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1.  Lower Levels of Sodium Intake and Reduced Cardiovascular Risk 
Circulation  2014;129(9):981-989.
Recent studies have raised the possibility of adverse effects of low sodium, particularly less than 2300 mg/24hr, on cardiovascular disease (CVD). However, these paradoxical findings might have resulted from suboptimal measurement of sodium and potential biases related to indication or reverse causation.
Methods and Results
Phases I and II of the Trials of Hypertension Prevention (TOHP) collected multiple 24-hour urine specimens among pre-hypertensive individuals. During extended post-trial surveillance, 193 cardiovascular events or CVD deaths occurred among 2275 participants not in a sodium reduction intervention with 10 (TOHP II) or 15 (TOHP I) years of post-trial follow-up. Median sodium excretion was 3630 mg/24hr, with 1.4% of the participants having intake <1500 mg/24hr and 10% <2300 mg/24hr, consistent with national levels. Compared to those with sodium excretion of 3600 to <4800 mg/24hr, risk for those with sodium <2300 mg/24hr was 32% lower after multivariable adjustment (HR=0.68, 95%CI = 0.34–1.37, p for trend = 0.13). There was a linear 17% increase in risk per 1000 mg/24hr (p=0.05). Spline curves supported a linear association of sodium with cardiovascular events, continuing to descend from 3600 to 2300 and 1500 mg/24hr, although the data were sparse at the lowest levels. Controlling for creatinine levels had little effect on these results.
Results from the TOHP studies, which overcome the major methodological challenges of prior studies, are consistent with overall health benefits of reducing sodium intake to the 1500 to 2300 mg/day range in the majority of the population, in agreement with current dietary guidelines.
PMCID: PMC4181831  PMID: 24415713
sodium; salt intake; cardiovascular disease prevention; nutrition; diet
2.  Alternate-Day Low-Dose Aspirin and Cancer Risk: Long-term Observational Follow-up of a Randomized Trial 
Annals of internal medicine  2013;159(2):77-85.
Observational studies and meta-analyses of trials suggest daily aspirin use may affect cancer risk, particularly for colorectal cancer, but evidence regarding alternate-day use is scant.
To examine the association between long-term use of alternate-day low-dose aspirin and cancer incidence in healthy women.
Observational follow-up of a randomized controlled trial.
U.S. female health professionals.
39,876 women aged 45 and over in the Women’s Health Study, 33,682 of whom continued observational follow-up.
100 mg of aspirin or placebo administered every other day until March 2004, with a median 10-year follow-up. Post-trial observational follow-up continued through March 2012.
Incidence of cancer.
5,071 cancers were confirmed throughout follow-up, including 2,070 breast, 451 colorectal, 431 lung cancers, and 1,391 cancer deaths. Over the entire follow-up there was no overall effect of aspirin on total (hazard ratio (HR) = 0.97, 95% confidence interval (CI) = 0.92-1.03, p=0.31), breast (HR=0.98, 95% CI = 0.90-1.07 p=0.65) or lung (HR=1.04, 95% CI = 0.86-1.26, p=0.67) cancer. Incidence of colorectal cancer was lower in the aspirin group (HR=0.80, 95% CI = 0.67-0.97, p=0.021), primarily due to a reduction in proximal colon cancer (HR=0.73, 95% CI = 0.55-0.95, p=0.022), with the effect emerging after 10 years. The post-trial reduction in colorectal cancer was 42% (HR=0.58, 95% CI = 0.42-0.80, p<0.001). There was no extended effect on cancer deaths or colorectal polyps. There were more reported gastrointestinal bleeds (HR=1.14, 95% CI=1.06-1.22, p<0.001) and peptic ulcers (HR=1.17, 95% CI=1.09-1.27, p<0.001) in the aspirin group.
Data were available only for women. Not all women received extended follow-up, and the possibility of ascertainment bias post-trial cannot be ruled out. Gastrointestinal bleeding, peptic ulcer, and polyp information was obtained only from self-report during extended follow-up.
Long-term use of alternate-day, low-dose aspirin may reduce risk for colorectal cancer in healthy women.
PMCID: PMC3713531  PMID: 23856681
3.  The Use and Magnitude of Reclassification Measures for Individual Predictors of Global Cardiovascular Risk 
Annals of internal medicine  2009;150(11):795-802.
Models for risk prediction are widely used in clinical practice to risk stratify and assign treatment strategies. The contribution of new biomarkers has largely been based on the area under the receiver operating characteristic curve, but this measure can be insensitive to important changes in absolute risk. Methods based on risk stratification have recently been proposed to compare predictive models. These include the reclassification calibration statistic, the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI). This work demonstrates the use of reclassification measures, and illustrates their performance for well-known cardiovascular risk predictors in a cohort of women. These measures are targeted at evaluating the potential of new models and markers to change risk strata and alter treatment decisions.
