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1.  Prediagnosis Soy Food Consumption and Lung Cancer Survival in Women 
Journal of Clinical Oncology  2013;31(12):1548-1553.
We recently reported an inverse association between soy food intake and lung cancer risk among nonsmoking women. The effect size for aggressive lung cancers was larger than that observed for other types of lung cancer. Therefore, we hypothesized that soy consumption may favorably affect the overall survival of patients with lung cancer.
Patients and Methods
This analysis included 444 women with incident lung cancer identified from the Shanghai Women's Health Study. Prediagnosis soy food intake was assessed at enrollment and reassessed 2 years later. Proportional hazards models were used to evaluate the association between soy food intake and overall survival.
Of the 444 patients with lung cancer, 318 died during follow-up. Initial analyses including all patients showed that higher intake of soy food was associated with better overall survival after adjusting for demographic and lifestyle characteristics and other nonclinical factors. Larger effect sizes for the association were found after additional adjustment for tumor stage and treatment in analyses including 301 patients with data available on these clinical factors. Compared with the median intake of soy food, fully adjusted hazard ratios for total mortality associated with the 10th, 30th, 70th, and 90th percentiles of intake were 1.81 (95% CI, 1.26 to 2.59), 1.25 (95% CI, 1.09 to 1.42), 0.88 (95% CI, 0.80 to 0.97), and 0.89 (95% CI, 0.68 to 1.16), respectively. Similar inverse associations were observed for dietary isoflavone intake.
This study suggests, to the best of our knowledge for the first time, that, among women with lung cancer, prediagnosis intake of soy food is associated with better overall survival.
PMCID: PMC3625711  PMID: 23530109
2.  Principal component analysis of dietary and lifestyle patterns in relation to risk of subtypes of esophageal and gastric cancer 
Annals of epidemiology  2011;21(7):543-550.
To perform pattern analyses of dietary and lifestyle factors in relation to risk of esophageal and gastric cancers.
We evaluated risk factors for esophageal adenocarcinoma (EA), esophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma (GCA), and other gastric cancers (OGA) using data from a population-based case-control study conducted in Connecticut, New Jersey, and western Washington state. Dietary/lifestyle patterns were created using principal component analysis (PCA). Impact of the resultant scores on cancer risk was estimated through logistic regression.
PCA identified six patterns: meat/nitrite, fruit/vegetable, smoking/alcohol, legume/meat alternate, GERD/BMI, and fish/vitamin C. Risk of each cancer under study increased with rising meat/nitrite score. Risk of EA increased with increasing GERD/BMI score, and risk of ESCC rose with increasing smoking/alcohol score and decreasing GERD/BMI score. Fruit/vegetable scores were inversely associated with EA, ESCC, and GCA.
PCA may provide a useful approach for summarizing extensive dietary/lifestyle data into fewer interpretable combinations that discriminate between cancer cases and controls. The analyses suggest that meat/nitrite intake is associated with elevated risk of each cancer under study, while fruit/vegetable intake reduces risk of EA, ESCC, and GCA. GERD/obesity were confirmed as risk factors for EA and smoking/alcohol as risk factors for ESCC.
PMCID: PMC3109225  PMID: 21435900
esophageal adenocarcinoma; gastric cardia adenocarcinoma; esophageal squamous cell carcinoma; diet; principal components
3.  Night-Shift Work and Breast Cancer Risk in a Cohort of Chinese Women 
American Journal of Epidemiology  2010;171(9):953-959.
Shift work involving disruption of circadian rhythms has been classified as a probable cause of human cancer by the International Agency for Research on Cancer, based on limited epidemiologic evidence and abundant experimental evidence. The authors investigated this association in a population-based prospective cohort study of Chinese women. At baseline (1996–2000), information on lifetime occupational history was obtained from 73,049 women. Lifetime night-shift exposure indices were created using a job exposure matrix. During 2002–2004, self-reported data on frequency and duration of night-shift work were collected. Hazard ratios and 95% confidence intervals, adjusted for major breast cancer risk factors, were calculated. During follow-up through 2007, 717 incident cases of breast cancer were diagnosed. Breast cancer risk was not associated with ever working the night shift on the basis of the job exposure matrix (adjusted hazard ratio = 1.0, 95% confidence interval: 0.9, 1.2) or self-reported history of night-shift work (adjusted hazard ratio = 0.9, 95% confidence interval: 0.7, 1.1). Risk was also not associated with frequency, duration, or cumulative amount of night-shift work. There were no indications of effect modification. The lack of an association between night-shift work and breast cancer adds to the inconsistent epidemiologic evidence. It may be premature to consider shift work a cause of cancer.
