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1.  Reproducibility of metabolomic profiles among men and women in two large cohort studies 
Clinical chemistry  2013;59(11):10.1373/clinchem.2012.199133.
Rigorous studies are necessary to demonstrate suitability of metabolomics platforms to profile metabolites in archived plasma within epidemiologic studies of human disease, for which attenuation of effect estimates due to measurement error is a key concern.
Using a liquid chromatography-tandem mass spectrometry platform, we quantified 257 metabolites from archived plasma to evaluate metabolite inter-assay reproducibility, reproducibility with delayed processing, and within-person reproducibility over time. Inter-assay reproducibility was assessed with coefficients of variation (CVs) from 60 duplicate plasma samples donated by Nurses’ Health Study and Health Professionals Follow-up Study participants, and 20 quality control pool plasma replicates. Metabolite reproducibility over a 24- to 48-hour processing delay (n=48 samples) and within-person reproducibility over 1-2 years (n=80 samples) were assessed using Spearman and intraclass correlation coefficients (ICCs).
CVs were <20% for 92% of metabolites and generally were similar by plasma anticoagulant type (Heparin or EDTA) and fasting time. Approximately 75% of metabolites were reproducible over delays in processing of blood specimens (Spearman correlation or ICC ≥0.75, comparing immediate and 24-hour delayed processing). Carbohydrates and purine/pyrimidine derivatives were most adversely affected by the processing delay. Ninety percent of metabolites were reproducible over 1-2 years within individuals (Spearman correlation or ICC ≥0.4).
For potential use in epidemiologic studies, the majority of plasma metabolites had low CVs and were reproducible over a 24-hour processing delay and within individuals over 1-2 years. Certain metabolites, such as carbohydrates and purine/pyrimidine derivatives, may be challenging to evaluate if samples have delayed processing.
PMCID: PMC3812240  PMID: 23897902
Blood sample collection; Cohort studies; Metabolomics; Reproducibility of Results; Tandem mass spectrometry
2.  Risk factors for fecal incontinence in older women 
To estimate the prevalence of fecal incontinence (FI) in older women, and examine associations between potential risk factors and prevalent FI.
We conducted a cross-sectional study of prevalent FI in 64,559 women, aged 62–87 years, in the Nurses' Health Study. Since 1976, participants provided information on health and lifestyle on mailed biennial questionnaires. Data on FI were collected in 2008. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for FI were calculated using logistic regression models.
The reported prevalence of liquid or solid stool incontinence at least monthly increased from 9% in women age 62 to 64 years to 17% in women age 85 to 87. Prevalent FI was 50% less common in black women compared with white women (6% vs. 12%, respectively). Other variables associated with increased odds of FI at least monthly were pregnancy, higher body mass index, lower physical activity, functional limitations, current cigarette smoking, type 2 diabetes, high blood pressure, and neurologic disease. Urinary incontinence (UI) was a strong correlate of FI, with 63% of women with FI reporting UI at least monthly compared with 45% of women in the whole study population.
FI is a common condition among older women, and often co-occurs with UI. Potentially modifiable risk factors include body mass index, physical activity, and cigarette smoking.
PMCID: PMC3537864  PMID: 23090350
3.  Caffeine Intake and Risk of Urinary Incontinence Progression Among Women 
Obstetrics and Gynecology  2012;119(5):950-957.
To estimate the association between long-term caffeine intake and risk of urinary incontinence (UI) progression over 2 years among women with moderate UI.
We conducted a prospective cohort study in 21,564 women with moderate UI enrolled in the Nurses’ Health Study and Nurses’ Health Study II. Incontinence progression was identified from questionnaires during 2 years of follow-up. Baseline caffeine intake (ie, average intake during the past year) and change in caffeine intake during the 4 years prior to baseline were measured using food frequency questionnaires. Odds ratios (ORs) for incontinence progression according to caffeine intake were calculated for each cohort separately, and then for both cohorts combined.
The percentage of women with UI progression was similar across categories of baseline level of caffeine intake and change in caffeine intake prior to baseline. For example, percentages were 21% versus 22% comparing 450 mg or more to less than 150 mg of caffeine per day (adjusted OR 0.87, 95% confidence interval [CI] 0.70-1.08). Comparing women with increased caffeine intake to those with stable caffeine intake, percentages with progression were 22% versus 20% (OR 1.08, 95% CI 0.95-1.22). Results were similar in separate analyses of urgency and stress UI.
Long-term caffeine intake over one year was not associated with risk of UI progression over 2 years among women with moderate incontinence, although we could not examine acute effects of caffeine. Improved understanding of the effect of caffeine on the bladder is needed to better advise women with incontinence about caffeine intake.
PMCID: PMC3336097  PMID: 22525905
4.  The relation between insulin, insulin-related factors, and plasma amyloid beta peptide levels at mid-life in a population-based study 
Little is known regarding factors associated with soluble amyloid beta peptide (Aβ) concentrations in humans at late midlife, when Aβ is likely most critical to Alzheimer disease pathogenesis. We examined the association between insulin, insulin-related factors, and plasma Aβ at late midlife. Plasma Aβ42, Aβ40, fasting insulin, and c-peptide were measured in 468 women without diabetes, aged 59–69 years (median 63 years). Prior to blood draw, participants reported body mass index, waist circumference, physical activity, alcohol intake, hypertension, and diabetes family history. Linear regression was used to calculate age-adjusted mean differences in Aβ42 to Aβ40 ratio, and Aβ42 levels, by insulin and insulin-related factors. The ratio of Aβ42 to Aβ40 was statistically significantly lower in women with diabetes family history, and Aβ42 was significantly lower with less physical activity, greater waist circumference, hypertension, and diabetes family history (p<0.05 for all). Aβ42 to Aβ40 ratio, and Aβ42 levels, appeared lower with higher c-peptide levels (p-trend=0.07 and 0.06, respectively), although these were not statistically significant. In summary, insulin-related factors appear associated with lower plasma Aβ42 to Aβ40 ratio, and Aβ42, at late mid-life, consistent with increased brain sequestration of Aβ42 (relative to Aβ40), suggesting insulin merits focus in strategies to prevent dementia.
