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We aimed to examine the association between the use of metformin and other anti‐diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994–2016) and the NHSII (1995–2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti‐diabetes medications, and other covariates was self‐reported at baseline and repeatedly assessed by follow‐up questionnaires every 2 years. Breast cancer cases were self‐reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person‐years of follow‐up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81–1.15) nor other anti‐diabetic medications use (HR = 1.11; 95% CI = 0.90–1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74–1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48–0.94), current use (HR = 1.01; 95% CI = 0.80–1.27) and longer duration of metformin use were not associated with breast cancer (each 2‐year interval: HR = 1.01; 95% CI = 0.95–1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the role of low‐carbohydrate diets after breast cancer diagnosis in relation to breast cancer–specific and all‐cause mortality. Methods: For 9621 women with stage I–III breast cancer from two ongoing cohort studies, the Nurses' Health Study and Nurses' Health Study II, overall low‐carbohydrate, animal‐rich low‐carbohydrate, and plant‐rich low‐carbohydrate diet scores were calculated by using food frequency questionnaires collected after breast cancer diagnosis. Results: Participants were followed up for a median 12.4 years after breast cancer diagnosis. We documented 1269 deaths due to breast cancer and 3850 all‐cause deaths. With the use of Cox proportional hazards regression and after controlling for potential confounding variables, we observed a significantly lower risk of overall mortality among women with breast cancer who had greater adherence to overall low‐carbohydrate diets (hazard ratio for quintile 5 vs. quintile 1 [HRQ5vsQ1], 0.82; 95% CI, 0.74–0.91; ptrend =.0001) and plant‐rich low‐carbohydrate diets (HRQ5vsQ1, 0.73; 95% CI, 0.66–0.82; ptrend <.0001) after breast cancer diagnosis but not animal‐rich low‐carbohydrate diets (HRQ5vsQ1, 0.93; 95% CI, 0.84–1.04; ptrend =.23). However, greater adherence to overall, animal‐rich, or plant‐rich low‐carbohydrate diets was not significantly associated with a lower risk of breast cancer–specific mortality. Conclusions: This study showed that greater adherence to low‐carbohydrate diets, especially plant‐rich low‐carbohydrate diets, was associated with better overall survival but not breast cancer–specific survival among women with stage I–III breast cancer. Greater adherence to low‐carbohydrate diets, especially plant‐rich low‐carbohydrate diets, was associated with better overall survival but not breast cancer–specific survival among women with stage I–III breast cancer. [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]

In 2022, more than 100 000 non‐Hodgkin lymphoma (NHL) diagnoses are expected, yet few risk factors are confirmed. In this study, data from six US‐based cohorts (568 717 individuals) were used to examine body size and risk of NHL. Over more than 20 years of follow‐up, 11 263 NHLs were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) estimated associations with NHLs for adult body mass index (BMI), height, weight change, waist circumference and predicted fat mass. Adult height was broadly associated with NHL, but most strongly with B‐cell NHLs among non‐White participants (e.g. HRBLACK = 2.06, 95% CI: 1.62–2.62). However, the strongest association among the anthropometric traits examined was for young adult BMI and risk of diffuse large B‐cell lymphoma (DLBCL), particularly those who maintained a higher BMI into later adulthood. Individuals with BMI over 30 kg/m2 throughout adulthood had more than double the DLBCL risk (HR = 2.67, 95% CI: 1.71–4.17) compared to BMI 18.5–22.9 kg/m2. Other anthropometric traits were not associated with NHL after controlling for BMI. These results suggest that sustained high BMI is a major driver of DLBCL risk. If confirmed, we estimate that up to 23.5% of all DLBCLs (and 11.1% of all NHLs) may be prevented with avoidance of young adult obesity. [ABSTRACT FROM AUTHOR]

Purpose: Metabolomic and preclinical studies suggest that branched‐chain amino acids (BCAA) may be inversely associated with neurodegenerative diseases including glaucoma. We therefore assessed the long‐term association between dietary intake of BCAA and incident primary open‐angle glaucoma (POAG) and POAG subtypes. Methods: We followed biennially participants of the Nurses' Health Study (NHS; 65 531 women: 1984–2016), Health Professionals Follow‐up Study (42 254 men: 1986–2016) and NHSII (66 904 women; 1991–2017). Eligible participants were 40+ years old and reported eye examinations. Repeated validated food frequency questionnaires were used to assess dietary intake of BCAA. Incident cases of POAG and POAG subtypes defined by visual field (VF) loss and untreated intraocular pressure (IOP) were confirmed by medical record review. Multivariable‐adjusted relative risks (MVRRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Results: We identified 1946 incident POAG cases. The pooled MVRRs of POAG for the highest quintile (Q5 = 17.1 g/day) versus lowest quintile (Q1 = 11.2 g/day) of total BCAA intake was 0.93 (95% CI, 0.73–1.19; ptrend = 0.45; pheterogeneity by sex = 0.24). For subtypes of POAG defined by IOP level or POAG with only peripheral VF loss, no associations were observed for men or women (ptrend ≥ 0.20); however, for the POAG subtype with early paracentral VF loss, there was a suggestion of an inverse association in women (MVRRQ5versusQ1 = 0.80 [95% CI, 0.57–1.12; ptrend = 0.12]) but not in men (MVRRQ5versusQ1 = 1.38 [95% CI, 0.81–2.34; ptrend = 0.28; pheterogeneity by sex = 0.06]). Conclusion: Higher dietary intake of BCAA was not associated with POAG risk. [ABSTRACT FROM AUTHOR]

Background: The activation of insulin pathways is hypothesized to promote tumor growth and worsen breast cancer survival. Sugar‐sweetened beverages (SSBs) can lead to a higher risk of insulin resistance and may affect survival. The authors prospectively evaluated the relation of postdiagnostic SSB and artificially sweetened beverage (ASB) consumption with mortality among women with breast cancer. Methods: In total, 8863 women with stage I through III breast cancer were identified during follow‐up of the Nurses' Health Study (NHS; 1980‐2010) and Nurses' Health Study II (NHSII; 1991‐2011). Women completed a validated food frequency questionnaire every 4 years after diagnosis and were followed until death or the end of follow‐up (2014 for the NHS and 2015 for the NHSII). Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer‐specific and all‐cause mortality after adjusting for measures of adiposity and other potential predictors of cancer survival. Results: With a median follow‐up of 11.5 years, 2482 deaths were prospectively documented, including 1050 deaths from breast cancer. Compared with women who had no consumption, women who had SSB consumption after diagnosis had higher breast cancer‐specific mortality (>1 to 3 servings per week: HR, 1.31 [95% CI, 1.09‐1.58]; >3 servings per week: HR, 1.35 [95% CI, 1.12‐1.62]; Ptrend =.001) and all‐cause mortality (>1 to 3 servings per week: HR, 1.21 [95% CI, 1.07‐1.37]; >3 servings per week: HR, 1.28 [95% CI, 1.13‐1.45]; Ptrend =.0001). In contrast, ASB consumption was not associated with higher breast cancer‐specific or all‐cause mortality. Furthermore, replacing 1 serving per day of SSB consumption with 1 serving per day of ASB consumption was not associated with a lower risk of mortality. Conclusions: Higher postdiagnostic SSB consumption among breast cancer survivors was associated with higher breast cancer‐specific mortality and death from all causes. High consumption of sugar‐sweetened beverages after diagnosis may be associated with an increased risk of mortality from breast cancer and all causes among women with nonmetastatic breast cancer. The current findings indicate that it is prudent for practitioners and public health officials to promote limiting or eliminating sugar‐sweetened beverage consumption to reduce breast cancer mortality in the United States and worldwide. [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]

