The performance of prediction models can be assessed using a variety of different 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). Moreover, decision–analytic measures have been proposed, including decision curves to plot the net benefit achieved by making decisions based on model predictions.
We aimed to define the role of these relatively novel approaches in the evaluation of the performance of prediction models. For illustration we present a case study of predicting the presence of residual tumor versus benign tissue in patients with testicular cancer (n=544 for model development, n=273 for external validation).
We suggest that reporting discrimination and calibration will always be important for a prediction model. Decision-analytic measures should be reported if the predictive model is to be used for making clinical decisions. Other measures of performance may be warranted in specific applications, such as reclassification metrics to gain insight into the value of adding a novel predictor to an established model.
Few prospective studies have explored the association between renal function and risk of incident atrial fibrillation (AF) in apparently healthy populations. A total of 24,746 women participating in the Women’s Health Study who were free of cardiovascular disease (CVD), AF and provided a blood sample at baseline were prospectively followed for incident AF from 1993 to 2010. AF events were confirmed by medical chart review. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine using the Chronic Kidney Disease – Epidemiology equation. Cox models were used to estimate hazard ratios (HR) and 95% CI for incident AF across eGFR categories controlling for AF risk factors. During 15.4 years (median) of follow-up, 786 incident AF events occurred. The multivariable-adjusted HR for incident AF across eGFR categories (<60, 60–74.9, 75–89, and ≥ 90 ml/min/1.73 m2) were:1.36 (1.00–1.84), 0.90 (0.71–1.14), 0.99 (0.84–1.18) and 1.00, respectively, without evidence of a linear association (P for trend, 0.48). Similarly, there was no significant curvilinear association (P quadratic, 0.10) in multivariable analysis across categories. As compared to women with an eGFR ≥ 60 ml/min/1.73 m2, the 1008 women with an eGFR < 60 ml/min/1.73 m2 had a multivariable adjusted HR for AF of 1.39 (1.04–1.86, p value 0.03). In conclusion, no significant linear or curvilinear relationship was observed between incident AF and less severe impairment of renal function in this large prospective cohort of women. However, a significant elevation in AF risk was observed at a threshold eGFR of < 60 ml/min/1.73 m2.
atrial fibrillation; renal function
Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2×2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (Omacor® fish oil, eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1 g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥50 and women aged ≥55. The mean treatment period will be 5 years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.
Cancer; cardiovascular disease; cholecalciferol; primary prevention; omega-3 fatty acids; vitamin D; randomized controlled trial
To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics.
Methods and results
Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50.
Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.
Trial registration information: Clinicaltrials.gov identifier number: NCT00000479.
Aspirin; Primary prevention; Treatment effect prediction; Net benefit
Adiponectin is linked to reduced diabetes risk and may be anti-atherogenic, yet clinical data show no consistent relationship with incident cardiovascular events, especially among women. To our knowledge, no prior prospective studies have evaluated adiponectin, including high-molecular-weight (HMW) adiponectin, and incident peripheral artery disease (PAD).
Methods & Results
We evaluated the relationship of total, HMW and the HMW-to-total adiponectin ratio with incident symptomatic PAD in a prospective, nested case-control study conducted within the Women’s Health Study (n=110 cases, n=230 controls, frequency matched in strata defined by five-year age categories, smoking, fasting status and follow-up time; median cohort follow-up=13.2 yrs). Baseline median levels of HMW and total adiponectin were significantly lower in women developing PAD than those remaining event-free(HMW: 3.3 vs. 3.8 μg/mL, P=0.0005; total: 5.6 vs. 7.4 μg/mL, P<0.0001). The ratio did not differ significantly between groups. Age-adjusted PAD odds ratios (95% CI) across tertiles were 1.0, 0.66 (0.39–1.13) and 0.40 (0.22–0.74)for HMW and 1.0, 0.74 (0.43–1.25) and 0.35 (0.18–0.65) for total adiponectin (P-trend=0.004 and 0.001, respectively). Results were similar after adjustment for traditional cardiovascular risk factors, use of post-menopausal hormone therapy, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, leptin, hemoglobin A1c and fasting insulin [adjusted OR and 95% CI for HMW: 1.0, 0.62 (0.29–1.34), 0.30 (0.12–0.74); total: 1.0, 0.46 (0.22–1.00), 0.30 (0.12–0.76 );Ptrend=0.01 for both].