PMCID: PMC2782591  PMID: 19487714
4.  Clinically Relevant Measures of Fit? A Note of Caution 
American Journal of Epidemiology  2012;176(6):488-491.
Risk reclassification methods have become popular in the medical literature as a means of comparing risk prediction models. In this issue of the Journal, Pencina et al. (Am J Epidemiol. 2012;176(6):492–494) present further results for continuous measures of model discrimination and describe their characteristics in nested models with normally distributed variables. Measures include the change in the area under the receiver operating characteristic curve, the integrated discrimination improvement, and the continuous net reclassification improvement. Although theoretically interesting, these continuous measures may not be the most appropriate to assess clinical utility. The continuous net reclassification improvement, in particular, is a measure of effect rather than model improvement and can sometimes exhibit erratic behavior, as illustrated in 2 examples. Caution is needed before using this as a measure of improvement. Further, the test of the continuous net reclassification improvement and that for the integrated discrimination improvement are similar to the likelihood ratio test in nested models and may be overinterpreted. Reclassification in risk strata, while requiring thresholds, may be more relevant clinically with its ability to examine potential changes in treatment decisions.
PMCID: PMC3530355  PMID: 22875759
calibration; discrimination; model fit; risk prediction
5.  Clinical Utility of Lp-PLA2 for Cardiovascular Disease Prediction in a Multiethnic Cohort of Women 
Clinical chemistry  2012;58(9):1352-1363.
Findings regarding the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass with incident cardiovascular disease (CVD) have been inconsistent, and their role in risk prediction is uncertain.
A case-cohort sample from the Women’s Health Initiative Observational Study (WHI-OS) comprised 1,821 CVD cases and a subcohort of 1,992. Cox regression models with inverse sampling weights assessed the association of Lp-PLA2 mass and activity with CVD (myocardial infarction [MI], stroke, and CVD mortality).
Subcohort means were 184.3 mmol/min/mL for Lp-PLA2 activity and 499.2 ng/mL for Lp-PLA2 mass, with 99% having mass above 200 ng/mL, the clinically recommended cut-point. Both activity and mass were positively associated with incident CVD in age- and race/ethnicity-adjusted analyses. Following adjustment by CVD risk factors, the association with activity became null (hazard ratio [HR] = 1.02 for top vs. bottom quartile, 95% confidence interval [CI] = 0.79-1.33, p-trend=0.65), but the association with mass remained (HR = 1.84, 95% CI = 1.45-2.34, p-trend <0.0001). In contrast to blood pressure, HDL, and hsCRP, reclassification statistics for Lp-PLA2 mass did not suggest improvement for overall CVD after full adjustment.
In the WHI-OS Lp-PLA2 mass, but not activity, was independently associated with CVD. However, model fit did not significantly improve with Lp-PLA2, and assay calibration remains a clinical concern.
PMCID: PMC3621122  PMID: 22859728
6.  Comparison of the Framingham and Reynolds Risk Scores for Global Cardiovascular Risk Prediction in the Multiethnic Women’s Health Initiative 
Circulation  2012;125(14):1748-1756.
Framingham-based and Reynolds risk scores for cardiovascular disease (CVD) prediction have not been directly compared in an independent validation cohort.
Methods and Results
We selected a case-cohort sample of the multi-ethnic Women’s Health Initiative Observational Cohort, comprising 1722 cases of major CVD (752 MIs, 754 ischemic strokes, and 216 other CVD deaths) and a random subcohort of 1994 women without prior CVD. We estimated risk using the ATP-III score, the Reynolds risk score, and the Framingham CVD model, reweighting to reflect cohort frequencies. Predicted 10-year risk varied widely between models, with 10% or higher risk in 6%, 10%, and 41% of women using the ATP-III, Reynolds, and Framingham CVD models, respectively. Calibration was adequate for the Reynolds model, but the ATP-III and Framingham CVD models over-estimated risk for CHD and major CVD, respectively. After recalibration, the Reynolds model demonstrated improved discrimination over the ATP-III model through a higher c-statistic (0.765 vs. 0.757, p=0.03), positive net reclassification improvement (NRI) (4.9%, p=0.02) and positive integrated discrimination improvement (IDI) (4.1%, p<0.0001) overall, excluding diabetics (NRI=4.2%, p=0.01), and in white (NRI=4.3%, p=0.04) and black (NRI=11.4, p=0.13) women. The Reynolds (NRI=12.9, p<0.0001) and ATP-III (NRI=5.9%, p=0.0001) models demonstrated better discrimination than the Framingham CVD model.
