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Virology  2013;0:10.1016/j.virol.2013.10.026.
Kaposi’s sarcoma-associated herpesvirus LANA (1162 residues) mediates episomal persistence of viral genomes during latency. LANA mediates viral DNA replication and segregates episomes to daughter nuclei. A 59 residue deletion immediately upstream of the internal repeat elements rendered LANA highly deficient for DNA replication and modestly deficient for the ability to segregate episomes, while smaller deletions did not. The 59 amino acid deletion reduced LANA episome persistence by ~14-fold, while sequentially smaller deletions resulted in ~3-fold, or no deficiency. Three distinct LANA regions reorganized heterochromatin, one of which contains the deleted sequence, but the deletion did not abolish LANA’s ability to alter chromatin. Therefore, this work identifies a short internal LANA sequence that is critical for DNA replication, has modest effects on episome segregation, and substantially impacts episome persistence; this region may exert its effects through an interacting host cell protein(s).
PMCID: PMC3857964  PMID: 24314665
2.  Regular aspirin use and risk of multiple myeloma: a prospective analysis in the Health Professionals Follow-up Study and Nurses’ Health Study 
Multiple myeloma (MM) is a lethal malignancy with an unknown etiology and no prevention strategy. Aspirin inhibits several pathways mediated by nuclear factor (NF)-κB, cyclooxygenase (COX)-2, or their targets that are important in MM pathogenesis. We conducted prospective analyses in the Health Professionals Follow-up Study and Nurses’ Health Study cohorts to examine whether regular aspirin use influences MM risk. We used biennially updated data to characterize aspirin use from baseline through a cancer diagnosis, death, or 2008. We applied a four-year lag in exposure classification to diminish the influence of preclinical MM on aspirin use habits. We obtained hazard ratios (HR) and 95% confidence intervals (CI) from multivariable proportional hazard models to assess the association of aspirin use with MM risk. We tested for trend across increasing quantity and duration of use. During 2,395,458 person-years, we confirmed 328 incident MM diagnoses, including 265 with prospective information on typical aspirin dose and frequency. Participants with a cumulative average of ≥5 adult strength (325-mg) tablets/week had a 39% lower MM risk than non-users (HR, 95% CI: 0.61, 0.39–0.94; tablets/week, P-trend=0.06). Persons with ≥11 years of continuous regular aspirin use also had a lower MM risk (HR, 95% CI: 0.63, 0.41–0.95; duration, P-trend=0.17). The associations appeared stronger in men than in women, possibly reflecting gender differences in aspirin use patterns. This prospective study of aspirin use and MM supports an etiologic role for aspirin-inhibited (i.e., NF-κB- or COX-2-mediated) pathways. The utility of aspirin for MM chemoprevention warrants further evaluation.
PMCID: PMC3899896  PMID: 24282256
multiple myeloma; aspirin; epidemiology; prospective; risk factors
3.  A prospective cohort study of dietary indices and incidence of epithelial ovarian cancer 
Several dietary indices have been developed to measure overall diet quality, including the Healthy Eating Index-2005 (HEI-2005), which measures adherence to the 2005 Dietary Guidelines from the USDA; the Alternative Healthy Eating Index-2010 (AHEI-2010), which is based on foods and nutrients predictive of chronic disease risk; and the Alternate Mediterranean Diet Score (aMDS), which is an index that characterizes traditional food patterns of Mediterranean countries. Few studies have evaluated diet quality and ovarian cancer risk.
We assessed the associations of the HEI-2005, AHEI-2010, and aMDS with risk of epithelial ovarian cancer prospectively among women in the Nurses’ Health Study. We used Cox proportional hazards models, adjusting for known ovarian cancer risk factors.
During 24 years of follow-up, we documented 696 incident epithelial ovarian cancer cases among 82,948 women with diet information. The multivariate adjusted hazard ratios (95% confidence interval; Ptrend) of epithelial ovarian cancer comparing the highest with the lowest quintile were 1.03 (0.80-1.34; 0.77) for the AHEI-2010, 0.85 (0.65-1.12; 0.57) for the HEI-2005, and 0.91 (0.71-1.18; 0.44) for the aMDS.
We did not observe any clear association of three diet quality scores with ovarian cancer risk. Further work should other metrics of evaluating diet quality that may be more relevant cancer risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s13048-014-0112-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4263215  PMID: 25477244
Alternative healthy eating index; Healthy eating index; Mediterranean diet score; Dietary pattern; Ovarian cancer; Prospective cohort; Epidemiology
4.  Adiposity and Different Types of Screen Time 
Pediatrics  2013;132(6):e1497-e1505.
Few prospective studies have examined separate forms of screen time in relation to adiposity. Our objective was to assess independent relations of television, electronic games (video/computer), and digital versatile disc (DVD)/videos and total screen time with change in adolescent BMI.
