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BACKGROUND: It remains unclear whether in utero and childhood exposure to air pollution affects pubertal development, particularly age of menarche in girls. OBJECTIVE: The aim of this study was to determine whether residential ambient particulate matter (PM) exposure in utero and during childhood is associated with age of menarche. METHODS: We studied 5,201 girls in the Growing Up Today Study 2 (2004-present) who were 10-17 y of age at enrollment (47.7% premenarchal; 52.3% postmenarchal). Exposure to three size fractions of PM [fine PM with aerodynamic diameter ≤ 2.5 μm (PM2.5), PM with aerodynamic diameters between 2.5 μm and 10 μm (PM2.5-10), and PM with aerodynamic diameter 10 μm (PM10)] was assigned based on maternal residential address, updated every 2 y, using nationwide spatiotemporal models. We estimated average PM exposure in utero, and time-varying windows: annual average exposure in the prior 1 and 2 y and cumulative average from birth. Age of menarche was self-reported on three surveys administered in 2004, 2006, and 2008. We calculated hazard ratios (HR) for menarche for an interquartile range (IQR) increase in PM exposure using Cox proportional hazard models adjusting for potential confounders. RESULTS: Girls attained menarche at 12.3 y of age on average. In the adjusted model, higher residential exposure to ambient PM2.5 during all time windows was associated with earlier age of menarche. The HRs of menarche for each IQR (4 μg/m³) increase in exposure to PM2.5 during the in utero period, 1 y prior to menarche, and throughout childhood were 1.03 [95% confidence interval (CI): 1.00, 1.06], 1.06 (95% CI: 1.02, 1.10) and 1.06 (95% CI: 1.02, 1.10), respectively. Effect estimates for PM10 exposure were similar, albeit attenuated, for all time windows. PM2.5-10 exposure was not associated with age of menarche. DISCUSSION: Among a large, nationwide, prospective cohort of U.S. girls, higher exposure to PM2.5 and PM10 in utero and throughout childhood was associated with an earlier age of menarche. Our results suggest that PM2.5 and PM10 may have endocrine-disrupting properties that could lead to altered timing of menarche. [ABSTRACT FROM AUTHOR]

The Kaplan–Meier estimator is ubiquitously used to estimate survival probabilities for time-to-event data. It is nonparametric, and thus does not require specification of a survival distribution, but it does assume that the risk set at any time t consists of independent observations. This assumption does not hold for data from paired organ systems such as occur in ophthalmology (eyes) or otolaryngology (ears), or for other types of clustered data. In this article, we estimate marginal survival probabilities in the setting of clustered data, and provide confidence limits for these estimates with intra-cluster correlation accounted for by an interval-censored version of the Clayton–Oakes model. We develop a goodness-of-fit test for general bivariate interval-censored data and apply it to the proposed interval-censored version of the Clayton–Oakes model. We also propose a likelihood ratio test for the comparison of survival distributions between two groups in the setting of clustered data under the assumption of a constant between-group hazard ratio. This methodology can be used both for balanced and unbalanced cluster sizes, and also when the cluster size is informative. We compare our test to the ordinary log rank test and the Lin-Wei (LW) test based on the marginal Cox proportional Hazards model with robust standard errors obtained from the sandwich estimator. Simulation results indicate that the ordinary log rank test over-inflates type I error, while the proposed unconditional likelihood ratio test has appropriate type I error and higher power than the LW test. The method is demonstrated in real examples from the Sorbinil Retinopathy Trial, and the Age-Related Macular Degeneration Study. Raw data from these two trials are provided. [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]

The area under the true ROC curve (AUC) is routinely used to determine how strongly a given model discriminates between the levels of a binary outcome. Standard inference with the AUC requires that outcomes be independent of each other. To overcome this limitation, a method was developed for the estimation of the variance of the AUC in the setting of two-level hierarchical data using probit-transformed prediction scores generated from generalized estimating equation models, thereby allowing for the application of inferential methods. This manuscript presents an extension of this approach so that inference for the AUC may be performed in a three-level hierarchical data setting (e.g., eyes nested within persons and persons nested within families). A method that accounts for the effect of tied prediction scores on inference is also described. The performance of 95% confidence intervals around the AUC was assessed through the simulation of three-level clustered data in multiple settings, including ones with tied data and variable cluster sizes. Across all settings, the actual 95% confidence interval coverage varied from 0.943 to 0.958, and the ratio of the theoretical variance to the empirical variance of the AUC varied from 0.920 to 1.013. The results are better than those from existing methods. Two examples of applying the proposed methodology are presented. [ABSTRACT FROM AUTHOR]

Background Insulin resistance and hyperinsulinemia play important roles in the progression of multiple chronic disease and conditions. Diet modulates insulin response; however, evidence is limited regarding whether diets with higher insulinemic potential increase the risk of invasive breast cancer. Objectives We aimed to prospectively evaluate the association between a food-based empirical dietary index for hyperinsulinemia (EDIH) and the incidence of invasive breast cancer. Methods We prospectively followed 76,686 women from the Nurses' Health Study (NHS; 1984–2016) and 93,287 women from the Nurses' Health Study II (NHSII; 1991–2017). Diet was assessed by food-frequency questionnaires every 4 y. The insulinemic potential of diet was evaluated using the previously established EDIH based on circulating C-peptide concentrations. Higher scores indicate higher insulinemic potential of the diet. Covariates included reproductive, hormonal, and anthropometric factors (height and BMI at age 18 y); race; socioeconomic status; total alcohol intake; total caloric intake; and physical activity. Results During 4,216,106 person-years of follow-up, we documented 10,602 breast cancer cases (6689 NHS, 3913 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIH quintile (Q) were at higher breast cancer risk (HRQ5 vs. Q1 = 1.15; 95% CI: 1.07, 1.24; P -trend < 0.01). Although heterogeneity by estrogen receptor (ER) status was nonsignificant, the strongest association between EDIH and breast cancer was observed for ER-negative tumors (HRQ5 vs. Q1 = 1.21; 95% CI: 1.00, 1.46; P -trend = 0.02). Among tumor molecular subtypes, the strongest associations were observed for human epidermal growth factor receptor 2 (HER2)–enriched tumors (HRQ5 vs. Q1 = 1.62; 95% CI: 1.01, 2.61; P -trend = 0.02). Conclusions A dietary pattern contributing to hyperinsulinemia and insulin resistance was associated with greater breast cancer risk, especially ER-negative and HER2-enriched tumors. Our findings suggest that dietary modifications to reduce insulinemic potential may reduce the risk of breast cancer. [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 Due to the increasing disease burden, strategies to predict and prevent heart failure (HF) are urgently needed. Objective We aimed to investigate whether the Alternative Healthy Eating Index (AHEI) and the clinically abbreviated Prime Diet Quality Score (PDQS) are associated with the risk of overall HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). Methods Our study included 44,525 men from the Health Professionals Follow-up Study (HPFS) who were free from cardiovascular disease and cancer at baseline. The AHEI and PDQS were computed based on dietary data repeatedly measured using semiquantitative FFQs. HF, HFpEF, and HFrEF were adjudicated based on review of medical records through 2008. Associations of diet quality with incident HF were estimated with multivariate-adjusted Cox proportional hazards models. Results During 929,911 person-years of follow-up, 803 HF cases were documented, including 184 with HFpEF and 181 with HFrEF among those with ejection fraction (EF) data. Adjusting for potential confounders, we did not observe a significant association between the AHEI and overall HF (HR per SD: 0.96; 95% CI: 0.89, 1.04; P -trend = 0.57) or between the PDQS and overall HF (HR per SD: 0.98; 95% CI: 0.91, 1.06; P -trend = 0.82). Both dietary indices were not significantly associated with HFpEF. However, a higher AHEI was associated with lower risk of HFrEF upon comparison of the extreme quintiles (HR per SD: 0.81; 95% CI: 0.69, 0.96; P -trend = 0.02). Every SD increment in the PDQS was associated with 20% lower risk of HFrEF (HR per SD: 0.80; 95% CI: 0.68, 0.95; P -quadratic = 0.03). Conclusions A healthy overall diet was associated with lower risk of HFrEF, and associations were similar with the AHEI and PDQS. We did not observe a significant association between dietary indices and either overall HF or HFpEF. [ABSTRACT FROM AUTHOR]

