Faculty Bibliography

BACKGROUND:Many studies have addressed effects of dietary supplementation with soy protein, but most have been inconsistent and few have been long-term studies in men. OBJECTIVES/OBJECTIVE:This study was a secondary analysis of body weight, blood pressure, thyroid hormones, iron status, and clinical chemistry in a 2-y trial of soy protein supplementation in middle-aged to older men. METHODS:Data were analyzed as secondary outcomes of a randomized controlled trial of dietary supplementation with 20 g/d soy protein isolate, providing 41 mg/d total isoflavones and 23 mg/d genistein, in 44- to 75-y-old men who were at risk of cancer recurrence following prostatectomy randomized to soy (n = 50) or a casein-based placebo (n  = 43). Weight, blood pressure, and blood samples were collected at baseline, every 2 mo in year 1, and every 3 mo in year 2. RESULTS:Compared with casein, soy supplementation did not affect body weight, blood pressure, serum total cholesterol, calcium, phosphorus, and thyroid hormones. Serum ferritin concentrations doubled over 2 y in both groups (117-129%), whereas hemoglobin and hematocrit increased slightly. In an exploratory subgroup analysis of soy group data, weight increased in subjects producing equol but not in nonproducers. Blood pressure was reduced in nonequol producers but not in producers. Other endpoints were not affected by equol production status. CONCLUSIONS:Soy protein supplementation for 2 y compared with a casein-based placebo did not affect body weight, blood pressure, serum total cholesterol, iron status parameters, calcium, phosphorus, and thyroid hormones. Exploratory analysis suggests that equol production status of subjects on soy may modify effects of soy on body weight and possibly blood pressure. This trial was registered at clinicaltrials.gov as NCT00765479.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m², respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.

Sub-cohort sampling designs, such as nested case-control (NCC) and case-cohort (CC) studies, have been widely used to estimate biomarker-disease associations because of their cost effectiveness. These designs have been well studied and shown to maintain relatively high efficiency compared to full-cohort designs, but their performance of building risk prediction models has been less studied. Moreover, sub-cohort sampling designs often use matching (or stratifying) to further control for confounders or to reduce measurement error. Their predictive performance depends on both the design and matching procedures. Based on a dataset from the NYU Women's Health Study (NYUWHS), we performed Monte Carlo simulations to systematically evaluate risk prediction performance under NCC, CC, and full-cohort studies. Our simulations demonstrate that sub-cohort sampling designs can have predictive accuracy (i.e. discrimination and calibration) similar to that of the full-cohort design, but could be sensitive to the matching procedure used. Our results suggest that researchers can have the option of performing NCC and CC studies with huge potential benefits in cost and resources, but need to pay particular attention to the matching procedure when developing a risk prediction model in biomarker studies.

Previously, we found that risk of colorectal cancer (CRC) is increased in individuals with serum antibody response to both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA) toxin or Streptococcus gallolyticus (SGG) pilus protein Gallo2178. In the present analysis, we tested the hypothesis that combined seropositivity to both antigens is a better indicator of CRC risk than seropositivity to single antigens. We used multiplex serologic assays to analyze pre-diagnostic serum for antibody responses from 4063 incident CRC cases and 4063 matched controls from 10 US cohorts. To examine whether combined SGG Gallo2178 and HP VacA sero-status was associated with CRC risk, we used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to dual sero-negative individuals, there was no increased risk for individuals sero-positive to SGG Gallo2178 only (OR: 0.93; 95% CI: 0.66-1.31) or to HP VacA only (OR: 1.08; 95% CI: 0.98-1.19). However, dual sero-positive individuals had a >50% increased odds of developing CRC (OR: 1.54; 95% CI: 1.16-2.04), suggesting an interaction between antibody responses to these two pathogens and CRC risk (p_interaction = 0.06). In conclusion, this study suggests that dual sero-positivity to HP VacA and SGG Gallo2178 is an indicator of increased risk of CRC.