Using data from the 2004, 2006, and 2008 waves of the ongoing Growing up Today Study II, we assessed baseline and 2-year change in reported screen time in relation to concurrent change in BMI among 4287 girls and 3505 boys aged 9 to 16 years in 2004. Gender-specific models adjusted for previous BMI, age, race/ethnicity, growth/development, months between questionnaires, and physical activity.
Among girls and boys, each hour per day increase in reported television viewing was associated with a 0.09 increase in BMI (Ps < .001), and each hour per day increase in total screen time was associated with a 0.07 increase among girls and 0.05 increase among boys (Ps < .001). Among girls only, greater baseline television, games, and total screen time and change in DVDs/videos were associated with gains in BMI (Ps < .05). BMI gains associated with change in television and total screen time were stronger among overweight girls than lean girls (Ps-heterogeneity < .001).
Television, which remains the steadiest source of food advertising, was most consistently associated with BMI gains. Among girls, electronic games and DVDs/videos were also related to increased BMI, possibly due to influences of product placements and advergames on diet and/or distracted eating. Adolescents, especially overweight adolescents, may benefit from reduced time with multiple types of media.
PMCID: PMC3838528  PMID: 24276840
television; video games; sedentary lifestyle; BMI; body weight; adolescent; adiposity; longitudinal studies
5.  Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle# 
Science (New York, N.Y.)  2014;344(6184):649-652.
Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. Here, we demonstrate that the circulating protein Growth Differentiation Factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.
PMCID: PMC4104429  PMID: 24797481
6.  Reproductive Factors and Risk of Premenopausal Breast Cancer by Age at Diagnosis: Are There Differences Before and After Age 40? 
Breast cancer research and treatment  2013;142(1):10.1007/s10549-013-2721-9.
We examined the relationship between reproductive factors and risk of premenopausal breast cancer among women less than age 40 compared with older premenopausal women.
We documented 374 incident cases of breast cancer diagnosed before age 40 and 2,533 cases diagnosed at age 40 and older among premenopausal women in the Nurses’ Health Study cohorts. Biennial questionnaires were used to determine age at menarche, age at first birth, parity, breastfeeding and other reproductive factors. Multivariate relative risks (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models within age at diagnosis groups.
Tumors in younger women were significantly more likely to be higher grade, larger size, and hormone receptor negative than were tumors in older premenopausal women (p< 0.0001). There was no significant heterogeneity according to age in associations between reproductive factors and risk of premenopausal breast cancer. First birth at age 30 or older increased breast cancer risk in both age groups (age <40: RR: 1.10, 95% CI: 0.80, 1.50; age ≥40: RR: 1.16, 95% CI: 1.02, 1.32; p-heterogeneity= 0.44). Risk of premenopausal breast cancer decreased with each additional year of age at menarche in both age groups (age <40 RR: 0.93, 95% CI: 0.87, 0.99; p-trend=0.02; age ≥ 40 RR: 0.94, 95% CI: 0.91, 0.97; p-trend=<0.0001). Among premenopausal parous women, breastfeeding was protective regardless of age at diagnosis (age <40 RR: 0.84, 95% CI 0.57, 1.22; age ≥40: RR: 0.85, 95% CI 0.72, 0.99; p-heterogeneity=0.79).
In the largest prospective examination of reproductive risk factors and risk of breast cancer before and after age 40, we found that younger women were more likely to develop tumors with less favorable prognostic characteristics. However, associations between reproductive factors and risk of breast cancer were similar regardless of age at diagnosis of premenopausal breast cancer.
PMCID: PMC3850283  PMID: 24136668
breast cancer; age at diagnosis; young women; reproductive factors
7.  Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study 
Objective To determine whether use of oral contraceptives is associated with all cause and cause specific mortality.
Design Prospective cohort study.
Setting Nurses’ Health Study, data collected between 1976 and 2012.
Population 121 701 participants were prospectively followed for 36 years; lifetime oral contraceptive use was recorded biennially from 1976 to 1982.
Main outcome measures Overall and cause specific mortality, assessed throughout follow-up until 2012. Cox proportional hazards models were used to calculate the relative risks of all cause and cause specific mortality associated with use of oral contraceptives.
Results In our population of 121 577 women with information on oral contraceptive use, 63 626 were never users (52%) and 57 951 were ever users (48%). After 3.6 million person years, we recorded 31 286 deaths. No association was observed between ever use of oral contraceptives and all cause mortality. However, violent or accidental deaths were more common among ever users (hazard ratio 1.20, 95% confidence interval 1.04 to 1.37). Longer duration of use was more strongly associated with certain causes of death, including premature mortality due to breast cancer (test for trend P<0.0001) and decreased mortality rates of ovarian cancer (P=0.002). Longer time since last use was also associated with certain outcomes, including a positive association with violent or accidental deaths (P=0.005).