PMCID: PMC3140548  PMID: 21502851
amyloid beta peptide; insulin; epidemiology
5.  Fluid intake and risk of stress, urgency, and mixed urinary incontinence 
We investigated the relation between total fluid intake and incident urinary incontinence in the Nurses’ Health Study cohorts.
Study Design
We measured daily fluid intake using food frequency questionnaires among 65,167 women, aged 37–79 years, without urinary incontinence at study baseline (2000–2001). Women reported incontinence incidence on questionnaires during 4 years of follow-up. Multivariable-adjusted hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards models.
We found no association between total fluid intake and risk of incident incontinence (hazard ratio 1.04, 95% confidence interval 0.98–1.10 comparing top versus bottom quintile of fluid intake). In analyses of incontinence type, total fluid intake was not associated with risks of incident stress, urgency, or mixed incontinence.
No significant risk of incident urinary incontinence was found with higher fluid intake in women. These findings suggest that women should not restrict their fluid intake to prevent incontinence development.
PMCID: PMC3135667  PMID: 21481835
epidemiology; fluid intake; urinary incontinence
6.  Caffeine intake and risk of stress, urgency, and mixed urinary incontinence 
The Journal of urology  2011;185(5):1775-1780.
Although caffeine consumption is common, and is generally believed to affect bladder function, little is known regarding caffeine intake and incident urinary incontinence.
Materials and Methods
We conducted a prospective cohort study of 65,176 women without incontinence, aged 37–79 years, in the Nurses’ Health Studies. Incident incontinence was identified from questionnaires, during 4 years of follow-up. Caffeine intake was measured using food frequency questionnaires administered prior to incontinence development. Multivariable-adjusted relative risks for the relation between caffeine intake and incontinence risk were calculated, as well as attributable risks.
Caffeine was not associated with incontinence monthly or more, but there was a modest, significantly increased risk of incontinence at least weekly among women with the highest versus the lowest intake (RR 1.19, 95% CI 1.06–1.34, comparing >450 vs. <150 mg/day) and a significant trend of increasing risk with increasing intake (p-value for trend=0.01). This risk appeared focused in incident urgency incontinence (RR 1.34, 95% CI 1.00–1.80 comparing >450 vs. <150 mg/day, p-value for trend=0.05), but not stress or mixed incontinence (p-values for trend=0.75 and 0.19, respectively). The attributable risk for urgency incontinence associated with high caffeine intake was 25%.
Our findings suggest that high caffeine intake, but not lower levels, is associated with a modest increase in incidence of frequent urgency incontinence; one-quarter of these cases among women with the highest level of caffeine consumption might be eliminated if high caffeine intake was eliminated. Confirmation of these findings in other studies is needed before recommendations can be made.
PMCID: PMC3077934  PMID: 21420114
urinary incontinence; caffeine; epidemiology
7.  Remission and progression of urinary incontinence among Asian, black, and white women in the United States 
The American journal of nursing  2011;111(4):26-35.
Growing evidence suggests that urinary incontinence prevalence and incidence in women vary by race. However, little is known regarding potential racial differences in remission and progression of incontinence, which would have meaningful implications for clinicians who treat incontinence.
To compare changes in incontinence frequency over two years among Asian, black, and white women with incontinence.
Participants in the Nurses’ Health Study cohorts provided information on their race and incontinence frequency on mailed questionnaires. Prospective analyses over two years of follow-up included 57,900 women aged 37–79 years with at least monthly incontinence at baseline.
Changes in incontinence frequency appeared to vary by race, even after adjusting for a large variety of risk factors for incontinence. Specifically, compared with white women, black women were more likely to report no incontinence at follow-up (14% remission in black women vs. 9% in white women). Asian women were more likely to report any decrease in incontinence frequency (40% improvement in Asian women vs. 31% in white women). Incontinence improvement was also more common in black versus white women in analyses restricted to older women, although reports of improvement were similar among black and white women aged 54 years and younger. Black women were less likely to report a higher frequency of incontinence at follow-up (30% progression in black women vs. 34% in white women), and this difference was borderline statistically significant.
Higher odds of incontinence remission in black women, and improvement in Asian American women, compared with white women, may account for some of the previously observed differences in incontinence prevalence across racial groups, and were independent of health and lifestyle factors. Although incontinence is a common condition in women of all races, clinicians should be aware that the natural history of incontinence may differ across racial groups.
PMCID: PMC3201776  PMID: 21451292
urinary incontinence; race; epidemiology
8.  The relation of midlife diet to healthy aging: a cohort study 
Annals of internal medicine  2013;159(9):584-591.
Understanding how to maintain health and well-being in aging populations is critical.
To examine the relation of dietary patterns in midlife to the prevalence of healthy aging.
Cross-sectional observational study.
Nurses’ Health Study.
10,670 women with dietary data and no major chronic diseases in 1984–1986, when they were in their late 50’s and early 60s (median age = 59 years); all women provided information on multiple aspects of aging an average 15 years later.
