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1.  Maté drinking and esophageal squamous cell carcinoma in South America: pooled results from two large multi-center case-control studies 
Maté tea is non-alcoholic infusion widely consumed in southern South America, and may increase risk of esophageal squamous cell carcinoma (ESCC) and other cancers due to polycyclic aromatic hydrocarbons and/or thermal injury.
We pooled two case-control studies: a 1988–2005 Uruguay study and a 1986–1992 multinational study in Argentina, Brazil, Paraguay and Uruguay, including 1,400 cases and 3,229 controls. We computed odds ratios (OR) and fitted a linear excess odds ratio (EOR) model for cumulative maté consumption in liters/day-year (LPDY).
The adjusted OR for ESCC with 95% confidence interval (CI) by ever compared with never use of maté was 1.60 (1.2,2.2). ORs increased linearly with LPDY (test of non-linearity, P=0.69). The estimate of slope (EOR/LPDY) was 0.009 (0.005,0.014) and did not vary with daily intake, indicating maté intensity did not influence the strength of association. EOR/LPDY estimates for consumption at warm, hot and very hot beverage temperatures were 0.004 (−0.002,0.013), 0.007 (0.003,0.013) and 0.016 (0.009,0.027), respectively, and differed significantly (P<0.01). EOR/LPDY estimates were increased in younger (<65) individuals and never alcohol drinkers, but these evaluations were post hoc, and were homogeneous by sex.
ORs for ESCC increased linearly with cumulative maté consumption and were unrelated to intensity, so greater daily consumption for shorter duration or lesser daily consumption for longer duration resulted in comparable ORs. The strength of association increased with higher mate temperatures.
Increased understanding of cancer risks with maté consumption enhances the understanding of the public health consequences given its purported health benefits.
PMCID: PMC3947123  PMID: 24130226
2.  Risk Factors for Inflammatory Breast Cancer and Other Invasive Breast Cancers 
We investigated risk factors for inflammatory breast cancer (IBC), a rare, aggressive, and poorly understood breast cancer that is characterized by diffuse breast skin erythema and edema.
We included 617 IBC case subjects in a nested case–control study from the Breast Cancer Surveillance Consortium database (1994–2009). We also included 1151 noninflammatory, locally advanced, invasive breast cancers with chest wall/breast skin involvement (LABC), 7600 noninflammatory invasive case subjects without chest wall/breast skin involvement (BC), and 93 654 control subjects matched to case subjects on age and year at diagnosis and mammography registry. We present estimates of rate ratios (RRs) and 95% confidence intervals (CI) from conditional logistic regression analyses for each case group vs control subjects based on multiply imputed datasets.
First-degree family history of breast cancer and high mammographic breast density increased risk of IBC, LABC, and BC. High body mass index (BMI) increased IBC risk irrespective of menopausal status and estrogen receptor (ER) expression; rate ratios for BMI 30 and greater vs BMI less than 25 were 3.90 (95% CI = 1.50 to 10.14) in premenopausal women and 3.70 (95% CI = 1.98 to 6.94) in peri/postmenopausal women not currently using hormones. BMI 30 and greater slightly increased risk of ER-positive BC (RR = 1.40; 95% CI = 1.11 to 1.76). Statistically significant reductions in risk of ER-negative IBC with older age at first birth and of ER-positive IBC with higher education were not seen for LABC and BC of the same ER status.
Different associations with BMI, age at first birth, and education between IBC and/or LABC and BC suggest a distinct etiology for IBC.
PMCID: PMC3776263  PMID: 24046390
3.  Metabolic syndrome increases the risk of primary liver cancer in the United States: a population-based case-control study 
Hepatology (Baltimore, Md.)  2011;54(2):463-471.
Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the U.S. We therefore examined the association between metabolic syndrome and the development of these cancers. All persons diagnosed with HCC and ICC between 1993 and 2005 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. For comparison, a 5% sample of individuals residing in the same regions as the SEER registries of the cases was selected. The prevalence of metabolic syndrome as defined by the U.S. National Cholesterol Education Program Adult Treatment Panel III criteria, and other risk factors for HCC (hepatitis B virus, hepatitis C virus, alcoholic liver disease, liver cirrhosis, biliary cirrhosis, hemochromatosis, Wilson’s disease) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, hepatitis B virus, hepatitis C virus, alcoholic liver disease, cirrhosis, inflammatory bowel disease) were compared among persons who developed cancer and those who did not. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The inclusion criteria were met by 3649 HCC cases, 743 ICC cases and 195,953 comparison persons. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than the comparison group (17.1%, p<0.0001). In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio=2.13; 95%CI=1.96–2.31, p<0.0001) and ICC (odds ratio=1.56; 95% CI= 1.32–1.83, p<0.0001).
Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population.