Suboptimal pregnancy conditions may affect ovarian development in the fetus and be associated with early natural menopause (ENM) for offspring. A total of 106,633 premenopausal participants in Nurses' Health Study II who provided data on their own prenatal characteristics, including diethylstilbestrol (DES) exposure, maternal cigarette smoking exposure, multiplicity, prematurity, and birth weight, were followed from 1989 to 2017. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of in utero exposures with ENM. During 1.6 million person-years of follow-up, 2,579 participants experienced ENM. In multivariable models, women with prenatal DES exposure had higher risk of ENM compared with those without it (HR = 1.33, 95% CI: 1.06, 1.67). Increased risk of ENM was observed for those with low (<5.5 pounds (<2.5 kg)) versus normal (7.0–8.4 pounds (3.2–3.8 kg)) birth weight (HR = 1.21, 95% CI: 1.01, 1.45). Decreasing risk was observed per 1-pound (0.45-kg) increase in birth weight (HR = 0.93, 95% CI: 0.90, 0.97). Prenatal smoking exposure, being part of a multiple birth, and prematurity were not associated with ENM. In this large cohort study, lower birth weight and prenatal DES exposure were associated with higher risk of ENM. Our results support a need for future research to examine in utero exposures that may affect offspring reproductive health. [ABSTRACT FROM AUTHOR]

Background Diet is one of the modifiable risk factors for cognitive decline. However, studies on dietary protein intake and cognitive decline have remained limited and inconclusive. Objectives In this study, we aimed to investigate the associations between long-term dietary protein intake and subsequent subjective cognitive decline (SCD). Methods We included 49,493 women from the Nurses' Health Study (NHS) (1984–2006) and 27,842 men from the Health Professionals Follow-up Study (HPFS) (1986–2002). For the NHS, average dietary intake was calculated from 7 repeated semi-quantitative FFQs (SFFQs), and SCD was assessed in 2012 and 2014. For the HPFS, average dietary intake was calculated from 5 repeated SFFQs, and SCD was assessed in 2008 and 2012. Poisson regression was used to examine the associations between dietary protein, amino acids, and various protein food sources with subsequent SCD. Results Higher protein intake compared with total carbohydrates was associated with lower odds of SCD. When substituting 5% energy from protein for the equivalent percentage of energy from total carbohydrates, the pooled multivariable-adjusted ORs (95% CIs) were 0.89 (0.85, 0.94) for total protein, 0.89 (0.84, 0.94) for animal protein, and 0.74 (0.62, 0.88) for plant protein. When substituting 5% of energy from animal protein with plant protein, the OR was 0.84 (95% CI: 0.72, 0.97). For protein food sources, higher intakes of beans/legumes, fish, and lean poultry were significantly associated with lower odds of SCD, but higher intake of hotdogs was associated with higher odds of SCD. Conclusions Higher protein intake was associated with lower odds of SCD when compared isocalorically with carbohydrate. Plant protein sources were also associated with lower odds when compared with animal protein sources. Our findings suggest that adequate protein intake, and choices of protein sources could play a role in the maintenance of cognition and should be studied further. [ABSTRACT FROM AUTHOR]

The long-term inflammatory impact of diet could potentially elevate the risk of periodontal disease through modification of systemic inflammation. The aim of the present study was to prospectively investigate the associations between a food-based, reduced rank regression (RRR)-derived, empirical dietary inflammatory pattern (EDIP) and incidence of periodontitis. The study population was composed of 34 940 men from the Health Professionals Follow-Up Study, who were free of periodontal disease and major illnesses at baseline (1986). Participants provided medical and dental history through mailed questionnaires every 2 years and dietary data through validated semi-quantitative FFQ every 4 years. We used Cox proportional hazard models to examine the associations between EDIP scores and validated self-reported incidence of periodontal disease over a 24-year follow-up period. No overall association between EDIP and the risk of periodontitis was observed; the hazard ratio comparing the highest EDIP quintile (most proinflammatory diet) with the lowest quintile was 0·99 (95 % CI 0·89, 1·10, P-value for trend = 0·97). A secondary analysis showed that among obese non-smokers (i.e. never and former smokers at baseline), the hazard ratio for periodontitis comparing the highest EDIP quintile with the lowest was 1·39 (95 % CI 0·98, 1·96, P-value for trend = 0·03). In conclusion, no overall association was detected between EDIP and incidence of self-reported periodontitis in the study population. From the subgroups evaluated, EDIP was significantly associated with increased risk of periodontitis only among non-smokers who were obese. Hence, this association must be interpreted with caution. [ABSTRACT FROM AUTHOR]

Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45 years. Therefore, we aimed to evaluate risk of early natural menopause among 107,817 members of the Nurses' Health Study II who were followed from 1989 to 2011. Alcohol consumption overall and by subtypes, including beer, red wine, white wine, and liquor, was assessed throughout follow-up. We estimated hazard ratios in multivariable models that were adjusted for age, body mass index, parity, smoking, and other potential confounders. Women who reported moderate current alcohol consumption had lower risks of early menopause than did nondrinkers. Those who reported consuming 10.0–14.9 g/day had a lower risk of early menopause than did nondrinkers (hazard ratio = 0.81, 95% confidence interval: 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to consumption of white wine and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine and liquor. High consumption was not related to lower risk of early menopause. [ABSTRACT FROM AUTHOR]

Objective: To investigate the associations of different types of carbohydrate intake after breast cancer diagnosis with breast cancer-specific and all-cause mortality. Methods: We prospectively assessed post-diagnostic intake of total sugar, added sugar, and natural sugar as well as carbohydrate from different sources, among 8932 women with stage I–III breast cancer that were identified in the Nurses' Health Study from 1980 to 2010 and Nurses' Health Study II from 1991 to 2011. Participants completed a validated food frequency questionnaire every four years after diagnosis and were followed up for death. Results: We prospectively documented 1071 deaths due to breast cancer and 2532 all-cause deaths, over a mean of 11.5 years of follow-up. After adjustment for confounding variables, greater post-diagnostic total sugar intake was suggestively associated with greater risk of breast cancer-specific mortality [hazard ratio (HR)Q5vsQ1 = 1.16, 95% confidence interval (CI) = 0.95–1.41; Ptrend = 0.02] and significantly associated with greater risk of all-cause mortality (HRQ5vsQ1 = 1.23, 95% CI = 1.08–1.41; Ptrend = 0.0001). Greater post-diagnostic added sugar intake was significantly associated with greater risk of all-cause mortality (HRQ5vsQ1 = 1.20, 95% CI = 1.06–1.36; Ptrend = 0.001). Post-diagnostic natural sugar (occurring in foods and not added as an ingredient) intake was not associated with mortality risk. Greater post-diagnostic fructose intake was significantly associated with greater risk of breast cancer-specific mortality (HRQ5vsQ1 = 1.34, 95% CI = 1.10–1.64; Ptrend = 0.005) and all-cause mortality (HRQ5vsQ1 = 1.16, 95% CI = 1.02–1.32; Ptrend = 0.01). High post-diagnostic intake of sucrose was associated with higher risk of breast cancer-specific and all-cause mortality. Increased post-diagnostic intake of carbohydrate from fruit juice was significantly associated with higher risk of breast cancer-specific and all-cause mortality and carbohydrate from vegetables was significantly associated with lower risk of all-cause mortality. High post-diagnostic intake of carbohydrate from potatoes was suggestively associated with higher risk of breast cancer-specific mortality and carbohydrate from refined grains was suggestively associated with higher risk of all-cause mortality. Conclusions: We found that higher total sugar intake, especially added sugar, sucrose, and fructose, as well as carbohydrate from fruit juice after a breast cancer diagnosis were associated with poorer prognosis. High post-diagnostic intake of carbohydrate from vegetables was associated with reduced risk of mortality. [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]