The Reynolds Risk Score was better calibrated than the Framingham-based models in this large external validation cohort. The Reynolds score also showed improved discrimination overall and in black and white women. Large differences in risk estimates exist between models, with clinical implications for statin therapy.
PMCID: PMC3324658  PMID: 22399535
cardiovascular disease risk factors; models; prediction; risk score; statins
7.  Multi-Ancestral Analysis of Inflammation-Related Genetic Variants and C-Reactive Protein in the Population Architecture using Genomics and Epidemiology (PAGE) Study 
C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
Methods and Results
We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40,473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected p<3.1×10−3 for replication, p<2.0×10−4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (p=2.0×10−6) and rs646776 (p=3.1×10−5).
We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and LDL cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups, and of looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
PMCID: PMC4104750  PMID: 24622110
genetic epidemiology; inflammation; C-reactive protein; race and ethnicity; single nucleotide polymorphism; pleiotropy
8.  Assessing the Incremental Role of Novel and Emerging Risk Factors 
Many novel and emerging risk factors exhibit a significant association with cardiovascular disease, but have not been found to improve risk prediction. Statistical criteria used to evaluate such models and markers have largely relied on the receiver operating characteristic curve, which is an insensitive measure of improvement. Recently, new methods have been developed based on risk reclassification, or changes in risk strata following use of a new marker or model. Associated measures based on both calibration and discrimination have been proposed. This review describes previous methods used to evaluate models as well as the newly developed methods to evaluate clinical utility.
PMCID: PMC2904250  PMID: 20640227
9.  Mammographic Screening and Risk Factors for Breast Cancer 
American Journal of Epidemiology  2009;170(11):1422-1432.
Screening mammography can distort estimated effects in breast cancer risk models due to associations with other risk factors. Mammography information was available in the Nurses’ Health Study from 1988, and 1,815 incident breast cancers were accrued through 2000 among 55,625 women with risk factor data. Logistic models were fit for screening mammography, and inverse probability weighting was used to adjust parameters in an established breast cancer risk model. Approximately 80% of women in each 2-year follow-up period had screening mammograms, which were positively associated with history of benign breast disease, family history of breast cancer, hormone therapy, alcohol use, physical activity, multivitamins, and calcium supplements, and negatively associated with postmenopause, current smoking, and body mass index. Markers of medical attention, including hypertension, high cholesterol, and osteoarthritis, were positively associated, while cardiovascular disease was negative. Inverse probability weighting led to small changes in effects of benign breast disease, family history, and hormone therapy. An apparent reduced risk associated with current smoking in unadjusted models was eliminated after weighting. Thus, several risk factors for breast cancer and cancer diagnosis are associated with mammographic screening. Adjustment for screening had some impact on breast cancer prediction in this cohort, especially for hormone therapy and smoking.
PMCID: PMC2800262  PMID: 19875646
breast neoplasms; hormone replacement therapy; mammography; mass screening; probability weighting; risk factors
10.  CVD Risk Prediction in Women: Is There a Role for Novel Biomarkers? 
Clinical chemistry  2013;60(1):10.1373/clinchem.2013.202796.
Risk prediction is an integral part of the current US guidelines for cardiovascular disease in women. While current risk prediction algorithms exist to identify women at elevated 10-year risk of cardiovascular disease (CVD), clinicians and researchers have been interested in developing novel biomarkers that might improve predictive accuracy further. These biomarkers have led to important insights in the pathophysiology of CVD, but their ability to improve prediction or guide preventive therapy has been more mixed. Women have a lower incidence of CVD than men and the effect of a number of traditional biomarkers on CVD risk differs. Both of these factors influence the ability to accurately predict CVD risk.
In this article, we review the distinctive aspects of CVD risk prediction in women, discuss the statistical challenges to improved risk prediction, and discuss a number of biomarkers in varying stages of development with a range of performance in prediction.
A variety of biomarkers from different pathophysiologic pathways have evaluated for improving CVD risk. While many have been incompletely studied or have not been shown to improve risk prediction in women, others, such as high sensitivity troponin T, have shown promise in improving risk prediction. Increasing inclusion of women in CVD studies will be crucial to providing opportunities to evaluate future biomarkers.
PMCID: PMC3877731  PMID: 24100805
11.  A Randomized Trial of Long-term Multivitamin Supplementation and Cognitive Function in Men: The Physicians’ Health Study II 
Annals of internal medicine  2013;159(12):806-814.