PMCID: PMC4141525  PMID: 21538440
Hepatocellular Carcinoma; Intrahepatic Cholangiocarcinoma; Metabolic Syndrome; SEER-Medicare-linked database
4.  Trends in sex hormone concentrations in U.S. males: 1988–1991 to 1999–2004 
Previous studies suggest that male testosterone concentrations have declined over time. To explore this in a large US population, we examined testosterone and free testosterone concentrations in National Health and Nutrition Examination Surveys (NHANES) from 1988–1991 and 1999–2004. We also examined sex hormone-binding globulin (SHBG), estradiol, and androstanediol glucuronide (3α-diol-G) over the same period. Non-Hispanic white, non-Hispanic black, and Mexican-American men from 1988–1991 and 1999–2004 NHANES surveys who were ≥ 20 years old and had serum from morning blood draws were included in this analysis (1988–1991: N=1,413; 1999–2004: N=902). Testosterone, estradiol, and SHBG were measured by competitive electrochemiluminescence immunoassays and 3α-diol-G was measured by enzyme immunoassay. Free testosterone was calculated using testosterone and SHBG values. Adjusted mean hormone concentrations were estimated using linear regression, accounting for NHANES sampling weights and design, age, race/ethnicity, body mass index, waist circumference, alcohol use, and smoking. Differences in adjusted mean concentrations (Δ) and two-sided P-values were calculated; P<0.05 was statistically significant. Overall, 3α-diol-G and estradiol declined between 1988–1991 and 1999–2004, but there was little change in testosterone, free testosterone, or SHBG (Δ: 3α-diol-G =−1.83 ng/mL, P<0.01; estradiol=−6.07 pg/mL, P<0.01; testosterone=− 0.03 ng/mL, P=0.75; free testosterone=−0.001 ng/mL, P=0.67; SHBG=−1.17 nmol/L, P=0.19). Stratification by age and race revealed that SHBG and 3α-diol-G declined among whites 20–44 years old (Δ: SHBG=−5.14 nmol/L, P<0.01; 3α-diol-G =−2.89 ng/mL, P<0.01) and free testosterone increased among blacks 20–44 years old (Δ: 0.014, P=0.03). Estradiol declined among all ages of whites and Mexican-Americans. In conclusion, there was no evidence for testosterone decline between 1988–1991 and 1999–2004 in the US general population. Subgroup analyses suggest that SHBG and 3α-diol-G declined in young white men, estradiol declined in white and Mexican-American men, and free testosterone increased in young black men. These changes may be related to the increasing prevalence of reproductive disorders in young men.
PMCID: PMC4137971  PMID: 22150314
testosterone; androstanediol glucuronide; estradiol; sex hormone-binding globulin; epidemiology; National Health and Nutrition Examination Survey
5.  Dichlorodiphenyltrichloroethane (DDT) and risk of hepatocellular carcinoma 
Dichlorodiphenyltrichloroethane (p,p’-DDT), an organochlorine pesticide known to have deleterious health effects in humans, has been linked to hepatocellular carcinoma (HCC) in rodents. A recent study has reported that p,p’-DDT and its most persistent metabolite, dichlorodiphenyldichloroethylene (p,p’-DDE), may also be associated with HCC in humans.
To examine whether there is an association between p,p’-DDT and/or p,p’-DDE in a population at high-risk of developing HCC.
A nested case-control study was conducted within the 83,794 person Haimen City Cohort in China. Sera and questionnaire data were collected from all participants between 1992 and 1993. The current study included 473 persons who developed HCC and 492 who did not, frequency matched on sex, age and area of residence. p,p’-DDT and p,p’-DDE levels were determined by mass spectrometry. Hepatitis B viral infection status (based on hepatitis B virus surface antigen; HBsAg) was also determined. Adjusting for age, sex, area of residence, HBsAg, family history of HCC, history of acute hepatitis, smoking, alcohol, occupation (farmers) and levels of p,p’-DDT or p,p’-DDE, odds ratios (OR) and 95% confidence intervals (CI) were calculated via unconditional logistic regression,
p,p’-DDT and/or p,p’-DDE serum levels were significantly associated with sex, area of residence, occupation, alcohol consumption and cigarette smoking. Overall, the highest quintile of p,p’-DDT was associated with an increased risk of HCC, OR= 2.96 95% CI; 1.19–7.40. There were no statistically significant associations with p,p’-DDE.
Overall, these results suggest that recent exposure to p,p’-DDT may increase risk of HCC.
PMCID: PMC4127991  PMID: 22290210
DDT; DDE; hepatocellular carcinoma; cohort study; China; epidemiology
6.  Hypertension, Pulse, and Other Cardiovascular Risk Factors and Vitamin D Status in Finnish Men 
American Journal of Hypertension  2013;26(8):951-956.
Debate exists about the relationship between hypovitaminosis D and cardiovascular (CVD) risk.
This study investigated baseline (n=2,271) 25-hydroxyvitamin D (25(OH)D) and baseline and 4 year (n=1,957) CVD risk in a cohort of Finnish middle-aged male smokers.