Diet quality in midlife was ascertained using the Alternative Healthy Eating Index-2010 (AHEI-2010) and Alternate Mediterranean diet (A-MeDi) scores, averaged from two food frequency questionnaires (1984–1986). We defined “healthy” vs “usual” aging as of age 70 years; healthy aging was based on survival to 70+ years with maintenance of four health domains - no major chronic diseases, or major impairments in cognitive or physical function or mental health.
After multivariable adjustment, greater adherence to the AHEI-2010 (upper vs. lower quintile) in midlife was related to 34% (95% CI=9% to 66%, P-trend<0.001) greater odds of healthy versus usual aging. Greater adherence to A-MeDi was related to 46% (95% CI=17% to 83%, P-trend=0.002) greater odds of healthy aging. When the 4 components of healthy aging were analyzed separately, AHEI-2010 and A-MeDi were significantly associated with higher likelihood of no major limitations in physical function and mental health.
Possibility of residual confounding, although we controlled for many confounding factors; bias due to complex patterns of measurement error within diet scores cannot be excluded.
Better diet quality at midlife appears strongly linked to greater health and well-being among those surviving to older ages.
PMCID: PMC4193807  PMID: 24189593
9.  Risk Factors for Urinary, Fecal or Dual Incontinence in the Nurses’ Health Study 
Obstetrics and gynecology  2013;122(3):539-545.
To estimate the prevalence of urinary incontinence, fecal incontinence, and dual incontinence in a large cohort of older women and compare risk factors across the three conditions.
These cross-sectional analyses utilized data from the Nurses’ Health Study. The 2008 questionnaire, mailed to 96,480 surviving participants aged 62–87 years, included two separate items on prevalence of urinary and fecal incontinence. A response of leakage at least once per month defined incontinence for both urine and stool. Dual incontinence was defined by responses at this frequency for both conditions. Using a polytomous logistic regression model we assessed each risk factor for prevalence of urinary, fecal, and dual incontinence, respectively.
The survey was completed by 64,396 women. Thirty-eight percent had urinary incontinence alone, 4% had fecal incontinence alone, and 7% had dual incontinence. Age older than 80 years compared with age younger than 70 years was associated most strongly with dual incontinence (odds ratio [OR] 2.49, 95% confidence interval [CI] 2.28–2.73), followed by depression (OR 2.28, 95% CI 2.13–2.43), neurologic disease (OR 1.84, 95% CI 1.65–2.07), functional limitations (OR 1.86, 95% CI 1.71–2.02), multiparity (OR 1.66, 95% CI 1.41–1.94), and heavier fetal birth weight (OR 1.24, 95% CI 1.10–1.41). Obesity was associated only with urinary incontinence (OR 1.99, 95% CI 1.90–2.08) and type 2 diabetes was a stronger risk factor for fecal than urinary incontinence (OR 1.43, 95% CI 1.28–1.59). Black race was associated with a reduced risk of all types of incontinence, especially dual incontinence (OR 0.30, 95% CI 0.21–0.44).
In this large cohort, dual incontinence was primarily associated with advanced age, decompensating medical conditions, depression, and multiparity.
PMCID: PMC3952631  PMID: 23921863
10.  The incidence of urinary incontinence across Asian, black, and white women in the United States 
We calculated incidence rates of urinary incontinence by incontinence frequency and type over 4 years in Asian, black, and white women in the United States.
Study Design
Prospective analyses included 76,724 participants aged 37–79 years in the Nurses’ Health Study cohorts with no incontinence at baseline.
The 4-year incidence of incontinence at least monthly was higher in white women (7.3/100 person-years) compared with Asian (5.7/100 person-years, p=0.003) and black women (4.8/100 person-years, p<0.001). The incidence of at least weekly stress incontinence was significantly lower in black compared with white women (0.1 versus 0.8 per 100 person-years, p<0.001). The difference between black and white women in the incidence of any incontinence and stress incontinence remained significant after adjusting for known risk factors (p<0.001 for both).
Urinary incontinence incidence differs by race. Studies to confirm these results and better understand underlying mechanisms are needed.
PMCID: PMC2847676  PMID: 20042169
epidemiology; incidence; race; urinary incontinence
11.  The relation between moderate alcohol consumption and cognitive function in older women with type 2 diabetes 
To examine the association between moderate drinking, cognitive function, and cognitive decline in women with type 2 diabetes.
From 1995-2001, we assessed cognitive function in 1,698 women aged 71-80 years with type 2 diabetes in the Nurses' Health Study. Assessments were repeated twice at 2-year intervals. We used linear regression to estimate multivariable-adjusted mean differences in initial cognitive function and longitudinal models to estimate cognitive decline over 4 years, according to average alcohol intake between diagnosis with diabetes and the initial cognitive measurement.
At the initial assessment, the mean score on our test of general cognition was 0.31 (95% CI 0.02, 0.60) points higher in women who were moderate alcohol drinkers (those consuming 1.0-9.9 grams of alcohol, or about 1 drink, per day) compared with abstainers. However, moderate alcohol was not associated with cognitive decline. Higher alcohol consumption (10.0-30.0 grams of alcohol per day) was not associated with initial cognition or cognitive decline, although there was no apparent harm either.
Among women with type 2 diabetes, moderate alcohol was associated with better initial cognition, but not reduced rates of cognitive decline. Thus, we found no clear and consistent cognitive benefits of moderate alcohol in diabetes.