Despite widespread use of multivitamin supplements, their effect on cognitive health – a critical issue with aging – remains inconclusive. To date, there have been no long-term clinical trials to study multivitamin use and cognitive decline in older persons.
To evaluate whether long-term multivitamin supplementation affects cognitive health in later-life.
Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to June 1, 2011. The cognitive function sub-study began in 1998; we completed up to four repeated cognitive assessments by telephone interview over 12 years.
The Physicians’ Health Study II.
5,947 male physicians aged ≥ 65 years.
Daily multivitamin, or placebo.
A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary endpoint was a verbal memory score combining 4 tests of verbal memory, a strong predictor of Alzheimer disease.
There was no difference in the mean cognitive change over time between the multivitamin and placebo groups, or in the mean level of cognition at any of the four assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was −0.01 (95% confidence interval [CI] −0.04, 0.02) standard units, comparing treatment versus placebo. Similarly, there was no difference in cognitive performance between the treated and placebo groups on the secondary outcome, verbal memory (e.g., mean difference in cognitive change over follow-up=−0.005, 95% CI −0.04, 0.03).
Doses of vitamins may be too low, or population may be too well-nourished to benefit from multivitamin.
In male physicians aged ≥ 65 years, long-term use of a daily multivitamin did not provide cognitive benefits.
Trial Registration identifier: NCT00270647
PMCID: PMC3858850  PMID: 24490265
multivitamin; cognitive function; randomized clinical trial; men
12.  Lifestyle‐Based Prediction Model for the Prevention of CVD: The Healthy Heart Score 
Clinical practice focuses on the primary prevention of cardiovascular (CV) disease (CVD) through the modification and pharmacological treatment of elevated risk factors. Prediction models based on established risk factors are available for use in the primary prevention setting. However, the prevention of risk factor development through healthy lifestyle behaviors, or primordial prevention, is of paramount importance to achieve optimal population‐wide CV health and minimize long‐term CVD risk.
Methods and Results
We developed a lifestyle‐based CVD prediction model among 61 025 women in the Nurses’ Health Study and 34 478 men in the Health Professionals Follow‐up Study, who were free of chronic disease in 1986 and followed for ≤24 years. Lifestyle factors were assessed by questionnaires in 1986. In the derivation step, we used the Bayes Information Criterion to create parsimonious 20‐year risk prediction models among a random two thirds of participants in each cohort separately. The scores were validated in the remaining one third of participants in each cohort. Over 24 years, there were 3775 cases of CVD in women and 3506 cases in men. The Healthy Heart Score included age, smoking, body mass index, exercise, alcohol, and a composite diet score. In the validation cohort, the risk score demonstrated good discrimination (Harrell's C‐index, 0.72; 95% confidence interval [CI], 0.71, 0.74 [women]; 0.77; 95% CI, 0.76, 0.79 [men]), fit, and calibration, particularly among individuals without baseline hypertension or hypercholesterolemia.
The Healthy Heart Score accurately identifies individuals at elevated risk for CVD and may serve as an important clinical and public health screening tool for the primordial prevention of CVD.
PMCID: PMC4338684  PMID: 25398889
epidemiology; lifestyle; nutrition; prevention; risk assessment
13.  Alanine for Proline Substitution in the Peroxisome Proliferator–Activated Receptor Gamma-2 (PPARG2) Gene and the Risk of Incident Myocardial Infarction 
Recent studies have implicated the potential importance of peroxisome proliferator–activated receptors as a molecular mechanism involved in atherothrombosis. A common alanine (A) for proline (P) substitution at codon 12 in the peroxisome proliferator activated receptor gamma-2 gene (PPARG2) has been associated with reduced risk of developing type 2 diabetes mellitus. Because diabetes and atherothrombosis share common antecedents, we sought evidence that this polymorphism might also be associated with reduced risk of myocardial infarction.
Methods and Results
Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated a P12A polymorphism in the PPARG2 among 523 individuals who subsequently developed myocardial infarction and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. As hypothesized, presence of the A12 allele was associated with significantly reduced risk of myocardial infarction (odds ratio in an age- and smoking-adjusted dominant model of inheritance, 0.77; 95% CI, 0.60 to 0.98; P=0.034). This protective effect remained statistically significant in analyses controlling for traditional cardiovascular risk factors, was present among nondiabetic study participants, was observed to be of similar magnitude in analyses assuming codominant or dominant modes of inheritance, and was seen in fully adjusted post hoc analyses in which we limited our control group to those individuals specifically matched to myocardial infarction cases (OR, 0.71; 95% CI, 0.53 to 0.96; P=0.024).
In this cohort, a common A for P substitution at codon 12 in the PPARG2 was associated with reduced incidence of myocardial infarction. If confirmed in other cohorts, these data would have implications for novel treatments of cardiovascular disease, including development of PPARG-targeted therapy.