Objective: National initiatives and funding agencies may deprioritize voice disorders relative to conditions such as malignancy, pulmonary, or cardiac disease. It is unknown whether the impact of voice problems is outweighed by other potentially more serious disease states. Our objective was thus to quantify the extent to which voice contributes to general health status when adjusting for concurrent, more life-threatening comorbidities.Methods: Adults (n = 430) presenting to a tertiary care academic center with a primary voice complaint completed the Voice Handicap Index-10 (VHI-10) and the Patient-Reported Outcomes Measurement Information System global health short-form instrument (PROMIS). Medical comorbidities were categorized via the Deyo modification of the Charlson Comorbidity Index. The influence of voice and comorbid conditions on general health scores was assessed through multivariate ordinal regression. The potential for effect modification was also evaluated.Results: VHI-10 mean scores were 11.4 (95% confidence interval [CI], 10.5 to 12.4). PROMIS physical and mental health t scores were 49.0 (95% CI, 48.0 to 49.9) and 51.6 (95% CI, 50.6 to 52.5), respectively. Global and social item scores were 3.4 (95% CI, 3.3 to 3.5) and 3.7 (95% CI, 3.6 to 3.8), respectively. The most prevalent comorbid conditions were pulmonary disease, malignancy, and connective tissue disorders. In all analyses, voice handicap was a significant predictor of general health, even when adjusting for comorbid conditions (VHI-10 β = -1.349, P < 0.001 for physical health; β = -1.278, P < 0.001 for mental health; β = -1.691, P < 0.001 for social health; β = -0.956, P < 0.001 for the global overview item).Conclusion: In the observed population, voice health has a significant, multi-dimensional impact on general health, which is not subsumed by the presence of comorbidities.Level Of Evidence: 4 Laryngoscope, 130:2405-2411, 2020. [ABSTRACT FROM AUTHOR]

Inflammation and endogenous growth factors are important in multiple myeloma (MM) pathogenesis. Although diets that modulate these biologic pathways may influence MM patient survival, studies have not examined the association of dietary patterns with MM survival. We conducted pooled prospective survival analyses of 423 MM patients from the Nurses' Health Study (1986–2016) and the Health Professionals Follow‐up Study (1988–2016) using Cox regression models. We used data from repeated food frequency questionnaires (FFQ) to compute dietary patterns as of the last prediagnosis FFQ, including the Alternate Healthy Eating Index (AHEI)‐2010, alternate Mediterranean Diet, Dietary Approaches to Stop Hypertension, Prudent, Western and empirical dietary inflammatory patterns and empirical dietary indices for insulin resistance and hyperinsulinemia. During follow‐up, we documented 295 MM‐related deaths among 345 total deaths. MM‐specific mortality was 15–24% lower per one standard deviation (SD) increase (e.g., toward healthier habits) in favorable dietary pattern scores. For example, the multivariable‐adjusted hazard ratio [HR] and 95% confidence interval [CI] per 1‐SD increase in AHEI‐2010 score were 0.76, 0.67–0.87 (p < 0.001). In contrast, MM‐specific mortality was 16–24% higher per 1‐SD increase (e.g., toward less healthy habits) in "unhealthy" diet scores; for example, the multivariable‐adjusted HR, 95% CI per 1‐SD increase in Western pattern score were 1.24, 1.07–1.44 (p = 0.005). Associations were similar for all‐cause mortality. In conclusion, our consistent findings for multiple dietary patterns provide the first evidence that MM patients with healthier prediagnosis dietary habits may have longer survival than those with less healthy diets. What's new? Few previous studies have focused on non‐clinical factors that may influence survival of patients with multiple myeloma. This study included 423 multiple myeloma patients from two large cohort studies with diet data collected prior to diagnosis. Patients with healthier prediagnosis dietary habits, including diets previously associated with reduced inflammation and insulin resistance (which play a role in multiple myeloma), had lower multiple myeloma‐specific mortality and lower overall mortality. [ABSTRACT FROM AUTHOR]

Background: The anti-inflammatory effect associated with flavonoids containing foods and beverages could potentially impact the risk of periodontal disease. We prospectively investigate the associations between habitual flavonoid intake and incidence of periodontitis.Methods: The study population was 34,940 men from the Health Professionals Follow-Up Study, who were healthy and free of periodontal disease at baseline (1986). Participants in the study provided medical and dental history through mailed questionnaires biennially, and provided dietary data through semi-quantitative food frequency questionnaires every 4 years. We examined the associations between total flavonoids and six flavonoid subclasses (flavonoid polymers, anthocyanins, flavan-3-ols, flavanones, flavones, and flavonols) and incidence of periodontitis using Cox proportional hazard models. We adjusted for age, smoking, body mass index, physical activity, alcohol consumption, Alternative Healthy Eating Index, and diabetes.Results: There was no association between total flavonoids and the risk of periodontitis. The hazard ratio comparing the highest quintile of total flavonoid to the lowest quintile was 0.97 (95% confidence interval: 0.87 to 1.08, P-value for trend = 0.61). Similar comparisons for flavonoids subclasses also did not show significant associations.Conclusion: No association was detected between habitual flavonoid intake and risk of periodontitis in the study population. [ABSTRACT FROM AUTHOR]