PMCID: PMC2748648  PMID: 19625098
Alcohol consumption; Cognitive function; Type 2 diabetes
Hypertension  2013;62(1):27-32.
Animal studies and small-controlled studies in humans suggest that adiponectin may regulate blood pressure via brain-mediated and endothelium-mediated mechanisms. We conducted a systematic review and meta-analysis to evaluate the epidemiologic evidence on plasma adiponectin levels and hypertension in free-living adult population. A systematic search of Medline and EMBASE, up to February 2013, identified 43 non-prospective and 5 prospective studies that included 17,598 adults (8,220 with hypertension; mean age 19–69 years; and mean body mass index 22–38 kg/m2). Two investigators independently extracted data on adiponectin levels by hypertension status and dose-response relationship. We used a random-effects model to compute the weighted mean difference in adiponectin levels between hypertensive and normotensive adults and a 2-stage generalized linear-square methods to compute the odds ratio of hypertension per 1 μg/ml increase in adiponectin. Hypertensive adults had 1.64 μg/ml (95% confidence interval: −2.07, −1.21) lower adiponectin levels than normotensive adults. Every 1 μg/ml increase in adiponectin levels was associated with 6% reduced risk of hypertension (95% confidence interval: 0.92, 0.97). These findings were consistent across study design and characteristics, including age, gender, and body mass index (p>0.05). However, our meta-analysis was limited by unexplained large between-study heterogeneity, a small number of prospective studies, and selective reporting of dose-response data. In conclusion, epidemiologic evidence suggests that plasma adiponectin level is a biomarker and possible mediator in the development of adiposity-related hypertension. The question remains as to adiponectin as a potential therapeutic target and its relationship with other adipokines in blood pressure regulation.
PMCID: PMC3729220  PMID: 23716587
Adiponectin; hypertension; blood pressure; obesity; systematic review
13.  Association of Urinary Concentrations of Bisphenol A and Phthalate Metabolites with Risk of Type 2 Diabetes: A Prospective Investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts 
Environmental Health Perspectives  2014;122(6):616-623.
Background: Prospective evidence regarding associations for exposures to bisphenol A (BPA) and phthalates with type 2 diabetes (T2D) is lacking.
Objective: We prospectively examined urinary concentrations of BPA and phthalate metabolites with T2D risk.
Methods: We measured BPA and eight major phthalate metabolites among 971 incident T2D case–control pairs from the Nurses’ Health Study (NHS) (mean age, 65.6 years) and NHSII (mean age, 45.6 years).
Results: In the NHSII, BPA levels were not associated with incident T2D in multivariate-adjusted analysis until body mass index was adjusted: odds ratio (OR) comparing extreme BPA quartiles increased from 1.40 (95% CI: 0.91, 2.15) to 2.08 (95% CI: 1.17, 3.69; ptrend = 0.02) with such an adjustment. In contrast, BPA concentrations were not associated with T2D in the NHS (OR = 0.81; 95% CI: 0.48, 1.38; ptrend = 0.45). Likewise, urinary concentrations of total phthalate metabolites were associated with T2D in the NHSII (OR comparing extreme quartiles = 2.14; 95% CI: 1.19, 3.85; ptrend = 0.02), but not in the NHS (OR = 0.87; 95% CI: 0.49, 1.53; ptrend = 0.29). Summed metabolites of butyl phthalates or di-(2-ethylhexyl) phthalates were significantly associated with T2D only in the NHSII; ORs comparing extreme quartiles were 3.16 (95% CI: 1.68, 5.95; ptrend = 0.0002) and 1.91 (95% CI: 1.04, 3.49; ptrend = 0.20), respectively.
Conclusions: These results suggest that BPA and phthalate exposures may be associated with the risk of T2D among middle-aged, but not older, women. The divergent findings between the two cohorts might be explained by menopausal status or simply by chance. Clearly, these results need to be interpreted with caution and should be replicated in future studies, ideally with multiple urine samples collected prospectively to improve the measurement of these exposures with short half-lives.
Citation: Sun Q, Cornelis MC, Townsend MK, Tobias DK, Eliassen AH, Franke AA, Hauser R, Hu FB. 2014. Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts. Environ Health Perspect 122:616–623;
PMCID: PMC4050512  PMID: 24633239
14.  Plasma Levels of Fetuin‐A and Risk of Coronary Heart Disease in US Women: The Nurses' Health Study 
Fetuin‐A may be involved in the etiology of coronary heart disease (CHD) through opposing pathways (ie, promoting insulin resistance and inhibiting ectopic calcification). We aimed to explicitly examine whether systemic inflammation, a factor leading to elevated vascular calcification, may modify the association between fetuin‐A and CHD risk.
Method and Results
During 16 years of follow‐up (1990–2006), we prospectively identified and confirmed 466 incident fatal or nonfatal CHD case in the Nurses' Health Study. For each case, 1 healthy control was selected using risk‐set sampling from 26 245 eligible participants. Cases and controls were matched for age, smoking status, fasting status, and date of blood draw. After multivariate adjustment for lifestyle factors, body mass index, diet, and blood lipids, fetuin‐A levels were not associated with CHD risk in the whole population: odds ratio (OR) (95% CI) comparing extreme quintiles of fetuin‐A was 0.79 (0.44 to 1.40). However, a significant inverse association was observed among participants with higher C‐reactive protein levels (Pinteraction=0.04). The OR (95% CI) comparing highest versus lowest quintiles of fetuin‐A was 0.50 (0.26 to 0.97; Ptrend=0.004) when C‐reactive protein levels were above population median (0.20 mg/dL), whereas among the remainder of the participants, the corresponding OR (95% CI) was 1.09 (0.58 to 2.05; Ptrend=0.75).
