A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women.

Aims: To assess the joint influence of inflammatory biomarkers on the risk of incident atrial fibrillation (AF) in women.

Methods And Results: We performed a prospective cohort study among women participating in the Women's Health Study. All women were free of AF at study entry and provided a baseline blood sample assayed for high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and fibrinogen.

The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation the WHS (women's health study).

Objectives: The purpose of this study was to characterize the relationship between changes in body mass index (BMI) and incident atrial fibrillation (AF) in a large cohort of women.

Background: Obesity and AF are increasing public health problems. The importance of dynamic obesity-associated AF risk is uncertain, and mediators are not well characterized.

Common variants in cardiac ion channel genes are associated with sudden cardiac death.

Background: Rare variants in cardiac ion channel genes are associated with sudden cardiac death in rare primary arrhythmic syndromes; however, it is unknown whether common variation in these same genes may contribute to sudden cardiac death risk at the population level.

Methods And Results: We examined the association between 147 single nucleotide polymorphisms (SNPs) (137 tag, 5 noncoding SNPs associated with QT interval duration, and 5 nonsynonymous SNPs) in 5 cardiac ion channel genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, and sudden and/or arrhythmic death in a combined nested case-control analysis among 516 cases and 1522 matched control subjects of European ancestry enrolled in 6 prospective cohort studies. After accounting for multiple testing, 2 SNPs (rs2283222 located in intron 11 in KCNQ1 and rs11720524 located in intron 1 in SCN5A) remained significantly associated with sudden/arrhythmic death (false discovery rate=0.

Low-dose aspirin in the primary prevention of rheumatoid arthritis: the Women's Health Study.

Objective: Low-dose aspirin may reduce the risk of developing rheumatoid arthritis (RA) through its effect on cyclooxygenase activity and its antioxidant pathways. Previous randomized trial data have demonstrated a beneficial effect of low-dose aspirin in reducing other inflammatory diseases, such as asthma and colorectal adenomas, but no trial has evaluated the role of aspirin in RA prevention.

Methods: The Women's Health Study is a randomized, double-blind, placebo-controlled trial conducted between 1992 and 2004 designed to evaluate the risks and benefits of low-dose aspirin (100 mg every other day) and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health care professionals age > or =45 years throughout the US.

Plasma homocysteine and cysteine and risk of breast cancer in women.

Homocysteine and cysteine are associated with oxidative damage and metabolic disorders, which may lead to carcinogenesis. Observational studies assessing the association between circulating homocysteine or cysteine and breast cancer are very limited, and findings have been inconsistent. We prospectively evaluated plasma levels of homocysteine and cysteine in relation to breast cancer risk among 812 incident cases of invasive breast cancer and 812 individually matched control subjects from 28,345 women in the Women's Health Study; these women were >or=45 years old, provided blood samples, and had no history of cancer and cardiovascular disease at baseline.

Association between a literature-based genetic risk score and cardiovascular events in women.

Context: While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women.

Objective: To test the predictive ability of a literature-based genetic risk score for cardiovascular disease.

Design, Setting, And Participants: Prospective cohort of 19,313 initially healthy white women in the Women's Genome Health Study followed up over a median of 12.

Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women.

Objectives: Several lines of evidence have suggested that female hormones may lower the risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1), and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2).

Dietary, lifestyle, and clinical predictors of lipoprotein-associated phospholipase A2 activity in individuals without coronary artery disease.

Background: Elevated lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) may be positively associated with risk of coronary artery disease, yet little is known about potentially modifiable factors related to Lp-PLA(2).

Objective: The aim of this study was to determine dietary, lifestyle, and clinical measures associated with Lp-PLA(2) activity.

Design: We measured Lp-PLA(2) activity in 853 female participants of the Nurses' Health Study and 878 male participants of the Health Professionals Follow-Up Study who were free of cancer and cardiovascular disease.

Using relative utility curves to evaluate risk prediction.

Because many medical decisions are based on risk prediction models constructed from medical history and results of tests, the evaluation of these prediction models is important. This paper makes five contributions to this evaluation: (1) the relative utility curve which gauges the potential for better prediction in terms of utilities, without the need for a reference level for one utility, while providing a sensitivity analysis for missipecification of utilities, (2) the relevant region, which is the set of values of prediction performance consistent with the recommended treatment status in the absence of prediction (3) the test threshold, which is the minimum number of tests that would be traded for a true positive in order for the expected utility to be non-negative, (4) the evaluation of two-stage predictions that reduce test costs, and (5) connections among various measures of prediction performance. An application involving the risk of cardiovascular disease is discussed.

Assessing the performance of prediction models: a framework for traditional and novel measures.