Standard methods for two-sample tests such as the t-test and Wilcoxon rank sum test may lead to incorrect type I errors when applied to longitudinal or clustered data. Recent alternatives of two-sample tests for clustered data often require certain assumptions on the correlation structure and/or noninformative cluster size. In this paper, based on a novel pseudolikelihood for correlated data, we propose a score test without knowledge of the correlation structure or assuming data missingness at random. The proposed score test can capture differences in the mean and variance between two groups simultaneously. We use projection theory to derive the limiting distribution of the test statistic, in which the covariance matrix can be empirically estimated. We conduct simulation studies to evaluate the proposed test and compare it with existing methods. To illustrate the usefulness proposed test, we use it to compare self-reported weight loss data in a friends' referral group, with the data from the Internet self-joining group. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to investigate the association between BMI, waist circumference, and vertebral fracture (VF) risk in women.Methods: This prospective study was conducted in 54,934 Nurses' Health Study participants. BMI was assessed biennially, and waist circumference was assessed in the year 2000. Self-reports of VF were confirmed by record review. BMI reflects lean body mass, and waist circumference reflects abdominal adiposity when included in the same regression model.Results: This study included 536 VF cases (2002 to 2014). Compared with women with BMI of 21.0 to 24.9 kg/m2 , the multivariable-adjusted relative risk (RR) of VF for women with BMI ≥ 32.0 was 0.84 (95% CI: 0.61-1.14; Ptrend  = 0.08). After further adjustment for waist circumference, the multivariable-adjusted RR of VF for women with BMI ≥ 32.0 was 0.70 (95% CI: 0.49-0.98; Ptrend  = 0.003). Compared with women with waist circumference < 71.0 cm, the multivariable-adjusted RR of VF for women with waist circumference ≥ 108.0 cm was 1.76 (95% CI: 1.06-2.92; Ptrend  = 0.01), and after further adjustment for BMI, the multivariable-adjusted RR of VF was 2.49 (95% CI: 1.44-4.33; Ptrend  < 0.001).Conclusions: Greater lean body mass was independently associated with lower VF risk. Larger waist circumference was independently associated with higher VF risk. These findings suggest that fat distribution is an important predictor of VF and that avoiding central adiposity, as well as maintaining muscle mass, may potentially confer reduced risk of VF in older women. [ABSTRACT FROM AUTHOR]

Inflammation and hyperinsulinemia may drive associations between adiposity and colorectal cancer (CRC) risk, but few studies have examined this hypothesis using mediation analysis. We used inverse odds ratio weighting and logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for estimated total effects (ORTE) of body mass index, waist circumference, and adult weight gain on CRC risk, and estimated effects operating through seven inflammatory and metabolic biomarkers (natural indirect effect; ORNIE) or through paths independent of these biomarkers (natural direct effect; ORNDE) among 209 CRC cases and 382 matched controls nested within the Health Professionals Follow‐up Study, a prospective cohort of male health professionals. A one‐interquartile range (IQR) increase in body mass index (3.6 kg/m2) was associated with an ORTE of 1.40 (95% CI: 1.13, 1.73), which decomposed into an ORNIE of 1.26 (95% CI: 0.97, 1.52) and an ORNDE of 1.11 (0.87, 1.42), with possibly stronger mediation by these biomarkers for adult weight gain (IQR = 10.4 kg; ORTE = 1.32 [95% CI: 1.06, 1.64]; ORNIE = 1.47 [95% CI: 1.01, 1.81]; ORNDE = 0.89 [95% CI: 0.72, 1.11]), but no mediation for waist circumference. Mediation appeared to be stronger for the metabolic biomarkers than the inflammatory biomarkers. Inflammatory and metabolic mechanisms may mediate associations between both body mass index and adult weight gain with CRC risk. What's new? Adiposity is one of the strongest and most consistent modifiable risk factors for colorectal cancer. Adiposity also affects insulin resistance and is associated with low‐grade chronic inflammation ‐‐ both of which have been suggested as possible mechanisms for associations between adiposity and colorectal cancer risk. Using a novel mediation analysis method, here the authors demonstrate that metabolic and inflammatory biomarkers may jointly mediate associations between both BMI and adult weight gain with colorectal cancer risk in men, with stronger results for metabolic biomarkers. The findings offer mechanistic and methodologic insights into the underlying biology of adiposity and colorectal cancer risk. [ABSTRACT FROM AUTHOR]

Pooling data from multiple studies improves estimation of exposure-disease associations through increased sample size. However, biomarker exposure measurements can vary substantially across laboratories and often require calibration to a reference assay prior to pooling. We develop two statistical methods for aggregating biomarker data from multiple studies: the full calibration method and the internalized method. The full calibration method calibrates all biomarker measurements regardless of the availability of reference laboratory measurements while the internalized method calibrates only non-reference laboratory measurements. We compare the performance of these two aggregation methods to two-stage methods. Furthermore, we compare the aggregated and two-stage methods when estimating the calibration curve from controls only or from a random sample of individuals from the study cohort. Our findings include the following: (1) Under random sampling for calibration, exposure effect estimates from the internalized method have a smaller mean squared error than those from the full calibration method. (2) Under the controls-only calibration design, the full calibration method yields effect estimates with the least bias. (3) The two-stage approaches produce average effect estimates that are similar to the full calibration method under a controls only calibration design and the internalized method under a random sample calibration design. We illustrate the methods in an application evaluating the relationship between circulating vitamin D levels and stroke risk in a pooling project of cohort studies. [ABSTRACT FROM AUTHOR]

Prior epidemiologic findings for plasma folate and B‐vitamins and breast cancer risk are inconsistent and have not assessed the influence of folic acid fortification. Therefore, we examined the associations of plasma folate, B12, pyridoxal 5′‐phosphate (PLP), homocysteine, cysteine and cysteinylglycine with breast cancer risk, before and after fortification. We conducted a nested case–control study within the prospective Nurses' Health Study. In 1989–1990 (pre‐fortification), 32,826 women donated a blood sample and 18,743 donated an additional blood sample in 2000–2001 (post‐fortification). Between the first blood collection and 2006, 1874 incident breast cancer cases with at least one blood sample and 367 with two were 1:1 matched to controls. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) adjusting for breast cancer risk factors. Overall, higher plasma folate, B12, PLP, homocysteine, cysteine and cysteinylglycine levels were not associated with breast cancer risk. Associations did not vary by in situ/invasive, hormone receptor status, or tumor molecular subtype. Additionally, associations were null before and after fortification. For example, the RR (95% CI) for the highest versus lowest tertile of 1990 (pre‐fortification) plasma folate with 1990–2000 follow‐up was 0.93 (0.75–1.16) and for the 2000 plasma folate (post‐fortification) with 2000–2006 follow‐up the RR (95% CI) was 1.17 (0.79–1.74). Plasma folate, B12, PLP, homocysteine, cysteine and cysteinylglycine were not significantly associated with breast cancer overall, before and after fortification, or with specific tumor molecular subtypes. However, long term associations (>8 years) after the implementation of fortification could not be examined. What's new? With concerns of increased cancer risk, there has been discussion as to whether countries should implement folic acid fortification programs. However, few prospective studies have examined plasma folate and other B‐vitamins levels and breast cancer risk among populations whose food is fortified with folic acid. This study examines the association of plasma folate and other B‐vitamins on breast cancer risk, prior to and after mandatory folic acid fortification of grain products in the U.S. Plasma folate, B12, PLP, homocysteine, cysteine, and cysteinylglycine were not significantly associated with breast cancer overall, before and after fortification, or with specific tumor molecular subtypes. [ABSTRACT FROM AUTHOR]

