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Context Black women have a higher prevalence of hypertension as compared to White women. Differences in dietary sodium intake have been implicated as a contributing factor for the disparities in hypertension. Objective Our objective was to understand whether young Black women would have higher systolic blood pressure (SBP) than White women even on controlled sodium diets and to determine whether SBP differences were due to differences in dietary sodium intake and/or aldosterone regulation. Design The analyses included 525 hypertensive and normotensive women (ages 18-71) from the International Hypertensive Pathotype consortium, who were maintained on liberal sodium (LIB; >200 mEq sodium/day) and restricted sodium (RES; 10 mEq sodium/day) diets. Results Multivariate regression analyses (adjusted for age, race, study site, body mass index) found that Black women (ages 18-50) had significantly higher SBP than White women on both sodium diets: +8.7 ± 2.7 mmHg (P -value =.002) on a LIB diet and +8.5 ± 2.5 mmHg (P -value =.001) on a RES diet. Even among 18- to 35-year-olds—who were normotensive and nonobese—Black women had higher SBP: +7.9 ± 2.4 mmHg (P -value =.001) on a LIB diet and +7.6 ± 2.7 mmHg (P -value =.005) on a RES diet. Younger Black women also had higher plasma aldosterone concentration to plasma renin activity ratio (ARR) on both LIB and RES diets as well as a higher sodium-modulated aldosterone suppression-stimulation index—an indicator of aldosterone dysregulation. In younger Black women—but not in White women—there was a significant association between SBP and ARR on both LIB and RES diets. Conclusion Young Black women had increased SBP and ARR as compared to White women on LIB and RES diets, which offers insights into the possible mechanisms for the increased hypertension and cardiovascular disease risk in an at-risk and understudied population. [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]

We evaluated the validity and reproducibility of a semiquantitative food frequency questionnaire (FFQ) for measuring intakes of 149 foods and 25 food groups among 736 participants of the Women's Lifestyle Validation Study (WLVS, 2010–2012) and 649 participants of the Men's Lifestyle Validation Study (MLVS, 2011–2013). Validity of the FFQ compared with two 7-day dietary records measured 6 months apart and the reproducibility between 2 FFQs administered 1 year apart (FFQ1 and FFQ2) were assessed using Spearman correlations and intraclass correlation coefficients. The average 1-year reproducibility of FFQ-measured foods was 0.64 in both the WLVS and MLVS. Reproducibility of the food groups (mean = 0.71 among women and 0.72 among men) was generally higher than that for individual foods. Among women, the average validity correlation for individual foods was 0.59 when comparing FFQ2 with the 7-day dietary records. Among men, the corresponding average validity correlation was 0.61. Compared with individual foods, food groups had slightly higher validity correlations in both women (range, 0.45–0.92; mean = 0.61) and men (range, 0.46–0.88; mean = 0.65). This study reaffirms that the FFQ performs well in measuring most foods and food groups and provides data to adjust for measurement errors in epidemiologic studies of foods and food groups. [ABSTRACT FROM AUTHOR]

Participant‐level meta‐analysis across multiple studies increases the sample size for pooled analyses, thereby improving precision in effect estimates and enabling subgroup analyses. For analyses involving biomarker measurements as an exposure of interest, investigators must first calibrate the data to address measurement variability arising from usage of different laboratories and/or assays. In practice, the calibration process involves reassaying a random subset of biospecimens from each study at a central laboratory and fitting models that relate the study‐specific "local" and central laboratory measurements. Previous work in this area treats the calibration process from the perspective of measurement error techniques and imputes the estimated central laboratory value among individuals with only a local laboratory measurement. In this work, we propose a repeated measures method to calibrate biomarker measurements pooled from multiple studies with study‐specific calibration subsets. We account for correlation between measurements made on the same person and between measurements made at the same laboratory. We demonstrate that the repeated measures approach provides valid inference, and compare it to existing calibration approaches grounded in measurement error techniques in an example describing the association between circulating vitamin D and stroke. [ABSTRACT FROM AUTHOR]

Screening mammography aims to identify breast cancer early and secondarily measures breast density to classify women at higher or lower than average risk for future breast cancer in the general population. Despite the strong association of individual mammography features to breast cancer risk, the statistical literature on mammogram imaging data is limited. While functional principal component analysis (FPCA) has been studied in the literature for extracting image‐based features, it is conducted independently of the time‐to‐event response variable. With the consideration of building a prognostic model for precision prevention, we present a set of flexible methods, supervised FPCA (sFPCA) and functional partial least squares (FPLS), to extract image‐based features associated with the failure time while accommodating the added complication from right censoring. Throughout the article, we hope to demonstrate that one method is favored over the other under different clinical setups. The proposed methods are applied to the motivating data set from the Joanne Knight Breast Health cohort at Siteman Cancer Center. Our approaches not only obtain the best prediction performance compared to the benchmark model, but also reveal different risk patterns within the mammograms. [ABSTRACT FROM AUTHOR]