The relationship between body mass index (BMI; weight (kg)/height (m)2) and mortality among survivors of myocardial infarction (MI) remains controversial. We examined the relationships of BMI before and after MI and change in weight with all-cause mortality among participants in the Nurses' Health Study (1980–2016) and Health Professionals Follow-up Study (1988–2016) cohorts. During a follow-up period of up to 36 years, we documented 4,856 participants with incident nonfatal MI, among whom 2,407 died during follow-up. For pre-MI and post-MI BMI, overweight was not associated with lower mortality. Obesity (BMI ≥30) was associated with higher risk of mortality. Compared with participants with post-MI BMI of 22.5–24.9, hazard ratios were 1.16 (95% confidence interval (CI): 1.01, 1.34) for BMI 30.0–34.9 and 1.52 (95% CI: 1.27, 1.83) for BMI ≥35.0 (P for trend < 0.001). Compared with stable weight from before MI to after MI, a reduction of more than 4 BMI units was associated with increased mortality (hazard ratio = 1.53, 95%: CI: 1.28, 1.83). This increase was seen only among participants who lost weight without improving their physical activity or diet. Our findings showed no survival benefit of excess adiposity in relation to risk of mortality. Weight loss from before to after MI without lifestyle improvement may reflect reverse causation and disease severity. [ABSTRACT FROM AUTHOR]

Background Carotenoids represent 1 of few modifiable factors to reduce breast cancer risk. Elucidation of interactions between circulating carotenoids and genetic predispositions or mammographic density (MD) may help inform more effective primary preventive strategies in high-risk populations. Objectives We tested whether women at high risk for breast cancer due to genetic predispositions or high MD would experience meaningful and greater risk reduction from higher circulating levels of carotenoids in a nested case-control study in the Nurses' Health Studies (NHS and NHSII). Methods This study included 1919 cases and 1695 controls in a nested case-control study in the NHS and NHSII. We assessed both multiplicative and additive interactions. RR reductions and 95% CIs were calculated using unconditional logistic regressions, adjusting for matching factors and breast cancer risk factors. Absolute risk reductions (ARR) were calculated based on Surveillance, Epidemiology, and End Results incidence rates. Results We showed that compared with women at low genetic risk or low MD, those with higher genetic risk scores or high MD had greater ARRs for breast cancer as circulating carotenoid levels increase (additive P -interaction = 0.05). Among women with a high polygenic risk score, those in the highest quartile of circulating carotenoids had a significant ARR (28.6%; 95% CI, 14.8–42.1%) compared to those in the lowest quartile of carotenoids. For women with a high percentage MD (≥50%), circulating carotenoids were associated with a 37.1% ARR (95% CI, 21.7–52.1%) when comparing the highest to the lowest quartiles of circulating carotenoids. Conclusions The inverse associations between circulating carotenoids and breast cancer risk appeared to be more pronounced in high-risk women, as defined by germline genetic makeup or MD. [ABSTRACT FROM AUTHOR]

Previous studies suggest that the association between mammographic density (MD) and breast cancer risk might be modified by other breast cancer risk factors. In this study, we assessed multiplicative interactions between MD measures and established risk factors on the risk of invasive breast cancer overall and according to menopausal and estrogen receptor status. We used data on 2,137 cases and 4,346 controls from a nested case-control study within the Nurses' Health Study (1976–2004) and Nurses' Health Study II (1989–2007), whose data on percent mammographic density (PMD) and absolute area of dense tissue and nondense tissue (NDA) were available. No interaction remained statistically significant after adjusting for number of comparisons. For breast cancer overall, we observed nominally significant interactions (P  < 0.05) between nulliparity and PMD/NDA, age at menarche and area of dense tissue, and body mass index and NDA. Individual nominally significant interactions across MD measures and risk factors were also observed in analyses stratified by either menopausal or estrogen receptor status. Our findings help provide further insights into potential mechanisms underlying the association between MD and breast cancer. [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 Hyperinsulinemia and higher insulin-like growth factors may increase breast cancer risk. We evaluated a diabetes risk reduction diet (DRRD) and breast cancer risk. Objectives We prospectively evaluated the association between adherence to a DRRD and the incidence of breast cancer. Methods We followed 88,739 women from the Nurses' Health Study (NHS; 1980–2016) and 93,915 women from the NHSII (1991–2017). Incident breast cancer cases (n  = 11,943) were confirmed with medical records, and subtypes were determined by tissue microarray data and pathology reports. Information on diet and breast cancer risk factors was repeatedly ascertained in follow-up questionnaires. A DRRD score was derived with 9 factors: lower glycemic index of diet; lower intakes of trans fat, sugar-sweetened beverages/fruit juices, and red/processed meat; higher intakes of cereal fiber, coffee, nuts, and whole fruits; and a higher ratio of polyunsaturated to saturated fat (score range: 9–45). Multivariable-adjusted hazard ratios (MVHRs) and 95% CIs were calculated with Cox proportional hazards models. Results Being in the highest compared with the lowest DRRD adherence quintile was associated with a modestly lower breast cancer risk (MVHRQ5vsQ1: 0.89; 95% CI: 0.84, 0.95; P -trend = 0.0002); this was attenuated after adjusting for weight change since age 18 y (MVHRQ5vsQ1: 0.92; 95% CI: 0.87, 0.98; P -trend = 0.01). The inverse association was strongest among women with current BMI < 25 kg/m2 (MVHRQ5vsQ1: 0.89; 95% CI: 0.81, 0.98; P -trend = 0.004; P -interaction = 0.04). Among tumor molecular subtypes, the strongest inverse association was observed with basal-type tumors (MVHRQ5vsQ1: 0.67; 95% CI: 0.45, 1.01; P -trend = 0.04). Conclusions Greater DRRD-adherence was associated with lower breast cancer risk, likely mediated by less weight gain with a DRRD; however, independently of weight change, DRRD-adherence was modestly associated with lower breast cancer risk, particularly among lean women. [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 It is unclear whether adherence to diet recommendations for the prevention of cardiovascular disease (CVD) in the general population is also related to the risk of hypertensive disorders of pregnancy, including pre-eclampsia and gestational hypertension (GHTN). Objectives The aim was to evaluate the relation of prepregnancy adherence to the American Heart Association (AHA) diet recommendations and the Dietary Approaches to Stop Hypertension (DASH) with the risk of pre-eclampsia and GHTN. Methods Between 1991 and 2009, we prospectively followed 16,892 singleton pregnancies among 11,535 women who participated in the Nurses' Health Study II. Prepregnancy diet was assessed every 4 y, from which we calculated dietary pattern scores from the DASH diet (8 components) and the diet recommendations from the AHA 2020 Strategic Impact Goals (primary score: 5 components; secondary score: primary score plus 3 components). Pregnancy outcomes were self-reported, and we estimated the RR (95% CI) of pre-eclampsia and GHTN with log-binomial regression using generalized estimating equations to account for repeat pregnancies and adjusting for potential confounders. Results Women had a mean (SD) age of 34.4 (34.0) y at pregnancy. Pre-eclampsia was reported in 495 (2.9%) pregnancies and GHTN in 561 (3.3%) pregnancies. The RR (95% CI) of pre-eclampsia for women in the highest quintile of the DASH was 0.65 (0.48, 0.87) compared with women in the lowest score quintile. A similar inverse trend was observed for the AHA primary (0.74; 95% CI: 0.55, 1.00) and secondary (0.81; 95% CI: 0.61, 1.07) scores comparing women in the highest versus the lowest score quintile. Neither the DASH nor the AHA scores were related to GHTN. Conclusions Women with higher adherence to dietary recommendations for the prevention of CVD in the general population had a lower risk of pre-eclampsia—a common pregnancy complication related to higher CVD risk among women—than women with lower adherence to these recommendations. [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]