We evaluated the relation of fruit and vegetable consumption, including specific fruits and vegetables, with incident breast cancer characterized by menopausal status, hormone receptor status and molecular subtypes. Fruit and vegetable consumption, cumulatively averaged across repeated, validated questionnaires, was examined in relation to risk of invasive breast cancer among 182,145 women initially aged 27–59 years in the Nurses' Health Study (NHS, 1980–2012) and NHSII (1991–2013). Cox proportional hazards regression, adjusted for known risk factors, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and assessed tumors by hormone receptor status and molecular subtypes. We prospectively documented 10,911 invasive breast cancer cases. Greater intake of total fruits and vegetables, especially cruciferous and yellow/orange vegetables, was associated with significantly lower breast cancer risk (>5.5 vs. ≤2.5 servings/day HR = 0.89, 95% CI = 0.83–0.96; ptrend = 0.006). Intake of total vegetables was especially associated with lower risk of estrogen receptor negative tumors (HR per 2 additional servings/day as a continuous variable = 0.84, 95%CI = 0.77–0.93; pheterogeneity = 0.02). Among molecular subtypes, higher intake of total fruits and vegetables (HR per 2 additional servings/day as a continuous variable) was most strongly associated with lower risk of human epidermal growth factor receptor 2 (HER2)‐enriched (HR = 0.79, 95%CI = 0.67–0.93), basal‐like (HR = 0.84, 95%CI = 0.72–0.97) and luminal A (HR = 0.94, 95%CI = 0.89–0.99), but not with luminal B tumors (pheterogeneity = 0.03). In conclusion, our findings support that higher intake of fruits and vegetables, and specifically cruciferous and yellow/orange vegetables, may reduce the risk of breast cancer, especially those that are more likely to be aggressive tumors. What's new? Fruits and vegetables are rich in potentially anti‐carcinogenic nutrients including fiber, vitamins C and E, carotenoids, and other bioactive substances. However, many studies found no association between fruit and vegetable consumption and risk of breast cancer. In this analysis based on two large prospective cohorts, the authors found that higher total fruit and vegetable consumption during adulthood was associated with a modest, statistically significant lower invasive breast cancer incidence, with the strongest associations for ER‐negative, HER2‐enriched and basal‐like tumors. Higher intake of fruits and vegetables, and specifically cruciferous and yellow/orange vegetables, may reduce the risk of breast cancer, especially aggressive tumors. [ABSTRACT FROM AUTHOR]

Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non‐Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre‐diagnosis red blood cell (RBC) specimens in the Nurses’ Health Study (NHS) and Health Professionals Follow‐Up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T‐NHL), B cell NHL (B‐NHL) and three individual B‐NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B‐NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0 and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T‐NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B‐NHLs other than CLL/SLL and for VLCSFA and MUFA with T‐NHL suggest an influence of fatty acid metabolism on lymphomagenesis. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association between flavonoid intake and incident primary open‐angle glaucoma (POAG). Methods: We followed 65 516 women from the Nurses' Health Study (from 1984) and 42 156 men from the Health Professionals Follow‐up Study (from 1986) biennially to 2012, who were 40+ years old, free of POAG, and reported eye examinations. Dietary flavonoid intake was assessed with validated repeated semi‐quantitative food frequency questionnaires. Incident POAG cases (n = 1575) were confirmed with medical record review. Cohort‐specific multivariable‐adjusted relative risks (RRs) and 95% confidence intervals (CIs) were calculated and meta‐analysed. Results: Total flavonoid intake was not associated with risk of POAG development [RR for highest (Q5: median ~645 mg/day) versus lowest quintile (Q1: ~130 mg/day) = 0.91 (95% CI = 0.77, 1.08); p for trend (p‐trend) = 0.19]; the flavonoid subclasses of flavones, flavanones, polymeric flavanols or anthocyanidins were also not associated (Q5 versus Q1 comparison p‐values ≥0.05 and p‐trend ≥0.09). Higher intakes of flavonols and monomeric flavanols were nominally associated with lower POAG risk, based on the Q5 versus Q1 comparisons or p‐trends. The Q5 versus Q1 comparison RRs were: for flavonols, 0.82 (95% CI = 0.69, 0.97; p‐trend = 0.05; ~28 versus ~8 mg/day), and for monomeric flavanols, 0.86 (95% CI = 0.72, 1.02; p‐trend=0.04; ~110 versus 10 mg/day). The food/beverage that contributed most to both the variation of flavonols and monomeric flavanols was tea; consuming ~2 cups/day was associated with 18% lower POAG risk (RR=0.82; 95% CI = 0.68, 0.99; p‐trend = 0.02). Conclusion: Total flavonoid intake was not associated with POAG risk. Greater intakes of flavonols and monomeric flavanols and of tea showed suggestive modest associations with lower risk; these results need confirmation. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate associations between maternal history of rotating night shift nursing work before pregnancy and number of night shifts worked during pregnancy with offspring weight outcomes from early life through adolescence.Methods: More than 4,000 children, enrolled in the second phase of the Growing Up Today Study between 2004 and 2013, and their mothers participating in the Nurses' Health Study II were included in our analyses.Results: Children of women with and without a history of rotating night shift work before pregnancy were similar in birth weight and body size at age 5. However, for mothers with night shift work before pregnancy, their children had a modestly elevated risk of having overweight or obesity (relative risk = 1.11; 95% CI: 1.02-1.21), which was stronger for persistently having overweight or obesity during adolescence and early adulthood. Longer duration of rotating night shift work was not associated with any of these weight outcomes. Weight outcomes of children of women with versus without night shift work during pregnancy were similar, regardless of frequency of night shifts worked during pregnancy (all P > 0.09).Conclusions: Overall, nurses' night shift work before or during pregnancy did not affect offspring weight outcomes. Future larger studies should explore these associations in more detail. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa is one of the most common forms of inherited retinal degeneration. The electroretinogram (ERG) can be used to determine the severity of retinitis pigmentosa-the lower the ERG amplitude, the more severe the disease is. In practice for career, lifestyle, and treatment counseling, it is of interest to predict the ERG amplitude of a patient at a future time. One approach is prediction based on the average rate of decline for individual patients. However, there is considerable variation both in initial amplitude and in rate of decline. In this article, we propose an empirical Bayes (EB) approach to incorporate the variations in initial amplitude and rate of decline for the prediction of ERG amplitude at the individual level. We applied the EB method to a collection of ERGs from 898 patients with 3 or more visits over 5 or more years of follow-up tested in the Berman-Gund Laboratory and observed that the predicted values at the last (kth) visit obtained by using the proposed method based on data for the first k-1 visits are highly correlated with the observed values at the kth visit (Spearman correlation =0.93) and have a higher correlation with the observed values than those obtained based on either the population average decline rate or those obtained based on the individual decline rate. The mean square errors for predicted values obtained by the EB method are also smaller than those predicted by the other methods. [ABSTRACT FROM AUTHOR]