PMCID: PMC4231712  PMID: 12663371
genetics; epidemiology; myocardial infarction; risk prediction; polymorphism
14.  A Randomized Factorial Trial of Vitamins C, E, and Beta-Carotene in the Secondary Prevention of Cardiovascular Events in Women 
Archives of internal medicine  2007;167(15):1610-1618.
Randomized trials have largely failed to support an effect of antioxidant vitamins on risk of cardiovascular disease (CVD). Few trials have examined interactions among antioxidants, and no previous trial has examined the individual effect of vitamin C on CVD.
WACS tested the effects of vitamins C (500 mg daily), E (600 IU every other day), and beta-carotene (50 mg every other day) on the combined outcome of myocardial infarction (MI), stroke, coronary revascularization, or CVD death among 8,171 female health professionals at increased risk in a 2×2×2 factorial design. Participants were 40 years or older with a prior history of CVD or three or more CVD risk factors, and were followed an average 9.4 years, from 1995-96 to 2005.
1,450 women experienced one or more CVD outcomes. There was no overall effect of vitamin C (RR=1.02, 95% CI=0.92-1.13, p=0.71), vitamin E (RR=0.94, 95% CI=0.85-1.04, p=0.23), or beta-carotene (RR=1.02, 95% CI=0.92-1.13, p=0.71) on the primary combined endpoint, or on the individual secondary outcomes of MI, stroke, coronary revascularization, or CVD death. A marginally significant reduction in the primary outcome with active vitamin E was observed among the pre-specified subgroup of women with prior CVD (RR=0.89, 95% CI=0.79-1.00, p=0.04; p-interaction=0.07). There were no significant interactions between agents for the primary endpoint, but those randomized to both active vitamin C and E experienced fewer strokes (p for interaction=0.03).
There were no overall effects of vitamins C, E or beta-carotene on cardiovascular events among women at high risk for CVD.
Trial Registration Identifier: NCT00000541
PMCID: PMC2034519  PMID: 17698683
15.  Seafood Types and Age-Related Cognitive Decline in the Women’s Health Study 
Seafood consumption may prevent age-related cognitive decline. However, benefits may vary by nutrient contents in different seafood types. We examined associations between total seafood consumption and cognitive decline and whether these associations differ by seafood types.
We conducted a prospective cohort study of 5,988 women (mean age, 72 years) from the Women’s Health Study who self-reported seafood intake at Women’s Health Study baseline and also participated in telephone assessments of general cognition, verbal memory, and category fluency administered 5.6 years after Women’s Health Study baseline and 2 and 4 years thereafter. Primary outcomes were standardized composite scores of global cognition and verbal memory.
After adjusting for potential confounders, different amounts of total seafood consumption were not associated with changes in global cognition (p = .56) or verbal memory (p = .29). Considering seafood types, however, compared with women consuming less than once-weekly tuna or dark-meat finfish, those with once-weekly or higher consumption had significantly better verbal memory (0.079 standard units; p < .01) after 4 years—a difference comparable to that for women 2.1 years apart in age. There was also a statistically nonsignificant suggestion of better global cognition (p = .13) with once-weekly or higher tuna or dark-meat fish consumption. No significant associations were observed for light-meat finfish or shellfish.
The relation of seafood to cognition may depend on the types consumed. Total consumption levels of seafood were unrelated to cognitive change. However, consumption of tuna and dark-meat fish once weekly or higher was associated with lower decline in verbal memory for a period of 4 years.
PMCID: PMC3779629  PMID: 23554464
Cognition; Epidemiology; Nutrition.
16.  Dietary Glycemic Load and Breast Cancer Risk in the Women’s Health Study 
A diet with a high glycemic load (GL) may contribute to a metabolic environment that enhances tumorigenesis. Little is known, however, about whether high glycemic diets increase breast cancer risk in women. We examined the associations between baseline measurements of dietary GL and overall glycemic index (GI) and subsequent breast cancer in a cohort of 39,876 women, ages 45 years or older, participating in the Women’s Health Study. During a mean of 6.8 years of follow-up there were 946 confirmed cases of breast cancer. We found no association between dietary GL [multivariable-adjusted relative risk (RR), 1.01; confidence interval (CI), 0.76–1.35, comparing extreme quintiles; P for trend = 0.96] or overall GI (corresponding RR, 1.03; CI, 0.84–1.28; P for trend = 0.66) and breast cancer risk in the cohort as a whole. Exploratory analyses stratified by baseline measurements of menopausal status, physical activity, smoking history, alcohol use, and history of diabetes mellitus, hypertension, or hypercholesterolemia showed no significant associations, except in the subgroup of women who were premenopausal and reported low levels of physical activity (GL multivariable-adjusted RR, 2.35; CI, 1.03–5.37; P for trend = 0.07; GI multivariable-adjusted RR, 1.56; CI, 0.88–2.78; P for trend = 0.02, comparing extreme quintiles). Although we did not find evidence that a high glycemic diet increases overall breast cancer risk, the increase in risk in premenopausal women with low levels of physical activity suggests the possibility that the effects of a high glycemic diet may be modified by lifestyle and hormonal factors. Prospective studies of a larger sample size and longer duration are warranted to confirm our findings.