The prevalences of measured hypertension, high pulse rate, diabetes, and coronary heart disease were 63%, 16%, 5%, and 10% at baseline and were 64%, 20%, 6%, and 16% at 4 years after baseline. The mean 25(OH)D was 41±18 nmol/L. At baseline, systolic blood pressure (β = −0.048; P = 0.02), and pulse rate (β = −0.043; P = 0.04) were both associated with lower 25(OH)D levels but not coronary heart disease or diabetes prevalence. On remeasuring CVD risk 4 years after baseline, the only significant association with baseline 25(OH)D levels was high pulse rate (β = −0.077; P = 0.001). In addition, a higher 25(OH)D level at baseline was associated with a change in pulse rate (β = −0.055; P = 0.01). These trends for hypertension (baseline) and high pulse rate (baseline and 4 years after baseline) were also seen on adjusted categorical analysis (P trend < 0.05).
Vitamin D deficiency at baseline was associated with hypertension in Finnish male smokers, but not after 4 years. These results are consistent with recent findings in other large cohort studies with measured blood pressure. Change in pulse rate over time continued to be significantly associated with lower 25(OH)D baseline levels; this new finding should be investigated further.
PMCID: PMC3816321  PMID: 23598420
blood pressure; coronary heart disease; diabetes; hypertension; pulse/heart rate; vitamin D status; 25(OH)D.
7.  Gender-specific differences in birthweight and the odds of puberty: NHANES III, 1988–94 
The association between birthweight and the odds ratio (OR) of pubertal status in girls aged between 8 and 11 and in boys aged between 8 and 12 was examined using the 1988–94 Third National Health and Nutrition Examination Survey (NHANES III). Girls (n = 956), and boys (n = 1199), who had data on birthweight and Tanner staging were included. Maternal-reported birthweight, smoking in pregnancy and other information were provided in a home interview, while Tanner staging to assess pubertal status was part of a medical examination. Multiple logistic regression models were computed for the endpoints of the OR [95% confidence interval (CI)] of being Tanner Stage 2+ vs. 1 or being 2+ vs. 1 in an asynchronous pubertal pathway after adjustment for the complex sampling design of NHANES, age, race, height and body mass index (BMI).
Birthweight was not associated with the OR of Tanner stage 2+ among girls; however, boys who were low birthweight (<2500 g) and boys born higher than average birthweight (3500–3999 g) were more likely to be Tanner stage 2+ than 1. Childhood BMI was associated with the OR of having entered puberty among girls, but not boys. In an analysis of asynchronous maturation, girls born at high birthweight (>4000 g) were more likely to have breast development 3+ than girls of normal birthweight, OR = 3.18 [95% CI 1.39, 8.25]. Thus, the birthweight–puberty association varies by gender and by pubertal pathway. Our findings need replication in prospective longitudinal studies, and research to understand the mechanisms underlying the relation of early life exposures to cancer risk.
PMCID: PMC4119173  PMID: 20415751
puberty; birthweight; childhood BMI; NHANES
8.  Population-Attributable Fractions of Risk Factors for Hepatocellular Carcinoma in the United States 
Risk factors for hepatocellular carcinoma (HCC) include hepatitis B and C viruses (HBV, HCV), excessive alcohol consumption, rare genetic disorders and diabetes/obesity. The population attributable fractions (PAF) of these factors, however, have not been investigated in population-based studies in the United States.
Persons ≥ 68 years diagnosed with HCC (n = 6,991) between 1994 and 2007 were identified in the SEER-Medicare database. A 5 % random sample (n = 255,702) of persons residing in SEER locations were selected for comparison. For each risk factor, odds ratios (ORs), 95 % confidence intervals (95 % CI) and PAFs were calculated.
As anticipated, the risk of HCC was increased in relationship to each factor: HCV (OR 39.89, 95 % CI: 36.29–43.84), HBV (OR 11.17, 95 % CI: 9.18–13.59), alcohol-related disorders (OR 4.06, 95 % CI: 3.82–4.32), rare metabolic disorders (OR 3.45, 95 % CI: 2.97–4.02), and diabetes and/or obesity (OR 2.47, 95 % CI: 2.34–2.61). The PAF of all factors combined was 64.5 % (males 65.6 % ; females 62.2 %). The PAF was highest among Asians (70.1 %) and lowest among black persons (52.4 %). Among individual factors, diabetes/obesity had the greatest PAF (36.6 %), followed by alcohol-related disorders (23.5 %), HCV (22.4 %), HBV (6.3 %) and rare genetic disorders (3.2 %). While diabetes/obesity had the greatest PAF among both males (36.4 %) and females (36.7 %), alcohol-related disorders had the second greatest PAF among males (27.8 %) and HCV the second greatest among females (28.1 %). Diabetes/obesity had the greatest PAF among whites (38.9 %) and Hispanics (38.1 %), while HCV had the greatest PAF among Asians (35.4 %) and blacks (34.9 %). The second greatest PAF was alcohol-related disorders in whites (25.6 %), Hispanics (30.1 %) and blacks (and 18.5 %) and HBV in Asians (28.5 %).