In this population of US women, fetuin‐A levels were associated with lower CHD risk when C‐reactive protein levels were high, but null association was observed among participants with lower C‐reactive protein levels. This divergent pattern of association needs replication in future studies.
PMCID: PMC4309097  PMID: 24963103
coronary heart disease; fetuin‐A; inflammation
Introduction and hypothesis
Acidic fruits are commonly cited in the lay press as potential bladder irritants that may promote urinary incontinence (UI), but no epidemiologic studies have examined this issue. We hypothesized that higher intake of acidic fruits might be related to greater risk of UI incidence and progression in women.
In one set of analyses, we included women without UI at study baseline in the Nurses’ Health Studies (NHS), with 34,144 women aged 54–79 in NHS I and 31,024 women aged 37–54 in NHS II. These cohorts were established among women living in the United States. Incident UI was ascertained over four years of follow up, and acidic fruit consumption was measured by food frequency questionnaire prior to UI onset. In a second set of analyses, we examined UI progression over two years of follow up among 11,764 women in NHS I and 11,299 women in NHS II with existing UI. Multivariable-adjusted relative risks were calculated for the associations of acidic fruit intake and UI incidence and progression.
We found no relation between acidic fruit intake and risk of developing UI, including urgency, mixed, and stress UI. In addition, there was no association between consumption of acidic fruits and UI progression, regardless of UI type.
No associations were detected between acidic fruit intake and UI in this large, prospective study of women. These data have implications for the development of evidence-based dietary guidelines around acidic fruits and UI, particularly because acidic fruits likely have many health benefits.
PMCID: PMC3558558  PMID: 22878474
aging; cohort studies; diet; epidemiology; urinary incontinence
16.  Stability and Reproducibility of the Measurement of Plasma Nitrate in Large Epidemiologic Studies 
Inorganic nitrate has emerged as a therapeutic agent for cardiovascular disease; however, nitrate can also metabolize to carcinogenic nitrosamines under pathologic conditions. Few large epidemiologic studies have examined circulating levels of nitrate in relation to cardiovascular disease and cancer. Data on the validity of nitrate measurement in blood samples collected in typical epidemiologic settings are needed before nitrate can be evaluated as an exposure in large epidemiologic studies.
We measured plasma levels of nitrate in three pilot studies to evaluate its laboratory variability, stability with delayed processing, and reproducibility over time among women from the Nurses’ Health Study and healthy female volunteers.
Laboratory variability of nitrate levels was fairly low, with a coefficient variation (CV) of 7%. Plasma nitrate levels in samples stored as whole blood on ice for up to 48 hrs before processing were very stable; the overall intra-class correlation (ICC) from 0 to 48 hours was 0.89 (95%CI, 0.70–0.97). The within-person reproducibility over a one-year period was modest, with an ICC of 0.49 (95% CI, 0.33- 0.94).
Our results indicate that measurement of nitrate in plasma is reliable and stable in blood samples with delayed processing up to 48 hours. Within-person reproducibility was modest but data from this study can be used for measurement error correction in subsequent analyses. The measurement of nitrate cannot be widely used in epidemiologic research without the documentation of its stability and reproducibility.
PMCID: PMC3826455  PMID: 24244804
nitrate; stability; reproducibility; epidemiologic blood collection
The Journal of urology  2012;188(5):1816-1821.
Little research has investigated the epidemiology of urinary incontinence (UI) in individuals with type 2 diabetes (T2D). We examined prevalence, incidence, and risk factors for UI among women with T2D in the Nurses’ Health Study (NHS) and NHS II.
Materials and Methods
We obtained UI information at study baseline (2000 in NHS and 2001 in NHS II) and two follow ups (2002 and 2004 in NHS, and 2003 and 2005 in NHS II). Among women with T2D, we calculated UI prevalence for 9,994 women with baseline UI information, and UI incidence rates for 4,331 women with no UI at baseline and UI information during follow up. Multivariable-adjusted odds ratios (ORs) and relative risks (RRs) were estimated for associations between possible risk factors and UI.
Prevalence of at least monthly UI was 48% and at least weekly UI was 29% among women with T2D; corresponding incidence rates were 9.1 and 3.4 per 100 person-years, respectively. White race, higher BMI, higher parity, lower physical activity, current post-menopausal hormone use, and diuretic use were risk factors for prevalent and incident UI in this study, and hysterectomy, vascular disease, and longer duration of diabetes were associated with increased odds of prevalent UI only. Increasing age and microvascular complications were associated with greater risk of developing frequent UI.
UI was very common in this study of women with T2D. We identified multiple risk factors for UI in these women, several of which suggest ways for women with T2D to reduce UI.
PMCID: PMC3646531  PMID: 22999689
urinary incontinence; type 2 diabetes; epidemiology; women
18.  Fluorescent Oxidation Products and Risk of Coronary Heart Disease: A Prospective Study in Women 
Oxidative stress is implicated in the etiology of coronary heart disease (CHD). New measures to capture oxidative stress are warranted. Fluorescent oxidation products (FlOPs) can be measured in plasma and have been shown to reflect levels of oxidative stress and to predict risk of CHD in men over 6 years of follow‐up. The objective of this study is to determine whether measures of FlOPs are associated with risk of CHD in women over an extended follow‐up period.
