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Background: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. Methods: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). Results: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (β = 0.082 [0.02–0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18–2.85] and HER2-enriched, OR = 2.32 [1.46–3.69]), and PAM50 risk of recurrence score (β = 4.81 [1.71–7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10–2.25]). Conclusions: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies. [ABSTRACT FROM AUTHOR]

Background: We investigated the associations of reproductive factors known to influence breast cancer risk with the expression of breast stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples. Methods: We included 439 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII. The data on reproductive and other breast cancer risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was performed on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as % of cells that stained positive for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of reproductive factors with a log-transformed expression of each marker (in epithelium and stroma), adjusted for other breast cancer risk factors. Results: In multivariate analysis, the time between menarche and age at first birth was inversely associated with CD44 in epithelium (β per 5 years = -0.38, 95% CI -0.69; -0.06). Age at first birth and the time between menarche and age at first birth were inversely associated with ALDH1A1 (stroma: β per 5 years = -0.43, 95% CI -0.76; -0.10 and β = -0.47, 95% CI -0.79; -0.15, respectively; epithelium: β = -0.15, 95% CI -0.30; -0.01 and β = -0.17, 95% CI -0.30; -0.03, respectively). Time since last pregnancy was inversely associated with stromal ALDH1A1 (β per 5 years = -0.55, 95% CI -0.98; -0.11). No associations were found for CD24. The observed associations were similar in premenopausal women. In postmenopausal women, lifetime duration of breastfeeding was inversely associated with stromal ALDH1A1 expression (β for ≥24 vs. 0 to <1 months = -2.24, 95% CI 3.96; -0.51, p-trend = 0.01). Conclusion: Early-life reproductive factors may influence CD44 and ALDH1A1 expression in benign breast tissue. [ABSTRACT FROM AUTHOR]

Background To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models. Methods We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics. Results When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC. Conclusions Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to examine the relationship between alcohol consumption and hip osteoarthritis in women. Alcohol has been associated with both adverse and beneficial health effects generally; however, the relationship between alcohol consumption and hip osteoarthritis has been minimally studied. Methods: Among women in the Nurses' Health Study cohort in the US, alcohol consumption was assessed every 4 years, starting in 1980. Intake was computed as cumulative averages and simple updates with latency periods of 0–4 through 20–24 years. We followed 83,383 women without diagnosed osteoarthritis in 1988 to June 2012. We identified 1,796 cases of total hip replacement due to hip osteoarthritis defined by self‐report of osteoarthritis with hip replacement. Results: Alcohol consumption was positively associated with hip osteoarthritis risk. Compared with nondrinkers, multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) were HR 1.04 (95% CI 0.90, 1.19) for drinkers of >0 to <5 grams/day, HR 1.12 (95% CI 0.94, 1.33) for 5 to <10 grams/day, HR 1.31 (95% CI 1.10, 1.56) for 10 to <20 grams/day, and HR 1.34 (95% CI 1.09, 1.64) for ≥20 grams/day (P for trend < 0.0001). This association held in latency analyses of up to 16–20 years, and for alcohol consumption between 35–40 years of age. Independent of other alcoholic beverages, the multivariable HRs (per 10 grams of alcohol) were similar for individual types of alcohol intake (wine, liquor, and beer; P = 0.57 for heterogeneity among alcohol types). Conclusion: Higher alcohol consumption was associated with greater incidence of total hip replacement due to hip osteoarthritis in a dose‐dependent manner in women. [ABSTRACT FROM AUTHOR]

With mammography being the primary breast cancer screening strategy, it is essential to make full use of the mammogram imaging data to better identify women who are at higher and lower than average risk. Our primary goal in this study is to extract mammogram-based features that augment the well-established breast cancer risk factors to improve prediction accuracy. In this article, we propose a supervised functional principal component analysis (sFPCA) over triangulations method for extracting features that are ordered by the magnitude of association with the failure time outcome. The proposed method accommodates the irregular boundary issue posed by the breast area within the mammogram imaging data with flexible bivariate splines over triangulations. We also provide an eigenvalue decomposition algorithm that is computationally efficient. Compared to the conventional unsupervised FPCA method, the proposed method results in a lower Brier Score and higher area under the ROC curve (AUC) in simulation studies. We apply our method to data from the Joanne Knight Breast Health Cohort at Siteman Cancer Center. Our approach not only obtains the best prediction performance comparing to unsupervised FPCA and benchmark models but also reveals important risk patterns within the mammogram images. This demonstrates the importance of utilizing additional supervised image-based features to clarify breast cancer risk. [ABSTRACT FROM AUTHOR]

Background Many studies have linked intakes of fat and of specific fatty acids during pregnancy with preeclampsia; however, information on the association of intake before pregnancy with hypertensive disorders of pregnancy (HDP) is scant. Objectives We evaluated the associations of intakes of major and specific types of fat before pregnancy with the risks of HDP, including preeclampsia and gestational hypertension (GHTN). Methods We followed 11,535 women without chronic disease participating in the Nurses' Health Study II from 1991 and 2009. Pre-pregnancy dietary fat was assessed by an FFQ. Intakes of total fat, saturated fat, trans fatty acid (TFA), MUFAs, PUFAs, and fat subtypes (omega-3 and omega-6) were categorized into quintiles of intake. HDP were self-reported. The RRs (95% CIs) of HDP were estimated by log-binomial generalized estimating equation regression models, with an exchangeable correlation matrix to account for repeated pregnancies while adjusting for potential confounders. Results During 19 years of follow-up, there were 495 cases of preeclampsia (2.9%) and 561 (3.3%) cases of GHTN in 16,892 singleton pregnancies. The mean age at pregnancy was 34.6 years (SD, 3.9 years). Among major fat types, only pre-pregnancy TFA was related to a higher risk of HDP (RR, 1.32; 95% CI: 1.05–1.66), and only for preeclampsia (RR, 1.50; 95% CI: 1.07–2.10) but not for GHTN (RR, 1.21; 95% CI: 0.87–1.70). Among specific types of PUFAs, intake of arachidonic acid was positively related with GHTN (RR, 1.43; 95% CI: 1.00–2.04) but not preeclampsia (RR, 1.08; 95% CI: 0.75–1.57). In analyses restricted to pregnancies 1 year after the diet assessment, women with the highest intake of long-chain omega-3 fatty acids had a 31% lower risk of HDP (95% CI: 3%–51%), which was driven by preeclampsia (RR, 0.55; 95% CI: 0.33–0.92). Conclusions Pre-pregnancy intakes of total fat, saturated fat, and MUFA were unrelated to HDP, whereas TFA was positively related to HDP. These findings highlight the importance of ongoing efforts to eliminate TFA from the global food supply. [ABSTRACT FROM AUTHOR]