The dominant risk factors for HCC in the United States among persons ≥68 years differ by sex and race/ethnicity. Overall, eliminating diabetes/obesity could reduce the incidence of HCC more than the elimination of any other factor.
PMCID: PMC4105976  PMID: 23752878
9.  Racial Disparities in the Prevalence of Monoclonal Gammopathies: A population-based study of 12,482 persons from the National Health and Nutritional Examination Survey 
Leukemia  2014;28(7):1537-1542.
The incidence of multiple myeloma (MM) is markedly higher in blacks compared with whites. This may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS), the premalignant lesion that precedes MM. Our objective was to define the prevalence and risk factors of MGUS in blacks, Hispanics, and whites using a large cohort representative of the United States (U.S.) population.
Of 13,278 adults age ≥50 years enrolled in National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999–2004, stored serum samples to test for monoclonal proteins were available on 12,482 persons (2,331 non-Hispanic blacks considered “black”, 2,475 Hispanics, 7,051 non-Hispanic whites considered “white”, and 625 “others”). Agarose-gel electrophoresis, serum protein immunofixation, serum free light-chain assay, and typing of the M-protein was performed on sera from all subjects. Unadjusted and adjusted prevalence rates were computed from logistic regression analysis. Risk factors were studied using available survey information available from NHANES. Main outcomes and measures were prevalence of MGUS by age, gender, race, ethnicity, and risk factors from available survey information.
MGUS was identified in 365 participants, for an overall prevalence of 2.4%. Adjusted prevalence of MGUS was significantly higher (p<0.001) in blacks (3.7%) compared with whites (2.3%) (p=0.001) or Hispanics (1.8%). MGUS in blacks had characteristics that posed a greater risk of progression to MM. The prevalence of MGUS (adjusted for age, education, sex, race, smoking) was 3.1% and 2.1% for the North and Midwest versus South and West regions of the U.S., respectively (p=0.052).
MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. We also find a strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the U.S., which has etiologic implications.
PMCID: PMC4090286  PMID: 24441287
monoclonal gammopathy; prevalence; prognosis; biomarker; racial disparity
10.  Second to fourth digit ratio, handedness and testicular germ cell tumors 
Early human development  2013;89(7):463-466.
Research on early life exposures and testicular germ cell tumors (TGCT) risk has focused on a possible perinatal etiology with a well-known hypothesis suggesting that hormonal involvement during fetal life is associated with risk. Second-to-fourth digit ratio (2D:4D) and left hand dominance have been proposed as markers of prenatal hormone exposure.
To evaluate associations between 2D:4D digit ratio, right minus left 2D:4D (ΔR-L), and left-hand dominance and TGCT in the U.S. Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) Study.
A total of 246 TGCT cases and 236 non-testicular cancer controls participated in the current study, and completed a self-administered questionnaire. Associations between digit ratio, hand dominance and TGCT were estimated using unconditional logistic regression adjusting for identified covariates.
Right 2D:4D was not associated with TGCT [OR for a one-standard deviation (SD) increase in right hand 2D:4D: 1.12, 95% CI: 0.93–1.34]. The results were consistent when evaluating the association based on the left hand. The difference between right and left hand 2D:4D was also not associated with TGCT risk [OR for a one-SD increase in ΔR-L: 1.03, 95% CI: 0.87–1.23]. Compared to men who reported right-hand dominance, ambidexterity [OR (95% CI) = 0.65 (0.30–1.41)] and left-hand dominance [OR (95% CI) = 0.79 (0.44–1.44)] were not associated with risk.
These results do not support the hypothesis that prenatal hormonal imbalance is associated with TGCT risk. Given the limited sample size, further evaluation of the relationship between TGCT and prenatal hormonal factors using digit ratio, ΔR-L, or left-hand dominance and larger sample size are warranted.
PMCID: PMC3684556  PMID: 23623693
case-control; testicular cancer; hand pattern; left-handed dominance; digit ratio
11.  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
12.  Serum Levels of Vitamin D Metabolites and Breast Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
Experimental and epidemiologic studies suggest that vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)2D] and its precursor 25-hydroxyvitamin D [25(OH)D]) may reduce breast cancer risk. We examined subsequent breast cancer risk related to serum levels of these metabolites. In a cohort of women ages 55 to 74 years, who donated blood at baseline (1993–2001) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 1,005 incident breast cancer cases during follow-up through 2005 (mean time between blood draw and diagnosis, 3.9 years). Noncases (n = 1,005) were frequency matched to the cases based on age and year of entry. Sample weights that accounted for unequal probabilities of selecting cases and noncases were applied to make inferences that reflected the entire Prostate, Lung, Colorectal, and Ovarian cohort. Using Cox proportional hazards modeling, we computed breast cancer relative risks (RR) and 95% confidence intervals (95% CI) by quintile for each metabolite. The RR of breast cancer for the highest quintile of 25(OH)D concentration versus the lowest was 1.04 (95% CI, 0.75–1.45; Ptrend = 0.81). Similarly, the breast cancer RR for the highest quintile of 1,25(OH)2D compared with the lowest was 1.23 (95% CI, 0.91–1.68; Ptrend = 0.14). Excluding the first 2 years of follow-up did not materially alter these estimates. There was also no evidence of inverse risk in older women (≥60 years) versus younger women (<60 years). In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)2D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure.