Purpose: Previous studies suggest that coffee and caffeine intake may be associated with reduced breast cancer risk. To date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent caffeine intake with mammographic density in premenopausal women. Methods: This study included 751 cancer-free women within the Nurses' Health Study II cohort. Percent breast density (PD), absolute dense (DA) and non-dense areas (NDA) were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square root-transformed. Energy-adjusted adolescent caffeine intake was estimated using the data from a food frequency questionnaire. Information regarding breast cancer risk factors was obtained from questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations of caffeine intake with breast density measures. Results: In multivariable analyses, adolescent caffeine intake was not associated with any of the density phenotypes (caffeine 4th vs. 1st quartile: β = − 1.27, 95% CI − 4.62; 2.09, p-trend = 0.55 for percent density; β = − 0.21, 95% CI − 0.76, 0.34, p-trend = 0.65 for absolute dense area, and β = 0.23, 95% CI − 0.28, 0.74, p-trend = 0.50 for non-dense area). Additional adjustment of the models for body mass index at age 18 resulted in attenuation of the risk estimates. Conclusions: Our findings do not support the hypothesis that adolescent caffeine intake is associated with premenopausal mammographic breast density. [ABSTRACT FROM AUTHOR]

Early natural menopause, the cessation of ovarian function prior to age 45 years, affects approximately 10% of women and increases risk of cardiovascular disease and other adverse conditions. Laboratory evidence suggests a potential role of dairy foods in the ovarian aging process; however, no prior epidemiologic studies have evaluated how dairy-food intake is associated with risk of early menopause. We therefore evaluated how intakes of total, low-fat, high-fat, and individual dairy foods were associated with early menopause in Nurses' Health Study II. Women who were premenopausal at the start of follow-up in 1991 were followed until 2011 for early menopause. Food frequency questionnaires were used to assess dietary intake. In Cox proportional hazards models adjusting for age, smoking, and other factors, total baseline dairy-food intake of ≥4 servings/day versus <4 servings/week was associated with 23% lower risk of early menopause (hazard ratio = 0.77, 95% confidence interval: 0.64, 0.93; P for trend = 0.08). Associations appeared to be limited to low-fat dairy foods (for ≥2 servings/day vs. <3 servings/month, hazard ratio = 0.83, 95% confidence interval: 0.68, 1.01; P for trend = 0.02), whereas high-fat dairy-food intake was not associated with early menopause. Low-fat dairy foods may represent a modifiable risk factor for reducing risk of early menopause among premenopausal women. [ABSTRACT FROM AUTHOR]

Background: Many dietary indexes exist for chronic disease prevention, but the optimal dietary pattern for colorectal cancer prevention is unknown. Objective: We sought to determine associations between adherence to various dietary indexes and incident colorectal cancer in 2 prospective cohort studies. Design:We followed 78,012 women in the Nurses' Health Study and 46,695 men in the Health Professionals Follow-up Study from 1986 and 1988, respectively, until 2012. We created dietary index scores for the Dietary Approaches to Stop Hypertension (DASH) diet, Alternative Mediterranean Diet (AMED), and Alternative Healthy Eating Index-2010 (AHEI-2010) and used Cox regression to estimate HRs and 95% CIs for risk of colorectal cancer (CRC) and by anatomic subsite. We also conducted latency analyses to examine associations between diet and CRC risk during different windows of exposure. We conducted analyses in men and women separately, and subsequently pooled these results in a random-effects meta-analysis. Results: We documented 2690 colorectal cancer cases. Pooled multivariable HRs for colorectal cancer risk comparing the highest to lowest quintile of diet scores were 0.89 (95% CI: 0.74, 1.08; P-trend = 0.10) for DASH, 0.89 (95% CI: 0.73, 1.10; P-trend = 0.31) for AMED, and 0.95 (95% CI: 0.83, 1.09; P-trend = 0.56) for AHEI-2010 (P-heterogeneity = 0.07 for all). In sex-specific analyses, we observed stronger associations in men for all dietary indexes (DASH: multivariable HR = 0.81, 95% CI: 0.66, 0.98; P-trend = 0.003; AMED: multivariable HR = 0.80, 95% CI: 0.65, 0.98; P-trend = 0.02; AHEI-2010: multivariable HR = 0.88, 95% CI: 0.72, 1.07; P-trend = 0.04) than in women (multivariable HRs range from 0.98 to 1.01). Conclusions: Adherence to the DASH, AMED, and AHEI-2010 diets was inversely associated with colorectal cancer risk in men. These diets were not associated with colorectal cancer risk in women. This observational study was registered at clinicaltrials.gov as NCT03364582. [ABSTRACT FROM AUTHOR]

Menopause before 45 years of age affects roughly 5%-10% of women and is associated with a higher risk of adverse health conditions. Although smoking may increase the risk of early menopause, evidence is inconsistent, and data regarding smoking amount, duration, cessation, associated risks, and patterns over time are scant.We analyzed data of 116,429 nurses from the Nurses' Health Study II from 1989 through 2011 and used Cox proportional hazards models to estimate hazard ratios adjusted for confounders. Compared with never-smokers, current smokers (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.71, 2.11) and former smokers (HR = 1.10, 95% CI: 1.00, 1.21) showed an increased risk of early menopause. Increased risks were observed among women who reported current smoking for 11-15 pack-years (HR = 1.72, 95% CI: 1.36, 2.18), 16-20 pack-years (HR = 1.72, 95% CI: 1.38, 2.14), and more than 20 pack-years (HR = 2.42, 95%CI: 2.11, 2.77). Elevated risk was observed in former smokers who reported 11-15 pack-years (HR = 1.29, 95% CI: 1.07, 1.55), 16-20 pack-years (HR = 1.42, 95% CI: 1.13, 1.79), or more than 20 pack-years (HR = 1.54, 95% CI: 1.23, 1.93). Women who smoked 10 or fewer cigarettes/day but quit by age 25 had comparable risk to never-smokers (HR = 1.03, 95% CI: 0.91, 1.17). A dose-response relationship between smoking and early naturalmenopause risk, as well as reduced risk among quitters, may provide insights into the mechanisms of cigarette smoking in reproductive health. [ABSTRACT FROM AUTHOR]