Background: Some previous studies suggested that high supplemental vitamin C intake may be associated with an increased risk of breast cancer, although evidence is inconsistent.Objectives: Our objective was to study the association between vitamin C intake and breast cancer risks using regularly updated assessments of intake over a long follow-up.Methods: We prospectively followed 88,041 women aged 33 to 60 years from the Nurses' Health Study (1980-2014) and 93,372 women aged 26 to 45 years from the Nurses' Health Study II (1991-2013). A total of 11,258 incident invasive breast cancers among 181,413 women were diagnosed. Data on vitamin C intake were collected every 2-4 years via a validated FFQ and specific questions on dietary supplement use. Multivariate HRs and 95% CIs for incident invasive breast cancer were estimated with Cox models.Results: During follow-up, 82% of participants ever used supplements containing vitamin C, including multivitamins. Cumulative total vitamin C intake (HR for quintiles 5 compared with 1 = 0.97; 95% CI: 0.91-1.03; Ptrend = 0.81), dietary vitamin C intake (HR for quintiles 5 compared with 1 = 0.98; 95% CI: 0.92-1.04; Ptrend = 0.57), and supplemental vitamin C intake (HR for quintiles 5 compared with 1 in users = 1.02; 95% CI: 0.94-1.09; Ptrend = 0.77) were not associated with breast cancer risks. Results were unchanged when different exposure latencies were considered. The results did not differ by menopausal status, postmenopausal hormone therapy use, or BMI. No differences were observed by estrogen receptor status of the tumor.Conclusions: Our results do not support any important association between total, dietary, or supplemental vitamin C intake and breast cancer risks. [ABSTRACT FROM AUTHOR]

Background The associations between nut consumption and cancer risk have not been extensively investigated. Objectives We aimed to examine the associations between nut consumption, especially specific types of nuts (peanut, tree nut, walnut, and tree nut other than walnut), and cancer risk. Methods Nut consumption was assessed by FFQ at baseline and updated every 2–4 y in the Nurses' Health Study (1980–2014), the Nurses' Health Study II (1991–2015), and the Health Professionals Follow-up Study (1986–2018). We examined the associations between the intake of total and specific types of nuts and risk of total cancer and common cancers, including lung, colorectal, breast, bladder, and aggressive prostate cancer. Cox proportional-hazards models were used to obtain the HRs and 95% CIs in each cohort as well as pooled. Results During 5,873,671 person-years of follow-up in 180,832 women and 45,560 men, we documented 44,561 incident cancer cases. As compared with nonconsumers, the pooled multivariable HRs of total nut consumption for ≥5 times/wk were 0.99 (95% CI: 0.94, 1.04; P -trend = 0.54) for total cancer, 0.88 (95% CI: 0.74, 1.04; P -trend = 0.18) for lung cancer, 1.07 (95% CI: 0.92, 1.26; P -trend = 0.89) for colorectal cancer, 0.90 (95% CI: 0.71, 1.14; P -trend = 0.65) for bladder cancer, 0.96 (95% CI: 0.85, 1.08; P -trend = 0.36) for breast cancer, and 1.18 (95% CI: 0.92, 1.51; P -trend = 0.52) for aggressive prostate cancer Conclusions In 3 large prospective cohorts, frequent nut consumption was not associated with risk of total cancer and common individual cancers. [ABSTRACT FROM AUTHOR]

Background: In many applications of instrumental variable (IV) methods, the treatments of interest are intrinsically time-varying and outcomes of interest are failure time outcomes. A common example is Mendelian randomization (MR), which uses genetic variants as proposed IVs. In this article, we present a novel application of g-estimation of structural nested cumulative failure models (SNCFTMs), which can accommodate multiple measures of a time-varying treatment when modelling a failure time outcome in an IV analysis.Methods: A SNCFTM models the ratio of two conditional mean counterfactual outcomes at time k under two treatment strategies which differ only at an earlier time m. These models can be extended to accommodate inverse probability of censoring weights, and can be applied to case-control data. We also describe how the g-estimates of the SNCFTM parameters can be used to calculate marginal cumulative risks under nondynamic treatment strategies. We examine the performance of this method using simulated data, and present an application of these models by conducting an MR study of alcohol intake and endometrial cancer using longitudinal observational data from the Nurses' Health Study.Results: Our simulations found that estimates from SNCFTMs which used an IV approach were similar to those obtained from SNCFTMs which adjusted for confounders, and similar to those obtained from the g-formula approach when the outcome was rare. In our data application, the cumulative risk of endometrial cancer from age 45 to age 72 under the "never drink" strategy (4.0%) was similar to that under the "always ½ drink per day" strategy (4.3%).Conclusions: SNCFTMs can be used to conduct MR and other IV analyses with time-varying treatments and failure time outcomes. [ABSTRACT FROM AUTHOR]

Background: Whether consumption of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) is associated with the risk of breast cancer is of public health interest.Objectives: We sought to evaluate associations between consumption of SSBs and ASBs and risks of total and subtype-specific breast cancer.Methods: We followed 82,713 women from the Nurses' Health Study (1980 to 2016) and 93,085 women from the Nurses' Health Study II (1991 to 2017). Cumulatively averaged intakes of SSBs and ASBs from FFQs were tested for associations with incident breast cancer cases and subtypes using Cox regression models. We also evaluated the associations stratified by menopausal status, physical activity, BMI, and alcohol intake.Results: We documented 11,379 breast cancer cases during 4,655,153 person-years of follow-up. Consumption of SSBs or ASBs was not associated with total breast cancer risk: pooled HRs comparing extreme categories (≥1/day compared with <1/month) were 1.03 (95% CI, 0.95-1.12) and 0.96 (95% CI, 0.91-1.02), respectively. We observed a suggestive interaction by BMI using pooled data (P-interaction = 0.08), where a modestly higher risk of breast cancer with each serving per day increment of SSBs was found in lean women (HR, 1.06; 95% CI, 1.01-1.11) but not among overweight or obese women (HR, 1.00; 95% CI, 0.95-1.06). Moreover, in the pooled, fully adjusted analysis, compared to infrequent consumers (<1/month), those who consumed ≥1 serving of ASBs per day had a lower risk of luminal A breast tumors (HR, 0.90; 95% CI, 0.80-1.01; P-trend = 0.02).Conclusions: Although no significant associations were observed overall, consumption of SSBs was associated with a slightly higher risk of breast cancer among lean women. This finding could have occurred by chance and needs confirmation. Our findings also suggest no substantial increase in the risk of breast cancer with consumption of ASBs. [ABSTRACT FROM AUTHOR]