Conclusions All cause mortality did not differ significantly between women who had ever used oral contraceptives and never users. Oral contraceptive use was associated with certain causes of death, including increased rates of violent or accidental death and deaths due to breast cancer, whereas deaths due to ovarian cancer were less common among women who used oral contraceptives. These results pertain to earlier oral contraceptive formulations with higher hormone doses rather than the now more commonly used third and fourth generation formulations with lower estrogen doses.
PMCID: PMC4216099  PMID: 25361731
8.  Seafood Types and Age-Related Cognitive Decline in the Women’s Health Study 
Seafood consumption may prevent age-related cognitive decline. However, benefits may vary by nutrient contents in different seafood types. We examined associations between total seafood consumption and cognitive decline and whether these associations differ by seafood types.
We conducted a prospective cohort study of 5,988 women (mean age, 72 years) from the Women’s Health Study who self-reported seafood intake at Women’s Health Study baseline and also participated in telephone assessments of general cognition, verbal memory, and category fluency administered 5.6 years after Women’s Health Study baseline and 2 and 4 years thereafter. Primary outcomes were standardized composite scores of global cognition and verbal memory.
After adjusting for potential confounders, different amounts of total seafood consumption were not associated with changes in global cognition (p = .56) or verbal memory (p = .29). Considering seafood types, however, compared with women consuming less than once-weekly tuna or dark-meat finfish, those with once-weekly or higher consumption had significantly better verbal memory (0.079 standard units; p < .01) after 4 years—a difference comparable to that for women 2.1 years apart in age. There was also a statistically nonsignificant suggestion of better global cognition (p = .13) with once-weekly or higher tuna or dark-meat fish consumption. No significant associations were observed for light-meat finfish or shellfish.
The relation of seafood to cognition may depend on the types consumed. Total consumption levels of seafood were unrelated to cognitive change. However, consumption of tuna and dark-meat fish once weekly or higher was associated with lower decline in verbal memory for a period of 4 years.
PMCID: PMC3779629  PMID: 23554464
Cognition; Epidemiology; Nutrition.
9.  Vegetable protein and vegetable fat intakes in pre-adolescent and adolescent girls, and risk for benign breast disease in young women 
Previous investigations, of adolescent diet recalled in adulthood, found lower risk for benign breast disease (BBD) with higher intakes of vegetable fat and nuts during high school. We investigate whether vegetable protein and fat, derived from diets reported during pre-adolescence and adolescence, are associated with subsequent risk for BBD in young women. The Growing Up Today Study includes 9,039 females, 9–15 years in 1996, who completed questionnaires annually through 2001, and then in 2003, 2005, 2007, and 2010. Food frequency questionnaires (1996–2001) obtained intake data on a variety of foods. Beginning in 2005, women (18–30 years) reported whether they had ever been diagnosed with BBD that was confirmed by breast biopsy (n = 112 cases). Logistic regression estimated associations between intakes of vegetable protein and fat and biopsy-confirmed BBD. Those individual foods that were the largest contributors of protein and fat in this cohort were also investigated. In analyses of intakes from 1996 through 1998, when our cohort was youngest, vegetable fat (OR = 0.72/(10 gm/day), 95 % CI 0.53–0.98; p = 0.04) was inversely associated with BBD risk. The greatest sources of vegetable fat and protein in these girls were peanut butter, peanuts, nuts, beans (beans, lentils, and soybeans), and corn. A daily serving of any one of these was associated with lower risk (OR = 0.32/(serv/day), 95 % CI 0.13–0.79; p = 0.01). Peanut butter (and nuts) at age 11 years was inversely associated with risk (p = 0.01). In analyses of intakes at age 14 years, vegetable protein was associated with lower BBD risk (OR = 0.64/(10 gm/day), 95 % CI 0.43–0.95; p = 0.03). A daily serving at 14 years of any one of the foods was associated with lower risk (OR = 0.34, 95 % CI 0.16–0.75; p = 0.01), as was peanut butter (and nuts) (p = 0.02). Girls with a family history of breast cancer had significantly lower risk if they consumed these foods or vegetable fat. In conclusion, consumption of vegetable protein, fat, peanut butter, or nuts by older girls may help reduce their risk of BBD as young women.