Total and HMW adiponectin are inversely associated with incident PAD among initially healthy women. These prospective data support a protective role for this adipokine in peripheral atherosclerosis development.
adiponectin; biomarker; epidemiology; peripheral artery disease; women
It is unclear whether models which include hemoglobin A1c (HbA1c) levels only for diabetic patients improve ability to predict cardiovascular disease (CVD) risk when compared to the currently recommended classification of diabetes as a cardiovascular risk equivalent.
24,674 women (including 685 diabetic participants at baseline) and 11,280 men (including 563 diabetic participants at baseline) were followed prospectively for CVD. 125 CVD events occurred in diabetic women (666 in non-diabetic women) and 170 events occurred in diabetic men (1382 in non-diabetic men). Models for CVD risk were generated separately for men and women using the traditional CVD risk factors with the addition of a term for HbA1c levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared to classification of diabetes as a cardiovascular risk equivalent (10-year CVD-risk of at least 20%).
In women, the models including HbA1c levels in diabetic participants improved the c-statistic by 0.177 (p <0.001) over the risk equivalence model and showed improved reclassification (NRI of 26.7%, p = 0.001). In men, the improvements were more modest but still statistically significant (c-statistic change of 0.039, p=0.015; NRI of 9.2%, p= 0.042). Including HbA1c levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8%, p = 0.033) but not in men.
In both women and men with baseline diabetes, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA1c levels compared to classification of diabetes as a cardiovascular risk equivalent.
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.
The effects of physical activity on risk of myocardial infarction (MI) are well documented and may include beneficial changes in blood lipids, inflammatory markers, and insulin sensitivity. The degree to which these and other traditional and nontraditional cardiovascular biomarkers mediate the inverse association between physical activity and risk of MI in men remains unclear.
We conducted a nested case-control study among 18,225 men in the Health Professionals Follow-up Study followed from 1994 to 2004. A total of 412 men with incident MI were matched 1:2 with control participants on age and smoking status using risk-set sampling. From detailed responses to a modified Paffenbarger physical activity questionnaire, we determined the association between average hours of vigorous-intensity activity (activities requiring METs ≥ 6) and MI risk.
For a 3-hour per week increase in vigorous-intensity activity, the multivariate relative risk (RR) of MI was 0.78 (95% CI 0.61, 0.98). In models including pre-existing CVD-related conditions, further adjustment for HDL-C, vitamin D, apolipoprotein B, and hemoglobin A1c attenuated the RR by 70% (95% CI 12%, 127%) to a RR of 0.93 (95% CI 0.72, 1.19).
Participating in three hours per week of vigorous-intensity activity is associated with a 22% lower risk of MI among men. This inverse association can be partially explained by beneficial effects of physical activity on HDL-C, vitamin D, apolipoprotein B, and hemoglobin A1c. While the inverse association attributable to these biomarkers is substantial, future research should explore benefits of exercise beyond these biomarkers of risk.
exercise; men; epidemiology; coronary heart disease; risk factors
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.
breast neoplasms; hormone replacement therapy; mammography; mass screening; probability weighting; risk factors
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.
Concerns have been raised about the use of traditional measures of model fit in evaluating risk prediction models for clinical use, and reclassification tables have been suggested as an alternative means of assessing the clinical utility of a model. Several measures based on the table have been proposed, including the reclassification calibration (RC) statistic, the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI), but the performance of these in practical settings has not been fully examined. We used simulations to estimate the type I error and power for these statistics in a number of scenarios, as well as the impact of the number and type of categories, when adding a new marker to an established or reference model. The type I error was found to be reasonable in most settings, and power was highest for the IDI, which was similar to the test of association. The relative power of the RC statistic, a test of calibration, and the NRI, a test of discrimination, varied depending on the model assumptions. These tools provide unique but complementary information.