PMCID: PMC4039037  PMID: 18381472
13.  Risk of developing invasive breast cancer in Hispanic women: A look across Hispanic subgroups 
Cancer  2012;119(7):1373-1380.
Current evidence on breast cancer among US Hispanic women indicates a significant public health threat, although few studies assess the heterogeneity in breast cancer risk among Hispanics of different origin.
The 2000 and 2005 National Health Interview Survey (NHIS) Cancer Control Modules were used to examine the Breast Cancer Risk Assessment Tool (BCRAT) 5-year and lifetime risk of invasive breast cancer among Mexican/Mexican-American, Puerto Rican, Cuban/Cuban-American, Dominican (Republic), Central/South American, Other Hispanic and non-Hispanic white (NHW) women aged 35-84 years. Multiple linear regression models were used to compare the BCRAT 5-year and lifetime breast cancer risk between: i) Hispanics and NHWs and ii) Hispanic subgroups.
Hispanics had significantly lower mean BCRAT 5-year and lifetime breast cancer risk compared to NHWs (p<0.001). Among Hispanic subgroups, Cuban/Cuban-Americans had a higher BCRAT 5-year risk (p<0.05), while Dominicans had a higher lifetime risk (p<0.001), compared to Mexican/Mexican-American women. Approximately, 2.6% of Hispanic women were at high-risk for breast cancer (BCRAT 5-year risk ≥1.67%), ranging from 1.0% of Central/South Americans to 3.7% of Puerto Ricans; few Hispanics (0.2%) had a lifetime risk ≥20.0%.
Our findings indicate that Hispanics had significantly lower risk of breast cancer, compared to NHWs, though BCRAT risk significantly differed between specific Hispanic subgroups. We provide estimates of the number of US Hispanic women, from six subgroups, who would be eligible for prophylactic breast cancer chemoprevention. Future studies should further investigate the heterogeneity in breast cancer risk and risk factors between Hispanic women of different origins.
PMCID: PMC3604037  PMID: 23224859
Breast cancer; Risk assessment; Hispanic/Latino; BCRAT
14.  Five-year and Lifetime Risk of Breast Cancer among U.S. Subpopulations: Implications for Magnetic Resonance Imaging Screening 
Guidelines from the American Cancer Society recommend annual breast MRI screening for women with a projected lifetime risk of ≥20% based on risk models that use family history. Since MRI screening is costly and has limited specificity, estimates of the numbers of U.S. women with breast cancer risk ≥20% would be useful.
We used data from the 2000 and 2005 National Health Interview Survey and the National Cancer Institute’s (NCI) Breast Cancer Risk Assessment Tool (i.e. Gail Model 2 with a revision for African Americans) to calculate estimates of U.S. women by age and race/ethnicity categories with a lifetime absolute breast cancer risk of ≥20%. Distributions of 5-year and lifetime absolute risk of breast cancer are compared across demographic groups.
We estimated that 1.09% (95% CI = 0.95% to 1.24%) of women aged 30–84 years have a lifetime absolute breast cancer risk of ≥20%, which translates to 880,063 U.S. women eligible for MRI screening. The 5-year risks are highest for White non-Hispanics and lowest for Hispanics. The lifetime risks decrease with age and are generally highest for White non-Hispanics, lower for African American non-Hispanic and lowest for Hispanics.
We provide national estimates of the number of U.S. women who would be eligible for MRI breast screening and distributions of 5-year and lifetime risks of breast cancer using the NCI Breast Cancer Risk Assessment Tool.
These estimates inform the potential resources and public health demand for MRI screening and chemo-preventive interventions that might be required for U.S. women.
PMCID: PMC2952062  PMID: 20841391
15.  Alcohol consumption, folate intake, hepatocellular carcinoma and liver disease mortality 
Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH-AARP Diet and Health Study.
The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazard ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index and diabetes. HCC incidence (n=435) was determined through 2006 via linkage with cancer registries and liver disease mortality (n=789) was determined through 2008 via linkage to the National Death Index Plus.
Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.42–2.60) and liver disease mortality (HR: 5.84; 95%CI: 4.81–7.10), while folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (Pinteraction=0.03), but had no effect on the relationship between alcohol and liver disease mortality (Pinteraction=0.54).
These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC.
Folate intake may be beneficial in the prevention of alcohol-associated HCC.
PMCID: PMC3596467  PMID: 23307533
Folate; Alcohol; hepatocellular carcinoma; liver disease; epidemiology
16.  Derivation of Background Mortality by Smoking and Obesity in Cancer Simulation Models 
Simulation models designed to evaluate cancer prevention strategies make assumptions on background mortality–the competing risk of death from causes other than the cancer being studied. Researchers often use the U.S. lifetables and assume homogeneous other-cause mortality rates. However, this can lead to bias because common risk factors such as smoking and obesity also predispose individuals for deaths from other causes such as cardiovascular disease.