PMCID: PMC3903425  PMID: 24043428
Childhood diet; Vegetable protein; Vegetable fat; Peanut butter; BBD; Prospective
10.  A prospective analysis of body size during childhood, adolescence, and adulthood and risk of non-Hodgkin lymphoma 
The etiology of non-Hodgkin lymphoma (NHL) is poorly understood. Obesity is associated with inflammation, a cytokine milieu conducive to lymphocyte proliferation, and has been associated with NHL risk in some epidemiologic studies. To prospectively examine NHL risk in relation to adult and earlier life obesity, we documented 635 incident NHL diagnoses among 46,390 men in the Health Professionals Follow-up Study and 1254 diagnoses among 116,794 women in the Nurses’ Health Study over 22–32 years of follow-up. Using multivariable Cox proportional hazards models we estimated cohort-specific incidence rate ratios (RRs) and 95% confidence intervals (CI) for risk of NHL and major histologic subtypes associated with cumulative average middle and young adult (ages 18–21) body mass index (BMI) and adolescent and childhood somatotype. NHL risk was modestly increased in men (but not women) with a cumulative average middle adult BMI ≥30 kg/m2 (vs. 15–22.9 kg/m2; RR: 1.28; 95% CI: 0.92, 1.77; P-trend=0.05). In meta-analyses across cohorts, higher young adult BMI was associated with increased risk of all NHL (pooled RR per 5 kg/m2: 1.19; 95% CI: 1.05, 1.37), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (all P-trend≤0.02). Adolescent somatotype was also positively associated with all NHL, DLBCL, and FL in pooled analyses (all P-trend ≤0.03) while childhood somatotype was positively associated with NHL overall among women only (P-trend <0.01). These findings in two large prospective cohorts provide novel evidence that larger body size in childhood, adolescence, and young adulthood predicts increased risk of NHL, and particularly of DLBCL and FL.
PMCID: PMC3761937  PMID: 23803416
non-Hodgkin lymphoma; obesity; body mass index; anthropometry; epidemiology
11.  Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin 
Differentiating ovarian tumors based on developmental pathway may further our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (NECC) and two cohort studies (NHS/NHSII) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and non-dominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid, or clear cell, whereas non-dominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis, and age were more strongly associated with dominant (RRs = 0.60, 0.83, 1.58, 1.37, respectively) than non-dominant tumors (RRs = 1.03, 0.93, 0.84, 1.14 p-difference = 0.0001, 0.01, 0.0003, 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.
PMCID: PMC3690361  PMID: 23364849
ovarian cancer; cell of origin; epidemiology; risk factors
12.  A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development 
Cancer research  2013;73(15):4810-4819.
Understanding how the timing of exposure to endogenous hormones influences cancer development is critical to elucidating disease etiology. Prolactin increases proliferation and cell motility, processes important in later stage tumor development, suggesting that levels proximate (versus distant) to diagnosis may better predict risk. Thus, we calculated relative risks (RR) and 95% confidence intervals (CI) for prolactin levels on samples collected <10 (proximate) versus ≥10 (distant) years before diagnosis in the Nurses’ Health Study (NHS) and NHSII with breast cancer risk, including in a subset of NHS women providing two samples 10 years apart. We measured prolactin via immunoassay in cases diagnosed from 1990–2010 (NHS) and 1999–2009 (NHSII) and matched controls. Overall, 2,468 cases and 4,021 controls had prolactin measured <10 years and 953 cases and 1,339 controls >10 years before diagnosis/reference date. There was an increased risk for higher proximate prolactin levels (RR, >15.7 vs. ≤8.1 ng/mL [i.e. top vs. bottom quartiles]=1.20, 95%CI=1.03–1.40, p-trend=0.005), but not for distant levels (RR=0.97, p-trend=0.94); results were similar among women with two blood samples (p-interaction, proximate versus distant=0.07). The positive association was stronger for ER+ disease (RR=1.28, p-trend=0.003) and postmenopausal women (RR=1.37, p-trend=0.0002). Among postmenopausal women, the association was strongest for ER+ disease (RR=1.52) and lymph node positive cases (RR=1.63). Our data suggest that prolactin levels measured <10 years prior to diagnosis are most strongly associated with postmenopausal breast cancer risk, especially for ER+ tumors and metastatic disease. This corresponds with biologic data that prolactin is etiologically important in tumor promotion.
PMCID: PMC3738582  PMID: 23783576
Prolactin; breast cancer; estrogen receptor; postmenopausal
13.  Childhood Blood Pressure Trends and Risk Factors for High Blood Pressure: The NHANES experience 1988–2008 
Hypertension  2013;62(2):247-254.