Red meat and processed meat consumption has been hypothesized to increase risk of cancer, but the evidence is inconsistent. We performed a systematic review and meta-analysis of prospective studies to summarize the evidence of associations between consumption of red meat (unprocessed), processed meat, and total red and processed meat with the incidence of various cancer types. We searched in MEDLINE and EMBASE databases through December 2020. Using a random-effect meta-analysis, we calculated the pooled relative risk (RR) and 95% confidence intervals (CI) of the highest versus the lowest category of red meat, processed meat, and total red and processed meat consumption in relation to incidence of various cancers. We identified 148 published articles. Red meat consumption was significantly associated with greater risk of breast cancer (RR = 1.09; 95% CI = 1.03–1.15), endometrial cancer (RR = 1.25; 95% CI = 1.01-1.56), colorectal cancer (RR = 1.10; 95% CI = 1.03–1.17), colon cancer (RR = 1.17; 95% CI = 1.09-1.25), rectal cancer (RR = 1.22; 95% CI = 1.01-1.46), lung cancer (RR = 1.26; 95% CI = 1.09–1.44), and hepatocellular carcinoma (RR = 1.22; 95% CI = 1.01-1.46). Processed meat consumption was significantly associated with a 6% greater breast cancer risk, an 18% greater colorectal cancer risk, a 21% greater colon cancer risk, a 22% greater rectal cancer risk, and a 12% greater lung cancer risk. Total red and processed meat consumption was significantly associated with greater risk of colorectal cancer (RR = 1.17; 95% CI = 1.08–1.26), colon cancer (RR = 1.21; 95% CI = 1.09–1.34), rectal cancer (RR = 1.26; 95% CI = 1.09–1.45), lung cancer (RR = 1.20; 95% CI = 1.09-1.33), and renal cell cancer (RR = 1.19; 95% CI = 1.04–1.37). This comprehensive systematic review and meta-analysis study showed that high red meat intake was positively associated with risk of breast cancer, endometrial cancer, colorectal cancer, colon cancer, rectal cancer, lung cancer, and hepatocellular carcinoma, and high processed meat intake was positively associated with risk of breast, colorectal, colon, rectal, and lung cancers. Higher risk of colorectal, colon, rectal, lung, and renal cell cancers were also observed with high total red and processed meat consumption. [ABSTRACT FROM AUTHOR]

Background: We investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples.Methods: This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses' Health Study and Nurses' Health Study II cohorts. The percentage of each tissue type (epithelium, stroma, and fat) was measured on whole-section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with the percentage of tissue types, while adjusting for known breast cancer risk factors.Results: As compared to parous women, nulliparous women had a smaller percentage of epithelium (β = - 0.26, 95% confidence interval [CI] - 0.41, - 0.11) and fat (β = - 0.34, 95% CI - 0.54, - 0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, the number of children was inversely associated with the percentage of stroma (β per child = - 0.01, 95% CI - 0.02, - 0.00). The duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β = - 0.30, 95% CI - 0.54, - 0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma.Conclusions: Our findings suggest that being nulliparous as well as having a fewer number of children (both positively associated with breast cancer risk) is associated with a smaller proportion of epithelium and a greater proportion of stroma, potentially suggesting the importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

Background: Increased body mass index (BMI) is associated with higher postmenopausal breast cancer risk and lower premenopausal breast cancer risk. Less is known about the central adiposity-breast cancer risk association, particularly for tumor subtypes.Methods: We used prospective waist (WC) and hip circumference (HC) measures in the Nurses' Health Studies. We examined associations of WC, HC, and waist-to-hip ratio (WHR) with breast cancer independent of BMI, by menopausal status. Cox proportional hazards models estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for breast cancer risk factors, with and without BMI.Results: Adjusting for BMI, WC and HC were not associated, and WHR was positively associated with premenopausal breast cancer risk (WHR, quintile 5 vs 1: HRQ5vQ1, BMI-adjusted = 1.27, 95% CI = 1.04 to 1.54; Ptrend = .01), particularly for estrogen receptor-negative (ER-) and progesterone receptor-negative (PR-) and basal-like breast cancers. Premenopausal WC, HC, and WHR were not associated with postmenopausal breast cancer risk, with or without BMI adjustment. Postmenopausal WC, HC, and WHR were each positively associated with postmenopausal breast cancer (eg, WC HRQ5vsQ1 = 1.59, 95% CI = 1.36 to 1.86); after adjustment for BMI, only WC remained statistically significant (HRQ5vsQ1, BMI-adjusted = 1.38, 95% CI = 1.15 to 1.64; Ptrend = .002). In postmenopausal women, associations were stronger among never-users of hormone therapy and for ER+/PR+ breast cancers.Conclusions: Central adiposity was positively associated with pre- and postmenopausal breast cancers independent of BMI. This suggests that mechanisms other than estrogen may also play a role in the relationship between central adiposity and breast cancer. Maintaining a healthy waist circumference may decrease pre- and postmenopausal breast cancer risk. [ABSTRACT FROM AUTHOR]

Aim: To prospectively investigate the associations between major dietary patterns and incidence of periodontitis. Methods: We included 34,940 men from the Health Professionals Follow‐Up Study, free of periodontal disease and major illnesses at baseline. Detailed medical and dental history was collected through biennial mailed questionnaires, and dietary information was provided through quadrennial food frequency questionnaires. Using principal component analysis, we identified two major dietary patterns ("prudent" and "Western"). We used Cox proportional hazard models to examine the associations between the two dietary patterns and self‐reported incidence of periodontitis over a 24‐year follow‐up period. We investigated each pattern separately. Results: There was no overall association between Western or prudent dietary patterns and periodontitis. Among obese, however, the Western dietary pattern was significantly associated with incident periodontitis. The hazard ratio for those in the highest quintile of Western diet versus those in the lowest (reference) was 1.83 (95% confidence interval: 1.21–2.76). Conclusions: There was no overall association between Western or prudent dietary patterns and periodontitis; however, in subgroups analysis, the Western diet was significantly associated with higher periodontitis risk only among obese men, a finding that requires replication and biological explication. [ABSTRACT FROM AUTHOR]

