories=0.89, 95%-CI=0.74–1.06; p for trend=0.272). In analyses of head and neck cancer subtypes, the corresponding RRs for cancers of the oral cavity, pharynx, and larynx were 0.98 (95%-CI=0.75–1.29), 0.70 (95%-CI=0.45–1.08), and 0.82 (95%-CI=0.59–1.13), respectively.
Conclusions
Our findings suggest that physical activity is unlikely to play an important role in the prevention of head and neck cancer.
doi:10.1007/s10552-008-9211-0
PMCID: PMC3507337  PMID: 18704714
Head and neck cancer; oral cavity cancer; pharynx cancer; larynx cancer; physical activity
20.  Body mass index and risk of ovarian cancer 
Cancer  2009;115(4):812-822.
Convincing epidemiologic evidence links excess body mass to increased risks of endometrial and postmenopausal breast cancers but the relation of body mass index (BMI) to ovarian cancer risk remains inconclusive. Potential similarities regarding a hormonal mechanism in the etiology of female cancers highlight the importance of investigating associations according to menopausal hormone therapy (MHT) use. However, data addressing whether the relation of BMI to ovarian cancer differs by MHT use are very sparse. We prospectively investigated the association between BMI and ovarian cancer among 94,525 U.S. women, followed from 1996–1997 to December 31, 2003. During 7 years of follow-up, we documented 303 epithelial ovarian cancer cases. As compared with normal weight women (BMI 18.5–24.9 kg/m2), the multivariate relative risk (MVRR) of ovarian cancer for obese women (BMI ≥30 kg/m2) in the cohort as a whole was 1.25 (95%-CI=0.93–1.68). Among women who never used MHT, the MVRR for obese versus normal weight women was 1.80 (95%-CI=1.16–2.80). In contrast, no relation between BMI and ovarian cancer was apparent among women who ever used MHT (MVRR=0.96; 95%-CI=0.64–1.43; P-interaction=0.02). Exploratory analyses also suggested a positive association between BMI and ovarian cancer among women without a family history of ovarian cancer (MVRR comparing obese versus normal weight women=1.36; 95%-CI=0.99–1.85), but no relation with BMI was apparent among women with a positive family history of ovarian cancer (MVRR=0.73; 95%-CI=0.34–1.60; P-interaction=0.02). We suspect that obesity is associated with enhanced ovarian cancer risk through a hormonal mechanism.
doi:10.1002/cncr.24086
PMCID: PMC3507338  PMID: 19127552
21.  A prospective cohort study of obesity and risk of esophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health study 
Gut  2011;61(9):1261-1268.
Objective
Incidence of esophageal adenocarcinoma (EAC) has increased rapidly over the past forty years and accumulating evidence suggests that obesity, as measured by body mass index (BMI), is a major risk factor. However, it remains unclear whether abdominal obesity is associated with esophageal and gastric adenocarcinoma.
Design
Cox proportional hazards regression was used to examine associations between overall and abdominal obesity with EAC and gastric adenocarcinoma among 218,854 participants in the prospective NIH-AARP cohort.
Results
253 incident EAC, 191 gastric cardia adenocarcinomas, and 125 gastric non-cardia adenocarcinomas accrued to the cohort. Overall obesity (BMI) was positively associated with EAC and gastric cardia adenocarcinoma risk (highest [≥35 kg/m2] versus referent [18.5–<25 kg/m2]; hazard ratio (HR) 95% confidence interval (95% CI); 2.11 (1.09–4.09) and 3.67 (2.00–6.71), respectively). Waist circumference was also positively associated with EAC and gastric cardia adenocarcinoma risk, (highest versus referent; HR (95% CI) 2.01 (1.35–3.00) and 2.22 (1.43–3.47), respectively), whereas waist-to-hip ratio (WHR) was positively associated with EAC risk only (highest versus referent; HR (95% CI) 1.81 (1.24–2.64)); persisted in patients with normal BMI (18.5–<25 kg/m2). Mutual adjustment of WHR and BMI attenuated both, but did not eliminate the positive associations for either with risk of EAC. In contrast, the majority of the anthropometric variables were not associated with adenocarcinomas of the gastric non-cardia.
Conclusion
Overall obesity was associated with a higher risk of EAC and gastric cardia adenocarcinoma, whereas abdominal obesity was found to be associated with increased EAC risk; even in people with normal BMI.
doi:10.1136/gutjnl-2011-300551
PMCID: PMC3504700  PMID: 22174193
adenocarcinoma; epidemiology; esophageal cancer; gastric adenocarcinoma; obesity
22.  Dietary factors and risk of chronic lymphocytic leukemia and small lymphocytic lymphoma: a pooled analysis of two prospective studies 
Background
Other than male sex, family history, advanced age, and race, risk factors for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are unknown. Very few studies have investigated diet in relation to these leukemias, and no consistent associations are known.
Methods
Using two large prospective population-based studies, we evaluated the relationship between diet and CLL/SLL risk. Among 525,982 men and women free of cancer at enrollment, we identified 1,129 incident CLL/SLL cases during 11.2 years of follow-up.
Results
We found no associations between total fat, saturated fat, fiber, red meat, processed meat, fruit or vegetable intake and risk of CLL/SLL. We noted a suggestive positive association between body mass index (BMI) and CLL/SLL (hazard ratio =1.30; 95% confidence interval= 0.99-1.36).
Conclusion
We did not find any associations between foods or nutrients and CLL/SLL.