PMCID: PMC2877476  PMID: 20375193
breast neoplasms; China; prospective studies; work schedule tolerance
4.  Contemporary Renal Cell Cancer Epidemiology 
Cancer journal (Sudbury, Mass.)  2008;14(5):288-301.
We analyzed renal cell cancer incidence patterns in the United States and reviewed recent epidemiologic evidence with regard to environmental and host genetic determinants of renal cell cancer risk. Renal cell cancer incidence rates continued to rise among all racial/ethnic groups in the United States, across all age groups, and for all tumor sizes, with the most rapid increases for localized stage disease and small tumors. Recent cohort studies confirmed the association of smoking, excess body weight, and hypertension with an elevated risk of renal cell cancer, and suggested that these factors can be modified to reduce the risk. There is increasing evidence for an inverse association between renal cell cancer risk and physical activity and moderate intake of alcohol. Occupational exposure to TCE has been positively associated with renal cell cancer risk in several recent studies, but its link with somatic mutations of the VHL gene has not been confirmed. Studies of genetic polymorphisms in relation to renal cell cancer risk have produced mixed results, but genome-wide association studies with larger sample size and a more comprehensive approach are underway. Few epidemiologic studies have evaluated risk factors by subtypes of renal cell cancer defined by somatic mutations and other tumor markers.
PMCID: PMC3077538  PMID: 18836333
renal cell cancer; incidence trends; cohort studies; smoking; obesity; hypertension; diet; occupation; genetic polymorphism; somatic mutation
5.  Menstrual and reproductive factors and gastric cancer risk in a large prospective study of women 
Gut  2007;56(12):1671-1677.
Gastric cancer incidence rates are consistently lower in women than men in both high and low‐risk regions worldwide. Sex hormones, such as progesterone and estrogen, may protect women against gastric cancer.
To investigate the association of menstrual and reproductive factors and gastric cancer risk.
These associations were prospectively investigated in 73 442 Shanghai women. After 419 260 person‐years of follow‐up, 154 women were diagnosed with gastric cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models adjusted for age, body mass index, education, income, and cigarette use.
No associations were observed between gastric cancer risk and age of menarche, number of children, breast feeding, or oral contraceptive use. In contrast, associations were observed with age of menopause (HR 0.80 per five‐year increase in menopausal age, 95% CI 0.66–0.97), years of fertility (participants with less than 30 years of fertility were at increased risk compared with those with 30–36 years of fertility, HR 1.90, 95% CI 1.25–2.90), years since menopause (HR 1.26 per five years, 95% CI 1.03–1.53), and intrauterine device use (HR for users 1.61, 95% CI 1.08–2.39).
These results support the hypothesis that female hormones play a protective role in gastric cancer risk.
PMCID: PMC2095686  PMID: 17627962
stomach neoplasms; cohort studies; prospective studies; hormones
6.  Calibrating a population-based job-exposure matrix using inspection measurements to estimate historical occupational exposure to lead for a population-based cohort in Shanghai, China 
The epidemiologic evidence for the carcinogenicity of lead is inconsistent and requires improved exposure assessment to estimate risk. We evaluated historical occupational lead exposure for a population-based cohort of women (n=74,942) by calibrating a job-exposure matrix (JEM) with lead fume (n=20,084) and lead dust (n=5,383) measurements collected over four decades in Shanghai, China. Using mixed-effect models, we calibrated intensity JEM ratings to the measurements using fixed-effects terms for year and JEM rating. We developed job/industry-specific estimates from the random-effects terms for job and industry. The model estimates were applied to subjects’ jobs when the JEM probability rating was high for either job or industry; remaining jobs were considered unexposed. The models predicted that exposure increased monotonically with JEM intensity rating and decreased 20–50-fold over time. The cumulative calibrated JEM estimates and job/industry-specific estimates were highly correlated (Pearson correlation=0.79–0.84). Overall, 5% of the person-years and 8% of the women were exposed to lead fume; 2% of the person-years and 4% of the women were exposed to lead dust. The most common lead-exposed jobs were manufacturing electronic equipment. These historical lead estimates should enhance our ability to detect associations between lead exposure and cancer risk in future epidemiologic analyses.
