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1.  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
2.  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
3.  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.
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  A Prospective Evaluation of B-type Natriuretic Peptide Concentrations and the Risk of Type 2 Diabetes in Women 
Clinical chemistry  2013;59(3):557-565.
Animal data suggest that natriuretic peptides play an important role in energy metabolism, but prospective studies evaluating a relationship between these peptides and type 2 diabetes mellitus (T2DM) in humans are few and results are conflicting.
We used a prospective case-cohort approach (n=491 T2DM cases, n=561 reference subcohort) within the Women's Health Study to evaluate baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and the risk of incident T2DM. We also tested for associations between 4 common variants in the natriuretic peptide A and B genes (NPPA-NPPB) and NT-proBNP concentrations (n=458) and incident type 2 diabetes (n=1372 cases among 22607 women).
Case subjects had higher median baseline body mass index (29.4 vs. 25.0 kg/m2, P<0.001) and lower baseline median (IQR) NT-proBNP concentrations [46.8 ng/L (26.1, 83.2) vs 66.7 ng/L (39.3, 124.7), P<0.001]. In proportional hazards models adjusting for established diabetes risk factors, women in the highest quartile of baseline NT-proBNP (≥117.4 ng/L) had a 49% reduction in risk of T2DM (HR 0.51, 0.30–0.86, P=0.01) relative to those in the lowest quartile. Two of the 4 tested variants in NPPA-NPPB (rs632793, rs198389) associated with increased NT-proBNP concentrations and reduced risk of T2DM. For example, each copy of the minor allele of rs632793 was associated with increased NT-proBNP (β (SE)=0.201 (0.063), P<0.01) and decreased T2DM risk (HR 0.91, 0.84–0.989, P=0.026).
NT-proBNP concentrations that are high, but still within the reference interval, associate with reduced risk of incident diabetes in women and support a favorable role for natriuretic peptides in the development of T2DM.
PMCID: PMC3694412  PMID: 23288489
Natriuretic peptides; type 2 diabetes; women; epidemiology; prevention
12.  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
13.  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
14.  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
15.  Assessing Risk Prediction Models Using Individual Participant Data From Multiple Studies 
Pennells, Lisa | Kaptoge, Stephen | White, Ian R. | Thompson, Simon G. | Wood, Angela M. | Tipping, Robert W. | Folsom, Aaron R. | Couper, David J. | Ballantyne, Christie M. | Coresh, Josef | Goya Wannamethee, S. | Morris, Richard W. | Kiechl, Stefan | Willeit, Johann | Willeit, Peter | Schett, Georg | Ebrahim, Shah | Lawlor, Debbie A. | Yarnell, John W. | Gallacher, John | Cushman, Mary | Psaty, Bruce M. | Tracy, Russ | Tybjærg-Hansen, Anne | Price, Jackie F. | Lee, Amanda J. | McLachlan, Stela | Khaw, Kay-Tee | Wareham, Nicholas J. | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Jansson, Jan-Håkan | Wennberg, Patrik | Salomaa, Veikko | Harald, Kennet | Jousilahti, Pekka | Vartiainen, Erkki | Woodward, Mark | D'Agostino, Ralph B. | Bladbjerg, Else-Marie | Jørgensen, Torben | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Dekker, Jacqueline M. | Nijpels, Giel | Stehouwer, Coen D. A. | Kauhanen, Jussi | Salonen, Jukka T. | Meade, Tom W. | Cooper, Jackie A. | Cushman, Mary | Folsom, Aaron R. | Psaty, Bruce M. | Shea, Steven | Döring, Angela | Kuller, Lewis H. | Grandits, Greg | Gillum, Richard F. | Mussolino, Michael | Rimm, Eric B. | Hankinson, Sue E. | Manson, JoAnn E. | Pai, Jennifer K. | Kirkland, Susan | Shaffer, Jonathan A. | Shimbo, Daichi | Bakker, Stephan J. L. | Gansevoort, Ron T. | Hillege, Hans L. | Amouyel, Philippe | Arveiler, Dominique | Evans, Alun | Ferrières, Jean | Sattar, Naveed | Westendorp, Rudi G. | Buckley, Brendan M. | Cantin, Bernard | Lamarche, Benoît | Barrett-Connor, Elizabeth | Wingard, Deborah L. | Bettencourt, Richele | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Kavousi, Maryam | Witteman, Jacqueline C. | Hofman, Albert | Franco, Oscar H. | Howard, Barbara V. | Zhang, Ying | Best, Lyle | Umans, Jason G. | Onat, Altan | Sundström, Johan | Michael Gaziano, J. | Stampfer, Meir | Ridker, Paul M. | Michael Gaziano, J. | Ridker, Paul M. | Marmot, Michael | Clarke, Robert | Collins, Rory | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimäki, Mika | Ridker, Paul M. | Buring, Julie | Cook, Nancy | Ford, Ian | Shepherd, James | Cobbe, Stuart M. | Robertson, Michele | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S. | Angelantonio, Emanuele Di | Gao, Pei | Haycock, Philip | Kaptoge, Stephen | Pennells, Lisa | Thompson, Simon G. | Walker, Matthew | Watson, Sarah | White, Ian R. | Wood, Angela M. | Wormser, David | Danesh, John
American Journal of Epidemiology  2013;179(5):621-632.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
PMCID: PMC3927974  PMID: 24366051
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
16.  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
17.  Vigorous-intensity leisure-time physical activity and risk of major chronic disease in men 
Although studies have shown health benefits for moderate-intensity physical activity, there is limited evidence to support beneficial effects for high amounts of vigorous activity among middle-aged and older men. The objective of this study was to examine the relationship between vigorous-intensity physical activity, compared to moderate-intensity activity, and risk of major chronic disease in men.