The performance of prediction models can be assessed using a variety of methods and metrics. Traditional measures for binary and survival outcomes include the Brier score to indicate overall model performance, the concordance (or c) statistic for discriminative ability (or area under the receiver operating characteristic [ROC] curve), and goodness-of-fit statistics for calibration.Several new measures have recently been proposed that can be seen as refinements of discrimination measures, including variants of the c statistic for survival, reclassification tables, net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

A common variant at 9p21 is associated with sudden and arrhythmic cardiac death.

Background: Although a heritable basis for sudden cardiac death (SCD) is suggested by the impact of family history on SCD risk, common genetic determinants have been difficult to identify. We hypothesized that a common variant at chromosome 9p21 related to myocardial infarction would influence SCD risk.

Methods And Results: This was a prospective, nested, case-control analysis among individuals of European ancestry enrolled in 6 prospective cohort studies.

Mammographic screening and risk factors for breast cancer.

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.

Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and Apolipoprotein B among 6382 white women in genome-wide analysis with replication.

Background: Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.

Methods And Results: We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein(Apo) A1, and ApoB. Genome-wide associations (P < 5 x 10(-8)) were found at the PCSK9 gene, the APOB gene, theLPL gene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus.

Effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the LANCET randomized trial.

Context: As diabetes is in part an inflammatory condition, the initiation of insulin and/or metformin may beneficially reduce levels of inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP).

Objective: To determine whether insulin alone or combined with metformin lowers levels of hsCRP, IL-6, and soluble tumor necrosis factor receptor 2 (sTNFr2) in patients with recent-onset type 2 diabetes mellitus.

Design, Setting, And Participants: Randomized 2 x 2 factorial trial of open-label insulin glargine and placebo-controlled metformin in 500 adults with type 2 diabetes (median time from diagnosis, 2.

Kidney function and risk of cardiovascular disease and mortality in women: a prospective cohort study.

Objective: To evaluate the association of kidney function with cardiovascular disease and mortality among apparently healthy women.

Design: Prospective cohort study.

Setting: Women's Health Study, United States.

Effects of vitamins C and E and beta-carotene on the risk of type 2 diabetes in women at high risk of cardiovascular disease: a randomized controlled trial.

Background: Vitamin C, vitamin E, and beta-carotene are major antioxidants and as such may protect against the development of type 2 diabetes via reduction of oxidative stress.

Objective: The purpose of this study was to investigate the long-term effects of supplementation with vitamin C, vitamin E, and beta-carotene for primary prevention of type 2 diabetes.

Design: In the Women's Antioxidant Cardiovascular Study, a randomized trial that occurred between 1995 and 2005, 8171 female health professionals aged > or =40 y with either a history of cardiovascular disease (CVD) or > or =3 CVD risk factors were randomly assigned to receive vitamin C (ascorbic acid, 500 mg every day), vitamin E (RRR-alpha-tocopherol acetate, 600 IU every other day), beta-carotene (50 mg every other day), or their respective placebos.

Effect of homocysteine-lowering treatment with folic Acid and B vitamins on risk of type 2 diabetes in women: a randomized, controlled trial.

Objective: Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress, systemic inflammation, and endothelial dysfunction. We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes.

Research Design And Methods: The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized, double-blind, placebo-controlled trial of 5,442 female health professionals aged > or = 40 years with a history of cardiovascular disease (CVD) or three or more CVD risk factors, included 4,252 women free of diabetes at baseline.

Advances in measuring the effect of individual predictors of cardiovascular risk: the role of reclassification measures.

Models for risk prediction are widely used in clinical practice to stratify risk 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.

Amino-terminal pro-B-type natriuretic peptide and high-sensitivity C-reactive protein as predictors of sudden cardiac death among women.

Background: Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been found to predict risk of sudden cardiac death (SCD) in patients with known cardiac disease, and C-reactive protein levels have been found to predict risk among apparently healthy men. However, there are no data on SCD risk prediction for either of these markers in a population of women unselected on the basis of cardiovascular disease.

Methods And Results: In a prospective, nested, case-control analysis within the 121,700-participant Nurses' Health Study, 99 cases of definite or probable SCD were identified and matched to 294 controls.

Relation of vigorous exercise to risk of atrial fibrillation.

Limited data suggest that athletes may have a higher risk of developing atrial fibrillation (AF); however, there has been no large prospective assessment of the relation between vigorous exercise and AF. Logistic regression analyses stratified by time were used to assess the association between frequency of vigorous exercise and risk of developing AF in 16,921 apparently healthy men in the Physicians' Health Study. During 12 years of follow-up, 1,661 men reported developing AF.