Early menopause, which is the cessation of ovarian function before age 45 years, affects 5%-10% of Western women and is associated with an increased risk of adverse health outcomes. Literature suggests that high levels of vegetable protein intake may prolong female reproductive function.We evaluated the association of long-term intake of vegetable protein, animal protein, and specific protein-rich foods with incidence of early natural menopause in the Nurses' Health Study II cohort. Women included in analyses (n = 85, 682) were premenopausal at baseline (1991) and followed until 2011 for onset of natural menopause. Protein intake was assessed via food frequency questionnaire. In Cox proportional hazard models that were adjusted for age, smoking, body mass index, and other factors, women in the highest quintile of cumulatively averaged vegetable protein intake (median, 6.5% of calories) had a significant 16%lower risk of earlymenopause compared with women in the lowest quintile (3.9%of calories; 95%confidence interval: 0.73, 0.98; P for trend = 0.02). Intake of specific foods, including pasta, dark bread, and cold cereal, was also associated with lower risk (P < 0.05). Conversely, animal protein intake was unrelated to risk. High consumption of vegetable protein, equivalent to 3-4 servings per day of protein-rich foods, is associated with lower incidence of early menopause in US women. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate 2-year changes in soda consumption, weight, and waist circumference. Methods. We followed 11 218 women from the Mexican Teachers' Cohort from 2006 to 2008. Dietary data were collected using a semiquantitative food frequency questionnaire. Weight was self-reported, and waist circumference was self-measured. We used linear regression to evaluate changes in sugar-sweetened and sugar-free soda consumption in relation to changes in weight and waist circumference, adjusting for lifestyle and other dietary factors. Results. Compared with no change, a decrease in sugar-sweetened soda consumption by more than 1 serving per week was associated with less weight gain (-0.4 kg; 95% confidence interval [CI] = -0.6, -0.2). Conversely, relative to no change, an increase in sugar-sweetened soda bymore than 1 serving per weekwas associatedwith a 0.3-kilogram (95% CI = 0.2, 0.5) increase inweight. An increase of 1 serving per day of sugar-sweetened sodawas associatedwith a 1.0 kg (95%CI = 0.7, 1.2; P < .001) increase inweight. The results for waist circumference were similar. Conclusions. Moderate changes in consumption of sugar-sweetened soda over a 2-year period were associated with corresponding changes in weight and waist circumference among Mexican women. [ABSTRACT FROM AUTHOR]

In 2007, the International Agency for Research on Cancer declared shift work that involved circadian disruption to be a "probable" carcinogen (group 2A), noting that human evidence was limited. Using data from 2 prospective cohort studies, the Nurses' Health Study (1988-2012; n = 78,516) and Nurses' Health Study II (1989-2013; n = 114,559), we examined associations between rotating night-shift work and breast cancer risk. In the 2 cohorts, there were a total of 9,541 incident invasive breast malignancies and 24 years of follow-up. In the Nurses' Health Study, women with 30 years or more of shift work did not have a higher risk of breast cancer (hazard ratio (HR) = 0.95, 95% confidence interval (95% CI): 0.77, 1.17; P for trend = 0.63) compared with those who never did shift work, although follow-up occurred primarily after retirement from shift work. Among participants in the Nurses' Health Study II, who were younger than participants in the other cohort, the risk of breast cancer was significantly higher in women with 20 years or more of shift work at baseline, reflecting young-adult exposure (HR = 2.15, 95% CI: 1.23, 3.73; P for trend = 0.23), and was marginally significantly higher for women with 20 years or more of cumulative shift work when we used updated exposure information (HR = 1.40, 95% CI: 1.00, 1.97; P for trend = 0.74). In conclusion, long-term rotating night-shift work was associated with a higher risk of breast cancer, particularly among women who performed shift work during young adulthood. Further studies should explore the role of shift work timing on breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Dietary fat intake may contribute to non-Hodgkin lymphoma (NHL) pathogenesis by influencing carcinogen exposure or through immune modulation. Objective: We aimed to evaluate NHL risk associated with total and specific dietary fat intake. Design: We evaluated associations within the Nurses' Health Study (NHS) (n = 88,598) and the Health Professionals Follow-Up Study (HPFS) (n = 47,531) using repeated validated dietary assessments. We confirmed 1802 incident NHL diagnoses through 2010. Using multivariable Cox proportional hazards models, we estimated hazard ratios (HRs) for all NHL and common subtypes associated with a 1-SD increase in cumulative mean intakes of total, animal, saturated, trans, and vegetable fats and marine fatty acids. We pooled sex-specific HRs using random-effects meta-analysis. Results: Over 24-30 y of follow-up, neither total nor specific dietary fats were significantly associated with NHL risk overall. Higher total, animal, and saturated fat intakes were positively associated with the risk of the chronic lymphocytic leukemia/small lymphocytic lymphoma subtype among women only (253 cases; P-trend ≤ 0.05), driven by strong associations during 1980-1994. From baseline through 1994, among women and men combined, total fat intake was borderline-significantly positively associated with NHL overall (pooled HR per SD: 1.13; 95% CI: 0.99, 1.29) and was significantly associated with diffuse large B cell lymphoma (pooled HR per SD: 1.47; 95% CI: 1.06, 2.05), with similar trends for animal and saturated fat intake. For women only, trans fat was significantly positively associated with all NHL. In contrast, during 1994-2010, there was little evidence for associations of dietary fat intake with NHL overall or by subtype. Conclusion: Previous observations of an increased risk of NHL associated with intakes of total, animal, saturated, and trans fat with 14 y of follow-up did not persist with longer follow-up. [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]

The authors evaluated the validity of a 152-item semiquantitative food frequency questionnaire (SFFQ) by comparing it with two 7-day dietary records (7DDRs) or up to 4 automated self-administered 24-hour recalls (ASA24s) over a 1-year period in the women's Lifestyle Validation Study (2010-2012), conducted among subgroups of the Nurses' Health Studies. Intakes of energy and 44 nutrients were assessed using the 3 methods among 632 US women. Compared with the 7DDRs, SFFQ responses tended to underestimate sodium intake but overestimate intakes of energy, macronutrients, and several nutrients in fruits and vegetables, such as carotenoids. Spearman correlation coefficients between energy-adjusted intakes from 7DDRs and the SFFQ completed at the end of the data-collection period ranged from 0.36 for lauric acid to 0.77 for alcohol (mean r = 0.53). Correlations of the end-period SFFQ were weaker when ASA24s were used as the comparison method (mean r = 0.43). After adjustment for within-person variation in the comparison method, the correlations of the final SFFQ were similar with 7DDRs (mean r = 0.63) and ASA24s (mean r = 0.62). These data indicate that this SFFQ provided reasonably valid estimates for intakes of a wide variety of dietary variables and that use of multiple 24-hour recalls or 7DDRs as a comparison method provided similar conclusions if day-to-day variation was taken into account. [ABSTRACT FROM AUTHOR]