Background Trans fatty acid (TFA) intake persists in much of the world, posing ongoing threats to public health that warrant further elucidation. Published evidence suggests a positive association of self-reported TFA intake with non-Hodgkin lymphoma (NHL) risk. Objectives To confirm those reports, we conducted a prospective study of prediagnosis RBC membrane TFA levels and risk of NHL and common NHL histologic subtypes. Methods We conducted a nested case–control study in Nurses' Health Study and Health Professionals Follow-Up Study participants with archived RBC specimens and no history of cancer at blood draw (1989–1090 and 1994–1995, respectively). We confirmed 583 incident NHL cases (332 women and 251 men) and individually matched 583 controls on cohort (sex), age, race, and blood draw date/time. We analyzed RBC membrane TFA using GLC (in 2013–2014) and expressed individual TFA levels as a percentage of total fatty acids. We used unconditional logistic regression adjusted for the matching factors to estimate ORs and 95% CIs for overall NHL risk per 1 SD increase in TFA level and assessed histologic subtype-specific associations with multivariable polytomous logistic regression. Results Total and individual TFA levels were not associated with risk of all NHL or most subtypes. We observed a positive association of total TFA levels with diffuse large B cell lymphoma (DLBCL) risk [ n  = 98 cases; OR (95% CI) per 1 SD increase: 1.30 (1.05, 1.61); P  = 0.015], driven by trans 18:1n–9(ω-9)/elaidic acid [OR (95% CI): 1.34 (1.08, 1.66); P  = 0.007], trans 18:1n–7/vaccenic acid [OR (95% CI): 1.28 (1.04, 1.58); P  = 0.023], and trans 18:2n–6 t,t [OR (95% CI): 1.26 (1.01, 1.57); P  = 0.037]. Conclusions Our findings extended evidence for TFA intake and DLBCL risk but not for other NHL subtypes. Reduced TFA consumption through dietary choices or health policy measures may support prevention of DLBCL, an aggressive NHL subtype. [ABSTRACT FROM AUTHOR]

Background Whether egg consumption is associated with the risk of type 2 diabetes (T2D) remains unsettled. Objectives We evaluated the association between egg consumption and T2D risk in 3 large US prospective cohorts, and performed a systematic review and meta-analysis of prospective cohort studies. Methods We followed 82,750 women from the Nurses' Health Study (NHS; 1980–2012), 89,636 women from the NHS II (1991–2017), and 41,412 men from the Health Professionals Follow-up Study (HPFS; 1986–2016) who were free of T2D, cardiovascular disease, and cancer at baseline. Egg consumption was assessed every 2–4 y using a validated FFQ. We used Cox proportional hazard models to estimate HRs and 95% CIs. Results During a total of 5,529,959 person-years of follow-up, we documented 20,514 incident cases of T2D in the NHS, NHS II, and HPFS. In the pooled multivariable model adjusted for updated BMI, lifestyle, and dietary confounders, a 1-egg/d increase was associated with a 14% (95% CI: 7%, 20%) higher T2D risk. In random-effects meta-analysis of 16 prospective cohort studies (589,559 participants; 41,248 incident T2D cases), for each 1 egg/d, the pooled RR of T2D was 1.07 (95% CI: 0.99, 1.15; I 2 = 69.8%). There were, however, significant differences by geographic region (P for interaction = 0.01). Each 1 egg/d was associated with higher T2D risk among US studies (RR: 1.18; 95% CI: 1.10, 1.27; I 2 = 51.3%), but not among European (RR: 0.99; 95% CI: 0.85, 1.15; I 2 = 73.5%) or Asian (RR: 0.82; 95% CI: 0.62, 1.09; I 2 = 59.1%) studies. Conclusions Results from the updated meta-analysis show no overall association between moderate egg consumption and risk of T2D. Whether the heterogeneity of the associations among US, European, and Asian cohorts reflects differences in egg consumption habits warrants further investigation. This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42019127860. [ABSTRACT FROM AUTHOR]

Identifying the susceptible period when environmental factors affect disease risk is essential for understanding disease etiology. Most existing epidemiologic studies use oversimplified summaries of time-dependent exposures such as baseline or most current exposure, or the cumulative average of exposure over available follow-up periods. In this paper, we introduce a damped exponential weighting model for estimating optimal exposure weights for different time intervals. This model can accommodate flexible patterns of weights and can be fit using standard software. We applied the model to assess the latency of BMI and alcohol for post-menopausal breast cancer based on 30-year exposure history in the Nurses' Health Study. We have also performed a simulation study to assess the validity of the proposed hypothesis testing and estimation procedures in realistic conditions. We found that the type I error is close to 0.05; the bias in our parameter estimates is low and the coverage probability of interval estimates is close to 0.95. For ER+/PR+ breast cancer we found that recent BMI was a more important predictor of risk than more distant BMI; for ER−/PR− breast cancer, no latency was found and risk was characterized by cumulative high levels of BMI over a long period of time. For alcohol intake, we saw a strong positive association with cumulative intake for ER+/PR+ breast cancer; no significant association was found for cumulative intake or for any latency measure of risk for ER−/PR− breast cancer. Our results underscore the value of an easy-to-implement approach to latency analysis of exposure profiles for chronic disease. [ABSTRACT FROM AUTHOR]

Background: The relation between α-linolenic acid (ALA), a plant-derived omega-3 (n-3) fatty acid, and age-related macular degeneration (AMD) is unclear. European researchers reported that ≤40% of ALA can be present as trans forms. Objective: We aimed to evaluate the associations between intake of ALA and intermediate and advanced AMD. Design: Seventy-five thousand eight hundred eighty-nine women from the Nurses' Health Study and 38,961 men from Health Professionals Follow-Up Study were followed up from 1984 to 2012 and from 1986 to 2010, respectively. We assessed dietary intake by a validated food-frequency questionnaire at baseline and every 4 y thereafter. One thousand five hundred eighty-nine incident intermediate and 1356 advanced AMD cases (primarily neovascular AMD) were confirmed by medical record review. Results: The multivariable-adjusted HR for intermediate AMD comparing ALA intake at the top quintile to the bottom quintile was 1.28 (95% CI: 1.05, 1.56; P-trend = 0.01) in the analyses combining 2 cohorts. The HR in each cohort was in the positive direction but reached statistical significance only in the women. However, the positive association was apparent only in the pre-2002 era in each cohort and not afterward (P-time interaction = 0.003). ALA intake was not associated with advanced AMD in either time period. Using gas-liquid chromatography, we identified both cis ALA (mean ± SD: 0.13% ± 0.04%) and trans ALA isomers (0.05% ± 0.01%) in 395 erythrocyte samples collected in 1989-1990. In stepwise regression models, mayonnaise was the leading predictor of erythrocyte concentrations of cis ALA and one isomer of trans ALA. We also found trans ALA in mayonnaise samples. Conclusions: A high intake of ALA was associated with an increased risk of intermediate AMD before 2002 but not afterward. The period before 2002 coincides with the same time period when trans ALA was found in food and participants' blood; this finding deserves further study. [ABSTRACT FROM AUTHOR]