We obtained calendar year-, age- and sex-specific other-cause mortality rates by removing deaths due to a specific cancer from U.S. all-cause life tables. Prevalence across 12 risk factor groups (3 smoking (never, past, and current smoker) and 4 body mass index (BMI) categories (<25, 25-30, 30-35, 35+ kg/m2) were estimated from national surveys (National Health and Nutrition Examination Surveys (NHANES) 1971-2004). Using NHANES linked-mortality data, we estimated hazard ratios for death by BMI/smoking using a Poisson regression model. Finally, we combined these results to create 12 sets of BMI and smoking-specific other-cause life tables for U.S. adults aged 40 and older that can be used in simulation models of lung, colorectal, or breast cancer.
We found substantial differences in background mortality when accounting for BMI and smoking. Ignoring the heterogeneity in background mortality in cancer simulation models can lead to underestimation of competing risk of deaths for higher risk individuals (e.g. male, 60-year old, white obese smokers) by as high as 45%.
Not properly accounting for competing risks of death may introduce bias when using simulation modeling to evaluate population health strategies for prevention, screening, or treatment. Further research is warranted on how these biases may impact cancer screening strategies targeted to high-risk individuals.
PMCID: PMC3663442  PMID: 23132901
17.  Past body mass index and risk of mortality among women 
Epidemiologic studies of BMI in relation to mortality commonly exclude persons with health conditions and/or a history of smoking in order to prevent bias resulting from illness-related weight loss (“reverse causation”). Analysis of BMI from an earlier time period may minimize reverse causation without requiring exclusion of participants based on disease or smoking history.
We prospectively examined BMI based on technician measurements of weight and height from 10 years prior to start of follow-up in relation to subsequent mortality in a cohort of 50,186 women who were 40 to 93 years old at baseline in 1987–1989. Deaths were ascertained through the U.S. National Death Index. Proportional hazards regression was used to estimate hazard ratios of mortality, adjusted for age, education, race/ethnicity, income, menopausal hormone use, smoking, and physical activity.
During 10 years of follow-up through 1997, 5,201 women died. Overall, we observed a J-shaped association between BMI and mortality, with increased risk for women who were underweight, overweight, or obese. The hazard ratios and 95% confidence intervals of mortality for BMI categories of <18.5, 18.5–20.9, 21.0–23.4 (reference), 23.5–24.9, 25.0–27.4, 27.5–29.9, 30.0–34.9, and 35.0+ kg/m2 were 1.43 (1.19, 1.72), 1.07 (0.98, 1.17), 1.0 (reference), 1.10 (1.00, 1.20), 1.20 (1.11, 1.31), 1.23 (1.11, 1.37), 1.60 (1.44, 1.77), and 1.92 (1.64, 2.24). There was little evidence that preexisting conditions (heart disease, diabetes, and/or cancer) or smoking history modified the past BMI and mortality relation (p=0.54 and 0.76).
In this large cohort of women, BMI based on technician measurements of weight and height from 10 years prior to baseline showed increased risk for mortality across the range of overweight and obesity, regardless of disease and smoking history. Observed associations between overweight, obesity, and mortality in healthy individuals may also apply to persons with a history of disease or smoking.
PMCID: PMC3051416  PMID: 18209736
Body mass; weight; obesity; overweight; mortality; life-expectancy; epidemiology
18.  Sunlight and Other Determinants of Circulating 25-Hydroxyvitamin D Levels in Black and White Participants in a Nationwide US Study 
American Journal of Epidemiology  2013;177(2):180-192.
Circulating 25-hydroxyvitamin D (25(OH)D), a marker for vitamin D status, is associated with bone health and possibly cancers and other diseases; yet, the determinants of 25(OH)D status, particularly ultraviolet radiation (UVR) exposure, are poorly understood. Determinants of 25(OH)D were analyzed in a subcohort of 1,500 participants of the US Radiologic Technologists (USRT) Study that included whites (n = 842), blacks (n = 646), and people of other races/ethnicities (n = 12). Participants were recruited monthly (2008–2009) across age, sex, race, and ambient UVR level groups. Questionnaires addressing UVR and other exposures were generally completed within 9 days of blood collection. The relation between potential determinants and 25(OH)D levels was examined through regression analysis in a random two-thirds sample and validated in the remaining one third. In the regression model for the full study population, age, race, body mass index, some seasons, hours outdoors being physically active, and vitamin D supplement use were associated with 25(OH)D levels. In whites, generally, the same factors were explanatory. In blacks, only age and vitamin D supplement use predicted 25(OH)D concentrations. In the full population, determinants accounted for 25% of circulating 25(OH)D variability, with similar correlations for subgroups. Despite detailed data on UVR and other factors near the time of blood collection, the ability to explain 25(OH)D was modest.