PMCID: PMC3508334  PMID: 22910004
lead; cancer; exposure assessment; occupational exposure; job exposure matrix; mixed-effects model
7.  Use of Nephron Sparing Surgery among Renal Cell Carcinoma Patients with Diabetes and Hypertension 
Urologic oncology  2013;32(1):10.1016/j.urolonc.2012.09.014.
Nephron-sparing surgery (NSS) is recommended for renal cell carcinoma (RCC) patients at risk for chronic kidney disease. We assessed the prevalence of NSS among RCC patients with pre-existing diabetes and/or hypertension who participated in a population-based epidemiological RCC study.
Methods and Materials
Patients with RCC were enrolled in the United States Kidney Cancer Study (KCS), a case–control study in the metropolitan areas of Detroit and Chicago from 2002-2007. After determining whether patients had diabetes and/or hypertension, we ascertained the proportion of patients from the Detroit site who received NSS. Bivariate and multivariate analyses were performed to evaluate associations between these CKD risk factors and receipt of NSS.
We identified 835 patients treated with radical nephrectomy (78%) or NSS (22%) from 2002-2007. Among this cohort, 60% had pre-existing diabetes and/or hypertension. Patients with both diabetes and hypertension were more than twice as likely to receive NSS (OR 2.42, 95% CI 1.47-3.96). Conversely, patients with only hypertension (OR 1.33, 95% CI 0.92-1.93) or diabetes (OR 0.97, 95% CI 0.92-1.93) were no more likely to receive NSS than patients with neither risk factor.
The more frequent utilization of NSS among patients with both diabetes and hypertension suggests growing recognition by urologists of the importance of these risk factors for future development of CKD among patients facing surgical therapy for RCC. However, the concurrent observation that patients with only one of these CKD risk factors did not receive increased utilization of NSS highlights an immediate opportunity to improve the surgical treatment of patients with RCC.
PMCID: PMC3762909  PMID: 23419677
renal cell carcinoma; nephrectomy; diabetes; hypertension; physician practice patterns
8.  A genome-wide association study of renal cell carcinoma among African Americans 
Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) in populations of European ancestry have identified four susceptibility loci. No GWAS has been conducted among African Americans (AAs), who experience a higher incidence of RCC. We conducted a GWAS in which we analyzed 1,136,723 common single-nucleotide polymorphisms (SNPs) among 255 cases and 375 controls of African ancestry, and further investigated 16 SNPs in a replication set (140 cases, 543 controls). The 12p11.23 variant rs10771279, located 77kb from the European-ancestry RCC marker rs718314, was associated with RCC risk in the GWAS (P=1.2 × 10−7) but did not replicate (P=0.99). Consistent with European-ancestry findings, the A allele of rs7105934 on 11q13.3 was associated with decreased risk [odds ratio (OR)=0.76, 95% confidence interval (CI)=0.64–0.91; P=0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07 respectively among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR=0.56; P=7.4 × 10−7) and absent for cases of other or unknown histology (OR=1.02; P=0.86). Analyses of rs7105934 by subtype among European-ancestry participants from these studies yielded similar findings (ORs 0.69 and 0.92 respectively). This study provides, to our knowledge, the first evidence that rs7105934 is an RCC susceptibility locus among AAs. Our finding that the association with this SNP may be specific to ccRCC is novel and requires additional investigation. Additional investigation of rs10771279 and other suggestive GWAS findings is also needed.
PMCID: PMC3901793  PMID: 24220910
9.  Diet and lifestyle factors and risk of subtypes of esophageal and gastric cancer: classification tree analysis 
Annals of epidemiology  2013;24(1):50-57.
Although risk factors for squamous cell carcinoma of the esophagus (SCC) and adenocarcinomas of the esophagus (EA), gastric cardia (GC) and other (non-cardia) gastric sites (OG) have been identified, little is known about interactions among risk factors. We sought to examine interactions of diet, other lifestyle, and medical factors with risks of subtypes of esophageal and gastric cancer.