Background Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. Methods We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O]   =   1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O   =   1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O   =   0.55, 95% CI = 0.51 to 0.59). Conclusions Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations. [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 Physical activity is generally associated with better outcomes following diagnosis; however, few studies have evaluated change in pre- to postdiagnosis activity and repeated measures of activity by intensity and type. Methods We evaluated physical activity and survival following a breast cancer diagnosis in the Nurses' Health Study and Nurses' Health Study II (n = 9308 women, n = 1973 deaths). Physical activity was evaluated as updated cumulative average of metabolic equivalent of task (MET)-h/wk (assigned per activity based on duration and intensity) and change in pre- to postdiagnosis activity. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Higher postdiagnosis activity was inversely associated with breast cancer–specific mortality in categories from ≥9 MET-h/wk (vs <3 MET h/wk, HR≥9 to <18 = 0.74 [95% CI = 0.55 to 0.99]; HR≥27 = 0.69 [95% CI = 0.50 to 0.95]; P trend = .04) and all-cause mortality from ≥3 MET-h/wk (HR≥3 to <9 = 0.73 [95% CI = 0.61 to 0.88]; HR≥27 = 0.51 [95% CI = 0.41 to 0.63]; P trend < .001). Associations were predominantly observed for estrogen receptor–positive tumors and in postmenopausal women. Walking was associated with lower risk of all-cause mortality (≥9 vs <3 MET-h/wk, HR= 0.69 [95% CI = 0.57 to 0.84]) as was strength training. Relative to stable activity pre- to postdiagnosis (±3 MET-h/wk), increases from ≥3 to 9 MET-h/wk were associated with lower all-cause mortality risk (P trend < .001). Results were robust to adjustment for prediagnosis physical activity. Conclusions Physical activity was associated with lower risk of death following diagnosis. Increased pre- to postdiagnosis activity corresponding to at least 1-3 h/wk of walking was associated with lower risk of death. These results provide further impetus for women to increase their activity after a breast cancer diagnosis, though reverse causation cannot be fully excluded. [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]

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]

Background Circulating branched-chain amino acid (BCAA) levels reflect metabolic health and dietary intake. However, associations with breast cancer are unclear. Methods We evaluated circulating BCAA levels and breast cancer risk within the Nurses' Health Study (NHS) and NHSII (1997 cases and 1997 controls). A total of 592 NHS women donated 2 blood samples 10 years apart. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer risk in multivariable logistic regression models. We conducted an external validation in 1765 cases in the Women's Health Study (WHS). All statistical tests were 2-sided. Results Among NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with lower breast cancer risk (eg, isoleucine highest vs lowest quartile, multivariable OR = 0.86, 95% CI = 0.65 to 1.13, P trend =.20), with statistically significant linear trends among fasting samples (eg, isoleucine OR = 0.74, 95% CI = 0.53 to 1.05, P trend =.05). In contrast, among postmenopausal women, proximate measures (<10 years from blood draw) were associated with increased breast cancer risk (eg, isoleucine OR = 1.63, 95% CI = 1.12 to 2.39, P trend =.01), with stronger associations among fasting samples (OR = 1.73, 95% CI = 1.15 to 2.61, P trend =.01). Distant measures (10-20 years since blood draw) were not associated with risk. In the WHS, a positive association was observed for distant measures of leucine among postmenopausal women (OR = 1.23, 95% CI = 0.96 to 1.58, P trend =.04). Conclusions No statistically significant associations between BCAA levels and breast cancer risk were consistent across NHS and WHS or NHSII and WHS. Elevated circulating BCAA levels were associated with lower breast cancer risk among predominantly premenopausal NHSII women and higher risk among postmenopausal women in NHS but not in the WHS. Additional studies are needed to understand this complex relationship. [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]

Context: High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects.Objective: We investigated the prospective associations between HDL subspecies containing and lacking apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3.Design, Setting, and Participants: A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years.Main Measures: Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method.Results: The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III.Conclusion: Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment. [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]

Among 626 participants of the Men's Lifestyle Validation Study (2011–2013), we evaluated the validity and reproducibility of a self-administered 152-item semiquantitative food frequency questionnaire (SFFQ) using two 7-day dietary records (7DDRs), 4 Automated Self-Administered 24-hour dietary recalls (ASA24s), four 24-hour urine samples, 1 doubly labeled water measurement (repeated in 104 participants), and 2 fasting blood samples, collected over 15 months. Compared with 7DDRs, SFFQs underestimated energy intake, macronutrients, and sodium intake but overestimated some micronutrients. The mean of the Spearman correlation coefficients was 0.66 (range, 0.38–0.88) between 46 energy-adjusted nutrients estimated from 7DDRs and the final SFFQ, deattenuated for within-person variation in the 7DDRs. These deattenuated correlations were similar using ASA24s as the comparison. Relative to biomarkers, SFFQs underestimated energy, sodium, and protein intakes, as well as the sodium:potassium ratio. The energy-adjusted correlations between the final SFFQ and the biomarkers were slightly lower than the correlations between the SFFQ and 7DDRs. Using the method of triads to calculate validity coefficients, the median validity coefficient between SFFQ and true intake was 0.65 and 0.69 using 7DDRs and ASA24s, respectively, as the third method. These data indicate that this SFFQ provided reasonably valid estimates for a wide range of nutrients when evaluated by multiple comparison methods. [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]

Background: Hormone receptor signaling is critical in the progression of breast cancers, although the role of the androgen receptor (AR) remains unclear, particularly for estrogen receptor (ER)-negative tumors. This study assessed AR protein expression as a prognostic marker for breast cancer mortality.Methods: This study included 4147 pre- and postmenopausal women with invasive breast cancer from the Nurses' Health Study (diagnosed 1976-2008) and Nurses' Health Study II (1989-2008) cohorts. AR protein expression was evaluated by immunohistochemistry and scored through pathologist review and as a digitally quantified continuous measure. Hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer mortality were estimated from Cox proportional hazards models, adjusting for patient, tumor, and treatment covariates.Results: Over a median 16.5 years of follow-up, there were 806 deaths due to breast cancer. In the 7 years following diagnosis, AR expression was associated with a 27% reduction in breast cancer mortality overall (multivariable HR = 0.73, 95% CI = 0.58 to 0.91) a 47% reduction for ER+ cancers (HR = 0.53, 95% CI = 0.41 to 0.69), and a 62% increase for ER- cancers (HR = 1.62, 95% CI = 1.18 to 2.22) (P heterogeneity < .001). A log-linear association was observed between AR expression and breast cancer mortality among ER- cancers (HR = 1.14, 95% CI = 1.02 to 1.26 per each 10% increase in AR), although no log-linear association was observed among ER+ cancers.Conclusions: AR expression was associated with improved prognosis in ER+ tumors and worse prognosis in ER- tumors in the first 5-10 years postdiagnosis. These findings support the continued evaluation of AR-targeted therapies for AR+/ER- breast cancers. [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]