Methods and Results
We measured FlOP by spectrofluorometer in a nested case–control study within the Nurses' Health Study, with baseline blood collection in 1990 and follow‐up of 397 incident CHD cases through 2004 matched 1:2 with controls. Level of FlOPs was independently associated with CHD. The relative risk across extreme quintiles was 1.64 (95% confidence interval [CI], 1.06 to 2.53) when adjusted for lifestyle factors, lipids and C‐reactive protein (P trend across quintiles=0.01). A slightly stronger association was observed when analyses were restricted to women fasting >8 hours at blood draw (RR, 1.91; 95% CI, 1.16 to 3.15). In exploratory time to event analyses, high levels of FlOPs measured ≥5 years before the CHD event, but not closer to the CHD event, were associated with the risk of CHD.
Higher levels of FlOPs were associated with the risk of CHD in women. The association appeared strongest for long‐term prediction of CHD events.
PMCID: PMC3835219  PMID: 24103570
follow‐up studies; myocardial infarction; oxidative stress; risk factors; women
19.  Within-person reproducibility of urinary bisphenol A and phthalate metabolites over a 1 to 3 year period among women in the Nurses’ Health Studies: a prospective cohort study 
Environmental Health  2013;12:80.
Associations of bisphenol A and phthalates with chronic disease health outcomes are increasingly being investigated in epidemiologic studies. The majority of previous studies of within-person variability in urinary bisphenol A and phthalate metabolite concentrations have focused on reproducibility over short time periods. Long-term reproducibility data are needed to assess the potential usefulness of these biomarkers for prospective studies, particularly those examining risk of diseases with long latency periods. Low within-person reproducibility may attenuate relative risk estimates and reduce statistical power to detect associations with disease. Therefore, we assessed within-person reproducibility of bisphenol A, eight phthalate metabolites, and phthalic acid in spot urine samples over 1 to 3 years among women enrolled in two large cohort studies.
Women in the Nurses’ Health Study and Nurses’ Health Study II provided two spot urine samples, 1 to 3 years apart (n = 80 women for analyses of bisphenol A; n = 40 women for analyses of phthalate metabolites; n = 34 women for analyses of phthalic acid). To measure within-person reproducibility, we calculated Spearman rank correlation coefficients and intraclass correlation coefficients for creatinine-adjusted concentrations of bisphenol A, phthalate metabolites, and phthalic acid.
Over 1 to 3 years, within-person variability of bisphenol A was high relative to total variability (intraclass correlation coefficient = 0.14) and rankings of bisphenol A levels between time-points were weakly correlated (Spearman correlation = 0.19). Seven of the eight phthalate metabolites and phthalic acid demonstrated moderate within-person stability over time (Spearman correlation or intraclass correlation coefficient = 0.39-0.55). Restricting analyses to first-morning urine samples did not alter results.
Single measurements of bisphenol A in spot urine samples were highly variable within women over 1 to 3 years, indicating that investigation of associations between a single urinary bisphenol A measurement and disease risk may be challenging in epidemiologic studies. The majority of urinary phthalate metabolites and phthalic acid appeared moderately reproducible within women over time, suggesting single measurements may be useful in epidemiologic studies, although observed relative risks can be substantially attenuated.
PMCID: PMC3847616  PMID: 24034517
Adult; Biological markers/urine; Bisphenol a; Phthalate metabolites; Reproducibility
20.  Female reproductive factors and risk of Seizure or Epilepsy: Data from the Nurses’ Health Study II 
Epilepsia  2011;53(1):e1-e4.
Reproductive factors are associated with seizures in women with epilepsy. We prospectively examined the association between reproductive factors and the risk of adult-onset isolated seizure, epilepsy, or any unprovoked seizure (defined as single unprovoked seizure or epilepsy) among 114,847 Nurses’ Health Study II participants followed from 1989–2005. Validated seizure questionnaires and medical records were used to confirm incident cases of isolated seizure (n=95) or epilepsy (n=151). Overall, there were no significant associations between any reproductive factor and risk of any unprovoked seizure (n=196). However, menstrual irregularity at ages 18–22 years was specifically associated with an increased risk of epilepsy (Relative Risk (RR) = 1.67, 95% Confidence Interval (CI), 1.12, 2.51). Menstrual irregularity during follow-up (RR = 2.21, 95% CI, 1.16, 4.20) and early age at menarche (<12 years vs. 12–13 years; RR=1.76, 95% CI, 1.10, 2.81) increased the risk of isolated seizure. Oral contraceptive use and parity were not associated with isolated seizure or epilepsy. Thus, menstrual factors were associated with risk of seizure/epilepsy.
PMCID: PMC3253207  PMID: 22050476
epidemiology; oral contraceptives; menstrual irregularities; hormones; women
21.  Specific Subjective Memory Complaints in Older Persons May Indicate Poor Cognitive Function 
To examine the association between the type and number of subjective memory complaints (SMCs) and performance on objective cognitive tests.
Nurses’ Health Study.
Sixteen thousand nine hundred sixty-four women (mean age 74) who provided information on SMCs.
Telephone cognitive assessments and seven questions regarding SMCs were administered. Cognitive impairment was defined as a score of less than 31 on the Telephone Interview for Cognitive Status (TICS) and below the 10th percentile on other cognitive measures. To assess associations with SMCs, multivariable logistic regression was used to calculate odds ratios for cognitive impairment and multivariable linear regression to calculate mean differences in cognitive test scores, adjusting for age and depressive symptoms.