The relationship between various diet quality indices and risk of type 2 diabetes (T2D) remains unsettled. We compared associations of 4 diet quality indices--the Alternate Mediterranean Diet Index, Healthy Eating Index 2010, Alternate Healthy Eating Index 2010, and the Dietary Approaches to Stop Hypertension (DASH) Index-- with reported T2D in the Women's Health Initiative, overall, by race/ethnicity, and with/without adjustment for overweight/obesity at enrollment (a potential mediator). This cohort (n= 101,504) included postmenopausal women without T2D who completed a baseline food frequency questionnaire from which the 4 diet quality index scores were derived. Higher scores on the indices indicated a better diet. Cox regression was used to estimate multivariate hazard ratios for T2D. Pearson coefficients for correlation among the indices ranged from 0.55 to 0.74. Follow-up took place from 1993 to 2013. Duringamedian 15 years of follow-up, 10,815 incident cases of T2D occurred. For each diet quality index, a 1-standard-deviation higher score was associated with 10%-14% lower T2D risk (P< 0.001). Adjusting for overweight/obesity at enrollment attenuated but did not eliminate associations to 5%-10% lower risk per 1-standard-deviation higher score (P< 0.001). For all 4 dietary indices examined, higher scores were inversely associated with T2D overall and across racial/ethnic groups. Multiple forms of a healthful diet were inversely associated with T2D in these postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but few studies have explored associations with folate and Bα vitamins. No effective therapeutic strategy for geographic atrophy (GA) is available, and prevention could be of great value. Objective: We investigated associations between dietary folate, B vitamins, and progression to GA and whether these associations might be modified by genetic susceptibility. Design: Among 2525 subjects (4663 eyes) in the Age-Related Eye Disease Study, 405 subjects (528 eyes) progressed to GA over 13 y. Folate and B vitamins were log transformed and calorie adjusted separately for men and women. Ten loci in 7 AMD genes [complement factor H, age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1, complement component 2, complement component 3, complement factor B, collagen type VIII a 1, and RAD51 paralog B] were examined. Survival analysis was used to assess associations between incident GA and dietary intake of folate and B vitamins. Interaction effects between these nutrients and genetic variation on AMD risk were also evaluated. Subjects with at least one eye free of advanced AMD at baseline were included in these analyses. Results: There was a reduced risk of progression to GA with increasing intake of thiamin, riboflavin, and folate after adjusting for age, sex, and total energy intake (P-trend = 0.01, 0.03, and 0.001, respectively). After adjustment for demographic, behavioral, ocular, and genetic covariates, trends remained statistically significant for folate (P-trend = 0.007) and were borderline for thiamin (P-trend = 0.05). Riboflavin did not retain statistical significance (P-trend = 0.20). Folate was significantly associated with lower risk of incident GA among subjects homozygous for the complement component 3 (C3) R102G rs2230199 nonrisk genotype (CC) (HR = 0.43; 95% CI: 0.27, 0.70; P = 0.0005) but not subjects carrying the risk allele (G) (P = 0.76). Neither folate nor any B vitamin was significantly associated with neovascular AMD. Conclusions: High folate intake was associated with a reduced risk of progression to GA. This relation could be modified by genetic susceptibility, particularly related to the C3 genotype. [ABSTRACT FROM AUTHOR]

Most studies of sleep and health outcomes rely on self-reported sleep duration, although correlation with objective measures is poor. In this study, we defined sociodemographic and sleep characteristics associated with mis-reporting and assessed whether accounting for these factors better explains variation in objective sleep duration among 2,086 participants in the Hispanic Community Health Study/Study of Latinos who completed more than 5 nights of wrist actigraphy and reported habitual bed/wake times from 2010 to 2013. Using linear regression, we examined self-report as a predictor of actigraphy-assessed sleep duration. Mean amount of time spent asleep was 7.85 (standard deviation, 1.12) hours by self-report and 6.74 (standard deviation, 1.02) hours by actigraphy; correlation between them was 0.43. For each additional hour of self-reported sleep, actigraphy time spent asleep increased by 20 minutes (95% confidence interval: 19, 22). Correlations between self-reported and actigraphy-assessed time spent asleep were lower with male sex, younger age, sleep efficiency <85%, and night-to-night variability in sleep duration ≥1.5 hours. Adding sociodemographic and sleep factors to self-reports increased the proportion of variance explained in actigraphy-assessed sleep slightly (18%-32%). In this large validation study including Hispanics/Latinos, we demonstrated a moderate correlation between self-reported and actigraphy-assessed time spent asleep. The performance of self-reports varied by demographic and sleep measures but not by Hispanic subgroup. [ABSTRACT FROM AUTHOR]

Background: There is limited evidence that supports etiologically distinct molecular subtypes of prostate cancer, the identification of which may improve prevention. Given their antioxidant properties, we hypothesized that lycopene and tomato sauce may be especially protective against diseases harboring the common gene fusion trans-membrane protease, serine 2 (TMPRSS2):v-ets avian erythroblastosis virus E26 oncogene homolog (ERG). Objective: We aimed to examine associations between estimated lycopene and tomato sauce intake and the risk of prostate cancer defined by ERG protein expression subtype. Design: Our study population consisted of a prospective cohort of 46,719 men from the Health Professionals Follow-Up Study. TMPRSS2:ERG was assessed by ERG immunohistochemistry on tumor tissue microarrays constructed from radical prostatectomy specimens. We used multivariable competing risk models to calculate HRs and 95% CIs for the risk of ERG-positive and, separately, ERG-negative disease. We implemented inverse probability weighting to account for evaluating ERG status only in surgically treated cases. Results: During 23 y of follow-up, 5543 men were diagnosed with prostate cancer, among whom 884 were assayed for ERG (426 ERG-positive). With inclusion of only the latter cases, increasing cumulative average tomato sauce intake was associated with a decreased risk of prostate cancer overall (≥2 servings/wk compared with <1 serving/mo; multivariable HR: 0.70; 95% CI: 0.52, 0.95; P-trend = 0.002). With respect to molecular subtypes, cumulative average tomato sauce intake was associated with a decreased risk of ERG-positive disease (HR: 0.54; 95% CI: 0.37, 0.81; P-trend = 0.004) but not with ERG-negative disease (HR: 0.96; 95% CI: 0.62, 1.50; P-trend = 0.10) (P-heterogeneity = 0.04). Increasing quintiles of lycopene intake were associated with a decreased risk of both subtypes (P-heterogeneity = 0.79). Inverse probability weighting did not materially change the results. Conclusions: Our results lend some support to the hypothesis that prostate cancers that harbor TMPRSS2:ERG may be etiologically distinct from fusion-negative cancers. In particular, tomato sauce consumption may play a role in reducing TMPRSS2:ERG-positive disease. [ABSTRACT FROM AUTHOR]