Study Question: Is physical activity associated with incident early menopause?Summary Answer: Physical activity is not associated with incident early menopause.What Is Known Already: Lifestyle factors such as physical activity may influence menopause timing, but results from prior research are inconsistent.Study Design, Size, Duration: We evaluated the association between physical activity and the occurrence of early natural menopause in a prospective cohort study, the Nurses' Health Study II. Women were followed prospectively from 1989 to 2011.Participants/materials, Setting, Methods: Our analysis included 107 275 women who were premenopausal at baseline. Menopause status was self-reported biennially. Time per week participating in specific activities was reported approximately every 4 years and used to calculate metabolic task hours per week (MET h/week). We used Cox proportional hazards model to evaluate the association between physical activity and incidence of natural menopause before age 45 years while controlling for potential confounding factors.Main Results and the Role Of Chance: There were 2 786 study members who experienced menopause before the age of 45. After adjustment for age, smoking and other factors, we observed no association between adulthood physical activity and early menopause. For example, compared to women reporting <3 MET h/week, the hazard ratio for women in the highest category (≥42 MET h/week) of cumulatively-averaged total physical activity was 0.89 (95% confidence interval: 0.76-1.04; P-trend: 0.26). Neither moderate nor strenuous activity in adolescence and young adulthood were related to risk. The relation of physical activity and early menopause did not vary across strata of body mass index or smoking status.Limitations, Reasons For Caution: Physical activity and menopausal status were self-reported, but repeated assessment of physical activity and prospective report of menopause status likely reduce the potential for non-differential misclassification. While the majority of our study participants were white, it is unlikely that the physiological relation of activity and early menopause varies by ethnicity.Wider Implications Of the Findings: Findings from our large prospective study do not support an important association between physical activity and early menopause.Study Funding/competing Interest(s): This project was supported by UM1CA176726 and R01HD078517 from the National Institutes of Health, Department of Health and Human Services. No competing interests are declared.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Are anti-Müllerian hormone (AMH) levels assessed in women aged 32-44 associated with risk of incident early natural menopause?Summary Answer: We observed strong, significant associations between lower AMH levels and higher risk of early menopause.What Is Known Already: The ability to predict risk early menopause, defined as menopause before age 45, prior to fertility decline would improve options for family planning and cardiovascular disease prevention. Though AMH is an established marker of menopause timing in older reproductive-aged women, whether AMH is associated with risk of early menopause has not been evaluated.Study Design, Size, Duration: We assessed these relations in a nested case-control study within the prospective Nurses' Health Study II cohort. Premenopausal blood samples were collected in 1996-1999. Participants were followed until 2011 for early natural menopause, with follow-up rates >94%.Participants/materials, Setting, Methods: Early menopause cases (n = 327) were women reporting natural menopause between blood collection and age 45. Controls (n = 491) experienced menopause after age 45 and included 327 cases matched to controls on the basis of age at blood draw (±4 months) and other factors. AMH levels up to 12 years before early menopause were assayed in 2016.Main Results and the Role Of Chance: In multivariable conditional logistic regression models adjusting for matching factors, body mass index, smoking, parity, oral contraceptive use, and other factors, each 0.10 ng/ml decrease in AMH was associated with a 14% higher risk of early menopause (95% confidence interval (CI) 1.10 to 1.18; P < 0.001). In polynomial regression models including linear and quadratic terms for AMH, odds ratios for early menopause for women with AMH levels of 1.5, 1.0 and 0.5 ng/ml compared to 2.0 ng/ml were 2.6, 7.5 and 23 (all P < 0.001). Significant associations were observed irrespective of smoking status, adiposity, infertility history and menstrual cycle characteristics. Furthermore, models assessing the predictive ability of AMH showed high concordance, and C-statistics were high, ranging from 0.68 (age ≤35) to 0.93 (age 42).Limitations, Reasons For Caution: Our population was relatively homogenous with respect to race/ethnicity. Further work in more ethnically diverse populations is needed.Wide Implication Of the Findings: To our knowledge, this is the first prospective study to evaluate whether AMH levels are associated with early menopause. These findings support the utility of AMH as a clinical marker of early menopause in otherwise healthy women.Study Funding/competing Interest(s): This project was supported by UM1CA176726, R01CA67262, and R01HD078517 from the U.S. Department of Health and Human Services, National Institutes of Health. No competing interests declared. [ABSTRACT FROM AUTHOR]