The obesity epidemic in children makes it plausible that prevalence rates of elevated blood pressure are increasing over time. Yet, previous literature is inconsistent due to small sample sizes. Also, it is unclear whether adjusting for risk factors can explain longitudinal trends in prevalence of elevated blood pressure. Thus, we analyzed a population-based sample of 3,248 children in National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and 8,388 children in continuous NHANES (1999–2008), ages 8–17. Our main outcome measure was elevated blood pressure (systolic blood pressure (SBP) or diastolic blood pressure (DBP) ≥ 90th percentile or SBP/DBP ≥ 120/80mmHg). We found that the prevalence of elevated blood pressure (bp) increased from NHANES III to NHANES 99-08 (Boys: 15.8% to 19.2%, p=0.057; Girls: 8.2% to 12.6%, p=0.007). Body mass index (BMI) (Q4 vs Q1, Odds Ratio (OR) =2.00, p<0.001), waist circumference (Q4 vs Q1, OR=2.14, p<0.001) and sodium (Na) intake (≥3,450mg vs <2,300mg/2,000 calories, OR=1.36, p=0.024) were independently associated with prevalence of elevated blood pressure. Also, mean SBP, but not DBP was associated with increased Na intake in children (quintile 5 (Q5) vs. quintile 1 (Q1) of Na intake, Beta = 1.25 ± 0.58, p=0.034). In conclusion, we demonstrate an association between high Na intake and elevated bp in children. After adjustment for age, gender, race/ethnicity, BMI, waist circumference and sodium intake, OR for elevated bp in NHANES 99-08 vs. NHANES III = 1.27, p=0.069.
PMCID: PMC3769135  PMID: 23856492
blood pressure; body mass index; NHANES; nutrition; pediatrics; sodium intake; waist circumference
14.  Breast Cancer Risk Prediction with Heterogeneous Risk Profiles According to Breast Cancer Tumor Markers 
American Journal of Epidemiology  2013;178(2):296-308.
Relationships between some risk factors and breast cancer incidence are known to vary by tumor subtype. However, breast tumors can be classified according to a number of markers, which may be correlated, making it difficult to identify heterogeneity of risk factors with specific tumor markers when using standard competing-risk survival analysis. In this paper, we propose a constrained competing-risk survival model that allows for assessment of heterogeneity of risk factor associations according to specific tumor markers while controlling for other markers. These methods are applied to Nurses’ Health Study data from 1980–2006, during which 3,398 incident invasive breast cancers occurred over 1.4 million person-years of follow-up. Results suggested that when estrogen receptor (ER) and progesterone receptor (PR) status are mutually considered, some risk factors thought to be characteristic of “estrogen-positive tumors,” such as high body mass index during postmenopause and increased height, are actually significantly associated with PR-positive tumors but not ER-positive tumors, while other risk factors thought to be characteristic of “estrogen-negative tumors,” such as late age at first birth, are actually significantly associated with PR-negative rather than ER-negative breast cancer. This approach provides a strategy for evaluating heterogeneity of risk factor associations by tumor marker levels while controlling for additional tumor markers.
PMCID: PMC3816337  PMID: 23645624
breast cancer; competing risks; proportional hazards model
15.  Risk Models for Progression to Advanced Age-Related Macular Degeneration Using Demographic, Environmental, Genetic, and Ocular Factors 
Ophthalmology  2011;118(11):2203-2211.
To expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status.
Prospective, longitudinal study.
We included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up.
Cox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables.
Main Outcome Measures
Progression to advanced AMD, including geographic atrophy and neovascular disease.
In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered.
Factors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.
PMCID: PMC4097877  PMID: 21959373
16.  Mediterranean diet and cognitive function in older age: results from the Women’s Health Study 
Epidemiology (Cambridge, Mass.)  2013;24(4):490-499.
Adherence to a Mediterranean diet may help prevent cognitive decline in older age, but studies are limited. We examined the association of adherence to the Mediterranean diet with cognitive function and decline.
We included 6,174 participants, aged 65+ years, from the cognitive sub-study of the Women’s Health Study. Women provided dietary information in 1998 and completed a cognitive battery 5 years later, followed by two assessments at 2-year intervals. The primary outcomes were composite scores of global cognition and verbal memory. The alternate Mediterranean diet adherence 9-point-score was constructed based on intakes of: vegetables, fruits, legumes, whole grains, nuts, fish, red and processed meats, moderate alcohol, and the ratio of monounsaturated-to-saturated fats.
After multivariable adjustment, the alternate Mediterranean diet score was not associated with trajectories of repeated cognitive scores (P-trend across quintiles=0.26 and 0.40 for global cognition and verbal memory, respectively), nor with overall global cognition and verbal memory at older ages, assessed by averaging the three cognitive measures (P-trend=0.63 and 0.44, respectively). Among alternate Mediterranean diet components, higher monounsaturated-to-saturated fats ratio was associated with more favorable cognitive trajectories (P-trend=0.03 and 0.05 for global cognition and verbal memory, respectively). Greater whole grain intake was not associated with cognitive trajectories, but was related to better average global cognition (P-trend=0.02).
In this large study of older women, we observed no association of the Mediterranean diet with cognitive decline. Relations between individual Mediterranean diet components, particularly whole grains, and cognitive function merit further study.
PMCID: PMC3674216  PMID: 23676264
17.  Plasma Vitamin D Biomarkers and Leukocyte Telomere Length 
American Journal of Epidemiology  2013;177(12):1411-1417.
Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. In the present study, we examined the association between vitamin D and relative leukocyte telomere length by using both plasma 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) biomarkers. Vitamin D biomarker levels and leukocyte telomere length were measured using plasma samples collected in 1989–1990 from participants of the Nurses' Health Study, a study of nurses from 11 US states. In total, 1,424 participants had their 25(OH)D levels assessed and 837 had their 1,25(OH)2D levels assessed. Genotyping was performed on 480 participants on 12 single nucleotide polymorphisms in vitamin D–related genes. Linear and logistic regression models were used. Higher 25(OH)D levels were significantly associated with longer telomere length (P for trend = 0.05), and the odds ratio increased from 1.07 (P = 0.65) when comparing the second lowest quartile of 25(OH)D with the lowest to 1.59 (P = 0.01) when comparing the highest quartile with the lowest. Vitamin D–related single nucleotide polymorphisms and 1,25(OH)2D levels were not significantly associated with telomere length. Total calcium intake significantly modified the association between 25(OH)D and telomere length (P for interaction = 0.05). Higher plasma 25(OH)D levels may be associated with longer telomeres, and this association may be modified by calcium intake.
PMCID: PMC3676154  PMID: 23660800
epidemiology; 25(OH)D; 1,25(OH)2D; telomere length
18.  Plasma Enterolactone and Breast Cancer Risk in the Nurses’ Health Study II 
Lignans are plant-based phytoestrogens with both estrogenic and anti-estrogenic properties that may be important for breast carcinogenesis. Retrospective studies have observed decreased breast cancer risk associated with high circulating enterolactone concentrations, a biomarker of lignan intake, but results from prospective studies are conflicting.
To prospectively examine this association, we measured plasma enterolactone levels in 802 breast cancer cases and 802 matched controls nested among predominantly premenopausal women in the Nurses’ Health Study II (NHSII) cohort. We used conditional logistic regression and polytomous logistic regression models, adjusting for known breast cancer risk factors, to calculate relative risks (RR) and 95% confidence intervals (CI).
Compared to women with enterolactone concentrations ≤ 4nmol/L, the multivariate adjusted RRs for breast cancer were 1.18 (95% CI: 0.86–1.62), 0.91 (95% CI: 0.66–1.25), and 0.96 (95% CI: 0.70–1.33) for women with enterolactone levels in the 2nd to the 4th quartiles, respectively; Ptrend=0.60. Results were similar across tumors defined by estrogen and progesterone receptor status. Among premenopausal women with follicular estradiol levels below the median (<47 pg/mL), women in the highest category of enterolactone levels had a 51% lower breast cancer risk compared to those in the lowest category (95% CI: 0.27–0.91); Ptrend=0.02. No association was observed among women with high follicular estradiol levels (≥47 pg/mL), (comparable RR=1.39, 95% CI: 0.73–2.65; Pinteraction=0.02).
We did not observe an overall association between plasma enterolactone and breast cancer risk in a large nested case-control study of US women. However, a significant inverse association was observed among premenopausal women with low follicular estradiol levels, suggesting that enterolactone may be important in a low estrogen environment. This should be confirmed in future studies.
PMCID: PMC3736336  PMID: 23760859
enterolactone; lignan; breast cancer; biomarker; prospective study; premenopausal
19.  Mammographic Breast Density and Subsequent Risk of Breast Cancer in Postmenopausal Women according to the Time Since the Mammogram 
Few studies have shown that the association between mammographic breast density and breast cancer persists for up to 10 years after the mammogram. We investigated associations of percent density, absolute dense and non-dense areas with breast cancer risk according to the time since the mammogram.
This study included 1,028 incident breast cancer cases diagnosed within the Nurses’ Health Study and 1,780 matched controls. Breast density was measured from digitized film images with computerized techniques. Information on breast cancer risk factors was obtained prospectively from the biennial questionnaires before the date of cancer diagnosis for cases and their matched controls. The data were analyzed with logistic regression.
Breast cancer risk increased with increasing percent density and increasing absolute dense area and decreased with increasing non-dense. In multivariate analysis, the magnitude of the association between percent density and breast cancer was similar when the time since the mammogram was <2, 2–<5, and 5–<10 years (density ≥50% vs.<10%: ORs 3.12 [95%CI 1.55–6.25], 5.35 [95%CI 2.93–9.76], and 3.91 [95%CI 2.22–6.88], respectively). Similarly, the magnitude of association between quartiles of dense and non-dense areas and breast cancer risk were similar across the time strata. We found no interactions between the time since the mammogram and breast density measures (p for all interactions>0.05).
Patterns of the associations between percent density, absolute dense and non-dense area with breast cancer risk persist for up to 10 years after the mammogram.
A one-time density measure can be used for long-term breast cancer risk prediction.