We prospectively examined the associations between vigorous- and moderate-intensity physical activity and risk of major chronic disease among 44,551 men aged 40–75 years in 1986. Leisure-time physical activity was assessed biennially by questionnaire. During 22 years of follow-up, we documented 14,162 incident cases of major chronic disease, including 4769 cardiovascular events, 6449 cancer events, and 2944 deaths from other causes.
The hazard ratio (HR) of major chronic disease comparing ≥ 21 to 0 MET-hours/week of exercise was 0.86 (95% CI: 0.81, 0.91) for vigorous-intensity activity and 0.85 (95% CI: 0.80, 0.90) for moderate activity. For CVD, the corresponding HR were 0.78 (95% CI: 0.70, 0.86) and 0.80 (95% CI: 0.72, 0.88), respectively. When examined separately, running, tennis, and brisk walking were inversely associated with CVD risk. Furthermore, more vigorous activity was associated with lower disease risk; the HR comparing >70 to 0 MET-hours/week of vigorous-intensity exercise was 0.79 (95% CI: 0.68, 0.92; P <0.0001 for trend) for major chronic disease and 0.73 (95% CI: 0.56, 0.96; P <0.0001 for trend) for CVD.
Vigorous- and moderate-intensity physical activity were associated with lower risk of major chronic disease and cardiovascular disease. Increasing amounts of vigorous activity remained inversely associated with disease risk, even among men in the highest categories of exercise.
PMCID: PMC3445709  PMID: 22543741
exercise; epidemiology; cardiovascular disease; cancer; risk factors
18.  Plasma Adiponectin and the Risk of Hypertension in White and Black Postmenopausal Women 
Clinical chemistry  2012;58(10):1438-1445.
Adiponectin may have a protective role in the development of obesity-related metabolic and vascular disorders including hypertension. We conducted a prospective, nested case-control study to investigate the relationship between baseline plasma adiponectin, measures of adiposity, and subsequent risk of hypertension.
We selected 400 White and 400 Black postmenopausal women, aged <70 years, who have developed incident hypertension during 5.9-year follow-up and an equal number of age and race matched controls in the Women's Health Initiative Observational Study. We measured plasma concentrations of total adiponectin in their baseline bloods.
In crude matched models, plasma adiponectin was inversely associated with risk of hypertension among both White and Black women. The association appeared to be non-linear in White women but dose-related in Black women. Adjustment for lifestyle factors, measures of obesity, and obesity-related clinical factors attenuated these associations. The multivariable relative risks (95% confidence interval) of hypertension across increasing quartiles of plasma adiponectin were 1.00, 0.98 (0.66-1.46), 0.63 (0.41-0.97), and 0.92 (0.60-1.42) in White women (p, trend: 0.38) and 1.00, 0.96 (0.64-1.46), 0.83 (0.53-1.29), and 0.58 (0.36-0.94) in Black women (p, trend: 0.02). Further adjustment for inflammatory markers and endothelial markers eliminated the association in White, but not Black, women.
In this prospective, nested case-control study, we found an inverse association between plasma adiponectin and risk of hypertension in White and Black postmenopausal women. The reduced risk of hypertension was limited to intermediate levels of adiponectin in White women while was graded across quartiles of adiponectin in Black women.
PMCID: PMC3462274  PMID: 22859729
adiponectin; hypertension; epidemiology; prospective study; postmenopausal women
19.  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
Atherosclerosis  2012;224(1):228-234.