Background: Early menopause, defined as the cessation of ovarian function before the age of 45 y, affects ~10% of women and is associated with higher risk of cardiovascular disease, osteoporosis, and other conditions. Few modifiable risk factors for early menopause have been identified, but emerging data suggest that high vitamin D intake may reduce risk. Objective: We evaluated how intakes of vitamin D and calcium are associated with the incidence of early menopause in the prospective Nurses' Health Study II (NHS2). Design: Intakes of vitamin D and calcium from foods and supplements were measured every 4 y with the use of a food-frequency questionnaire. Cases of incident early menopause were identified from all participants who were premenopausal at baseline in 1991; over 1.13 million person-years, 2041 women reported having natural menopause before the age of 45 y. We used Cox proportional hazards regression to evaluate relations between intakes of vitamin D and calcium and incident early menopause while accounting for potential confounding factors. Results: After adjustment for age, smoking, and other factors, women with the highest intake of dietary vitamin D (quintile median: 528 IU/d) had a significant 17% lower risk of early menopause than women with the lowest intake [quintile median: 148 IU/d; HR: 0.83 (95% CI: 0.72, 0.95); P-trend = 0.03]. Dietary calcium intake in the highest quintile (median: 1246 mg/d) compared with the lowest (median: 556 mg/d) was associated with a borderline significantly lower risk of early menopause (HR: 0.87; 95% CI: 0.76, 1.00; P-trend = 0.03). Associations were stronger for vitamin D and calcium from dairy sources than from nondairy dietary sources, whereas high supplement use was not associated with lower risk. Conclusions: Findings suggest that high intakes of dietary vitamin D and calcium may be modestly associated with a lower risk of early menopause. Further studies evaluating 25-hydroxyvitamin D concentrations, other dairy constituents, and early menopause are warranted. [ABSTRACT FROM AUTHOR]

Objectives. To review the contribution of the Nurses' Health Studies (NHSs) to diet assessment methods and evidence-based nutritional policies and guidelines. Methods. We performed a narrative review of the publications of the NHS and NHS II between 1976 and 2016. Results. Through periodic assessment of diet by validated dietary questionnaires over 40 years, the NHSs have identified dietary determinants of diseases such as breast and other cancers; obesity; type 2 diabetes; cardiovascular, respiratory, and eye diseases; and neurodegenerative and mental health disorders. Nutritional biomarkers were assessed using blood, urine, and toenail samples. Robust findings, from the NHSs, together with evidence from other large cohorts and randomized dietary intervention trials, have contributed to the evidence base for developing dietary guidelines and nutritional policies to reduce intakes of trans fat, saturated fat, sugar-sweetened beverages, red and processed meats, and refined carbohydrates while promoting higher intake of healthy fats and carbohydrates and overall healthful dietary patterns. Conclusions. The long-term, periodically collected dietary data in the NHSs, with documented reliability and validity, have contributed extensively to our understanding of the dietary determinants of various diseases, informing dietary guidelines and shaping nutritional policy. [ABSTRACT FROM AUTHOR]

Background: Oral contraceptive use has been associated with a higher breast cancer risk; however, evidence for the associations between different oral contraceptive formulations and breast cancer risk, especially by disease subtype, is limited.Objective: This study aimed to evaluate the associations between oral contraceptive use by formulation and breast cancer risk by disease subtype.Study Design: This prospective cohort study included 113,187 women from the Nurses' Health Study II with recalled information on oral contraceptive usage from 13 years of age to baseline (1989) and updated data on usage until 2009 collected via biennial questionnaires. A total of 5799 breast cancer cases were identified until the end of 2017. Multivariable Cox proportional hazards models estimated hazard ratios and 95% confidence intervals for the associations between oral contraceptive use and breast cancer risk overall and by estrogen and progesterone receptor and human epidermal growth factor receptor 2 status. Oral contraceptive use was evaluated by status of use (current, former, and never), duration of and time since last use independently and cross-classified, and formulation (ie, estrogen and progestin type).Results: Current oral contraceptive use was associated with a higher risk for invasive breast cancer (hazard ratio, 1.31; 95% confidence interval, 1.09-1.58) when compared with never use, with stronger associations observed for longer durations of current use (>5 years: hazard ratio, 1.56; 95% confidence interval, 1.23-1.99; ≤5 years: hazard ratio, 1.19; 95% confidence interval, 0.95-1.49). Among former users with >5 years since cessation, the risk was similar to that of never users (eg, >5 to 10 years since cessation: hazard ratio, 0.99; 95% confidence interval, 0.88-1.11). Associations did not differ significantly by tumor subtype. In analyses by formulation, current use of formulations containing levonorgestrel in triphasic (hazard ratio, 2.83; 95% confidence interval, 1.98-4.03) and extended cycle regimens (hazard ratio, 3.49; 95% confidence interval, 1.28-9.53) and norgestrel in monophasic regimens (hazard ratio, 1.91; 95% confidence interval, 1.19-3.06), all combined with ethinyl estradiol, was associated with a higher breast cancer risk when compared with never oral contraceptive use. No association was observed for current use of the other progestin types evaluated (norethindrone, norethindrone acetate, ethynodiol diacetate, desogestrel, norgestimate, and drospirenone), however, sample sizes were relatively small for some of the subgroups, limiting these analyses.Conclusion: Current oral contraceptive use was associated with a higher risk for invasive breast cancer regardless of disease subtype, however, the risk in former users was comparable with never users 5 years after cessation. In analyses by progestin type, associations were observed for select formulations containing levonorgestrel and norgestrel. Assessment of the associations for newer progestin types (desogestrel, norgestimate, drospirenone) was limited by sample size, and further research on more recently introduced progestins is warranted. [ABSTRACT FROM AUTHOR]

The article presents a study associating physical activity with breast cancer risk among postmenopausal women. Variation across levels of other risk factors is examined. Findings suggest that moderate physical activity including brisk walking, may reduce postmenopausal breast cancer risk. Body mass index (BMI), weight change since 18 years of age and use of postmenopausal hormones (PMH) were taken into account.