PMCID: PMC3590034  PMID: 23292956
dietary supplements; 25-hydroxyvitamin D; race; seasons; sex; sunlight; ultraviolet rays; vitamin D
19.  The association between chronic renal failure and renal cell carcinoma may differ between black and white Americans 
Cancer causes & control : CCC  2012;24(1):167-174.
In the United States, renal cell carcinoma (RCC) incidence is higher among blacks than among whites. Risk of RCC is elevated among end-stage renal disease patients, although no studies have looked at differences by race in the relationship between chronic renal failure and RCC.
We investigated RCC risk in relation to chronic renal failure in a population-based case-control study of blacks and whites in Chicago and Detroit. Data, including information on kidney disease, were collected from interviews with 1,217 RCC cases (361 blacks, 856 whites) and 1,235 controls (523 blacks, 712 whites). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression.
Risk of RCC was increased in relation to chronic renal failure (OR 4.7, 95% CI 2.2–10.1) and dialysis (OR 18.0, 95% CI 3.6–91). The association remained after defining exposure as those who had chronic renal failure ≥10 years prior to RCC diagnosis. Chronic renal failure was more strongly associated with RCC among blacks than among whites (OR 8.7, 95% CI 3.3–22.9 and 2.0, 0.7–5.6 respectively; Pinteraction=0.03) and among those without a history of diabetes relative to diabetic subjects (OR 8.3, 95% CI 3.1–22.7 and 1.9, 0.6–5.9 respectively; Pinteraction=0.03).
These results suggest that chronic renal failure is a strong risk factor for RCC, particularly among black and non-diabetic subjects. Our findings of differences in risk estimates by race, to our knowledge the first such report, require replication.
PMCID: PMC3531044  PMID: 23179659
renal cell carcinoma; kidney cancer; chronic renal failure; end-stage renal disease; racial disparities
20.  Serum leptin and adiponectin levels and risk of renal cell carcinoma 
Obesity (Silver Spring, Md.)  2013;21(7):1478-1485.
The incidence of renal cell carcinoma (RCC) has increased rapidly in the U.S., particularly among African Americans. Despite a well-established link between obesity and RCC, the mechanism through which obesity increases cancer risk has yet to be established. Adipokines, such as leptin and adiponectin, may link obesity and cancer, with different quantitative effects by race. We evaluated the association between leptin and adiponectin concentrations and RCC risk among Caucasians (581 cases, 558 controls) and African Americans (187 cases, 359 controls) in a case-control study conducted in Detroit and Chicago. Odds ratios(ORs) and 95% confidence intervals(95%CIs) were estimated using unconditional logistic regression. Among controls, Caucasians had higher median adiponectin than African Americans (males: 8.2 vs. 7.0µg/ml, p=0.001; females: 13.4 vs. 8.4µg/ml, p<0.0001), and lower median leptin than African Americans (males: 11.8 vs. 14.1ng/ml, p=0.04; females: 28.3 vs. 45.9ng/ml, p<0.0001). Among Caucasians, the ORs for RCC comparing the highest (Q4) to the lowest (Q1) sex-specific quartile of leptin were 3.2 (95%CI:1.9–5.2) for males and 4.7 (95%CI:2.6–8.6) for females. Serum leptin was not significantly associated with RCC among African American males (OR 1.5, 95%CI:0.7–3.1) or females (OR 2.1, 95%CI:0.8–5.5). Higher adiponectin was associated with RCC risk among African American males (Q4 vs. Q1: OR 2.3, 95%CI:1.1–4.6) and females (OR 2.1, 95%CI:1.2–6.7), but not significantly among Caucasian males (OR 1.6, 95%CI:0.99–2.7) and females (OR 1.6, 95%CI:0.9–3.1). In conclusion, we observed an association between both leptin and adiponectin concentrations and risk of RCC, which may differ by race. Confirmation in further investigations is needed.
PMCID: PMC3742622  PMID: 23666639
21.  Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma 
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.
We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health–AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.
Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.
Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.
PMCID: PMC3514167  PMID: 23197492
22.  Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men 
Cancer causes & control : CCC  2012;23(12):1881-1891.
To evaluate the association of body size – captured via whole body dual-energy x-ray absorptiometry (DXA) and physical measurement – with serum sex steroid hormones and sex hormone binding globulin (SHBG) we utilized cross-sectional data and serum samples from the National Health and Nutrition Examination Survey (NHANES; 1999-2004).
Testosterone, androstanediol glucuronide (3-alpha-diol-G), estradiol and SHBG were measured via immunoassay in serum samples from a total of 898 adult men (ages 20-90) participating in the morning examination. As part of the NHANES data collection DXA scans and measurements of weight, height and waist circumference were performed by trained staff. Linear regression was used to estimate associations between body size and hormone levels adjusted for potential confounders and NHANES sampling procedures.
Total bone area (cm2) was inversely associated with total testosterone (ng/mL) [beta=-0.12; p-value<0.01], while bone mineral density (g/cm2) was inversely associated with SHBG (nmol/L) [beta=-17.16; p-value=0.01]. Increased percent body fat was associated with lower concentrations of total testosterone [beta=-0.16; p-value<0.01] and SHBG [beta=-1.11; p-value<0.01] and higher concentrations of free estradiol (fg/mL) [beta=12.52; p-value<0.01].