We used classification tree analysis to analyze data from a population-based case-control study (1,095 cases, 687 controls) conducted in Connecticut, New Jersey, and western Washington State.
Frequency of reported gastroesophageal reflux (GERD) symptoms was the most important risk stratification factor for EA, GC, and OG, with dietary factors (EA, OG), smoking (EA, GC), wine intake (GC, OG), age (OG), and income (OG) appearing to modify risk of these cancer sites. For SCC, smoking was the most important risk stratification factor, with GERD, income, race, non-citrus fruit, and energy intakes further modifying risk.
Various combinations of risk factors appear to interact to affect risk of each cancer subtype. Replication of these data-mining analyses are required before suggesting causal pathways; however, the classification tree results are useful in partitioning risk and mapping multi-level interactions among risk variables.
PMCID: PMC4006990  PMID: 24239095
esophageal adenocarcinoma; gastric cardia adenocarcinoma; diet; gastroesophageal reflux; classification tree; CART
10.  Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett’s Esophagus, and Gastroesophageal Reflux 
Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett’s esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.
We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h2 g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.
We estimated a statistically significant genetic variance explained for BE (h2 g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10−9) and for EA (h2 g = 25 %; SE = 5%; one-sided P = 2 × 10−7). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10−6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.
We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
PMCID: PMC3833931  PMID: 24168968
11.  Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma 
Carcinogenesis  2013;34(11):2521-2524.
Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes and the risk of esophageal adenocarcinoma (EAC) has not been reported. In this study, we determined relative mtDNA copy number in peripheral blood leukocytes of 218 EAC cases and 218 frequency-matched controls. We calculated odds ratios and 95% confidence intervals using unconditional logistic regression, adjusting for age, sex and smoking status. MtDNA copy number was significantly lower in cases than in controls (mean ± SD, 1.16 ± 0.30 versus 1.27 ± 0.43, P = 0.002). Dichotomized at the median value of mtDNA copy number in the controls, low mtDNA copy number was significantly associated with an increased risk of EAC (odds ratio: 1.55, 95% confidence interval: 1.05–2.29). A significant dose–response relationship was observed between mtDNA copy number and risk of EAC in quartile analysis. Our results suggest that low mtDNA copy number in peripheral blood leukocytes is associated with increased susceptibility to EAC.
PMCID: PMC3810839  PMID: 23803692
12.  Polycyclic aromatic hydrocarbons and risk of gastric cancer in the Shanghai Women’s Health Study 
Purpose: Polycyclic aromatic hydrocarbons (PAHs) are byproducts of incomplete combustion of organic materials. Sources include tobacco smoke, charbroiled meat, and air pollution. Indirect evidence suggests that PAHs may be associated with carcinogenesis, but the association with gastric cancer is unclear. Methods: Using a nested case-control study design, we examined prediagnostic urinary concentrations of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite, in 153 gastric cancer cases and 306 matched controls within the Shanghai Women’s Health Study. Conditional logistic regression adjusted for potential risk factors was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: Urinary 1-OHPG concentrations were slightly higher among cases than controls, with medians of 0.29 μmol/mol Cr (interquartile range, 0.16-0.48) and 0.24 μmol/mol Cr (interquartile range, 0.12-0.45), respectively. Increasing concentrations of 1-OHPG appeared to be associated with elevated risk of gastric cancer, but not within the highest category of 1-OHPG (Q4 vs Q1: OR = 1.4; 95% CI = 0.8-2.5). Conclusions: Our findings suggest that higher concentrations of 1-OHPG are related to gastric cancer risk, but no clear dose-response relationship was observed.
PMCID: PMC4214261  PMID: 25379133
1-hydroxypyrene glucuronide; polycyclic aromatic hydrocarbons; gastric cancer; China
13.  Physical activity and renal cell carcinoma among black and white Americans: a case-control study 
BMC Cancer  2014;14(1):707.
Renal cell carcinoma (RCC) has a higher incidence in blacks than in whites. Physical activity may influence the risk of renal cell cancer, but the evidence is inconsistent. No previous study has investigated this relationship in the black population.
We examined the association between self-reported physical activity at different ages and risk of RCC in a population based case-control study of 1217 cases (361 black, 856 white) and 1235 controls (523 black, 712 white) frequency-matched on age, race, and gender. Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression.