We evaluated the performance of a semiquantitative food frequency questionnaire (SFFQ), the Automated Self-Administered 24-Hour Dietary Recall (ASA24), and 7-day dietary records (7DDRs), in comparison with biomarkers, in the estimation of nutrient intakes among 627 women in the Women's Lifestyle Validation Study (United States, 2010-2012). Two paper SFFQs, 1 Web-based SFFQ, 4 ASA24s (beta version), 2 7DDRs, 4 24-hour urine samples, 1 doubly labeled water measurement (repeated among 76 participants), and 2 fasting blood samples were collected over a 15-month period. The dietary variables evaluated were energy, energy-adjusted intakes of protein, sodium, potassium, and specific fatty acids, carotenoids, a-tocopherol, retinol, and folate. In general, relative to biomarkers, averaged ASA24s had lower validity than the SFFQ completed at the end of the data-collection year (SFFQ2); SFFQ2 had slightly lower validity than 1 7DDR; the averaged SFFQs had validity similar to that of 1 7DDR; and the averaged 7DDRs had the highest validity. The deattenuated correlation of energy-adjusted protein intake assessed by SFFQ2 with its biomarker was 0.46, similar to its correlation with 7DDRs (deattenuated r = 0.54). These data indicate that the SFFQ2 provides reasonably valid measurements of energy-adjusted intake for most of the nutrients assessed in our study, consistent with earlier conclusions derived using 7DDRs as the comparison method. The ASA24 needs further evaluation for use in large population studies, but an average of 3 days of measurement will not be sufficient for some important nutrients. [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]

Semen parameters are variable within individuals, but it is unclear whether 1 semen sample could represent a man's long-term average values in epidemiologic studies. Between 2005 and 2014, a total of 329 men from a fertility clinic in Boston, Massachusetts, provided 768 semen samples as part of the Environment and Reproductive Health (EARTH) Study. Total sperm count, sperm concentration, morphology, motility, and ejaculate volume were assessed. We used linear mixed models to compare values from men's first semen samples with their long-term averages and to calculate intraclass correlation coefficients for each parameter. We calculated positive predictive values (PPVs) and negative predictive values (NPVs) by comparing agreement in classification according to World Health Organization reference limits. There were no differences in mean semen parameters between men's first samples and the remaining replicates. Intraclass correlation coefficients ranged from 0.61 for morphology to 0.75 for concentration, indicating consistently greater between-man variability than within-man variability. Nevertheless, using 1 sample alone resulted in high NPVs but low PPVs (range, 43%-91%). The average of 2 samples was needed to achieve high PPVs (range, 86%-100%) and NPVs (range, 91%-100%). We conclude that 1 semen sample may suffice for studies aimed at identifying average differences in semen quality between individuals. Studies aimed at classifying men based on World Health Organization reference limits may benefit from collection of 2 or more samples. [ABSTRACT FROM AUTHOR]

Observational studies and randomized controlled trials of menopausal hormone therapy (HT) and chronic disease risk appear to have divergent results for cardiovascular disease. However, differences may be related to a modifying effect of age, time since menopause, and HT formulation. In the Nurses' Health Study (NHS) (enrolling during 1980-1994 and following participants until 2002), we investigated associations between the use of oral conjugated equine estrogens (CEE) (0.625 mg/day) plus medroxyprogesterone acetate (MPA) (<10 mg/day) or oral CEE alone and cardiovascular disease, cancer, all-cause mortality, and other major endpoints among postmenopausal women, aged 50-79 years at HT initiation. Among women aged 50-59 years at HT initiation, associations of CEE alone or CEE+MPA with most clinical outcomes were highly concordant between NHS and Women's Health Initiative (WHI). However, for myocardial infarction, results for CEE+MPA were in the direction of risk elevation in WHI and in the direction of risk reduction in NHS. When examined according to years since menopause onset (<10 years) rather than age group, results were nonsignificant and concordant for both studies. Because few women in the NHS initiated HT after age 60 years, we did not examine associations in this group. Discrepancies between NHS and WHI could largely be attributed to differences in the age structure of the populations and age at HT initiation. [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: Patient satisfaction in outpatient phlebotomy settings typically depends on wait time and venipuncture experience, and many patients equate their experiences with their overall satisfaction with the hospital. Methods: We compared patient service times and preanalytical errors pre- and postimplementation of an integrated electronic health record (EHR)-laboratory information system (LIS) and electronic specimen collection module. We also measured patient wait time and assessed patient satisfaction using a 5-question survey. Results: The percentage of patients waiting less than 10 minutes increased from 86% preimplementation to 93% postimplementation of the EHR-LIS (P ≤.001). The median total service time decreased significantly, from 6 minutes (IQR, 4-8 minutes), to 5 minutes (IQR, 3-6 minutes) (P = .005). The preanalytical errors decreased significantly, from 3.20 to 1.93 errors per 1000 specimens (P≤.001). Overall patient satisfaction improved, with an increase in excellent responses for all 5 questions (P ≤.001). Conclusions: We found several benefits of implementing an electronic specimen collection module, including decreased wait and service times, improved patient satisfaction, and a reduction in preanalytical errors. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the reproducibility and validity of a 61-item semiquantitative food frequency questionnaire used in a large prospective study among women. This form was administered twice to 173 participants at an interval of approximately one year (1980-1981), and four one-week diet records for each subject were collected during that period. Intradass correlation coefficients for nutrient intakes estimated by the one-week diet records (range = 0.41 for total vitamin A without supplements to 0.79 for vitamin B6 with supplements) were similar to those computed from the questionnaire (range = 0.49 for total vitamin A without supplements to 0.71 for sucrose), indicating that these methods were generally comparable with respect to reproducibility. With the exception of sucrose and total carbohydrate, nutrient intakes from the diet records tended to correlate more strongly with those computed from the questionnaire after adjustment for total caloric intake. Correlation coefficients between the mean calorie-adjusted intakes from the four one-week diet records and those from the questionnaire completed after the diet records ranged from 0.36 for vitamin A without supplements to 0.75 for vitamin C with supplements. Overall, 48% of subjects in the lowest quintile of calorie-adjusted intake computed from the diet records were also in the lowest questionnaire quintile, and 74% were in the lowest one of two questionnaire quintiles. Similarly, 49% of those in the highest diet record quintile were also in the highest questionnaire quintile, and 77% were in the highest one or two questionnaire quintiles. These data indicate that a simple self-administered dietary questionnaire can provide useful information about individual nutrient intakes over a one-year period. [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]