Background: Carbohydrate quality may be an important determinant of type 2 diabetes (T2D); however, relations between various carbohydrate quality metrics and T2D risk have not been systematically investigated. Objective: The purpose of this study was to prospectively examine the association between carbohydrates, starch, fibers, and different combinations of these nutrients and risk of T2D in women. Design: We prospectively followed 70,025 women free of cardiovascular disease, cancer, and diabetes at baseline from the Nurses' Health Study (1984-2008). Diet information was collected with the use of a validated questionnaire every 4 y. Cox regression was used to evaluate associations with incident T2D. Results: During 1,484,213 person-years of follow-up, we ascertained 6934 incident T2D cases. In multivariable analyses, when extreme quintiles were compared, higher carbohydrate intake was not associated with T2D (RR = 0.98; 95% CI: 0.89, 1.08; P-trend = 0.84), whereas starch was associated with a higher risk (RR = 1.23; 95% CI: 1.12, 1.35; P-trend,0.0001). Total fiber (RR = 0.80; 95% CI: 0.72, 0.89; P-trend < 0.0001), cereal fiber (RR = 0.71, 95% CI: 0.65, 0.78; P-trend < 0.0001), and fruit fiber (RR = 0.79; 95% CI: 0.72, 0.85; P-trend < 0.0001) were associated with a lower T2D risk. The ratio of carbohydrate to total fiber intake was marginally associated with a higher risk of T2D (RR = 1.09; 95% CI: 1.00, 1.20; P-trend = 0.04). On the other hand, we found positive associations between the ratios of carbohydrate to cereal fiber (RR = 1.28; 95% CI: 1.17, 1.39; P-trend < 0.0001), starch to total fiber (RR = 1.12; 95% CI: 1.02, 1.23; P-trend = 0.03), and starch to cereal fiber (RR = 1.39; 95% CI: 1.27, 1.53; P-trend < 0.0001) and T2D. Conclusions: Diets with high starch, low fiber, and a high starch-to-cereal fiber ratio were associated with a higher risk of T2D. The starch-to-cereal fiber ratio of the diet may be a novel metric for assessing carbohydrate quality in relation to T2D. [ABSTRACT FROM AUTHOR]

To examine the association between urinary excretion of isoflavonoids and risk of type 2 diabetes (T2D), we conducted a nested case–control study among 1111 T2D pairs identified during 1995–2008 in the Nurses’ Health Study (NHS) and NHSII, who were free of diabetes, CVD and cancer at urine sample collection. Urinary excretion of daidzein and genistein, as well as their metabolites O-desmethylangolensin (O-DMA), dihydrogenistein (DHGE) and dihydrodaidzein (DHDE) was assayed using liquid chromatography MS. Self-reported T2D incident cases were confirmed using a validated questionnaire. Higher urinary excretion of daidzein and genistein was associated with a lower risk of T2D in the combined cohorts. Comparing extreme tertiles of the urinary markers, the OR of T2D were 0·71 (95 % CI 0·55, 0·93) for daidzein and 0·74 (95 % CI 0·56, 0·97) for genistein, although the test for linear trend was not significant for genistein (Ptrend=0·03 and 0·15, respectively). DMA, DHDE and DHGE were non-significantly associated with a lower T2D risk. The inverse association of daidzein with T2D risk was stronger among post-menopausal women who did not use hormone replacement therapy (Pinteraction=0·001): the OR was 0·58 (95 % CI 0·34, 0·97) comparing extreme tertiles among these women. In conclusion, urinary excretion of isoflavones was associated with a lower T2D risk in US women, especially among post-menopausal women who did not use hormone. Further research is warranted to replicate these observations among western populations with similarly low overall isoflavone intake. [ABSTRACT FROM PUBLISHER]

Background: Adherence to a Mediterranean-type diet is linked to a lower risk of mortality and chronic disease, but the association with the progression of age-related macular degeneration (AMD) and genetic susceptibility is unknown. Objective: We examined the association of adherence to the Mediterranean diet and genetic susceptibility with progression to advanced AMD. Design: Among 2525 subjects in the AREDS (Age-Related Eye Disease Study), 1028 eyes progressed to advanced AMD over 13 y. Baseline data for demographic and behavioral covariates were collected by using questionnaires. Dietary data were collected from food-frequency questionnaires. The alternate Mediterranean diet (aMeDi) score (range: 0-9) was constructed from individual intakes of vegetables, fruit, legumes, whole grains, nuts, fish, red and processed meats, alcohol, and the ratio of monounsaturated to saturated fats. Ten genetic loci in 7 genes [complement factor H (CFH), age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2/HTRA1), complement component 2 (C2), complement factor B (CFB), complement component 3 (C3), collagen type VIII a 1 (COL8A1), and RAD51 paralog B (RAD51B)] were examined. Survival analysis was used to assess individual eyes for associations between incident AMD and aMeDi score, as well as interaction effects between aMeDi score and genetic variation on risk of AMD. Results: A high aMeDi score (score of 6-9) was significantly associated with a reduced risk of progression to advanced AMD after adjustment for demographic, behavioral, ocular, and genetic covariates (HR: 0.74; 95% CI: 0.61, 0.91; P-trend = 0.007). The aMeDi score was significantly associated with a lower risk of incident advanced AMD among subjects carrying the CFH Y402H nonrisk (T) allele (P-trend = 0.0004, P-interaction = 0.04). The aMeDi score was not associated with AMD among subjects who were homozygous for the risk (C) allele. Conclusion: Higher adherence to a Mediterranean diet was associated with reduced risk of progression to advanced AMD, which may be modified by genetic susceptibility. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that carotenoids, which are micronutrients in fruit and vegetables, reduce breast cancer risk. Whether carotenoids are important early or late in carcinogenesis is unclear, and limited analyses have been conducted by breast tumor subtypes. Objectives: We sought to examine issues of the timing of carotenoid exposure as well as associations by breast tumor subtypes. Design: We conducted a nested case-control study of plasma carotenoids measured by using reverse-phase high-performance liquid chromatography and breast cancer risk in the Nurses' Health Study. In 1989-1990, 32,826 women donated blood samples; in 2000-2002, 18,743 of these women contributed a second blood sample. Between the first blood collection and June 2010, 2188 breast cancer cases were diagnosed (579 cases were diagnosed after the second collection) and matched with control subjects. RRs and 95% CIs were calculated by using conditional logistic regression adjusted for several breast cancer risk factors. Results: Higher concentrations of α-carotene, β-carotene, lycopene, and total carotenoids were associated with 18-28% statistically significantly lower risks of breast cancer (e.g., β-carotene top compared with bottom quintile RR: 0.72; 95% CI: 0.59, 0.88; P-trend < 0.001). Associations were apparent for total carotenoids measured ≥10 y before diagnosis (top compared with bottom quintile RR: 0.69; 95% CI: 0.50, 0.95; P-trend = 0.01) as well as those <10 y before diagnosis (RR: 0.79; 95% CI: 0.64, 0.98; P-trend = 0.04, P-interaction = 0.11). Carotenoid concentrations were strongly inversely associated with breast cancer recurrence and death (e.g., β-carotene top compared with bottom quintile RR: 0.32; 95% CI: 0.21, 0.51; P-trend < 0.001) compared with not recurrent and not lethal disease (P-heterogeneity < 0.001). Conclusion: In this large prospective analysis with 20 y of followup, women with high plasma carotenoids were at reduced breast cancer risk particularly for more aggressive and ultimately fatal disease. [ABSTRACT FROM AUTHOR]

Equations based on simple anthropometric measurements to predict body fat percentage (BF%) are lacking in Chinese population with increasing prevalence of obesity and related abnormalities. We aimed to develop and validate BF% equations in two independent population-based samples of Chinese men and women. The equations were developed among 960 Chinese Hans living in Shanghai (age 46·2 (sd 5·3) years; 36·7 % male) using a stepwise linear regression and were subsequently validated in 1150 Shanghai residents (58·7 (sd 6·0) years; 41·7 % male; 99 % Chinese Hans, 1 % Chinese minorities). The associations of equation-derived BF% with changes of 6-year cardiometabolic outcomes and incident type 2 diabetes (T2D) were evaluated in a sub-cohort of 780 Chinese, compared with BF% measured by dual-energy X-ray absorptiometry (DXA; BF%-DXA). Sex-specific equations were established with age, BMI and waist circumference as independent variables. The BF% calculated using new sex-specific equations (BF%-CSS) were in reasonable agreement with BF%-DXA (mean difference: 0·08 (2 sd 6·64) %, P= 0·606 in men; 0·45 (2 sd 6·88) %, P< 0·001 in women). In multivariate-adjusted models, the BF%-CSS and BF%-DXA showed comparable associations with 6-year changes in TAG, HDL-cholesterol, diastolic blood pressure, C-reactive protein and uric acid (P for comparisons ≥ 0·05). Meanwhile, the BF%-CSS and BF%-DXA had comparable areas under the receiver operating characteristic curves for associations with incident T2D (men P= 0·327; women P= 0·159). The BF% equations might be used as surrogates for DXA to estimate BF% among adult Chinese. More studies are needed to evaluate the application of our equations in different populations. [ABSTRACT FROM PUBLISHER]