Among whites, increased risks of RCC were observed among participants reporting low levels of transportation-related activity in their 20’s (OR <1 hr/wk vs >7 hr/wk (95% CI): 1.42 (1.10, 1.83)) and leisure time activity in their 50’s (OR <1 hr/wk vs >7 hr/wk (95% CI): 1.49 (1.00, 2.20)). We found no association between physical activity and RCC risk among blacks.
Our results suggest that physical activity may be inversely associated with RCC risk in whites, but there was no evidence of such an association in blacks. As this is the first study evaluating the effect of physical activity on RCC risk among blacks, further investigations are needed to clarify the relationship in this population.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-707) contains supplementary material, which is available to authorized users.
PMCID: PMC4181698  PMID: 25253394
Renal cell carcinoma; Physical activities; Racial differences; Case-control study
14.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
PMCID: PMC4169232  PMID: 23143601
15.  Can a genotype for lactase persistence be used as a tool to assess the relationship between renal cell carcinoma and milk drinking? Pitfalls in the application of Mendelian randomization 
Increased risk of renal cell carcinoma (RCC) with milk consumption has been reported from observational studies including that involved here. Whether this represents causal association or whether it is the result of confounding or bias is unclear. We aimed to assess the potential for genetic variation in lactase persistence to be used as a tool for the interrogation of these relationships.
Using a large, hospital based case control study, we use a combination of observational genetic and phenotypic data to determine whether the MCM6 -13910 C/T(rs4988235) variant may be used as an non-confounded and unbiased marker for milk consumption.
Consumption of milk during adulthood was associated with increased risk of RCC (OR=1.35 95% CI 1.03, 1.76 p=0.03). Among controls, consumption of milk was associated with the lactase persistence genotype at rs4988235 (2.39[1.81, 3.15], p=6.9*10−10), however the same genotype was not associated with RCC (OR=1.01 95% CI 0.83, 1.22 p=0.9). In controls, milk consumption was associated with confounding factors including smoking, and educational attainment, while the lactase persistence genotype at rs4988235 genotype showed negligible association with confounding factors.
The absence of an association between the MCM6 genotype and RCC suggests that observational associations between milk consumption and RCC may be due to confounding or bias. However, if the association between genotype and behavioral exposure is weak, then the power of this test may be low. The nature of intermediate risk factor instrumentation is an important consideration in the undertaking and interpretation of this type of causal analysis experiment.
PMCID: PMC4141143  PMID: 20447925
Mendelian randomization; lactase persistence; renal carcinoma
16.  Age at Menarche and Natural Menopause and Number of Reproductive Years in Association with Mortality: Results from a Median Follow-Up of 11.2 Years among 31,955 Naturally Menopausal Chinese Women 
PLoS ONE  2014;9(8):e103673.
Studies conducted in Western countries suggest that early age at menarche and early age at menopause are both associated with increased total mortality, but limited data are available for Asian populations. We examined associations of age at menarche and natural menopause and duration of the reproductive span with mortality in a population-based cohort study of Chinese women.
We evaluated the effects of age at menarche, age at natural menopause, and number of reproductive years on total and cause-specific mortality among 31,955 naturally menopausal Chinese women who participated in the Shanghai Women's Health Study, a population-based, prospective cohort study.
A total of 3,158 deaths occurred during a median follow-up of 11.2 years. Results from Cox proportional hazards models showed that younger age at menopause (<46.64 years) was associated with higher risk of total mortality (Ptrend  = 0.02). Younger age at menarche (<14 years) was associated with higher risk of mortality from stroke (Ptrend  = 0.03) and diabetes (Ptrend = 0.02) but lower risk of mortality from respiratory system cancer (Ptrend  = 0.01). Women with a shorter reproductive span had lower risk of mortality from gynecological cancers (Ptrend = 0.03).
Our study found that menstrual characteristics are important predictors of mortality, suggesting an important role of sex hormones in biological aging.
PMCID: PMC4121137  PMID: 25090234
17.  Gastroesophageal Reflux in Relation to Adenocarcinomas of the Esophagus: A Pooled Analysis from the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) 
PLoS ONE  2014;9(7):e103508.