Background: Depression frequently co-occurs with cognitive decline, but the nature of this association is unclear. We examined relations of late-life depressive symptom patterns to subsequent domain-specific cognitive changes.Methods: Depressive symptoms were measured at up to 3 timepoints among 11,675 Nurses' Health Study participants prior to cognitive testing. Depressive symptom patterns were categorized as non-depressed, variable or persistent, based on published severity cutpoints. Outcomes were global, verbal, and executive function-attention composite scores.Results: Participants with persistent depressive symptoms had worse executive function-attention decline compared with non-depressed participants (multivariable-adjusted mean difference = -0.03 units/year, 95% CI: -0.05, -0.01; p = 0.003); this difference was comparable with 8 years of aging. However, being in the persistent versus non-depressed group was not significantly related to verbal (p = 0.71) or global score (p = 0.09) decline. By contrast, compared with the non-depressed group, those with variable depressive symptoms had worse verbal memory decline (multivariable-adjusted mean difference = -0.01 units/year, 95% CI: -0.02, -0.002; p = 0.03); this group showed no differences for global or executive function-attention decline.Conclusions: A variable pattern of depressive symptom severity related to subsequent decline in verbal memory, while a persistent pattern related to decline in executive function-attention. Findings could signal differences in underlying neuropathologic processes among persons with differing depression patterns and late-life cognitive decline. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: Piriformis syndrome is entrapment of the sciatic nerve by the piriformis muscle.Methods: In this article we describe a 56-person randomized, double-blind, controlled study involving physical therapy and incobotulinum toxin A or placebo. Inclusion criteria were 3-SD delay of posterior tibial (PT) or fibular (FN) H-reflexes on flexion, adduction, and internal rotation (FAIR) testing, and normal paraspinal electromyographic findings. Outcome measures included adverse side effects, visual analog scale (VAS) findings, and H-reflex delay on the FAIR test.Results: Mean intervention VAS score decreased significantly more compared with placebo at 2, 4, 6, 8, 10, and 12 weeks post-injection (P < 0.0001). FAIR test scores for PT, but not FN, decreased significantly more compared with placebo at 2, 4, 6, and 8 weeks post-injection (PT: P = 0.038, 0.003, 0.003, and 0.046). Adverse effects were minimal. VAS slope and PT FAIR test results varied significantly (P < 0.0001).Conclusion: Incobotulinum toxin A chemodenervation may be useful for treating piriformis syndrome as identified by the FAIR test. Muscle Nerve 56: 258-263, 2017. [ABSTRACT FROM AUTHOR]

It is well known that the sample correlation coefficient (Rxy ) is the maximum likelihood estimator of the Pearson correlation (ρxy ) for independent and identically distributed (i.i.d.) bivariate normal data. However, this is not true for ophthalmologic data where X (e.g., visual acuity) and Y (e.g., visual field) are available for each eye and there is positive intraclass correlation for both X and Y in fellow eyes. In this paper, we provide a regression-based approach for obtaining the maximum likelihood estimator of ρxy for clustered data, which can be implemented using standard mixed effects model software. This method is also extended to allow for estimation of partial correlation by controlling both X and Y for a vector U_ of other covariates. In addition, these methods can be extended to allow for estimation of rank correlation for clustered data by (i) converting ranks of both X and Y to the probit scale, (ii) estimating the Pearson correlation between probit scores for X and Y, and (iii) using the relationship between Pearson and rank correlation for bivariate normally distributed data. The validity of the methods in finite-sized samples is supported by simulation studies. Finally, two examples from ophthalmology and analgesic abuse are used to illustrate the methods. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Obesity is a well-established cause of postmenopausal breast cancer. However, early life adiposity is inversely associated with breast cancer incidence. To understand these conflicting relations, we use validated measures to assess adiposity in childhood and late adolescence, as well as weight change, in relation to total invasive breast cancer incidence and receptor subtypes. We conducted a prospective observational study among 74,177 women from the Nurses' Health Study from 1980-2012, with updated risk factors every 2 years during which 4,965 incident invasive breast cancers occurred. Overall, weight at age 18 was inversely associated with both premenopausal (HR per 30 kg = 0.52, 95% CI = 0.39-0.71) and postmenopausal (HR per 30 kg = 0.81, 95% CI = 0.72-0.92) breast cancer which was largely explained by adiposity at age 10. Long-term weight gain from age 18 both during premenopause and postmenopause were positively associated with postmenopausal breast cancer risk. However, premenopausal weight gain was not related to premenopausal breast cancer risk. Furthermore, weight gain since age 18 was positively associated with ER+/PR+ postmenopausal breast cancer (HR per 30 kg = 1.50, 95% CI = 1.36-1.65) but not ER+/PR− (HR per 30 kg = 0.96, 95% CI = 0.78-1.19) or ER−/PR− (HR per 30 kg = 1.16, 95% CI = 0.95-1.42) postmenopausal breast cancer. Overall, 17% of ER+/PR+ postmenopausal breast cancer and 14% of total postmenopausal breast cancer are attributable to weight gain of > 5 kg since age 18. [ABSTRACT FROM AUTHOR]

Breast tissue is particularly susceptible to exposures between menarche and first pregnancy, and a longer interval between these reproductive events is associated with elevated breast cancer risk. Physical activity during this time period may offset breast cancer risk, particularly for those at highest risk with longer menarche-to-first-pregnancy intervals. We used data from 65,576 parous women in the Nurses' Health Study II free of cancer in 1989 (baseline) and recalled their leisure-time physical activity at ages 12-34 in 1997. Current activity was collected at baseline and over follow-up. Relative risks (RRs) were estimated using multivariable Cox proportional hazards regression models. Between 1989 and 2011, 2,069 invasive breast cancer cases were identified. Total recreational activity between menarche and first pregnancy was not significantly associated with the risk of breast cancer. However, physical activity between menarche and first pregnancy was associated with significantly lower breast cancer risk among women in the highest category of a menarche-to first-pregnancy interval (≥20 years; RR for the highest versus the lowest quartile = 0.73, 95% confidence interval = 0.55-0.97; Ptrend = 0.045; Pinteraction = 0.048). This was not observed in women with a shorter interval. Physical activity between menarche and first pregnancy was associated with a lower risk of breast cancer among women with at least 20 years between these reproductive events. This may provide a modifiable factor that women can intervene on to mitigate their breast cancer risk associated with a longer interval. [ABSTRACT FROM AUTHOR]