Calibration; Discrimination; Model accuracy; Prediction; Reclassification
Very low levels of cardiac troponin T associate with increased risk of cardiovascular death in patients with stable chronic coronary disease. Whether high-sensitivity cardiac troponin T (hsTnT) levels associate with adverse cardiovascular outcomes in individuals without cardiovascular disease (CVD) has not been well studied.
Methods and Results
Utilizing two complementary study designs, we evaluated the relationship between baseline cardiac troponin and incident CVD events among diabetic and non-diabetic participants in the Women’s Health Study (median follow-up 12.3 years). All diabetic women with blood specimens were included in a cohort study (n=512 diabetic women, n=65 events) and non-diabetic women were sampled for inclusion in a case-cohort analysis (n=564 comprising the subcohort, n=479 events). HsTnT was detectable (≥0.003 μg/L) in 45.5% of diabetic women and 30.3% of non-diabetic women (P<0.0001). In models adjusted for traditional risk factors and hemoglobin A1c, detectable hsTnT was associated with subsequent CVD (myocardial infarction, stroke, cardiovascular death) in diabetic women (adjusted HR 1.79, 95% CI 1.04-3.07, P=0.036), but not non-diabetic women (adjusted HR 1.13, 95% CI 0.82-1.55, P=0.46). Further adjustment for NT-proBNP and estimated renal function did not substantially alter this relationship among diabetic women (HR 1.76, 95% CI 1.00-3.08, P=0.0499), which appeared to be driven by a threefold increase in CVD death that was not observed in non-diabetic women.
Very low but detectable levels of cardiac troponin T associate with total CVD and CVD death in women with diabetes. Among healthy non-diabetic women, detectable compared to undetectable troponin was not associated with CVD events.
Primary prevention; cardiovascular disease risk factors; troponin; diabetes mellitus type 2; women
Homozygosity for a common non-synonymous single nucleotide polymorphism (Gln27Glu) in the beta-2 adrenergic receptor gene (ADRB2) has been inconsistently associated with sudden cardiac death (SCD) in individual studies of small sample size.
To examine the association between the Gln27Glu polymorphism and SCD in a large combined sample of SCD cases.
Nested case-control analysis among individuals of Caucasian ancestry enrolled in six prospective cohort studies. Genotypes for the Gln27Glu variant were determined for 492 cases of SCD and 1388 controls matched on age, sex, cohort, follow-up time, and history of cardiovascular disease (CVD) and at the time of the blood draw. Individual studies were combined with conditional logistic regression with fixed effects meta-analysis assuming a recessive model.
Homozygosity for the Gln27 allele conferred a non-significant elevation of the age-adjusted odds ratio (OR=1.22; 95% CI, 0.98-1.53; P=0.08) for SCD, which became marginally significant after controlling for multiple cardiac risk factors (OR=1.30, 95% CI: 1.01-1.67; P=0.046). In secondary analyses using controls additionally matched for the development of nonfatal CVD after the blood draw, results were attenuated (OR=1.19, 95%CI: 0.92-1.52; P=0.19). When the results of the primary analysis were combined in meta-analysis with published reports, a significant association between ADRB2 genotype and SCD emerged (OR=1.35, 95% CI: 1.15-1.60; P=0.0003).
These data from a large prospective case-control series, when combined with published studies, provide further evidence for an association between ADRB2 genotype and SCD. The mechanism is unknown, but appears to be partly mediated by development of CVD.
Sudden Cardiac Death; Genetic Epidemiology; Sympathetic Nervous System; Beta-2 Adrenergic Receptor
This study sought to determine the relation between and discriminative capability of Lipoprotein-associated phospholipase A2 (Lp-PLA2) and coronary heart disease (CHD) in a large population of disease-free women.