Previous studies have evidenced an association between gastroesophageal reflux and esophageal adenocarcinoma (EA). It is unknown to what extent these associations vary by population, age, sex, body mass index, and cigarette smoking, or whether duration and frequency of symptoms interact in predicting risk. The Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) allowed an in-depth assessment of these issues.
Detailed information on heartburn and regurgitation symptoms and covariates were available from five BEACON case-control studies of EA and esophagogastric junction adenocarcinoma (EGJA). We conducted single-study multivariable logistic regressions followed by random-effects meta-analysis. Stratified analyses, meta-regressions, and sensitivity analyses were also conducted.
Five studies provided 1,128 EA cases, 1,229 EGJA cases, and 4,057 controls for analysis. All summary estimates indicated positive, significant associations between heartburn/regurgitation symptoms and EA. Increasing heartburn duration was associated with increasing EA risk; odds ratios were 2.80, 3.85, and 6.24 for symptom durations of <10 years, 10 to <20 years, and ≥20 years. Associations with EGJA were slighter weaker, but still statistically significant for those with the highest exposure. Both frequency and duration of heartburn/regurgitation symptoms were independently associated with higher risk. We observed similar strengths of associations when stratified by age, sex, cigarette smoking, and body mass index.
This analysis indicates that the association between heartburn/regurgitation symptoms and EA is strong, increases with increased duration and/or frequency, and is consistent across major risk factors. Weaker associations for EGJA suggest that this cancer site has a dissimilar pathogenesis or represents a mixed population of patients.
PMCID: PMC4116205  PMID: 25075959
18.  Pre-existing type 2 diabetes and risk of lung cancer: a report from two prospective cohort studies of 133 024 Chinese adults in urban Shanghai 
BMJ Open  2014;4(7):e004875.
Observational studies of type 2 diabetes (T2D) and lung cancer risk are limited and controversial. We thus examined the association between T2D and risk of incident lung cancer using a cohort design.
Data from two ongoing population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002–2006 and the Shanghai Women's Health Study, SWHS, 1996–2000) were used. Cox proportional-hazards regression models with T2D as a time-varying exposure were modelled to estimate HRs and 95% CIs.
The study population included 61 491 male participants aged 40–74 years from SMHS and 74 941 female participants aged 40–70 years from SWHS.
Outcome measure
Lung cancer cases were identified through annual record linkage to the Shanghai Cancer Registry and Shanghai Municipal Registry of Vital Statistics, and were further verified through home visits and a review of medical charts by clinical and/or pathological experts. Outcome data until 31 December 2010 for men and women were used for the present analysis.
After a median follow-up of 6.3 years for SMHS and 12.2 years for SWHS, incident lung cancer cases were detected in 492 men and 525 women. A null association between T2D and lung cancer risk was observed in men (HR=0.87, 95% CI 0.62 to 1.21) and women (HR=0.92, 95% CI 0.69 to 1.24) after adjustments for potential confounders. Similar results were observed among never smokers.
There is little evidence that pre-existing T2D may influence the incidence of lung cancer.
PMCID: PMC4091264  PMID: 24993754
19.  Predictors and Variability of Repeat Measurements of Urinary Phenols and Parabens in a Cohort of Shanghai Women and Men 
Environmental Health Perspectives  2014;122(7):733-740.
Background: Exposure to certain phenols is ubiquitous because of their use in many consumer and personal care products. However, predictors of exposure have not been well characterized in most populations.
Objectives: We sought to identify predictors of exposure and to assess the reproducibility of phenol concentrations across serial spot urine samples among Chinese adults.
Methods: We measured 2,4-dichlorophenol, 2,5-dichlorophenol, butyl paraben, methyl paraben, propyl paraben, benzophenone-3, bisphenol A, and triclosan in urine collected during 1997–2006 from 50 participants of the Shanghai Women’s Health Study cohort and during 2002–2006 from 50 participants of the Shanghai Men’s Health Study cohort. We investigated predictors of concentrations using the Satterthwaite t-test, and assessed reproducibility among serial samples using intraclass correlation coefficients (ICCs) and Spearman correlation coefficients (SCCs).