PMCID: PMC4166477  PMID: 14744735
17.  Dietary Glycemic Load and Risk of Colorectal Cancer in the Women’s Health Study 
Although diet is believed to influence colorectal cancer risk, the long-term effects of a diet with a high glycemic load are unclear. The growing recognition that colorectal cancer may be promoted by hyperinsulinemia and insulin resistance suggests that a diet inducing high blood glucose levels and an elevated insulin response may contribute to a metabolic environment conducive to tumor growth. We prospectively followed a cohort of 38 451 women for an average of 7.9 years and identified 174 with incident colorectal cancer. We used baseline dietary intake measurements, assessed with a semiquantitative food-frequency questionnaire, to examine the associations of dietary glycemic load, overall dietary glycemic index, carbohydrate, fiber, nonfiber carbohydrate, sucrose, and fructose with the subsequent development of colorectal cancer. Cox proportional hazards models were used to estimate relative risks (RRs). Dietary glycemic load was statistically significantly associated with an increased risk of colorectal cancer (adjusted RR = 2.85, 95% confidence interval [CI] = 1.40 to 5.80, comparing extreme quintiles of dietary glycemic load; Ptrend = .004) and was associated, although not statistically significantly, with overall glycemic index (corresponding RR = 1.71, 95% CI = 0.98 to 2.98; Ptrend = .04). Total carbohydrate (adjusted RR = 2.41, 95% CI = 1.10 to 5.27, comparing extreme quintiles of carbohydrate; Ptrend = .02), nonfiber carbohydrate (corresponding RR = 2.60, 95% CI = 1.22 to 5.54; Ptrend = .02), and fructose (corresponding RR = 2.09, 95% CI = 1.13 to 3.87; Ptrend = .08) were also statistically significantly associated with increased risk. Thus, our data indicate that a diet with a high dietary glycemic load may increase the risk of colorectal cancer in women.
PMCID: PMC4165491  PMID: 14759990
18.  Childhood Blood Pressure Trends and Risk Factors for High Blood Pressure: The NHANES experience 1988–2008 
Hypertension  2013;62(2):247-254.
The obesity epidemic in children makes it plausible that prevalence rates of elevated blood pressure are increasing over time. Yet, previous literature is inconsistent due to small sample sizes. Also, it is unclear whether adjusting for risk factors can explain longitudinal trends in prevalence of elevated blood pressure. Thus, we analyzed a population-based sample of 3,248 children in National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and 8,388 children in continuous NHANES (1999–2008), ages 8–17. Our main outcome measure was elevated blood pressure (systolic blood pressure (SBP) or diastolic blood pressure (DBP) ≥ 90th percentile or SBP/DBP ≥ 120/80mmHg). We found that the prevalence of elevated blood pressure (bp) increased from NHANES III to NHANES 99-08 (Boys: 15.8% to 19.2%, p=0.057; Girls: 8.2% to 12.6%, p=0.007). Body mass index (BMI) (Q4 vs Q1, Odds Ratio (OR) =2.00, p<0.001), waist circumference (Q4 vs Q1, OR=2.14, p<0.001) and sodium (Na) intake (≥3,450mg vs <2,300mg/2,000 calories, OR=1.36, p=0.024) were independently associated with prevalence of elevated blood pressure. Also, mean SBP, but not DBP was associated with increased Na intake in children (quintile 5 (Q5) vs. quintile 1 (Q1) of Na intake, Beta = 1.25 ± 0.58, p=0.034). In conclusion, we demonstrate an association between high Na intake and elevated bp in children. After adjustment for age, gender, race/ethnicity, BMI, waist circumference and sodium intake, OR for elevated bp in NHANES 99-08 vs. NHANES III = 1.27, p=0.069.
PMCID: PMC3769135  PMID: 23856492
blood pressure; body mass index; NHANES; nutrition; pediatrics; sodium intake; waist circumference
19.  Mediterranean diet and cognitive function in older age: results from the Women’s Health Study 
Epidemiology (Cambridge, Mass.)  2013;24(4):490-499.