Sex steroid hormones have been postulated to involve in blood pressure (BP) regulation. We examine the association of endogenous sex hormone levels with longitudinal change of BP and risk of developing hypertension in initially normotensive postmenopausal women.
We conducted prospective analysis among 619 postmenopausal women free of hypertension at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Change of BP and development of incident hypertension were assessed during a mean of 4.8 years follow-up.
After adjusting for age, race/ethnicity, and lifestyle factors, baseline serum estradiol (E2), total and bioavailable testosterone (T), dehydroepiandrosterone (DHEA) were each positively and sex- hormone binding globulin (SHBG) was inversely associated with risk of hypertension. Additional adjustment for body mass index eliminated the associations for E2 and T but only attenuated the associations for DHEA and SHBG. The corresponding multivariable hazard ratios (95% CIs) in the highest quartile were 1.28 (0.83–1.97) for E2, 1.38 (0.89–2.14) for total T, 1.42 (0.90–2.23) for bioavailable T, 1.54 (1.02–2.31) for DHEA, and 0.48 (0.30–0.76) for SHBG. Adjustment for fasting glucose, insulin, and C-reactive protein further attenuated the association for DHEA but not SHBG. Associations of sex hormones with longitudinal BP change were similar.
In postmenopausal women, higher endogenous E2, T, and DHEA and lower SHBG were associated with higher incidence of hypertension and greater longitudinal rise in BP. The associations for E2, T, and DHEA were mostly explained by adiposity, while the association for SHBG was independent of measures of adiposity, insulin resistance, and systemic inflammation.
PMCID: PMC3428144  PMID: 22862963
sex steroid hormones; hypertension; blood pressure; postmenopausal women; prospective study; epidemiology
21.  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
22.  Dietary fat types and 4-year cognitive change in community-dwelling older women 
Annals of Neurology  2012;72(1):124-134.
To relate dietary fat types to cognitive change in healthy community-based elders.
Among 6,183 older participants in the Women’s Health Study, we related intake of major fatty acids (FAs) (saturated [SFA], mono-unsaturated [MUFA], total poly-unsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years post-dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariable-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake.
Higher SFA intake was associated with worse global cognitive (p-linear-trend=0.008) and verbal memory (p-linear-trend=0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest vs. lowest SFA quintiles: the multivariable-adjusted odds ratio (OR) (95% confidence interval, CI) was 1.64 (1.04,2.58) for global cognition and 1.65 (1.04,2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive (p-linear-trend<0.001) and verbal memory (p-linear-trend=0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31,0.88]) and verbal memory (0.56 [0.34,0.94]). Total fat, PUFA, and trans fat intakes were not associated with cognitive trajectory.
Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, while higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging.
PMCID: PMC3405188  PMID: 22605573
23.  Aspirin in the primary prevention of cardiovascular disease in the Women’s Health Study: Effect of noncompliance 
European Journal of Epidemiology  2012;27(6):431-438.
Randomized evidence for aspirin in the primary prevention of cardiovascular disease (CVD) among women is limited and suggests at most a modest effect for total CVD. Lack of compliance, however, can null-bias estimated effects. We used marginal structural models (MSMs) to estimate the etiologic effect of continuous aspirin use on CVD events among 39,876 apparently healthy female health professionals aged 45 years and older in the Women’s Health Study, a randomized trial of 100 mg aspirin every other day versus placebo. As-treated analyses and MSMs controlled for time-varying determinants of aspirin use and CVD. Predictors of aspirin use differed by randomized group and prior use and included medical history, CVD risk factors, and intermediate CVD events. Previously reported intent-to-treat analyses found small non-significant effects of aspirin on total CVD (hazard ratio (HR) =0.91, 95% confidence interval (CI) =0.81–1.03) and CVD mortality (HR=0.95, 95% CI=0.74–1.22). As-treated analyses were similar for total CVD with a slight reduction in CVD mortality (HR=0.88, 95%CI=0.67–1.16). MSMs, which adjusted for non-compliance, were similar for total CVD (HR=0.93; 95% CI: 0.81, 1.07) but suggested lower CVD mortality with aspirin use (HR = 0.76; 95% CI: 0.54, 1.08). Adjusting for non-compliance had little impact on the estimated effect of aspirin on total CVD, but strengthened the effect on CVD mortality. These results support a limited effect of low-dose aspirin on total CVD in women, but potential benefit for CVD mortality.
PMCID: PMC3383873  PMID: 22699516
Aspirin; cardiovascular disease; marginal structural model; myocardial infarction; stroke
24.  Are we ready to recommend aspirin for the prevention of cancer? 
Lancet  2012;379(9826):1569-1571.
PMCID: PMC3415297  PMID: 22440945
25.  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

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