Results: Creatinine-corrected phenol concentrations were generally higher among women than men. Participants who had taken medicine within the previous 24 hr had higher concentrations of propyl paraben. Cigarette smoking was associated with lower concentrations of propyl and methyl parabens among men. Bottled water consumption was associated with higher bisphenol A, 2,4-dichlorophenol, and 2,5-dichlorophenol concentrations among women. Among men, reproducibility across serial samples was moderate for 2,4-dichlorophenol and 2,5-dichlorophenol (ICC = 0.54–0.60, SCC = 0.43–0.56), but lower for other analytes (ICC = 0.20–0.29). Reproducibility among women was low (ICC = 0.13–0.39), but increased when restricted to morning-only urine samples.
Conclusions: Among these 100 Shanghai residents, urinary phenol concentrations varied by sex, smoking, and consumption of bottled water. Our results suggest that a single urine sample may be adequate for ranking exposure to the precursors of 2,4-dichlorophenol and 2,5-dichlorophenol among men and, under certain circumstances, among women.
Citation: Engel LS, Buckley JP, Yang G, Liao LM, Satagopan J, Calafat AM, Matthews CE, Cai Q, Ji BT, Cai H, Engel SM, Wolff MS, Rothman N, Zheng W, Xiang YB, Shu XO, Gao YT, Chow WH. 2014. Predictors and variability of repeat measurements of urinary phenols and parabens in a cohort of Shanghai women and men. Environ Health Perspect 122:733–740;
PMCID: PMC4080538  PMID: 24659570
20.  Reproductive Factors and Kidney Cancer Risk in 2 US Cohort Studies, 1993–2010 
American Journal of Epidemiology  2013;177(12):1368-1377.
Clinical and experimental findings suggest that female hormonal and reproductive factors could influence kidney cancer development. To evaluate this association, we conducted analyses in 2 large prospective cohorts (the National Institutes of Health–AARP Diet and Health Study (NIH-AARP), 1995–2006, and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), 1993–2010). Cohort-specific and aggregated hazard ratios and 95% confidence intervals relating reproductive factors and kidney cancer risk were computed by Cox regression. The analysis included 792 incident kidney cancer cases among 283,952 postmenopausal women. Women who had undergone a hysterectomy were at a significantly elevated kidney cancer risk in both NIH-AARP (hazard ratio = 1.28, 95% confidence interval: 1.09, 1.50) and PLCO (hazard ratio = 1.41, 95% confidence interval: 1.06, 1.88). Similar results were observed for both cohorts after analyses were restricted to women who had undergone a hysterectomy with or without an oophorectomy. For the NIH-AARP cohort, an inverse association was observed with increasing age at menarche (P for trend = 0.02) and increasing years of oral contraceptive use (P for trend = 0.02). No clear evidence of an association with parity or other reproductive factors was found. Our results suggest that hysterectomy is associated with increased risk of kidney cancer. The observed associations with age at menarche and oral contraceptive use warrant further investigation.
PMCID: PMC3676151  PMID: 23624999
hysterectomy; kidney cancer; parity; pooled analysis; reproductive factors
21.  Associations of leukocyte telomere length with body anthropometric indices and weight change in Chinese women 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20321.
Telomeres are specialized chromatin structures essential for maintenance of chromosomal integrity and stability. Obesity has been proposed to be associated with telomere shortening; however, epidemiologic evidence has been conflicting. We conducted a study to evaluate the associations of telomere length with various anthropometric indices of general and abdominal obesity, as well as weight change.
Design and Methods
The study included 2,912 Chinese women ages 40–70 years. Monochrome multiplex quantitative PCR was applied to measure relative telomere length. ANOVA and the Dunnett test were used to compare log-transformed relative telomere length. Tests for linear trend were performed by entering the ordinal exposure as continuous parameters in the models.
There is an inverse association between telomere length and body mass index (BMI) (Ptrend = 0.005), waist circumference (Ptrend = 0.004), waist-to-height ratio (WHtR) (Ptrend = 0.004), weight (Ptrend = 0.010), and hip circumference (Ptrend = 0.026), but not waist-to-hip ratio (WHR) (Ptrend = 0.116) or height (Ptrend = 0.675). Weight change since age 50 was further evaluated among women over age 55. Women who maintained their weight within ±5% since age 50, particularly within a normal range (BMI = 18.5–24.9 kg/m2), or reduced their weight from overweight (BMI = 25–29.9 kg/m2) or obesity (BMI ≥30 kg/m2) to normal range, had a longer mean of current telomere length than women who gained weight since age 50 (Ptrend = 0.025), particularly those who stayed in obesity or gained weight from normal range or overweight to obesity (P = 0.023).