Introduction We examined the association between endogenous sex hormones and both objective and subjective measures of cognitive function. Methods We followed 3044 women up to 23 years in a prospective cohort study. We measured plasma levels of estrone, estrone sulfate, estradiol, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) in 1989–1990, conducted neuropsychologic testing in 1999–2008, and inquired about subjective cognition in 2012. Results Overall, we observed little relation between plasma levels of hormones and either neuropsychologic test performance or subjective cognition. However, after adjustment for age and education, we observed a borderline significant association of higher levels of plasma estrone with higher scores for both overall cognition ( P trend = .10) and verbal memory ( P trend = .08). Discussion There were no clear associations of endogenous hormone levels at midlife and cognition in later life, although a suggested finding of higher levels of plasma estrone associated with better cognitive function merits further research. [ABSTRACT FROM AUTHOR]

Several intrinsic breast cancer subtypes, possibly representing unique etiologic processes, have been identified by gene expression profiles. Evidence suggests that associations with reproductive risk factors may vary by breast cancer subtype. In the Nurses' Health Studies, we prospectively examined associations of reproductive factors with breast cancer subtypes defined using immunohistochemical staining of tissue microarrays. Multivariate-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over follow-up, we identified 2,063 luminal A, 1,008 luminal B, 209 HER2-enriched, 378 basal-like and 110 unclassified tumors. Many factors appeared associated with luminal A tumors, including ages at menarche ( pheterogeneity = 0.65) and menopause ( pheterogeneity = 0.05), and current HT use ( pheterogeneity = 0.33). Increasing parity was not associated with any subtype ( pheterogeneity = 0.76), though age at first birth was associated with luminal A tumors only (per 1-year increase HR = 1.03 95%CI (1.02-1.05), pheterogeneity = 0.04). Though heterogeneity was not observed, duration of lactation was inversely associated with risk of basal-like tumors only (7+ months vs. never HR = 0.65 95%CI (0.49-0.87), ptrend = 0.02), pheterogeneity = 0.27). Years between menarche and first birth was strongly positively associated with luminal A and non-luminal subtypes ( e.g. 22-year interval vs. nulliparous HR = 1.80, 95%CI (1.08-3.00) for basal-like tumors; pheterogeneity = 0.003), and evidence of effect modification by breastfeeding was observed. In summary, many reproductive risk factors for breast cancer appeared most strongly associated with the luminal A subtype. Our results support previous reports that lactation is protective against basal-like tumors, representing a potential modifiable risk factor for this aggressive subtype. [ABSTRACT FROM AUTHOR]

Alcohol consumption is a consistent risk factor for breast cancer, although it is unclear whether the association varies by breast cancer molecular subtype. We investigated associations between cumulative average alcohol intake and risk of breast cancer by molecular subtype among 105,972 women in the prospective Nurses' Health Study cohort, followed from 1980 to 2006. Breast cancer molecular subtypes were defined according to estrogen receptor (ER), progesterone receptor, human epidermal growth factor 2 (HER2), cytokeratin 5/6, and epidermal growth factor status from immunostained tumor microarrays in combination with histologic grade. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Competing risk analyses were used to assess heterogeneity by subtype. We observed suggestive heterogeneity in associations between alcohol and breast cancer by subtype (phet = 0.06). Alcohol consumers had an increased risk of luminal A breast cancers [n = 1,628 cases, per 10 g/day increment HR (95%CI) = 1.10(1.05-1.15)], and an increased risk that was suggestively stronger for HER2-type breast cancer [n = 160 cases, HR (95%CI) = 1.16(1.02-1.33)]. We did not observe statistically significant associations between alcohol and risk of luminal B [n = 631 cases, HR (95%CI) = 1.08(0.99-1.16)], basal-like [n = 254 cases, HR (95%CI) = 0.90(0.77-1.04)], or unclassified [n = 87 cases, HR (95%CI) = 0.90(0.71-1.14)] breast cancer. Alcohol consumption was associated with increased risk of luminal A and HER2-type breast cancer, but not significantly associated with other subtypes. Given that ERs are expressed in luminal A but not in HER2-type tumors, our findings suggest that other mechanisms may play a role in the association between alcohol and breast cancer. [ABSTRACT FROM AUTHOR]

A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non-neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available. [ABSTRACT FROM AUTHOR]

Objective: To examine associations of chronic insufficient sleep with diet and whether diet explains the sleep-adiposity relationship.Methods: In Project Viva, 1,046 parents reported children's sleep duration at 6 m and annually until midchildhood (7 y). The main exposure was a sleep curtailment score (6 m-7 y) ranging from 0 (maximal curtailment) to 13 (adequate sleep). In mid-childhood, parents reported children's diet; researchers measured height/weight. Multivariable linear regression assessed associations of sleep with diet (Youth Healthy Eating Index [YHEI]); sleep with BMI z-score adjusting for YHEI; and, secondarily, joint associations of sleep and YHEI with BMI.Results: Mean (SD) sleep and YHEI scores were 10.21 (2.71) and 58.76 (10.37). Longer sleep duration was associated with higher YHEI in mid-childhood (0.59 points/unit sleep score; 95% CI: 0.32, 0.86). Although higher YHEI was associated with lower BMI z-score (-0.07 units/10-point increase; 95% CI: -0.13, -0.01), adjustment for YHEI did not attenuate sleep-BMI associations. Children with sleep and YHEI scores below the median (<11 and <60) had BMI z-scores 0.34 units higher (95% CI: 0.16, 0.51) than children with sleep and YHEI scores above the median.Conclusions: While parent-reported diet did not explain inverse associations of sleep with adiposity, both sufficient sleep and high-quality diets are important to obesity prevention. [ABSTRACT FROM AUTHOR]

Assessing risk of colorectal adenoma at first-time colonoscopy that are of higher likelihood of developing advanced neoplasia during surveillance could help tailor first-line colorectal cancer screening. We developed prediction models for high-risk colorectal adenoma (at least one adenoma ≥1 cm, or with advanced histology, or ≥3 adenomas) among 4,881 asymptomatic white men and 17,970 women who underwent colonoscopy as their first-time screening for colorectal cancer in two prospective US studies using logistic regressions. C-statistics and Hosmer-Lemeshow tests were used to evaluate discrimination and calibration. Ten-fold cross-validation was used for internal validation. A total of 330 (6.7%) men and 678 (3.8%) women were diagnosed with high-risk adenoma at first-time screening colonoscopy. The model for men included age, family history of colorectal cancer, BMI, smoking, sitting watching TV/VCR, regular aspirin/NSAID use, physical activity, and a joint term of multivitamin and alcohol. For women, the model included age, family history of colorectal cancer, BMI, smoking, alcohol, beef/pork/lamb as main dish, regular aspirin/NSAID, calcium, and oral contraceptive use. The C-statistic of the model for men was 0.67 and 0.60 for women (0.64 and 0.57 in cross-validation). Both models calibrated well. The predicted risk of high-risk adenoma for men in the top decile was 15.4% vs. 1.8% for men in the bottom decile (Odds Ratio [OR] = 9.41), and 6.6% vs. 2.1% for women (OR = 3.48). In summary, we developed and internally validated an absolute risk assessment tool for high-risk colorectal adenoma among the US population that may provide guidance for first-time colorectal cancer screening. [ABSTRACT FROM AUTHOR]