We expanded and updated our colon cancer risk model to evaluate colorectal cancer (CRC) and whether subsite-specific risk models are warranted. Using data from 1980-2010 for 90,286 women enrolled in the Nurses' Health Study, we performed competing-risks regression and tests for subsite heterogeneity (proximal colon: n = 821 ; distal colon: n = 521 ; rectum: n = 376). Risk factors for CRC were consistent with those in our colon cancer model. Processed meat consumption was associated with a higher risk of distal (hazard ratio (HR) = 1.45; P = 0.02) but not proximal (HR = 0.95; P = 0.72) colon cancer. Smoking was associated with both colon (HR = 1.21) and rectal (HR = 1.27) cancer and was more strongly associated with proximal (HR = 1.31) than with distal (HR = 1.04) colon cancer (P = 0.029). We observed a significant trend of cancer risk for smoking in subsites from the cecum (HR = 1.41) to the proximal colon (excluding the cecum; HR = 1.27) to the distal colon (HR = 1.04; P for trend = 0.040). The C statistics for colorectal (C = 0.607), colon (C = 0.603), and rectal (C = 0.639) cancer were similar, although C was slightly higher for rectal cancer. Despite evidence for site-specific differences for several risk factors, overall our findings support the application of risk prediction models for colon cancer to CRC. [ABSTRACT FROM AUTHOR]

Background: The role of body fatness in the aetiology of breast cancer is complex. We evaluated the independent and synergistic effects of body fatness, at different stages throughout a woman's life course, on premenopausal breast cancer risk.Methods: Premenopausal participants of the Nurses' Health Study II (NHSII) were followed from 1991 up to 2009. Body fatness factors including birthweight, somatotype (a 9-level pictogram with level 1 being the leanest) at ages 5 and 10 years and body mass index (BMI) at age 18 were collected at baseline. Current BMI was updated biennially. Multivariate Cox regression models were used to evaluate the association between each body fatness factor as well as cross-classification of all factors and the incidence of breast cancer.Results: Based on 1574 incident premenopausal breast cancer cases and 1 133 893 person-years of follow-up, a lower incidence was associated with lower birthweight: hazard ratio (HR) [95% confidence interval (CI)] = 0.74 (0.58-0.95) for <2.5kg vs 3.9+kg, P for trend < 0.001; higher somatotype at age 5: HR=0.57 (95% CI 0.44-0.73) for 5-9 vs 1, P fortrend < 0.0001]; and at age 10: HR=0.61 (95% CI 0.49-0.75) for 5-9 vs 1, P for trend < 0.0001]; and BMI at age 18: HR=0.67 (95% 0.47-0.95) for ≥ 27.5 kg/m2 vs < 18.5 kg/m2, P for trend = 0.009], after adjusting for age and body fatness measures earlier in life and other risk factors, respectively. No significant interaction between body fatness measures was found. Women with the lowest birthweight, the highest somatotype at ages 5 and 10 and the highest BMI at age 18 and currently had a 72% (95% CI 54%-83%) lower incidence of invasive premenopausal breast cancer than women with the opposite extreme of each body fatness indicator.Conclusion: The lowest incidence of premenopausal breast cancer was associated with the lowest birthweight and the highest childhood, adolescent and early adult body fatness. [ABSTRACT FROM AUTHOR]

Background: The role of body fatness in the aetiology of breast cancer is complex. We evaluated the independent and synergistic effects of body fatness, at different stages throughout a woman's life course, on premenopausal breast cancer risk. Methods: Premenopausal participants of the Nurses' Health Study II (NHSII) were followed from 1991 up to 2009. Body fatness factors including birthweight, somatotype (a 9-level pictogram with level 1 being the leanest) at ages 5 and 10 years and body mass index (BMI) at age 18 were collected at baseline. Current BMI was updated biennially. Multivariate Cox regression models were used to evaluate the association between each body fatness factor as well as cross-classification of all factors and the incidence of breast cancer. Results: Based on 1574 incident premenopausal breast cancer cases and 1 133 893 personyears of follow-up, a lower incidence was associated with lower birthweight: hazard ratio (HR) [95% confidence interval (CI)]=0.74 (0.58-0.95) for <2.5kg vs 3.9þkg, P for trend<0.001; higher somatotype at age 5: HR=0.57 (95% CI 0.44-0.73) for 5-9 vs 1, P fortrend<0.0001]; and at age 10: HR=0.61 (95% CI 0.49-0.75) for 5-9 vs 1, P for trend<0.0001]; and BMI at age 18: HR=0.67 (95% 0.47-0.95) for ≥ 27.5 kg/m² vs < 18.5 kg/m², P for trend=0.009], after adjusting for age and body fatness measures earlier in life and other risk factors, respectively. No significant interaction between body fatness measures was found. Women with the lowest birthweight, the highest somatotype at ages 5 and 10 and the highest BMI at age 18 and currently had a 72% (95% CI 54%-83%) lower incidence of invasive premenopausal breast cancer than women with the opposite extreme of each body fatness indicator. Conclusion: The lowest incidence of premenopausal breast cancer was associated with the lowest birthweight and the highest childhood, adolescent and early adult body fatness. [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]