Our findings provide strong evidence supporting the hypothesis that telomere shortening is associated with obesity and that maintaining body weight within a normal range helps maintain telomere length.
PMCID: PMC3676725  PMID: 23408544
22.  An investigation of risk factors for renal cell carcinoma by histologic subtype in two case-control studies 
To investigate whether renal cell carcinoma (RCC) histologic subtypes possess different etiologies, we conducted analyses of established RCC risk factors by subtype (clear cell, papillary, chromophobe) in two case-control studies conducted in the United States (1,217 cases, 1,235 controls) and Europe (1,097 cases, 1,476 controls). Histology was ascertained for 706 U.S. cases (58% of total) and 917 European cases (84%) through a central slide review conducted by a single pathologist. For the remaining cases, histology was abstracted from the original diagnostic pathology report. Case-only analyses were performed to compute odds ratios (ORs) and 95% confidence intervals (CI) summarizing subtype differences by age, sex, and race. Case-control analyses were performed to compute subtype-specific ORs for other risk factors using polytomous regression. In case-only analyses, papillary cases (N=237) were older (OR=1.2, 95% CI=1.1–1.4 per 10-year increase), less likely to be female (OR=0.5, 95 % CI=0.4- 0.8) and more likely to be black (OR=2.6, 95% CI=1.8–3.9) compared to clear cell cases (N=1,524). In case-control analyses, BMI was associated with clear cell (OR=1.2, 95% CI=1.1–1.3 per 5kg/m2 increase) and chromophobe RCC (N=80; OR=1.2, 95% CI=1.1- 1.4), but not papillary RCC (OR=1.1, 95% CI=1.0–1.2; test vs. clear cell, P=0.006). No subtype differences were observed for associations with smoking, hypertension or family history of kidney cancer. Our findings support the existence of distinct age, sex and racial distributions for RCC subtypes, and suggest that the obesity-RCC association differs by histology.
PMCID: PMC3717609  PMID: 23150424
Renal cell carcinoma; histology; case-control studies; body mass index
24.  A prospective study of leukocyte telomere length and risk of renal cell carcinoma 
It has been hypothesized that genomic instability related to telomere dysfunction may contribute to carcinogenesis. There is some evidence from case-control studies suggesting that short leukocyte telomere length (TL) may be associated with an increased risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively.
We conducted a nested case-control study (209 cases, 410 controls) of RCC risk in relation to pre-diagnostic leukocyte TL in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.
Leukocyte TL was not significantly associated with future risk of RCC (highest quartile vs. lowest: OR=0.8, 95% CI=0.5–1.5; Ptrend=0.6). Analyses stratified by sex, age, and time from blood collection to RCC diagnosis were similarly null.
The results of this study, to our knowledge the first prospective investigation of its kind, do not support an association between pre-diagnostic leukocyte TL and risk of RCC.
In contrast to some earlier reports, our findings add to the evidence that leukocyte TL is not a biomarker of risk related to the etiology of RCC.
PMCID: PMC3655903  PMID: 23513041
telomeres; telomere length; renal cell carcinoma; kidney cancer
25.  Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications 
Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiological studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies.
Using LC-MS and GC-MS platforms, 385 metabolites were measured in 60 women at baseline and year-1 of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening study.
Although the authors found high technical reliability (median intra-class correlation = 0.8), reliability over time within an individual was low. Taken together, variability in the assay and variability within the individual accounted for the majority of variability for 64% of metabolites. Given this, a metabolite would need, on average, a Relative Risk of 3 (comparing upper and lower quartiles of “usual” levels) or 2 (comparing quartiles of observed levels) to be detected in 38%, 74% and 97% of studies including 500, 1000, and 5000 individuals. Age, gender, and fasting status, factors which are often of less interest in epidemiological studies were associated with 30%, 67%, and 34% of metabolites, respectively, but the associations were weak, and explained only a small proportion of the total metabolite variability.
Metabolomics will require large, but feasible, sample sizes to detect the moderate effect sizes typical for epidemiological studies.
We offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology.
PMCID: PMC3617076  PMID: 23396963
metabolomics; power; variance components; measurement error

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