Some SMCs, such as trouble following a group conversation or finding one’s way around familiar streets, were more highly associated than others with odds of cognitive impairment. The complaint of forgetting things from one second to the next, generally considered part of normal aging, was not associated with cognitive impairment. In addition, there were strong, linear trends of increasingly worse scores on cognitive tests with increasing numbers of memory complaints. For each additional SMC endorsed, the odds of cognitive impairment increased approximately 20% when each SMC was weighted equally.
SMCs are associated with objective cognitive status and may be considered by primary care physicians in determining whether follow-up is warranted.
PMCID: PMC3315361  PMID: 21919893
memory complaints; cognitive function; aging
22.  Adiposity and weight change in mid-life in relation to healthy survival after age 70 in women: prospective cohort study 
Objective To examine the hypothesis that mid-life adiposity is associated with a reduced probability of maintaining an optimal health status among those who survive to older ages.
Design Prospective cohort study.
Setting The Nurses’ Health Study, United States.
Participants 17 065 women who survived until at least the age of 70, provided information on occurrence of chronic disease, cognitive function, physical function, and mental health at older ages, and were free from major chronic diseases at mid-life (mean age was 50 at baseline in 1976).
Main outcome measures Healthy survival to age 70 and over was defined as having no history of 11 major chronic diseases and having no substantial cognitive, physical, or mental limitations.
Results Of the women who survived until at least age 70, 1686 (9.9%) met our criteria for healthy survival. Increased body mass index (BMI) at baseline was significantly associated with linearly reduced odds of healthy survival compared with usual survival, after adjustment for various lifestyle and dietary variables (P<0.001 for trend). Compared with lean women (BMI 18.5-22.9), obese women (BMI ≥30) had 79% lower odds of healthy survival (odds ratio 0.21, 95% confidence interval 0.15 to 0.29). In addition, the more weight gained from age 18 until mid-life, the less likely was healthy survival after the age of 70. The lowest odds of healthy survival were among women who were overweight (BMI ≥25) at age 18 and gained ≥10 kg weight (0.18, 0.09 to 0.36), relative to women who were lean (BMI 18.5-22.9) and maintained a stable weight.
Conclusions These data provide evidence that adiposity in mid-life is strongly related to a reduced probability of healthy survival among women who live to older ages, and emphasise the importance of maintaining a healthy weight from early adulthood.
PMCID: PMC3230231  PMID: 19789407
23.  Alcohol Consumption at Midlife and Successful Ageing in Women: A Prospective Cohort Analysis in the Nurses' Health Study 
PLoS Medicine  2011;8(9):e1001090.
Using the Nurses' Health Study, Qi Sun and colleagues examine whether moderate alcohol intake is associated with overall health and well-being among women who survive to older age.
Observational studies have documented inverse associations between moderate alcohol consumption and risk of premature death. It is largely unknown whether moderate alcohol intake is also associated with overall health and well-being among populations who have survived to older age. In this study, we prospectively examined alcohol use assessed at midlife in relation to successful ageing in a cohort of US women.
Methods and Findings
Alcohol consumption at midlife was assessed using a validated food frequency questionnaire. Subsequently, successful ageing was defined in 13,894 Nurses' Health Study participants who survived to age 70 or older, and whose health status was continuously updated. “Successful ageing” was considered as being free of 11 major chronic diseases and having no major cognitive impairment, physical impairment, or mental health limitations. Analyses were restricted to the 98.1% of participants who were not heavier drinkers (>45 g/d) at midlife. Of all eligible study participants, 1,491 (10.7%) achieved successful ageing. After multivariable adjustment of potential confounders, light-to-moderate alcohol consumption at midlife was associated with modestly increased odds of successful ageing. The odds ratios (95% confidence interval) were 1.0 (referent) for nondrinkers, 1.11 (0.96–1.29) for ≤5.0 g/d, 1.19 (1.01–1.40) for 5.1–15.0 g/d, 1.28 (1.03–1.58) for 15.1–30.0 g/d, and 1.24 (0.87–1.76) for 30.1–45.0 g/d. Meanwhile, independent of total alcohol intake, participants who drank alcohol at regular patterns throughout the week, rather than on a single occasion, had somewhat better odds of successful ageing; for example, the odds ratios (95% confidence interval) were 1.29 (1.01–1.64) and 1.47 (1.14–1.90) for those drinking 3–4 days and 5–7 days per week in comparison with nondrinkers, respectively, whereas the odds ratio was 1.10 (0.94–1.30) for those drinking only 1–2 days per week.
These data suggest that regular, moderate consumption of alcohol at midlife may be related to a modest increase in overall health status among women who survive to older ages.
Please see later in the article for the Editors' Summary
Editors' Summary
People have always drunk alcoholic beverages but throughout history there have been arguments about the risks and benefits of beer, wine, and spirits. It is clear that excessive alcohol use—heavy drinking (an average of more than two drinks per day for men or more than one drink per day for women; in the US, a “drink” is defined as 15 g of alcohol or, roughly speaking, a can of beer or a small glass of wine) or binge drinking (five or more drinks on a single occasion for men; 4 or more drinks at one time for women)—is harmful. It causes liver damage and increases the risk of developing some types of cancer. It contributes to depression and violence and interferes with relationships. And it is often implicated in fatal traffic accidents. However, in contrast to these and other harms associated with excessive alcohol use, moderate alcohol consumption seems to reduce the risk of specific diseases such as heart disease, stroke, and cognitive decline (deterioration in learning, reasoning, and perception).
Why Was This Study Done?