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: The Breast Cancer Risk Assessment Tool (BCRAT, "Gail model") is commonly used for breast cancer prediction; however, it has not been validated for women age 75 years and older.Methods: We used Nurses' Health Study (NHS) data beginning in 2004 and Women's Health Initiative (WHI) data beginning in 2005 to compare BCRAT's performance among women age 75 years and older with that in women age 55 to 74 years in predicting five-year breast cancer incidence. BCRAT risk factors include: age, race/ethnicity, age at menarche, age at first birth, family history, history of benign breast biopsy, and atypia. We examined BCRAT's calibration by age by comparing expected/observed (E/O) ratios of breast cancer incidence. We examined discrimination by computing c-statistics for the model by age. All statistical tests were two-sided.Results: Seventy-three thousand seventy-two NHS and 97 081 WHI women participated. NHS participants were more likely to be non-Hispanic white (96.2% vs 84.7% in WHI, P < .001) and were less likely to develop breast cancer (1.8% vs 2.0%, P = .02). E/O ratios by age in NHS were 1.16 (95% confidence interval [CI] = 1.09 to 1.23, age 57-74 years) and 1.31 (95% CI = 1.18 to 1.45, age ≥ 75 years, P = .02), and in WHI 1.03 (95% CI = 0.97 to 1.09, age 55-74 years) and 1.10 (95% CI = 1.00 to 1.21, age ≥ 75 years, P = .21). E/O ratio 95% confidence intervals crossed one among women age 75 years and older when samples were limited to women who underwent mammography and were without significant illness. C-statistics ranged between 0.56 and 0.58 in both cohorts regardless of age.Conclusions: BCRAT accurately predicted breast cancer for women age 75 years and older who underwent mammography and were without significant illness but had modest discrimination. Models that consider individual competing risks of non-breast cancer death may improve breast cancer risk prediction for older women. [ABSTRACT FROM AUTHOR]

Higher folate has been associated with a reduced colorectal cancer (CRC) risk, but excessive folate may promote tumor progression. The role of unmetabolized folic acid (UFA) from high folic acid consumption in carcinogenesis is largely unexplored. We evaluated prediagnostic plasma levels of UFA in relation to CRC risk in nested case-control studies (618 CRC case patients and 1207 matched control) with blood samples collected prior to folic acid fortification. UFA was detected in 21.4% of control UFA levels were not associated with CRC risk. Compared with undetectable levels, the multivariable relative risks (RRs) of CRC were 1.03 (95% confidence interval [CI] = 0.73 to 1.46) for less than 0.5 nmol/L and 1.12 (95% CI = 0.81 to 1.55) for 0.5 nmol/L or more (Ptrend = .32). A positive association between UFA levels and CRC risk was observed among men (RR = 1.57, 95% CI = 0.99 to 2.49 for ≥0.5 nmol/L vs undetectable, Pinteraction = .04), and a positive association was also observed among those with the methylene-tetrahydrofolate reductase (MTHFR) CT/TT genotype (RR = 2.20, 95% CI = 1.22 to 3.94 for ≥0.5 nmol/L vs undetectable, Pinteraction=0.02). In conclusion, prediagnostic plasma levels of UFA from the prefortification period were not associated with risk of CRC. [ABSTRACT FROM AUTHOR]

Background: Over 25 years, the National Cancer Institute's Division of Cancer Prevention has entered some 800 agents into a chemopreventive agent testing program. Two critical steps involve: 1) in vitro/in vivo morphologic assays and 2) animal tumor assays (incidence/multiplicity reduction). We sought to determine how accurately the earlier-stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays.Methods: Focusing on 210 agents tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the six most commonly used morphologic assays predicted drug efficacy in animal tumor assays. Using multimodel inference, three statistical models were generated to evaluate the ability of these six morphologic assays to predict tumor outcomes in three different sets of animal tumor assays: 1) all tumor types, 2) mammary cancer only, and 3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the three different sets of animal tumor assays.Results: We demonstrated differences in the predictive value of specific morphologic assays for positive animal tumor assay results. Some of the morphologic assays were strongly predictive of meaningful positive efficacy outcomes in animal tumor assays representing specific cancer types, particularly the aberrant crypt focus (ACF) assay for colon cancer. Moreover, less strongly predictive assays can be combined and sequenced, resulting in enhanced composite predictive ability.Conclusions: Predictive models such as these could be used to guide selection of preventive agents as well as morphologic and animal tumor assays, thereby improving the efficiency of our approach to chemopreventive agent development. [ABSTRACT FROM AUTHOR]

Background The role of lycopene in prostate cancer prevention remains controversial. We examined the associations between dietary lycopene intake and prostate cancer, paying particular attention to the influence of prostate-specific antigen screening, and evaluated tissue biomarkers in prostate cancers in relation to lycopene intake. Methods Among 49898 male health professionals, we obtained dietary information through questionnaires and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Cox regression was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Tissue microarrays and immuno-histochemistry were used to assess tumor biomarker expression in a subset of men. Two-sided χ² tests were used to calculate the P values. Results Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: HR = 0.72; 95% CI = 0.56 to 0.94; Ptrend = .04). In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; Ptrend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential. Conclusions Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor. Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening. [ABSTRACT FROM AUTHOR]