BACKGROUND:Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS:To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS:We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS:By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

BACKGROUND:Prevalence of Helicobacter pylori infection, the main risk factor for gastric cancer, has been decreasing in the US; however, there remains a substantial racial disparity. Moreover, the time-trends for prevalence of CagA-positive H. pylori infection, the most virulent form, are unknown in the US population. We sought to assess prevalence of CagA-positive Helicobacter pylori infection over time by race, in the US. METHODS:We utilized multiplex serology to quantify antibody responses to H. pylori antigens in 4,476 participants across 5 cohorts that sampled adults from 1985 to 2009. Using log-binomial regression models, we calculated prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between H. pylori-CagA sero-prevalence and birth year by race. RESULTS:African Americans were 3-times more likely to be H. pylori-CagA sero-positive than whites. After adjustment, H. pylori-CagA sero-prevalence was lower with increasing birth year among whites (Ptrend=0.001), but remained stable for African Americans. When stratified by sex and education separately, the decline in H. pylori-CagA sero-positivity among whites remained only for females (Ptrend<0.001) and was independent of educational attainment. Among African Americans, there was no difference by sex; further, sero-prevalence increased with increasing birth year among those with a high-school education or less (P=0.006). CONCLUSIONS:Among individuals in the US born from the 1920s to 1960s, H. pylori-CagA sero-prevalence has declined among whites, but not among African Americans. IMPACT/CONCLUSIONS:Our findings suggest a widening racial disparity in the prevalence of the most virulent form of Helicobacter pylori, the main cause of gastric cancer.

BACKGROUND:Epithelial ovarian, fallopian tube, and primary peritoneal cancer have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites. METHODS:We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests. RESULTS:Most associations did not vary by tumor site (phet≥0.05). Associations between first pregnancy (phet=0.04), tubal ligation (phet=0.01) and early-adult (age 18-21 years) body mass index (BMI) (phet=0.02) and risk differed between ovarian and peritoneal cancers. The association between early adult BMI and risk further differed between peritoneal and fallopian tube cancer (phet=0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases. CONCLUSIONS:Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site. IMPACT/CONCLUSIONS:Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.

Mean residual life (MRL) is the remaining life expectancy of a subject who has survived to a certain time point and can be used as an alternative to hazard function for characterizing the distribution of a time-to-event variable. Inference and application of MRL models have primarily focused on full-cohort studies. In practice, case-cohort and nested case-control designs have been commonly used within large cohorts that have long follow-up and study rare diseases, particularly when studying costly molecular biomarkers. They enable prospective inference as the full-cohort design with significant cost-saving benefits. In this paper, we study the modeling and inference of a family of generalized MRL models under case-cohort and nested case-control designs. Built upon the idea of inverse selection probability, the weighted estimating equations are constructed to estimate regression parameters and baseline MRL function. Asymptotic properties of the proposed estimators are established and finite-sample performance is evaluated by extensive numerical simulations. An application to the New York University Women's Health Study is presented to illustrate the proposed models and demonstrate a model diagnostic method to guide practical implementation.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (+/- 500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn's disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P-values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (+/- 500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn's disease, and inflammatory bowel disease remained associated with PDAC (P-values = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P-value = 0.22) and primary sclerosing cholangitis (P-value = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn's disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.

BACKGROUND:Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk. METHODS:Associations between weight change and risk of breast cancer were examined among women aged ≥50 years in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (Interval 1 median= 5.2 years; Interval 2 median = 4.0 years). Sustained weight loss was defined as ≥ 2kg lost in Interval 1 that was not regained in Interval 2. Among 180,885 women, 6,930 invasive breast cancers were identified during follow-up. RESULTS:Compared with women with stable weight (± 2kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5kg lost: Hazard Ratio (HR)= 0.82, 95% confidence interval (CI): 0.70-0.96; >4.5-<9kg lost: HR = 0.75, 95% CI: 0.63-0.90; ≥9kg lost: HR = 0.68, 95% CI: 0.50-0.93). Women who lost ≥9kg and gained some (but not all) of it back were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight. CONCLUSIONS:These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged ≥50 years. Breast cancer prevention may be a strong weight loss motivator for the two-thirds of American women who are overweight or obese.