The authors developed a comprehensive model of colon cancer incidence that allows for nonproportional hazards and accounts for the temporal nature of risk factors. They estimated relative risk based on cumulative incidence of colon cancer by age 70 years. Using multivariate, nonlinear Poisson regression, they determined colon cancer risk among 83,767 participants in the Nurses’ Health Study. The authors observed 701 cases of colon cancer between 1980 and June 1, 2004. There was increased risk for a positive family history of colon or rectal cancer (55%), 10 or more pack-years of cigarette smoking before age 30 years (16%), and tallness (67 inches (170 cm) vs. 61 inches (155 cm): 19%). Reduced risk was observed for current postmenopausal hormone use (−23%), being physically active (21 metabolic equivalent (MET)-hours/week vs. 2 MET-hours/week: −49%), taking aspirin (7 tablets/week vs. none: −29%), and being screened (−24%). Women who smoked, had a consistently high relative weight, had a low physical activity level, consumed red or processed meat daily, were never screened, and consumed low daily amounts of folate had almost a 4-fold higher cumulative risk of colon cancer by age 70 years. For women with a high risk factor profile, adopting a healthier lifestyle could dramatically reduce colon cancer risk. [ABSTRACT FROM PUBLISHER]

Purpose: In prospective studies of incident cataract, a person may have developed two or all three of cortical, nuclear sclerotic and posterior subscapsular cataract at the time when clinically significant cataract is apparent. One can compare the impact of risk factors on different types of cataract with methods of competing risk survival analysis that account for tied events. Methods: We studied risk factors for incident cataract among 20,599 participants in the Physicians' Health Study; 1,923 of whom developed cataract that reduced visual acuity over a median follow-up of 13.0 years. Among incident cases, 45% had two types of cataract and an additional 12% had all three. Proportional hazards models, adjusted for tied failures through use of generalized estimating equations, provided comparisons across different cataract types. Stratified analyses by type with age as the time scale were used to accommodate the strong but different relationships of age with occurrence of different cataract types. Results: Analyses found different relationships of diabetes and body mass index, but similar relationships of smoking, family history of coronary disease and multivitamin use, across different cataract types. A simplified model provided common estimates for relative risks associated with those characteristics with similar effects across cataract types. Conclusions: Whereas polytomous logistic regression has proven useful for comparisons of risks across cataract types in retrospective and cross-sectional studies, this approach based on methods of survival analysis has greater flexibility in prospective studies with variable follow-up and frequently tied event times for different cataract types. [ABSTRACT FROM AUTHOR]

The authors compared, in the context of diabetic retinopathy, alternative methods of quantifying the extent to which disease progression in one eye increases the risk of subsequent progression in the other eye. Data were gathered on 478 US patients with insulin-dependent diabetes mellitus who participated in the 1983–1988 Sorbinil Retinopathy Trial and were followed up for a median of 41 months. During that time, diabetic retinopathy progressed in 93 right eyes and 77 left eyes. Crude incidence rates of progression for right eyes were 7.7 times higher after the left eye had progressed and, for left eyes, were 4.4 times higher after the right eye had progressed. In eye-specific proportional hazards models that adjusted for increasing rates of progression over time and for baseline risk factors, the comparable relative risks associated with progression in the other eye were 2.6 (95% confidence interval (Cl): 1.5, 4.7) for right eyes and 1.4 (95% Cl: 0.72, 2.9) for left eyes. Two alternative proportional hazards models that included data on both eyes and accounted for their correlation produced estimated relative risks of 1.9 (95% Cl: 1.2, 2.9) and 2.7 (95% Cl: 1.8, 3.5), respectively. The more complex models for joint survival integrate information on both eyes and provide more stable estimates than do separate analyses of right or left eyes. Am J Epidemiol 2000; 151: 965-74. [ABSTRACT FROM PUBLISHER]

The article examines the relation between birthplace, area of residence, and asthma in Puerto Rican children. Information was collected in a household survey of 2,491 children and their primary caretakers in San Juan and Caguas metropolitan areas in Puerto Rico and in Bronx, New York. The study showed that Puerta Rican children in Puerto Rico had a higher risk of asthma than Puerto Rican children in South Bronx.

Methods for formal comparison of competing risks may clarify uncertainties about the associations of atherosclerotic risk factors with the development of venous thromboembolism (VTE). For a median of 20.1 years, the Physicians' Health Study (1982–2003) followed 18,662 US male physicians with no prior myocardial infarction, stroke, VTE, or cancer and for whom reported risk factor information was available at baseline. The authors used methods of competing risk survival analysis to compare relative hazard rates associated with age, hypertension, elevated cholesterol, diabetes, cigarette smoking, alcohol consumption, exercise frequency, body mass index, and height. During follow-up, coronary heart disease (CHD) occurred first in 1,348 men, stroke in 902 men, and VTE in 358 men. Incidence of all three outcomes increased with age, but the rate of increase was strongest for stroke. Hypertension, elevated cholesterol, diabetes, and smoking were associated with increased rates of CHD and stroke, with comparable magnitudes, but had no association with VTE. Conversely, higher body mass index was more strongly associated with risk of VTE than of either CHD or stroke, and taller men had a significantly increased risk of VTE but a lower risk of CHD. CHD and stroke have broadly comparable risk factor profiles that differ widely from the profile for VTE. [ABSTRACT FROM AUTHOR]