PMCID: PMC3681889  PMID: 23603205
breast density; breast cancer risk; postmenopausal breast cancer; case-control design; risk factors
20.  Radial scars and subsequent breast cancer risk: Results from the Nurses’ Health Studies 
Radial scars (RS) are benign proliferative lesions associated with an increased risk of subsequent breast cancer. However, it remains unclear whether RS are an independent risk factor for breast cancer or whether their association with breast cancer is due to their common occurrence with other proliferative lesions known to increase breast cancer risk.
We performed an updated analysis of the association between RS and subsequent breast cancer risk in a nested case-control study among 460 cases and 1792 controls with benign breast disease (BBD) in the Nurses’ Health Studies. Logistic regression was used to estimate associations between RS in BBD biopsy specimens and breast cancer risk, adjusted for matching factors and breast cancer risk factors, including histologic category of concurrent BBD.
In multivariable models prior to adjustment for histologic category of BBD, RS were associated with a two-fold increased risk of breast cancer (odds ratio [OR] = 2.0; 95% confidence interval [95% CI]: 1.4, 2.8). This association was attenuated but still significant after adjustment for BBD histologic category (OR = 1.6; 95% CI: 1.1, 2.3). In models adjusted for BBD histologic category and other covariates, risk appeared greater among women with multiple RS (1 RS, OR = 1.5; 95% CI: 0.9, 2.3; ≥2 RS, OR = 2.7; 95% CI: 1.5, 5.0; p-heterogeneity = 0.12). There were also suggestions of a greater risk associated with RS among women age ≥50 years at biopsy (p-heterogeneity = 0.07) and for estrogen receptor-negative/progesterone receptor-negative (ER−/PR−) tumors compared with other hormone receptor subtypes (p-heterogeneity = 0.19).
RS appear to be an independent histologic risk factor for breast cancer. Larger studies are needed to further evaluate whether risk is increased when multiple RS are present and whether associations vary by age at biopsy or by hormone receptor status of the breast tumor.
PMCID: PMC3689547  PMID: 23609472
benign breast disease; breast cancer; breast pathology; nested case-control; radial scars
21.  Plasma carotenoid- and retinol-weighted multi-SNP scores and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium 
Dietary and circulating carotenoids have been inversely associated with breast cancer risk, but observed associations may be due to confounding. Single nucleotide polymorphisms (SNPs) in β-carotene 15,15′-monooxygenase 1 (BCMO1), a gene encoding the enzyme involved in the first step of synthesizing vitamin A from dietary carotenoids, have been associated with circulating carotenoid concentrations and may serve as unconfounded surrogates for those biomarkers. We determined associations between variants in BCMO1 and breast cancer risk in a large cohort consortium.
We used unconditional logistic regression to test four SNPs in BCMO1 for associations with breast cancer risk in 9,226 cases and 10,420 controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also tested weighted multi-SNP scores composed of the two SNPs with strong, confirmed associations with circulating carotenoid concentrations.
Neither the individual SNPs nor the weighted multi-SNP scores were associated with breast cancer risk (odds ratio (95% confidence interval) comparing extreme quintiles of weighted multi-SNP scores =1.04 (0.94–1.16) for β-carotene, 1.08 (0.98–1.20) for α-carotene, 1.04 (0.94–1.16) for β-cryptoxanthin, 0.95 (0.87–1.05) for lutein/zeaxanthin, and 0.92 (0.83–1.02) for retinol). Furthermore, no associations were observed when stratifying by estrogen receptor status, but power was limited.
Our results do not support an association between SNPs associated with circulating carotenoid concentrations and breast cancer risk.
Future studies will need additional genetic surrogates and/or sample sizes at least three times larger to contribute evidence of a causal link between carotenoids and breast cancer.
PMCID: PMC3650115  PMID: 23515144
breast cancer; BCMO1; β-carotene 15,15′-monooxygenase 1; carotenoids; single nucleotide polymorphism
22.  Dietary Omega-3 Fatty Acids, Other Fat Intake, Genetic Susceptibility and Progression to Incident Geographic Atrophy 
Ophthalmology  2013;120(5):1020-1028.
To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD) and progression to geographic atrophy (GA).
Observational analysis of a prospective cohort.
2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not.
Eyes without advanced AMD (GA or neovascular disease) at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements were collected at baseline using questionnaires. Dietary data was collected from food frequency questionnaires (FFQ) at baseline. Dietary fats, including omega-3 fatty acids (docosahexaenoic acid or DHA and eicosapentaenoic acid or EPA), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated and total fat were sex and calorie adjusted and divided into quintiles. Eight single nucleotide polymorphisms (SNPs) in 7 genes: CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, LIPC were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids, and interaction effects between dietary fat intake and genetic variation on risk of GA.