Among participants of the Nurses’ Health Study who provided a blood sample, there were 421 cases of incident myocardial infarction (MI) during 14 years of follow-up. Controls were matched to cases 2:1 using risk-set sampling based on age, smoking, and blood draw date.
Conditioning on the matching factors, Lp-PLA2 activity was significantly associated with MI (RR=2.86 for extreme quartiles; 95% Confidence Interval (CI): 1.98, 4.12). After adjustment for lipid, inflammatory, and clinical risk factors, the relative risk remained statistically significant was assessed by (RR=1.75; 95%CI: 1.09, 2.84). The discriminative capability of Lp-PLA2 comparing area under the receiver operating characteristic curves (AUROC) for models with and without Lp-PLA2, and by calculating the net reclassification improvement index (NRI). Adding Lp-PLA2 activity to a multivariable-adjusted model increased the AUROC from 0.720 to 0.733, and significantly improved the NRI (p = 0.004).
Levels of Lp-PLA2 activity were significantly associated with incident CHD among women. In addition, Lp- PLA2 activity added significantly to CHD risk discrimination.
Background A 2000 meta-analysis indicated no overall association between breast implants and risk of connective-tissue diseases (CTDs). However, a large retrospective cohort study we previously conducted suggested, instead, a small increased risk of CTDs. Because of limitations inherent to the retrospective cohort study design, we sought clarification by conducting a prospective cohort study of the association of breast implants with CTD risk.
Methods Participants were 23 847 US women (mean age 56.6 years), 3950 of whom had breast implants and 19 897 did not. Women reported their breast implant status at baseline in 2001 and were followed for a median of 3.63 years. During follow-up, women reported incident CTD, confirmed using a CTD screening questionnaire (CSQ) and medical records.
Results In multivariate analyses, the rate ratios for self-reported CTD (113 vs 377 cases in the implanted and non-implanted group, respectively) were 1.60 [95% confidence interval (CI) 1.28–2.00], for CSQ-confirmed CTD (77 vs 226 cases), 1.80 (1.37–2.38) and for medical record confirmed CTD (21 vs 74 cases), 1.39 (0.82–2.35).
Conclusions Although this prospective cohort study represented a stronger design than the retrospective cohort study, the present data should still be viewed cautiously because of remaining methodological limitations, including the potential for differential self-reporting of CTD and CTD symptoms among women with and without breast implants, the difficulty of obtaining medical records for women reporting CTD and the low and possibly differential confirmation of self-reported disease against medical records. A reasonable conclusion is the lack of a large increase in CTD risk (e.g. ≥2-fold) associated with breast implants.
Breast implants; cohort studies; connective-tissue diseases; women’s health
This study examines C-reactive protein (CRP) levels predict cardiovascular events (CVE) among hormone therapy (HT) users and non-users.
CRP levels are higher in women who use oral HT than in non-users; however, whether the same CRP cutpoints determine increased cardiovascular risk remains unanswered.
CRP was measured at baseline in 10,953 HT users and 15,838 non-users in the Women’s Health Study. In HT non-users and users, Cox-proportional hazard models adjusted for age, cardiovascular risk factors, BMI, and menopausal status were constructed using AHA/CDC-recommended CRP cut-points for low, average, and high cardiovascular risk as well as HT non-user-and user-derived quantiles of CRP to predict incident cardiovascular events(CVE).
CVE risk increased with lnCRP for both HT users and non-users. After adjusting for cardiovascular risk factors including lipids, the multivariable relative risk (RR) per log unit of CRP was 1.27 (95% CI, 1.13 to 1.44) for HT non-users and 1.22 (95% CI, 1.07 to 1.40) for HT users. In order to compare the risk associated with AHA/CDC CRP categories across HT use groups, we fit a model in which non-users with CRP <1 mg/L were the reference group. After adjusting for other risk factors including lipids, HT users with CRP ≥3 had a RR of 1.93 (1.38–2.69) while non-users had a RR of 1.92 (1.35–2.72).