Background: Studies of fruit and vegetable consumption in relation to overall health are limited. We evaluated the relationship between fruit and vegetable intake and the incidence of cardiovascular disease and cancer and of deaths from other causes in two prospective cohorts. Methods: A total of 71 910 female participants in the Nurses' Health study and 37 725 male participants in the Health Professionals' Follow-up Study who were free of major chronic disease completed baseline semiquantitative food-frequency questionnaires in 1984 and 1986, respectively. Dietary information was updated in 1986, 1990, and 1994 for women and in 1990 and 1994 for men. Participants were followed up for incidence of cardiovascular disease, cancer, or death through May 1998 (women) and January 1998 (men). Multivariable-adjusted relative risks were calculated with Cox proportional hazards analysis. Results: We ascertained 9329 events (1964 cardiovascular, 6584 cancer, and 781 other deaths) in women and 4957 events (1670 cardiovascular diseases, 2500 cancers, and 787 other deaths) in men during follow-up. For men and women combined, participants in the highest quintile of total fruit and vegetable intake had a relative risk for major chronic disease of 0.95 (95% confidence interval [CI] = 0.89 to 1.01) times that of those in the lowest. Total fruit and vegetable intake was inversely associated with risk of cardiovascular disease but not with overall cancer incidence, with relative risk for an increment of five servings daily of 0.88 (95% CI = 0.81 to 0.95) for cardiovascular disease and 1.00 (95% CI = 0.95 to 1.05) for cancer. Of the food groups analyzed, green leafy vegetable intake showed the strongest inverse association with major chronic disease and cardiovascular disease. For an increment of one serving per day of green leafy vegetables, relative risks were 0.95 (95% CI = 0.92 to 0.99) for major chronic disease and 0.89 (95 % CI = 0.83 to 0.96) for cardiovascular disease. Conclusions: Increased fruit and vegetable consumption was associated with a modest although not statistically significant reduction in the development of major chronic disease. The benefits appeared to be primarily for cardiovascular disease and not for cancer. [ABSTRACT FROM AUTHOR]

Background: Recent case-control studies suggest that, given equal smoking exposure, women may have a higher relative risk of developing lung cancer than men. Despite prospective data that conflict with this hypothesis, mechanistic studies to find a biologic basis for a sex difference continue. Methods: We addressed the hypothesis directly by analyzing prospective data from former and current smokers in two large cohorts—the Nurses' Health Study of women and the Health Professionals Follow-up Study of men. We calculated incidence rates and hazard ratios of lung cancer in women compared with men, adjusting for age, number of cigarettes smoked per day, age at start of smoking, and time since quitting, using Cox proportional hazards models. We also reviewed published results from prospective analyses. Results: From 1986 through 2000, 955 and 311 primary lung cancers were identified among 60 296 women and 25 397 men, respectively, who ranged in age from 40 to 79 years. Incidence rates per 100 000 person-years for women and men were 253 and 232, respectively, among current smokers and 81 and 73, respectively, among former smokers. The hazard ratio in women ever smokers compared with men was 1.11 (95% confidence interval = 0.95 to 1.31). Six published prospective cohort studies allowed assessment of comparative susceptibility to lung cancer by sex. None supported an excess risk of lung cancer for women. Conclusions: Women do not appear to have a greater susceptibility to lung cancer than men, given equal smoking exposure. Research should be focused on enhancing preventive interventions for all. [ABSTRACT FROM AUTHOR]

Several studies have suggested that high intake of fats and fat-rich foods may increase the risk of ovarian cancer. The authors examined these relations in the Nurses’ Health Study cohort. Dietary intake was assessed in 1980, 1984, 1986, and 1990 by using a self-administered food frequency questionnaire. Food data were used to calculate intake of various fats and fatty acids. For best reflection of long-term intake, an updated, cumulative, averaged measure of fat intake was used to predict incidence of ovarian cancer. Between 1980 and 1996, 301 incident cases of invasive epithelial ovarian cancer were confirmed among the 80,258 participants who completed the baseline food frequency questionnaire. There was no evidence of a positive association between intake of any type of fat and ovarian cancer risk, even after adjustment of fat subtypes for one another. Women in the highest quintile of total fat intake were not at increased risk compared with those in the lowest quintile (multivariate relative risk = 1.03, 95 percent confidence interval: 0.72, 1.45, p for trend = 0.97). Intakes of fat-rich foods were also not appreciably associated with ovarian cancer risk, although an increase in risk with frequent intake of eggs was observed. Overall, results suggest no association between intake of any type of fat and ovarian cancer. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate the relationship between intake of total and specific types of fat and risk for advanced age-related macular degeneration (AMD), the leading cause of irreversible blindness in adults. Design: A multicenter eye disease case-control study. Setting: Five US clinical ophthalmology centers. Patients: Case subjects included 349 individuals (age range, 55-80 years) with the advanced, neovascular stage of AMD diagnosed within 1 year of their enrollment into the study who resided near a participating clinical center. Control subjects included 504 individuals without AMD but with other ocular diseases. Controls were from the same geographic areas as cases and were frequencymatched to cases by age and sex. Main Outcome Measures: Relative risk for AMD according to level of fat intake, controlling for cigarette smoking and other risk factors. Results: Higher vegetable fat consumption was associated with an elevated risk for AMD. After adjusting for age, sex, education, cigarette smoking, and other risk factors, the odds ratio (OR) was 2.22 (95% confidence interval [CI], 1.32-3.74) for persons in the highest vs those in the lowest quintiles of intake (P for trend, .007). The risk for AMD was also significantly elevated for the highest vs lowest quintiles of intake of monounsaturated (OR, 1.71) and polyunsaturated (OR, 1.86) fats (Ps for trend, .03 and .03, respectively). Higher consumption of linoleic acid was also associated with a higher risk for AMD (P for trend, .02). Higher intake of (ω-3 fatty acids was associated with a lower risk for AMD among individuals consuming diets low in linoleic acid, an ω-6 fatty acid (P for trend, .05; P for continuous variable, .03). Similarly, higher frequency of fish intake tended to reduce risk for AMD when the diet was low in linoleic acid (P for trend, .05). Conversely, neither (ω-3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake.... [ABSTRACT FROM AUTHOR]

Body mass index (BMI) has become the most commonly used index of body composition in epidemiologic research. It has displaced weight, height, and other measures of body composition. In this paper, the authors show that use of BMI alone does not always capture adequately the joint relation of body composition and body size to health outcomes, and that such use often represents implausible restrictions on the relation. Use of body mass index and height or weight and height will often be needed to describe this relation and to control confounding by these variables. Am J Epidemiol 1998;147:167–72 [ABSTRACT FROM AUTHOR]

To determine the relations of diet with risk of clinical noninsulin-dependent diabetes, we analyzed data from a prospective cohort of 84360 US women. During 6 y of follow-up we identified 702 definite incident cases. Because body mass index (BMI) is a powerful risk factor for diabetes, we examined the relations of fat (including type), fiber, sucrose, and other components of diet to risk of diabetes, among women with BMIs (in kg/m²) < 29 kg/ m². After controlling for body mass index, previous weight change, and alcohol intake, we observed no associations between intakes of energy, protein, sucrose, carbohydrate, or fiber and risk of diabetes. Compared with women in the lowest quintile of energy-adjusted intake, the relative risks (and tests for trend) for those in the highest quintile were 0.61 (P trend = 0.03) for vegetable fat, 0.62 (P trend = 0.008) for potassium, 0.70 (P trend = 0.005) for calcium, and 0.68 (P trend = 0.02) for magnesium. These inverse associations were attenuated among obese women (BMIs ≥ 29). [ABSTRACT FROM AUTHOR]

Examines the association between the dietary intake of supplements and cataract extraction in women in the United States. Participation of female registered nurses in the study; Incidence of extraction of senile cataracts; Support of the findings to the antioxidant hypothesis of cataract prevention.