Main Outcome Measures
Associations between dietary fat intake reported from FFQs, genetic variants and incident GA.
Increased intake of DHA was significantly associated with reduced risk of progression to GA in multivariate models with behavioral factors (Model A) and behavioral factors with genetic variants (Model B) (P-trend=0.008 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in Model B variants (P-trend =0.02). Monounsaturated fat was associated with increased risk in Model A (P=0.05).. DHA intake in the 5th quintile was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (HR = 0.4, P = 0.002, P – interaction between gene and fat intake = 0.05), whereas DHA was not associated with reduced risk of GA among those with the homozygous non-risk genotype (HR = 1.0, P= 0.90).
Increased self- reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA.
PMCID: PMC3758110  PMID: 23481534
Cancer causes & control : CCC  2013;24(4):695-704.
Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.
The National Cancer Institute developed an innovative concept to establish a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the Centers.
Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes 3 animal studies, 3 cohort studies, 4 randomized clinical trials, 1 cross-sectional study, and 2 modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.
The NIH Science of Team Science group will evaluate the value-added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk for cancer as well as cancer survivors.
PMCID: PMC3602225  PMID: 23378138
energetics; obesity; diet; physical activity; cancer; transdisciplinary
Cancer causes & control : CCC  2013;24(4):731-739.
The incidence of estrogen receptor positive (ER+) breast cancer is higher among white women relative to black women. In two large prospective cohorts, the Black Women’s Health Study (BWHS) and the Nurses’ Health Study II (NHSII), we investigated whether reproductive factors explain the difference.
During 1,582,083 person-years of follow-up of 140,914 women observed from 1995-2007, 327 ER+ breast cancers were identified among black women in BWHS and NHSII and 1179 among white women in NHSII. Cox proportional hazards regression models, stratified by race and pooled, were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of race, parity, age at first birth, and lactation in relation to risk of ER+ cancer with adjustment for age and other breast cancer risk factors.
Age at first birth differed markedly in the two groups, with 66% of parous black women having their first child before age 25 as compared with 36% of white women. Each additional year of age at first birth was associated with a 4% increased risk of ER+ breast cancer among both racial groups. Relative to nulliparous women, parous women were at decreased risk of ER+ breast cancer (HR 0.59, 95% CI: 0.20, 1.77), in black women and (HR 0.63, 95% CI: 0.45, 0.87) in white women. The HR for the association of black race with ER+ cancer was 0.67 (95% CI: 0.53, 0.84) in a model that adjusted for age only, 0.77 (95% CI: 0.61, 0.99) in a model that controlled for parity, age at first birth, and other reproductive/hormonal factors, and 0.83 (95% CI: 0.70, 0.98) in a model that additionally controlled for other breast cancer risk factors such as alcohol consumption and use of hormone supplements. Similar associations were seen among premenopausal women and in an analysis restricted to ER+PR+ tumors.
Reproductive factors explained some of the higher incidence of ER+ tumors among white women as compared to black women.
PMCID: PMC3602276  PMID: 23380944
breast carcinoma; race; estrogen receptor; reproductive factors; incidence; black; African-American
25.  Acrylamide Hemoglobin Adduct Levels and Ovarian Cancer Risk: a nested case-control study 
Acrylamide is a probable human carcinogen formed during cooking of starchy foods. Two large prospective cohort studies of dietary acrylamide intake and ovarian cancer risk observed a positive association, although two other studies reported no association.
We measured acrylamide exposure using red blood cell acrylamide and glycidamide hemoglobin adducts among women in two large prospective cohorts: the Nurses’ Health Study and Nurses’ Health Study II. Between blood collection and 2010, we identified 263 incident cases of epithelial ovarian cancer, matching two controls per case. We used logistic regression models to examine the association between acrylamide exposure and ovarian cancer risk, adjusting for matching factors, family history of ovarian cancer, tubal ligation, oral contraceptive use, body mass index (BMI), parity, alcohol intake, smoking, physical activity, and caffeine intake.
The multivariate-adjusted relative risk (RR) of ovarian cancer comparing the highest versus lowest tertile of total acrylamide adducts was 0.79 (95% CI: 0.50–1.24, P trend = 0.08). The comparable RR of ovarian cancer among non-smokers at blood draw was 0.85 (95% CI: 0.57–1.27, P trend =0.14). The association did not differ by tumor histology (serous invasive versus not), P for heterogeneity=0.41. Individual adduct types (acrylamide or glycidamide) were not associated with risk.
We observed no evidence that acrylamide exposure as measured by adducts to hemoglobin is associated with an increased risk of ovarian cancer.
Our finding indicates that acrylamide intake may not increase risk of ovarian cancer.
PMCID: PMC3617048  PMID: 23417989
acrylamide; ovarian cancer; hemoglobin adducts; epidemiology; prospective

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