Background Adult alcohol consumption during the previous year is related to breast cancer risk. Breast tissue is particularly susceptible to carcinogens between menarche and first full-term pregnancy. No study has characterized the contribution of alcohol consumption during this interval to risks of proliferative benign breast disease (BBD) and breast cancer. Methods We used data from 91005 parous women in the Nurses’ Health Study II who had no cancer history, completed questions on early alcohol consumption in 1989, and were followed through June 30, 2009, to analyze breast cancer risk. A subset of 60093 women who had no history of BBD or cancer in 1991 and were followed through June 30, 2001, were included in the analysis of proliferative BBD. Relative risks (RRs) were estimated using Cox proportional hazard regression. Results We identified 1609 breast cancer cases and 970 proliferative BBD cases confirmed by central histology review. Alcohol consumption between menarche and first pregnancy, adjusted for drinking after first pregnancy, was associated with risks of breast cancer (RR = 1.11 per 10g/day intake; 95% confidence interval [CI] = 1.00 to 1.23) and proliferative BBD (RR = 1.16 per 10g/day intake; 95% CI = 1.02 to 1.32). Drinking after first pregnancy had a similar risk for breast cancer (RR = 1.09 per 10g/day intake; 95% CI = 0.96 to 1.23) but not for BBD. The association between drinking before first pregnancy and breast neoplasia appeared to be stronger with longer menarche to first pregnancy intervals. Conclusions Alcohol consumption before first pregnancy was consistently associated with increased risks of proliferative BBD and breast cancer. [ABSTRACT FROM PUBLISHER]

Background: Seafood consumption may prevent age-related cognitive decline. However, benefits may vary by nutrient contents in different seafood types. We examined associations between total seafood consumption and cognitive decline and whether these associations differ by seafood types.Methods: We conducted a prospective cohort study of 5,988 women (mean age, 72 years) from the Women's Health Study who self-reported seafood intake at Women's Health Study baseline and also participated in telephone assessments of general cognition, verbal memory, and category fluency administered 5.6 years after Women's Health Study baseline and 2 and 4 years thereafter. Primary outcomes were standardized composite scores of global cognition and verbal memory.Results: After adjusting for potential confounders, different amounts of total seafood consumption were not associated with changes in global cognition (p = .56) or verbal memory (p = .29). Considering seafood types, however, compared with women consuming less than once-weekly tuna or dark-meat finfish, those with once-weekly or higher consumption had significantly better verbal memory (0.079 standard units; p < .01) after 4 years-a difference comparable to that for women 2.1 years apart in age. There was also a statistically nonsignificant suggestion of better global cognition (p = .13) with once-weekly or higher tuna or dark-meat fish consumption. No significant associations were observed for light-meat finfish or shellfish.Conclusions: The relation of seafood to cognition may depend on the types consumed. Total consumption levels of seafood were unrelated to cognitive change. However, consumption of tuna and dark-meat fish once weekly or higher was associated with lower decline in verbal memory for a period of 4 years. [ABSTRACT FROM AUTHOR]

Introduction: Approximately 60%–70% of cigarette smokers who try to quit relapse by 2 weeks postcessation. We tested the efficacy of a front-loaded (FL) counseling intervention whose goal was to increase the likelihood of successful early abstinence and subsequent long-term abstinence. Methods: We randomized 278 adult smokers to an FL or weekly behavioral smoking cessation counseling schedule. The total number of sessions across treatment was the same for both groups. However, those assigned to the FL schedule received 6 counseling sessions in the first 2 weeks postcessation, while those in the weekly condition received 2 sessions. Participants in both groups also received standard nicotine patch treatment. Results: At 1 year postcessation, FL participants were significantly less likely to have relapsed when continuous abstinence was used as the definition of abstinence/relapse (11.7% abstinent vs. 6.3%, hazard ratio [HR] = 0.69, p = .007); and there were nonsignificant trends for FL subjects to have better outcomes when abstinence was defined as never smoking for 7 or more consecutive days nor for 7 or more consecutive episodes (18.4% abstinent vs. 14.8%, HR = 0.83, p = .20) and as point prevalence abstinence (15.6% abstinent vs. 12.9%, p = .11). The relationship between FL counseling treatment and continuous abstinence was partially mediated by higher postcessation levels of social support perceived from counseling and greater use of cessation-related coping strategies. Conclusions: We conclude that FL counseling is a promising treatment model that should be evaluated further, perhaps using modifications of the FL schedule used in this study. [ABSTRACT FROM PUBLISHER]

Background Few studies that investigated the associations between breast density and subsequent breast cancer according to tumor characteristics have produced inconclusive findings. We aimed to determine whether the associations between breast density and subsequent breast cancer varied by tumor characteristics. Methods We included 1042 postmenopausal women diagnosed with breast cancer between June 1, 1989, and June 30, 2004, and 1794 matched control subjects from the Nurses’ Health Study, an ongoing prospective cohort study of 121 701 registered female nurses across the United States. Breast density was estimated from digitized images using computerized techniques. Information on breast cancer risk factors was obtained prospectively from biennial questionnaires before the date of cancer diagnosis for case subjects and matched control subjects. Polychotomous logistic regression was used to assess associations of breast density with tumor subtypes based on invasiveness, histology, size, grade, receptor status, and involvement of lymph nodes. All tests of statistical significance were two-sided. Results The risk of breast cancer increased progressively with increase in percent breast density (Ptrend < .001). Women with higher breast density (≥50%) showed a 3.39-fold (odds ratio = 3.39, 95% confidence interval = 2.46 to 4.68) increased risk of breast cancer compared with women with lower breast density (<10%). The associations between breast density and breast cancer risk were stronger for in situ compared with invasive tumors (Pheterogeneity < .01), high-grade compared with low-grade tumors (Pheterogeneity = .02), larger (>2 cm) compared with smaller (≤2 cm) tumors (Pheterogeneity < .01), and estrogen receptor–negative compared with estrogen receptor–positive tumors (Pheterogeneity = .04). There were no differences in associations by tumor histology, involvement of lymph nodes, and progesterone receptor and HER2 status (Pheterogeneity > .05). Conclusions The findings suggest that higher mammographic density is associated with more aggressive tumor characteristics and also with in situ tumors. [ABSTRACT FROM PUBLISHER]