Impact
Our large prospective study indicates that diet may not play a role in CLL/SLL development.
doi:10.1158/1055-9965.EPI-10-0585
PMCID: PMC3501724  PMID: 20929883
diet; chronic lymphocytic leukemia; body mass index; cohort study
23.  Associations between food patterns defined by cluster analysis and colorectal cancer incidence in the NIH-AARP Diet and Health Study 
Objectives
To examine associations between food patterns, constructed with cluster analysis, and colorectal cancer incidence within the National Institutes of Health (NIH)–AARP Diet and Health Study.
Design
A prospective cohort, aged 50–71 years at baseline in 1995–96, followed until the end of 2000.
Subjects and Method
Food patterns were constructed, separately in men (n=293 576) and women (n=198 730), with 181 food variables (daily intake frequency per 1 000 kilocalories) from a food frequency questionnaire. Four large clusters were identified in men and three in women. Cox proportional hazards regression examined associations between patterns and cancer incidence.
Result
In men, a Vegetable and Fruit Pattern was associated with reduced colorectal cancer incidence (multivariate HR: 0.85 95%CI: 0.76, 0.94), when compared to less salutary food choices. Both the Vegetable and Fruit pattern and a Fat-Reduced Foods pattern were associated with reduced rectal cancer incidence in men. In women, a similar Vegetable and Fruit pattern was associated with colorectal cancer protection (age-adjusted HR: 0.82 95%CI: 0.70, 0.95), but the association was not statistically significant in multivariate analysis.
Conclusion
These results, together with findings from previous studies support the hypothesis that micronutrient dense, low-fat, high-fiber food patterns protect against colorectal cancer.
doi:10.1038/ejcn.2008.40
PMCID: PMC3500882  PMID: 18685556
food patterns; cluster analysis; colorectal cancer; prospective cohort
24.  Concentration of folate in colorectal tissue biopsies predicts prevalence of adenomatous polyps 
Gut  2010;60(1):66-72.
Background and aims
Folate has been implicated as a potential etiologic factor for colorectal cancer. Prior research has not adequately exploited concentrations of folate in normal colonic mucosal biopsies to examine the issue.
Methods
We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of adenoma according to tissue concentration of folate using asymptomatic average-risk women (40–70 years) in a colorectal cancer screening study. Of the 1,593 eligible women who were offered enrollment, 1,483 (93%) participated. Colonoscopy was complete to the cecum in 98.7% (1,463/1,483) of the subjects and normal colonic tissue biopsies were obtained from 813 (56%) of these, of whom 170 had at least one adenoma.
Results
We observed a marginal reduction in risk for proximal adenomas (OR=0.56, 95% CI 0.29–1.09) but not distal adenomas (OR=1.01, 95% CI 0.43–2.37) among women in the highest quintile of tissue folate concentration. We observed a significant reduction in risk for advanced adenoma for women in the highest quintile of tissue folate concentration (OR=0.24, 95% CI 0.06–0.93). Defining the outcome as proximal adenomatous and/or hyperplastic polyps, we also observed statistically significant inverse associations with tissue concentrations of folate (OR=0.54, 95% CI 0.31–0.95 for Q5 vs. Q1).
Conclusions
These findings are consistent with the hypothesis that folate status of colonic mucosa is an exposure that is etiologically important in determining the risk of particular molecular sub-types of colorectal cancer.
doi:10.1136/gut.2010.208074
PMCID: PMC3500908  PMID: 21068136
Adenoma; folic acid; DNA microsatellite instability; colon carcinogenesis; methylation
25.  Ongoing Colorectal Cancer Risk Despite Surveillance Colonoscopy: The Polyp Prevention Trial Continued Follow-up Study 
Gastrointestinal endoscopy  2009;71(1):111-117.
Background
Despite regular colonoscopy, interval colorectal cancer (CRC) may occur. Long-term studies examining CRC rates in patients with previous colonoscopy are lacking.
Objective
We examined the rate of interval CRC in the Polyp Prevention Trial-Continued Follow-up Study (PPT-CFS), an observational study of participants which began after the Polyp Prevention Trial (PPT) ended.
Design
Prospective
Setting
A national U.S. community-based polyp prevention trial
Main Outcome Measurements
Medical records of CRC were collected, reviewed, and abstracted in a standardized fashion.
Results
Among 2,079 PPT participants, 1,297 (62.4%) agreed to participate in the PPT-CFS. They were followed for a median of 6.2 years after 4.3 years of median follow up in the main PPT. Nine cases of CRC were diagnosed over 7,626 person years of observation (PYO) for an incidence rate of 1.2/1000 PYO. The ratio of CRCs observed compared to that expected by SEER was 0.64 (95% CI 0.28–1.06). Including all CRCs (N=22) since the beginning of the PPT trial, the observed compared to expected rate by SEER was 0.74 (95% CI 0.47–1.05). Of patients who developed CRC in the PPT-CFS, 78% had a history of an advanced adenoma compared to only 43% among patients who remained cancer-free (p=0.04).
Limitations
A relatively small number of interval cancers were detected.
Conclusions
Despite frequent colonoscopy during the PPT trial, in the years subsequent to the trial, there was a persistent ongoing risk for cancer. Subjects with a history of advanced adenoma are at increased risk for subsequent cancer and should be followed closely with continued surveillance.
doi:10.1016/j.gie.2009.05.010
PMCID: PMC3501210  PMID: 19647250
Colorectal cancer; colonoscopy; surveillance

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