Examines relative weight and height in relation to subsequent breast cancer risk among women 30 to 55 years of age and free from cancer in 1976. Decrease in breast cancer risk with increasing relative weight; Suggestion that obesity among premenopausal and early postmenopausal women does not increase breast cancer risk substantially; Possibility that higher alcohol intake might explain the increased risk of breast cancer in lean premenopausal women.

Purpose: Genetic variants CFH and ARMS2/HTRA1 gene regions as well as high-sensitivity C-reactive protein (CRP) levels are related to age-related macular degeneration (AMD). We evaluated their independent and combined effects on risk of AMD, as well as their interactions. Design: Case-control study. Participants: Subjects with AMD (n = 244) or no or minimal maculopathy (n = 209) in the Age Related Eye Disease Ancillary Study. Methods: Risk factors, genotypes, and biomarkers were assessed by questionnaire, direct measurement, and analyses of blood specimens. The independent and joint effects of serum CRP and CFH (rs1061170) and ARMS2/HTRA1 (rs10490924) genotypes were assessed using logistic regression analyses, adjusting for age, gender, education, smoking, body mass index, and vitamin/mineral supplementation. Main Outcome Measures: We defined AMD as large drusen, geographic atrophy, or neovascular disease. Results: Higher CRP levels were associated with a higher risk of AMD, controlling for genotype and demographic and behavioral risk factors, with odds ratio 2.6 for levels of 3.0 mg/L and above versus below 1.0 mg/L (95% confidence interval, 1.01–6.7). Single nucleotide polymorphisms (SNPs) in both genes were also independently associated with risk of AMD, controlling for the level of CRP and other factors. Presence of both highest level of CRP together with risk genotypes for both SNPs, conferred the highest risk of AMD (OR 5.4, 95% CI 1.4-21.1). Conclusions: High-sensitivity CRP and polymorphisms in the CFH and ARMS2/HTRA1 genes are independently associated with risk of AMD. Higher CRP level tends to confer a higher risk of AMD within most genotype groups. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the associations between intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the intermediate and advanced stages of age-related macular degeneration (AMD). Design Prospective cohort study. Participants We followed 75 889 women from the Nurses' Health Study and 38 961 men from the Health Professionals Follow-Up Study who were at least 50 years old, from 1984 to 2012 and 1986 to 2010, respectively. Cohort participants are mostly white (≥95%). Methods We assessed dietary intake by a validated food frequency questionnaire (FFQ) at baseline and every 4 years. We calculated cumulative average intakes of EPA and DHA from FFQs and also computed predicted erythrocyte and plasma scores directly from food intake using regression models. Cox proportional hazards models were used to compute the associations with AMD outcomes. Main Outcome Measures We confirmed 1589 incident intermediate and 1356 advanced AMD cases (primarily neovascular AMD) with a visual acuity of 20/30 or worse, owing primarily to AMD, by medical record review. Results For intermediate AMD, the pooled hazard ratio (HR) between the 2 cohorts for DHA comparing the extreme quintiles of intake was 0.78 (95% confidence interval [CI], 0.66–0.92; P trend, 0.008) and for EPA + DHA was 0.83 (95% CI, 0.71–0.98; P trend, 0.03). The pooled HR for fatty fish, comparing ≥5 servings per week to almost never, was 0.61 (95% CI, 0.46–0.81; P trend, <0.001). For advanced AMD, the pooled HR for DHA was 1.01 (95% CI, 0.84–1.21; P trend, 0.75) and for fatty fish was 0.80 (95% CI, 0.59–1.08; P trend, 0.11). Secondary analyses using predicted erythrocyte and plasma scores of EPA and DHA yielded slightly stronger inverse associations for intermediate AMD and similar results for advanced AMD. Conclusions Higher intakes of EPA and DHA may prevent or delay the occurrence of visually significant intermediate AMD. However, the totality of current evidence for EPA and DHA and advanced AMD is discordant, though there was no association with advanced AMD in the present study. [ABSTRACT FROM AUTHOR]

Purpose Tooth loss or periodontal disease is associated with systemic endothelial dysfunction, which has been implicated in primary open-angle glaucoma (POAG). The relationship between oral health and POAG has received limited attention. Thus, we evaluated the association between oral health history and risk of POAG and POAG subtypes. Design Prospective cohort study. Participants Health Professionals Follow-up Study participants (40 536 men) followed biennially from 1986 to 2012. At each 2-year risk period, eligible participants were aged 40+ years, were free of POAG, and reported eye examinations. Methods By using validated questions, we updated participants' status on number of natural teeth, teeth lost, periodontal disease with bone loss, and root canal treatments. Main Outcome Measures During follow-up, 485 incident cases of POAG were confirmed with medical records and classified into subtypes defined by intraocular pressure (IOP; ≥ or <22 mmHg) or visual field (VF) loss pattern at diagnosis (peripheral loss only or early paracentral loss). Multivariable relative risks (MVRRs) and 95% confidence intervals (CIs) were estimated. Results Number of natural teeth, periodontal disease, and root canal treatment were not associated with POAG. However, compared with no report of tooth loss, a report of losing teeth within the past 2 years was associated with a 1.45-fold increased risk of POAG (95% CI, 1.06–1.97); in particular, a report within the past 2 years of both losing teeth and having a prevalent diagnosis of periodontal disease was associated with a 1.85-fold increased risk of POAG (95% CI, 1.07–3.18). The associations with recent tooth loss were not significantly different for the POAG subtypes ( P for heterogeneity ≥0.36), although associations were strongest in relation to the POAG subtypes with IOP <22 mmHg (MVRR, 1.93; 95% CI, 1.09–3.43) and early paracentral VF loss (MVRR, 2.27; 95% CI, 1.32–3.88). Conclusions Although the number of natural teeth was not associated with risk of POAG, recent tooth loss was associated with an increased risk of POAG. Because these findings may be due to chance, they need confirmation in larger studies. [ABSTRACT FROM AUTHOR]

Purpose: 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. Design: Prospective, longitudinal study. Participants: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]