ABSTRACT This study assessed whether hypertension, a circulating factor, influences local keloid severity. This retrospective cross-sectional study involved 304 consecutive patients (13-78 years old) with keloids who were surgically treated in our hospital between January 2011 and August 2013. Their blood pressure (BP), age and gender, and the size and number of their keloids before surgery were recorded. Ordinal logistic regression analyses showed that BP associated significantly with both keloid size and number (all p < 0.0001). Age also associated with keloid size ( p < 0.0001). However, a Goodness-of-fit chi-square test showed that the prevalence of hypertension was not higher among keloid patients than in the general Japanese population. This study provides epidemiological evidence for the possibility that primary hypertension may aggravate keloids. We propose that the skin, along with the heart and liver, is a target organ of hypertension. The observations of this study, which require validation with large-scale prospective interventional trials, suggest that keloid patients should be screened for hypertension and that antihypertensive treatments may be of prophylactic and therapeutic value for skin fibrosis. [ABSTRACT FROM AUTHOR]

Nutrient intake is often measured with substantial error both in commonly used surrogate instruments such as a food frequency questionnaire (FFQ) and in gold standard-type instruments such as a diet record (DR). If there is a correlated error between the FFQ and DR, then standard measurement error correction methods based on regression calibration can produce biased estimates of the regression coefficient ( λ) of true intake on surrogate intake. However, if a biomarker exists and the error in the biomarker is independent of the error in the FFQ and DR, then the method of triads can be used to obtain unbiased estimates of λ, provided that there are replicate biomarker data on at least a subsample of validation study subjects. Because biomarker measurements are expensive, for a fixed budget, one can use a either design where a large number of subjects have one biomarker measure and only a small subsample is replicated or a design that has a smaller number of subjects and has most or all subjects validated. The purpose of this paper is to optimize the proportion of subjects with replicated biomarker measures, where optimization is with respect to minimizing the variance of [ABSTRACT FROM AUTHOR]

Objective Sales of regular soda were declining, but sales of other sweetened beverages, such as sports drinks, were increasing. Our objective was to determine the prospective associations between sports drinks and body mass index (BMI) gains among adolescents and young adults. Methods 4121 females and 3438 males in the Growing Up Today Study II, aged 9-16 in 2004, from across the United States were followed prospectively. Data were collected by questionnaire in 2004, 2006, 2008, and 2011. Servings per day of various beverages were assessed with a food frequency questionnaire. Results Among the girls, each serving per day of sports drink predicted an increase of 0.3 BMI units (95% confidence interval (CI) CI 0.03-0.54) more than their peers over the next 2-3 years. Among the males, each serving of sports drinks predicted a 0.33 BMI (95% CI 0.09, 0.66) increase. In addition, boys who increased their intake over the 2-3 year interval gained significantly more than their peers during the same time interval. Conclusions Intake of sports drinks predicted larger increases in BMI among both females and males. Our results suggest that school policies focused on obesity prevention should be augmented to restrict sports drinks. [ABSTRACT FROM AUTHOR]

Differentiating ovarian tumors based on developmental pathway may further enhance our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests that some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (New England Case-Control [NECC] Study) and two cohort studies (Nurses' Health Study [NHS]/Nurses' Health Study II [NHSII]) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and nondominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid or clear cell, whereas nondominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis and age were more strongly associated with dominant tumors (rate ratio [RR] = 0.60, 0.83, 1.58 and 1.37, respectively) than nondominant tumors (RR = 1.03, 0.93, 0.84 and 1.14, respectively; p-difference = 0.0001, 0.01, 0.0003 and 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies. [ABSTRACT FROM AUTHOR]

Objective: A study was undertaken to relate dietary fat types to cognitive change in healthy community-based elders. Methods: Among 6,183 older participants in the Women's Health Study, we related intake of major fatty acids (saturated [SFA], monounsaturated [MUFA], total polyunsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years after dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory, and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariate-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake. Results: Higher SFA intake was associated with worse global cognitive ( p for linear trend = 0.008) and verbal memory ( p for linear trend = 0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest versus lowest SFA quintiles; the multivariate-adjusted odds ratio (OR) with 95% confidence interval (CI) was 1.64 (1.04-2.58) for global cognition and 1.65 (1.04-2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive ( p for linear trend < 0.001) and verbal memory ( p for linear trend = 0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31-0.88]) and verbal memory (0.56 [0.34-0.94]). Total fat, PUFA, and trans-fat intakes were not associated with cognitive trajectory. Interpretation: Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, whereas higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging. ANN NEUROL 2012; [ABSTRACT FROM AUTHOR]

BACKGROUND: Breast cancer (BC) patients wonder how their daughters might reduce their risk. The authors investigated childhood/adolescent risk factors for benign breast disease (BBD), a well-documented risk factor for BC, among girls with a family history. METHODS: GUTS (the Growing Up Today Study) includes females, aged 9 to 15 years in 1996, who completed annual questionnaires during 1996 to 2001, then in 2003, 2005, and 2007. Participants provided information regarding alcohol, menarche, height, and body mass index (BMI; kg/m2). Peak height growth velocity (PHV; in./y) was estimated from longitudinal heights. On 2005-2007 surveys, 6888 women (18-27 years old) reported whether they were diagnosed with biopsy-confirmed BBD (n = 67 cases); 6741 women (noncases) reported no BBD. Participants' mothers reported their own biopsy-confirmed BBD and BC, and BC in their sisters and mothers. Stratified by family history, logistic models investigated BBD risk factors. RESULTS: Young women whose mothers or aunts had BC were more likely to be diagnosed with BBD (odds ratio [OR], 2.34; P = .01), as were those with maternal BBD (OR, 1.59; P = .095). Adolescents with BC family history (mother, aunt, grandmother) who consumed alcohol (7 drinks/wk) doubled their BBD risk (OR, 2.28; P = .01), similar to those with maternal BBD (OR, 1.96; P = .02). Girls whose mother or aunt had BC saw their BBD risk elevated with higher PHV (OR, 1.82 [inch/yr]; P = .05). Among girls with no family history, BBD risk appeared to be related to other factors: childhood BMI, adolescent waist circumference, and adult height. CONCLUSIONS: Adolescents with family history may reduce their risk by avoiding alcohol. Separate risk factors were observed among girls with family history versus girls with no family history, possibly reflecting different causes of BC. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D may have a protective role in the etiology of multiple sclerosis (MS), but the effect of gestational vitamin D on adult onset MS has not been studied. Methods: In 2001, 35,794 mothers of participants of the Nurses' Health Study II completed a questionnaire inquiring about their experiences and diet during pregnancy with their nurse daughters. We studied the association of maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy and their daughters' risk of developing MS. Results: MS was diagnosed in 199 women. The relative risk of MS was lower among women born to mothers with high milk or vitamin D intake during pregnancy. The multivariate adjusted rate ratio (RR) of MS was 0.62 (95% confidence interval [CI], 0.40-0.95; p trend = 0.001) for nurses whose mothers consumed 2 to 3 glasses of milk per day compared with those whose mothers consumed <3 glasses per month, and 0.57 (95% CI, 0.35-0.91; p trend = 0.002) for nurses with mothers in the highest quintile of dietary vitamin D intake compared with those in the lowest. The predicted 25(OH)D level in the pregnant mothers was also inversely associated with the risk of MS in their daughters. Comparing extreme quintiles, the adjusted RR was 0.59; (95% CI, 0.37-0.92; p trend = 0.002). Interpretation: Higher maternal milk and vitamin D intake during pregnancy may be associated with a lower risk of developing MS in offspring. ANN NEUROL 2011; [ABSTRACT FROM AUTHOR]