The Wilcoxon rank sum test is widely used for two-group comparisons of nonnormal data. An assumption of this test is independence of sampling units both within and between groups, which will be violated in the clustered data setting such as in ophthalmological clinical trials, where the unit of randomization is the subject, but the unit of analysis is the individual eye. For this purpose, we have proposed the clustered Wilcoxon test to account for clustering among multiple subunits within the same cluster (, Biometrics , 1089-1098; 2006, Biometrics , 1251-1259). However, power estimation is needed to plan studies that use this analytic approach. We have recently published methods for estimating power and sample size for the ordinary Wilcoxon rank sum test (, Biometrics , 188-197). In this article we present extensions of this approach to estimate power for the clustered Wilcoxon test. Simulation studies show a good agreement between estimated and empirical power. These methods are illustrated with examples from randomized trials in ophthalmology. Enhanced power is achieved with use of the subunit as the unit of analysis instead of the cluster using the ordinary Wilcoxon rank sum test. [ABSTRACT FROM AUTHOR]

Few studies have examined multiple risk factors for mortality or formally compared their associations across specific causes of death. The authors used competing risks survival analysis to evaluate associations of lifestyle and dietary factors with all-cause and cause-specific mortality among 50,112 participants in the Nurses’ Health Study. There were 4,893 deaths between 1986 and 2004: 1,026 from cardiovascular disease, 931 from smoking-related cancers, 1,430 from cancers not related to smoking, and 1,506 from all other causes. Age, body mass index at age 18 years, weight change, height, current smoking and pack-years of smoking, glycemic load, cholesterol intake, systolic blood pressure and use of blood pressure medications, diabetes, parental myocardial infarction before age 60 years, and time since menopause were directly related to all-cause mortality, whereas there were inverse associations for physical activity and intakes of nuts, polyunsaturated fat, and cereal fiber. Moderate alcohol consumption was associated with decreased mortality. A model that incorporated differences in the associations of some risk factors with specific causes of death had a significantly better fit compared with a model in which all risk factors had common associations across all causes. In the future, this new model may be used to identify individuals at increased risk of mortality. [ABSTRACT FROM PUBLISHER]

Previous epidemiologic studies suggest that the major histologic subtypes of epithelial ovarian cancer may have different risk factor profiles; however, no known prospective study has systematically examined differences in risk by subtype. The authors used Cox proportional hazards regression, stratified by histologic subtype and time period, to examine the association between ovarian cancer risk factors and incidence of serous invasive, endometrioid, and mucinous ovarian cancers in the US Nurses’ Health Study (1976–2006) and Nurses’ Health Study II (1989–2005). For each exposure, they calculated P-heterogeneity using a likelihood ratio test comparing models with separate estimates for the 3 subtypes versus a single estimate across subtypes. Analysis included 221,866 women and 721 cases with the histologies of interest (496 serous invasive, 139 endometrioid, 86 mucinous). In analyses of reproductive/hormonal exposures, the associations with age, duration of breastfeeding, age at natural menopause, and duration of estrogen use differed significantly by subtype (all P-heterogeneity ≤0.05). The associations with several nonreproductive exposures also appeared to vary by subtype, but only the association with smoking differed significantly (P-heterogeneity = 0.03). Results suggest that associations with several ovarian cancer risk factors vary by subtype, and these differences are consistent with known similarities between each major histologic subtype and its normal tissue counterpart. [ABSTRACT FROM PUBLISHER]

Few studies have evaluated the validity of adolescent diet recall after many decades. Between 1943 and 1970, yearly diet records were completed by parents of adolescents participating in an ongoing US study. In 2005–2006, study participants who had been 13–18 years of age when the diet records were collected were asked to complete a food frequency questionnaire regarding their adolescent diet. Food frequency questionnaires and diet records were available for 72 participants. The authors calculated Spearman correlation coefficients between food, food group, and nutrient intakes from the diet records and food frequency questionnaire and deattenuated them to account for the effects of within-person variation measured in the diet records on the association. The median deattenuated correlation for foods was 0.30, ranging from −0.53 for a beef, pork, or lamb sandwich to 0.99 for diet soda. The median deattenuated correlation for food groups was 0.31 (range: −0.48 for breads to 0.70 for hot beverages); for nutrient intakes, it was 0.25 (range: −0.08 for iron to 0.82 for vitamin B12). Some dietary factors were reasonably recalled 3–6 decades later. However, this food frequency questionnaire did not validly measure overall adolescent diet when completed by middle-aged and older adults on average 48 years after adolescence. [ABSTRACT FROM PUBLISHER]

Screening mammography can distort estimated effects in breast cancer risk models due to associations with other risk factors. Mammography information was available in the Nurses’ Health Study from 1988, and 1,815 incident breast cancers were accrued through 2000 among 55,625 women with risk factor data. Logistic models were fit for screening mammography, and inverse probability weighting was used to adjust parameters in an established breast cancer risk model. Approximately 80% of women in each 2-year follow-up period had screening mammograms, which were positively associated with history of benign breast disease, family history of breast cancer, hormone therapy, alcohol use, physical activity, multivitamins, and calcium supplements, and negatively associated with postmenopause, current smoking, and body mass index. Markers of medical attention, including hypertension, high cholesterol, and osteoarthritis, were positively associated, while cardiovascular disease was negative. Inverse probability weighting led to small changes in effects of benign breast disease, family history, and hormone therapy. An apparent reduced risk associated with current smoking in unadjusted models was eliminated after weighting. Thus, several risk factors for breast cancer and cancer diagnosis are associated with mammographic screening. Adjustment for screening had some impact on breast cancer prediction in this cohort, especially for hormone therapy and smoking. [ABSTRACT FROM PUBLISHER]