Clinical measures of body fat (measured via DXA scan) and anthropometric measures of body fat (BMI and waist circumference) provided similar inferences regarding the association between increased body fat and hormone levels in men. Increased body fat was associated with lower circulating levels of testosterone (total and free) and SHBG and higher circulating levels of free estradiol in men, while decreased bone mineral density was associated with higher circulating levels of SHBG.
PMCID: PMC3499640  PMID: 23053790
dual-energy X-ray absorptiometry; DXA; estradiol; testosterone; androstanediol glucuronide; sex hormone binding globulin; National Health and Nutrition Examination Survey; NHANES; men
23.  Body Mass Index and Renal Cell Cancer: The Influence of Race and Sex 
Epidemiology (Cambridge, Mass.)  2012;23(6):821-828.
Obesity is a risk factor for renal cell (or renal) cancer. The increasing prevalence of obesity may be contributing to the rising incidence of this cancer over the past several decades. The effects of early-age obesity and change in body mass index (BMI) on renal cancer have been studied less thoroughly, and the influence of race has never been formally investigated.
Using data gathered as part of a large case-control study of renal cancer (1,214 cases and 1,234 controls), we investigated associations with BMI at several time points, as well as with height. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression modeling. Race- and sex-stratified analyses were conducted to evaluate subgroup differences.
Obesity (BMI ≥ 30 kg/m2) early in adulthood (OR=1.6 [95% CI=1.1 to 2.4]) and 5 years before diagnosis (1.6 [1.1 to 2.2]) was associated with renal cancer. The association with early-adult obesity was stronger among whites than blacks (Test for interaction, P=0.006), while the association with obesity near diagnosis was marginally stronger in women than men (Test for interaction, P=0.08). The strongest association with renal cancer was observed for obese whites both in early adulthood and prior to interview (2.6 [1.5 to 4.4]); this association was not present among blacks. Estimates of the annual excess rate of renal cancer (per 100,000 persons) attributed to both overweight and obesity (BMI > 25 kg/m2) ranged from 9.9 among black men to 5.6 among white women.
Obesity, both early and later in life, is associated with an increased risk of renal cancer. The association with early obesity appears to be stronger among whites than blacks.
PMCID: PMC3466395  PMID: 23007040
24.  Alcohol Consumption, One-Carbon Metabolites, Liver Cancer and Liver Disease Mortality 
PLoS ONE  2013;8(10):e78156.
Excess alcohol consumption adversely affects one-carbon metabolism and increases the risk of liver disease and liver cancer. Conversely, higher folate levels have been inversely associated with liver damage. The current study investigated the effects of alcohol and one-carbon metabolite intake on liver cancer incidence and liver disease mortality within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.
Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals (CIs) in a population of 27,086 Finnish males with 194 incident liver cancers and 213 liver disease deaths. In a nested case-control subset (95 liver cancers, 103 controls), logistic regression was used to calculate odds ratios and 95% CIs for serum one-carbon metabolites in relation to liver cancer risk.
Daily alcohol consumption of more than 20.44 g was associated with an increased risk of both liver cancer incidence (Hazard Ratio (HR) 1.52, 95%CI 1.06–2.18) and liver disease mortality (HR 6.68, 95%CI 4.16–10.71). These risks were unaffected by one-carbon metabolite intake. Similarly, in the case-control study, none of the serum one-carbon metabolites were associated with liver cancer.
The current study provided no convincing evidence for a protective association of one-carbon metabolite intake or serum level on the risk of liver cancer or liver disease mortality.
PMCID: PMC3810254  PMID: 24205137
25.  Pseudo semiparametric maximum likelihood estimation exploiting gene environment independence for population-based case–control studies with complex samples 
Biostatistics (Oxford, England)  2012;13(4):711-723.
Advances in human genetics have led to epidemiological investigations not only of the effects of genes alone but also of gene–environment (G–E) interaction. A widely accepted design strategy in the study of how G–E relate to disease risks is the population-based case–control study (PBCCS). For simple random samples, semiparametric methods for testing G–E have been developed by Chatterjee and Carroll in 2005. The use of complex sampling in PBCCS that involve differential probabilities of sample selection of cases and controls and possibly cluster sampling is becoming more common. Two complexities, weighting for selection probabilities and intracluster correlation of observations, are induced by the complex sampling. We develop pseudo-semiparametric maximum likelihood estimators (pseudo-SPMLE) that apply to PBCCS with complex sampling. We study the finite sample performance of the pseudo-SPMLE using simulations and illustrate the pseudo-SPMLE with a US case–control study of kidney cancer.
PMCID: PMC3616753  PMID: 22522235
Hardy–Weinberg equilibrium; Population weights; Selection probability; Stratified multistage cluster sampling; Taylor linearization

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