The article discusses research on the development of benign breast disease (BBD) in older girls and the risk of breast cancer in women during childhood and adolescent stage. The Growing Up Today Study in 1996 surveyed female participants aged 9 to 15 years old and monitored their menarche, height, and weight through 2007. Results of the study revealed that BBD risks are most visible to girls with rapid growth, thinner girls, and taller women.

To investigate the associations between antioxidant intake and risk of endometrial cancer, the authors analyzed data from the prospective Nurses' Health Study. From 1980 to 2006, 669 invasive adenocarcinoma cases were identified over 1.3 million person-years of follow-up. Information on dietary intake was collected in 1980 and updated every 2-4 years. Cox proportional hazard models were used to calculate the multivariate relative risks (RR), controlling for total energy and potential risk factors for endometrial cancer. Overall, the authors found no association between intakes of vitamins A, C, E or carotenoids from foods or supplements and cancer risk. The RR and 95% confidence intervals (CI) for the highest vs. lowest quintiles of vitamins A, C, E and total carotenoids were 1.09 (95% CI: 0.85-1.39), 0.98 (95% CI: 0.76-1.25), 1.07 (95% CI: 0.83-1.38) and 1.12 (95% CI: 0.86-1.45), respectively. Similarly, the use of multivitamins or specific vitamins A, C or E supplements was unassociated with risk. In subgroup analyses, several associations seemed to vary by postmenopausal hormone use. Our results suggest that there is no overall association between dietary antioxidant intake or use of antioxidant supplements with risk of endometrial cancer. [ABSTRACT FROM AUTHOR]

The articles presents information on a study which evaluated whether incorporating benign breast diseases (BBD) histologic lesions would improve the discriminatory power of risk classification models in breast cancer. A review of the related literature on BBD is offered. Data analyzed were from the Nurses' Health Study. The findings of the study are presented. It concludes that the clinical utility of BBD model will depend on the consistency of histologic classification of BBD lesions.

Time-to-event data with time-varying covariates pose an interesting challenge for statistical modeling and inference, especially where the data require a regression structure but are not consistent with the proportional hazard assumption. Threshold regression (TR) is a relatively new methodology based on the concept that degradation or deterioration of a subject's health follows a stochastic process and failure occurs when the process first reaches a failure state or threshold (a first-hitting-time). Survival data with time-varying covariates consist of sequential observations on the level of degradation and/or on covariates of the subject, prior to the occurrence of the failure event. Encounters with this type of data structure abound in practical settings for survival analysis and there is a pressing need for simple regression methods to handle the longitudinal aspect of the data. Using a Markov property to decompose a longitudinal record into a series of single records is one strategy for dealing with this type of data. This study looks at the theoretical conditions for which this Markov approach is valid. The approach is called threshold regression with Markov decomposition or Markov TR for short. A number of important special cases, such as data with unevenly spaced time points and competing risks as stopping modes, are discussed. We show that a proportional hazards regression model with time-varying covariates is consistent with the Markov TR model. The Markov TR procedure is illustrated by a case application to a study of lung cancer risk. The procedure is also shown to be consistent with the use of an alternative time scale. Finally, we present the connection of the procedure to the concept of a collapsible survival model. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Several recent studies have evaluated the association between dietary flavonoid intake and ovarian cancer risk, and all reported significant or suggestive inverse associations with certain flavonoids or flavonoid subclasses; however, most of these studies were small to moderate in size. We, therefore, examined this association in a large, population-based case-control study. We calculated intake of 5 common dietary flavonoids (myricetin, kaempferol, quercetin, luteolin, and apigenin), as well as total intake of these flavonoids, for 1,141 cases and 1,183 frequency-matched controls. We used unconditional logistic regression to estimate the relative risk (RR) of ovarian cancer for each quintile of flavonoid intake when compared with the lowest quintile. We did not observe an association between total flavonoid intake and ovarian cancer risk. The multivariable-adjusted RR for the highest versus lowest quintile of total flavonoid intake was 1.06 (95% confidence interval [CI] = 0.78-1.45). In analyses of each individual flavonoid, only intake of apigenin was associated with a borderline significant decrease in risk (RR, highest vs. lowest quintile = 0.79, 95% CI = 0.59-1.06; p-trend = 0.26), and this association was significant after adjustment for intake of the other 4 individual flavonoids (comparable RR = 0.72, 95% CI = 0.53-0.98; p-trend = 0.09). These results provide limited support for an association between flavonoid intake and ovarian cancer risk. However, given the findings of previous studies and the biologic plausibility of this association, additional studies are warranted. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Nutritional exposures are often measured with considerable error in commonly used surrogate instruments such as the food frequency questionnaire (FFQ) (denoted by Q i for the ith subject). The error can be both systematic and random. The diet record (DR) denoted by R i for the ith subject is considered an alloyed gold standard. However, some authors have reported both systematic and random errors with this instrument as well. One goal in measurement error research is to estimate the regression coefficient of T i (true intake for the ith subject) on Q i denoted by λ TQ. If the systematic errors in Q i and R i (denoted by q i and r i) are uncorrelated, then one can obtain an unbiased estimate of λ TQ by λ RQ obtained by regressing R i on Q i. However, if Corr( q i, r i)>0, then λ RQ>λ TQ. In this paper, we propose a method for indirectly estimating λ TQ even in the presence of correlated systematic error based on a longitudinal design where Q i (surrogate measure of dietary intake), R i (a reference measure of dietary intake), and M i (a biomarker) are available on the same subjects at 2 time points. In addition, between-person variation in mean levels of M i among people with the same dietary intake is also accounted for. The methodology is illustrated for dietary vitamin C intake based on longitudinal data from 323 subjects in the European Prospective Investigation of Cancer (EPIC)-Norfolk study who provided two measures of dietary vitamin C intake from the FFQ ( Q i) and a 7-day DR ( R i) and plasma vitamin C ( M i) 4 years apart. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]