Adherence to a Mediterranean diet may help prevent cognitive decline in older age, but studies are limited. We examined the association of adherence to the Mediterranean diet with cognitive function and decline.
We included 6,174 participants, aged 65+ years, from the cognitive sub-study of the Women’s Health Study. Women provided dietary information in 1998 and completed a cognitive battery 5 years later, followed by two assessments at 2-year intervals. The primary outcomes were composite scores of global cognition and verbal memory. The alternate Mediterranean diet adherence 9-point-score was constructed based on intakes of: vegetables, fruits, legumes, whole grains, nuts, fish, red and processed meats, moderate alcohol, and the ratio of monounsaturated-to-saturated fats.
After multivariable adjustment, the alternate Mediterranean diet score was not associated with trajectories of repeated cognitive scores (P-trend across quintiles=0.26 and 0.40 for global cognition and verbal memory, respectively), nor with overall global cognition and verbal memory at older ages, assessed by averaging the three cognitive measures (P-trend=0.63 and 0.44, respectively). Among alternate Mediterranean diet components, higher monounsaturated-to-saturated fats ratio was associated with more favorable cognitive trajectories (P-trend=0.03 and 0.05 for global cognition and verbal memory, respectively). Greater whole grain intake was not associated with cognitive trajectories, but was related to better average global cognition (P-trend=0.02).
In this large study of older women, we observed no association of the Mediterranean diet with cognitive decline. Relations between individual Mediterranean diet components, particularly whole grains, and cognitive function merit further study.
PMCID: PMC3674216  PMID: 23676264
20.  Effectiveness and Cost-Effectiveness of Blood Pressure Screening in Adolescents in the United States 
The Journal of pediatrics  2010;158(2):257-64.e1-7.
To compare the long-term effectiveness and cost-effectiveness of 3 approaches to managing elevated blood pressure (BP) in adolescents in the United States: no intervention, “screen-and-treat,” and population-wide strategies to lower the entire BP distribution.
Study design
We used a simulation model to combine several data sources to project the lifetime costs and cardiovascular outcomes for a cohort of 15-year-old U.S. adolescents under different BP approaches and conducted cost-effectiveness analysis. We obtained BP distributions from the National Health and Nutrition Examination Survey 1999–2004 and used childhood-to-adult longitudinal correlation analyses to simulate the tracking of BP. We then used the coronary heart disease policy model to estimate lifetime coronary heart disease events, costs, and quality-adjusted life years (QALY).
Among screen-and-treat strategies, finding and treating the adolescents at highest risk (eg, left ventricular hypertrophy) was most cost-effective ($18 000/QALY [boys] and $47 000/QALY [girls]). However, all screen-and-treat strategies were dominated by population-wide strategies such as salt reduction (cost-saving [boys] and $650/ QALY [girls]) and increasing physical education ($11 000/QALY [boys] and $35 000/QALY [girls]).
Routine adolescents BP screening is moderately effective, but population-based BP interventions with broader reach could potentially be less costly and more effective for early cardiovascular disease prevention and should be implemented in parallel.
PMCID: PMC4007283  PMID: 20850759
21.  Physical Activity, Genes for Physical Fitness, and Risk of Coronary Heart Disease 
Both physical activity and physical fitness are associated with decreased coronary heart disease (CHD) risk. Our objective was to determine whether genes associated with physical fitness modify the association between physical activity and CHD.
We conducted a prospective cohort study among 23,016 initially healthy women in the Women’s Genome Health Study. Leisure-time physical activity was reported at entry and during follow-up. 58 single nucleotide polymorphisms associated with physical fitness were identified from published literature and summed to create four separate genetic scores related to phenotypes of endurance, muscle strength, VO2max, and overall fitness.
During a median of 14.4 years, 320 incident CHD events occurred. Increased physical activity was associated with lower CHD risk in multivariable-adjusted models (P = 0.0008). Independent of physical activity, only muscle strength genetic score was inversely associated with CHD risk (P = 0.05). There was no evidence that the inverse relation between physical activity and CHD was modified by any of the genetic scores for physical fitness. For overall fitness genetic score, the hazard ratio (HR) per 500 kcal/week of physical activity was 0.85 (95% CI: 0.72, 1.00) in the highest quartile of genetic score; 0.79 (95% CI: 0.67, 0.92) in the lowest quartile (P, interaction = 0.50). For VO2max genetic score, the HR was 0.86 (95% CI 0.72, 1.02) and 0.84 (95% CI 0.72, 0.98), respectively (P, interaction = 0.59).