Although people who drink moderate amounts of alcohol have a reduced risk of premature death compared to abstainers or heavy drinkers, it is not known whether moderate alcohol consumption is associated with overall health among ageing populations. In many countries, elderly people are an increasingly large part of the population, so it is important to know how moderate alcohol consumption affects their well-being. In this study, the researchers examine the effect of alcohol consumption at midlife on successful ageing among the participants of the Nurses' Health Study. The researchers study the effect of midlife alcohol consumption because the chronic conditions that affect elderly people develop slowly and it is likely that factors in earlier life determine health in later life. Successful ageing is defined as being free of major chronic diseases such as cancer and heart disease, and having no major cognitive impairment, physical impairment, or mental health problems. The Nurses' Health Study enrolled 121,700 female registered nurses in 1976 to investigate the long-term effects of oral contraceptive use but has provided insights into many aspects of health and disease.
What Did the Researchers Do and Find?
The researchers assessed the alcohol consumption of the study participants at midlife (average age 58 years) from food frequency questionnaires completed in 1980 and 1984. Successful ageing for 13,984 participants who survived past 70 years was assessed by analyzing biennial health status questionnaires and cognitive function test results. One tenth of the women achieved successful ageing. After allowing for other factors that might affect their health such as smoking, women who drank light or moderate amounts of alcohol had a modestly increased chance of successful ageing compared to nondrinkers. For example, compared to nondrinkers, women who drank 5–15 g of alcohol per day (between one-third and one drink per day) had about a 20% higher chance of successful ageing. Independent of total alcohol intake, women who drank alcohol regularly had a better chance of successful ageing than occasional drinkers. Thus, compared to nondrinkers, women who drank five to seven days a week had nearly a 50% greater chance of successful ageing whereas women who drank only one or two days a week had a similar likelihood of successful ageing.
What Do These Findings Mean?
These findings suggest that regular, moderate consumption of alcohol at midlife may be related to a modest increase in overall health among women who survive to older ages. Because this is an observational study, it is possible that the women who drank moderately share other unknown characteristics that are actually responsible for their increased chance of successful ageing. Moreover, because all the study participants were women and most had European ancestry, these findings cannot be applied to men or to other ethnic groups. Nevertheless, these findings provide support for the 2010 US Department of Agriculture dietary guidelines, which state that consumption of up to one alcoholic drink per day for women and up to two alcoholic drinks per day for men may provide health benefits. Importantly, they also suggest that drinking alcohol regularly in moderation rather than occasional heavy drinking may be associated with a greater likelihood of successful ageing.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute on Alcohol Abuse and Alcoholism has detailed information about alcohol and its effects on health, including a fact sheet on women and alcohol and a booklet entitled Alcohol, a woman's health issue
The US Centers for Disease Control and Prevention has a website on alcohol and public health
The UK National Health Service Choices website provides detailed information about drinking and alcohol, including how to calculate consumption
The Nutrition Source, a website maintained by the Department of Nutrition at Harvard School of Public Health, has an article entitled Alcohol: balancing risks and benefits
MedlinePlus provides links to many other resources on alcohol and on seniors' health
Details of the Nurses' Health Study are available
The 2010 US Department of Agriculture dietary guidelines are available
PMCID: PMC3167795  PMID: 21909248
24.  A prospective study of smoking, caffeine, and alcohol as risk factors for seizures or epilepsy in young adult women: Data from the Nurses’ Health Study II 
Epilepsia  2009;51(2):198-205.
Seizures and epilepsy are associated with significant disability and substantial treatment costs, yet little is known about primary prevention. We prospectively examined the association of cigarette smoking, caffeine use, and alcohol intake with risk of seizure or epilepsy among women, aged 25-42 years, in the Nurses’ Health Study II.
Participants provided dietary and cigarette smoking information on multiple questionnaires beginning in 1989. Among 116,363 women at-risk for incident seizure or epilepsy, we confirmed 95 cases of seizure and 151 cases of epilepsy occurring from 1989 to 2005 using information from a detailed supplementary questionnaire and medical records. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression.
Compared with never smoking, current cigarette smoking was associated with an increased risk of seizure (RR 2.60, 95% CI 1.53-4.42), after adjustment for stroke and other potential confounding factors. Past smoking was not associated with risk of seizure, but was associated with modestly increased risk of epilepsy (RR 1.46, 95% CI 1.01-2.12). Long-term caffeine and moderate alcohol intake were not associated with seizure or epilepsy.
Cigarette smoking may be associated with increased risk of seizure. More prospective studies are needed to investigate potential factors to ultimately prevent the development of seizures or epilepsy.
PMCID: PMC3090289  PMID: 19694796
risk factors; epilepsy; seizures; epidemiology; smoking; alcohol; caffeine
25.  Incidence and Remission of Urinary Incontinence in Middle-aged Women 
To describe changes in urinary incontinence in middle-aged women.
Study Design
A prospective analysis of 64,650 women aged 36 to 55 years in the Nurses’ Health Study II. Participants reported urine leaking in 2001 and 2003. Among continent women, we estimated 2-year incidence proportions; among incontinent women, we estimated proportions with remission.
The 2-year incidence of incontinence was 13.7%. Incidence generally increased through age 50 years, then declined slightly between ages 51 and 55 years. Among women with incident incontinence at least once per week, the 2-year incidence of stress incontinence was 1.7%; this incidence increased through age 50 years. The incidence of urge incontinence was stable across age groups (overall 2-year incidence=0.4%). Complete remission of symptoms occurred in 13.9% of women with incontinence at baseline; remission was more common in younger than older women.
In our study, both incident urinary incontinence and remission of symptoms were common.
PMCID: PMC3025861  PMID: 17689637
Urinary Incontinence; Epidemiology; Incidence

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