Background: The frequency of soda consumption remains high in the United States. Soda consumption has been associated with poor bone health in children, but few studies have examined this relation in adults, and to our knowledge, no study has examined the relation of soda consumption with risk of hip fractures. Objective: We examined the association of soda, including specific types of soda, and risk of hip fracture in postmenopausal women. Design: An analysis was conducted in postmenopausal women from the Nurses' Health Study cohort (n = 73,572). Diet was assessed at baseline by using a semiquantitative food-frequency questionnaire and updated approximately every 4 y. In ≤30 y of follow-up, we identified 1873 incident hip fractures. We computed RRs for hip fractures by the amount of soda consumption by using Cox proportional hazards models with adjustment for potential confounders. Results: In multivariable models, each additional serving of total soda per day was associated with a significant 14% increased risk of hip fracture (RR: 1.14; 95% CI: 1.06, 1.23). The attributable risk in our cohort for total soda consumption was 12.5%. Risk was significantly elevated in consumers of both regular soda (RR: 1.19; 95% CI: 1.02, 1.38) and diet soda (RR: 1.12; 95% CI: 1.03, 1.21) and also did not significantly differ between colas and noncolas or sodas with or without caffeine. The association between soda and hip fractures did not differ by body mass index or diagnosis of diabetes. Conclusion: Increased soda consumption of all types may be associated with increased risk of hip fracture in postmenopausal women; however, a clear mechanism was not apparent on the basis of these observational data. [ABSTRACT FROM AUTHOR]

Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term surrogates of vitamin D exposure within the Nurses' Health Study (NHS) and NHSII. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of overall ovarian cancer and by histologic subtype using Cox proportional hazards models. Between 1976 and 2010 in NHS and 1989 and 2011 in NHSII, we identified a total of 1,225 incident epithelial ovarian cancer cases (NHS: 970, NHSII: 255) over 4,628,648 person-years of follow-up. Cumulative average UV-B exposure was not associated with ovarian cancer risk in NHS (Ptrend = 0.08), but was associated with reduced risk in NHSII (highest vs. lowest category RR = 0.67; 95% CI: 0.50, 0.89; Ptrend < 0.01). When stratified by histologic subtype, UV-B flux was positively associated with risk of serous tumors in NHS (Ptrend < 0.01), but inversely associated in NHSII (Ptrend = 0.01). Adjusted for confounders, ovarian cancer risk was not associated with vitamin D intake from food or supplements or with predicted 25(OH)D levels. Our study does not strongly support a protective role for vitamin D in ovarian cancer risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Background: Dietary and genetic factors involved in the one-carbon metabolism pathway may affect telomere length through DNA methylation and synthesis, but this has not been comprehensively investigated in epidemiologic studies. Objective: We cross-sectionally examined associations between dietary and genetic factors in the one-carbon metabolism pathway and relative peripheral blood leukocyte telomere length. Design: A total of 1715 participants from the Nurses' Health Study (NHS) had measurements of relative telomere length and plasma concentrations of folate, vitamin B-6, vitamin B-12, cysteine, and homocysteine. Food-frequency questionnaire (FFQ) measurements were also used for the assessment of folate, choline, methionine, riboflavin, vitamin B-6, vitamin B-12, and alcohol intakes. Genotyping was performed on 475 participants with telomere measurements on 29 mostly nonsynonymous single-nucleotide polymorphisms (SNPs) involved in one-carbon metabolism. Unconditional logistic and linear regression models were used. Results: There were no significant dose-response relations between any plasma- or FFQ-measured dietary factors and relative telomere length in multivariate analyses. For folate, vitamin B-6, and vitamin B-12, results from the use of FFQ data were consistent with plasma-biomarker findings. We showed no significant associations that involved SNPs and relative telomere length after we accounted for the false discovery rate. Conclusion: Our analyses involving plasma and questionnaire measurements of one-carbon metabolism factors show that some key dietary and genetic factors in this metabolic network are not associated with relative peripheral blood leukocyte telomere length. [ABSTRACT FROM AUTHOR]

Background: Data from mechanistic studies support a beneficial effect of specific Flavonoids on insulin sensitivity. However, few studies have evaluated the relation between intakes of different flavonoid subclasses and type 2 diabetes. Objective: The objective was to evaluate whether dietary intakes of major flavonoid subclasses (ie, flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) are associated with the risk of type 2 diabetes in US adults. Design: We followed up a total of 70,359 women in the Nurses' Health Study (NHS; 1984-2008), 89,201 women in the NHS II (1991-2007), and 41,334 men in the Health Professionals Follow-Up Study (1986-2006) who were free of diabetes, cardiovascular disease, and cancer at baseline. Results: During 3,645,585 person-years of follow-up, we docu-mented 12,611 incident cases of type 2 diabetes. Higher intakes of anthocyanins were significantly associated with a lower risk of type 2 diabetes (pooled HR for the 3 cohorts from a comparison of extreme quintiles: 0.85; 95% CI: 0.80, 0.91; P-trend < 0.001) after multivar-iate adjustment for age, BMI, and lifestyle and dietary factors. Con-sumption of anthocyanin-rich foods, particularly blueberries (pooled HR: 0.77 from a comparison of >2 servingsAvk with <1 serving/mo; 95% CI: 0.68, 0.87; P-trend < 0.001) and apples/pears (pooled HR: 0.77 from a comparison of >5 servingsAvk with < 1 serving/mo; 95% CI: 0.65, 0.83; P-trend < 0.001), was also associated with a lower risk of type 2 diabetes. No significant associations were found for total flavonoid intake or other flavonoid subclasses. Conclusion: A higher consumption of anthocyanins and anthocyanin-rich fruit was associated with a lower risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Purpose: Age at menopause, a major marker in the reproductive life, may bias results for evaluation of breast cancer risk after menopause. Methods: We followed 38,948 premenopausal women in 1980 and identified 2,586 who reported hysterectomy without bilateral oophorectomy and 31,626 who reported natural menopause during 22 years of follow-up. We evaluated risk factors for natural menopause, imputed age at natural menopause for women reporting a hysterectomy without bilateral oophorectomy, and estimated the hazard of reaching natural menopause in the next 2 years. We applied this imputed age at menopause to both increase sample size and to evaluate the relation between postmenopausal exposures and risk of breast cancer. Results: Age, cigarette smoking, age at menarche, pregnancy history, body mass index, history of benign breast disease, and history of breast cancer were each significantly related to age at natural menopause; duration of oral contraceptive use and family history of breast cancer were not. The imputation increased sample size substantially, and although some risk factors after menopause were weaker in the expanded model (height, and alcohol use), use of hormone therapy is less biased. Conclusions: Imputing age at menopause increases sample size, broadens generalizability making it applicable to women with hysterectomy, and reduces bias. [ABSTRACT FROM AUTHOR]