In this large prospective cohort of women, genes associated with physical fitness did not modify the inverse association between physical activity and CHD risk.
PMCID: PMC3605203  PMID: 23073218
exercise; epidemiology; genetics; cardiovascular disease
22.  A Bias Corrected Net Reclassification Improvement for Clinical Subgroups 
Comparing prediction models using reclassification within subgroups at intermediate risk is often of clinical interest.
To demonstrate a method for obtaining an unbiased estimate for the Net Reclassification Improvement (NRI) evaluated only on a subset, or the clinical NRI. Study Design and Setting: We derived the expected value of the clinical NRI under the null hypothesis using the same principles as the overall NRI. We then conducted a simulation study based on a logistic model with a known predictor and a potential predictor, varying the effects of the known and potential predictors to test the performance of our bias-corrected clinical NRI measure. Finally, data from the Women’s Health Study, a prospective cohort of 24,171 female health professionals, were used as an example of the proposed method.
Our bias-corrected estimate is shown to have a mean of zero in the null case under a range of simulated parameters and, unlike the naïve estimate, to be unbiased. We also provide two methods for obtaining a variance estimate, both with reasonable type 1 errors.
Our proposed method is an improvement over currently used methods of calculating the clinical NRI and is recommended to reduce overly optimistic results.
PMCID: PMC3605042  PMID: 23042826
23.  Decision Making in Advanced Heart Failure A Scientific Statement From the American Heart Association 
Circulation  2012;125(15):1928-1952.
PMCID: PMC3893703  PMID: 22392529
AHA Scientific Statements; communication; decision making; heart failure; heart-assist device; palliative care; prognosis; transplantation
24.  Patterns of deficits in brain function in bipolar disorder and schizophrenia: a cluster analytic study 
Psychiatry research  2012;200(2-3):272-280.
Historically, bipolar disorder and schizophrenia have been considered distinct disorders with different etiologies. Growing evidence suggests that overlapping genetic influences contribute to risk for these disorders and that each disease is genetically heterogeneous. Using cluster analytic methods, we empirically identified homogeneous subgroups of patients, their relatives, and controls based on distinct neurophysiologic profiles. Seven phenotypes were collected from two independent cohorts at two institutions. K-means clustering was used to identify neurophysiologic profiles. In the analysis of all participants, three distinct profiles emerged: “globally impaired”, “sensory processing”, and “high cognitive”. In a secondary analysis, restricted to patients only, we observed a similar clustering into three profiles. The neurophysiological profiles of the SZ and BPD patients did not support the DSM diagnostic distinction between these two disorders. Smokers in the globally impaired group smoked significantly more cigarettes than those in the sensory processing or high cognitive groups. Our results suggest that empirical analyses of neurophysiological phenotypes can identify potentially biologically relevant homogenous subgroups independent of diagnostic boundaries. We hypothesize that each neurophysiology subgroup may share similar genotypic profiles, which may increase statistical power to detect genetic risk factors.
PMCID: PMC3535009  PMID: 22925372
bipolar disorder; schizophrenia; K-means clustering; neurophysiologic profiles
25.  Effect of Combined Folic Acid, Vitamin B6, and Vitamin B12 on Colorectal Adenoma 
Folic acid, vitamin B6, and vitamin B12 act in concert in the one-carbon metabolism and may protect against colorectal neoplasia. We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma.
The Women’s Antioxidant and Folic Acid Cardiovascular Study was a randomized, double-blind, placebo-controlled trial of 5442 female health professionals at high risk for cardiovascular disease from April 1998 through July 2005. Participants were randomly assigned to receive a combination pill of folic acid (2.5mg), vitamin B6 (50mg), and vitamin B12 (1mg) or placebo. This study included 1470 participants who were followed up for as long as 9.2 years and underwent an endoscopy at any point during follow-up. We estimated relative risks using a generalized linear model with a natural logarithm link function and Poisson distributed errors. All statistical tests were two-sided.
The risk of colorectal adenoma was similar among participants receiving treatment (24.3%, 180 of 741 participants) vs placebo (24.0%, 175 of 729 participants) (multivariable adjusted relative risk = 1.00, 95% confidence interval = 0.83 to 1.20). Treatment was not associated with the risk of adenoma when data were analyzed by subsite, size, stage, and the number of adenomas. There was no statistically significant effect modification by alcohol intake, history of cancer or adenoma, or baseline plasma levels or intakes of folate, vitamin B6, or vitamin B12.
Our results indicate no statistically significant effect of combined folic acid, vitamin B6, and vitamin B12 treatment on colorectal adenoma among women at high risk for cardiovascular disease.
PMCID: PMC3611818  PMID: 23066166

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