CRP predicts CVE in a linear relationship among both HT users and non-users. CRP levels ≥3 mg/L were associated with increased cardiovascular risk in both non-users and HT users.
cardiovascular diseases; prevention; risk factors; hormones; C-reactive protein
Variation in the Fat-Mass and Obesity-Associated (FTO) gene has been associated with obesity, diabetes and hypertension. However, its association with cardiovascular disease (CVD) in healthy populations and any interaction with physical activity remain unclear.
The FTO rs8050136 allele was determined in a prospective cohort study of 21,674 apparently healthy Caucasian US women in the Women’s Genome Health Study.
During a mean follow-up of 12.7 ±2.0 years, 664 incident CVD events occurred. The risk allele (A) was associated with higher prevalence of hypertension, diabetes, and metabolic syndrome (all P<0.05). In a multivariate model, there was significant association of the risk allele with CVD (hazard ratio [HR] per allele copy 1.14 [95% confidence interval, 1.01–1.28]) that was no longer significant after additional adjustment for body mass index (BMI) (HR 1.10 [0.97–1.23]). There was statistical evidence of an interaction between FTO and physical activity, P=0.048. We found a significant association of FTO with CVD only among less active (≤8.8MET-hrs/wk) women (HR 1.19 [1.02–1.38]) in multivariate analyses that included BMI. More active women did not have this increased risk (HR 0.96 [0.79–1.16]). In a model that adjusted for BMI, less active/high-risk (A/A) women were at 54% increased risk of developing CVD (HR 1.54 [1.13–2.11]), compared to more active/low risk (T/T) women.
Carriers of the FTO risk allele have an increased risk of CVD, mediated by BMI. There appears to be an interaction with physical activity, such that this risk increase is only in less active women.
Few if any studies have assessed the relationship between birth weight and incident atrial fibrillation (AF).
Methods and Results
We prospectively followed from 1993 to 2009 27982 women who were >45 years and free of cardiovascular disease and AF at baseline. Information on birth weight was categorized into 5 different categories: <2.5, 2.5–3.2, 3.2–3.9, 3.9–4.5 and >4.5 kg. The primary outcome was time to incident AF. During 14.5 years of follow-up, 735 AF events occurred. Age-adjusted incidence rates for incident AF from the lowest to the highest birth weight category were 1.45, 1.82, 1.88, 2.57 and 2.55 events per 1000 person-years of follow-up. After multivariable adjustment, hazard ratios (HR) for incident AF (95% confidence intervals (CI)) across increasing birth weight categories were 1.0, 1.30 (0.96–1.75), 1.28 (0.96–1.69), 1.70 (1.23–2.37) and 1.71 (1.12–2.61) (p for linear trend 0.002). Adding body mass index, blood pressure and diabetes at study entry did not have a large effect on these estimates (p for linear trend 0.004). By contrast, including height in the multivariable model substantially attenuated the relationship between birth weight and AF (p for linear trend 0.17), and additional adjustment for maximum weight in young adulthood further attenuated this association (multivariable adjusted HR (95% CI) across birth weight categories 1.0, 1.27 (0.94–1.71), 1.10 (0.83–1.46), 1.41 (1.01–1.96) and 1.29 (0.84–1.98) (p for linear trend 0.23)).
Birth weight is significantly associated with incident AF among women, suggesting that early life determinants may play an important role in the pathogenesis of AF.
Atrial fibrillation; Birth weight; Women; Fetal development; Epidemiology
In their presentation on measures of predictive capacity Gu and Pepe say little about calibration. This comment distinguishes conditional and unconditional calibration and how these relate to the stated results.
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. To evaluate the joint effect of these three biomarkers, an inflammation score was created that ranged from 0 to 3 and reflected the number of biomarkers in the highest tertile per individual. During a median follow-up of 14.4 years, 747 of 24 734 women (3.0%) experienced a first AF event. Assessed individually, all three biomarkers were associated with incident AF, even after adjustment for traditional risk factors. When combined into an inflammation score, a strong and independent relationship between inflammation and incident AF emerged. Across increasing inflammation score categories, there were 1.66, 2.22, 2.73, and 3.25 AF events per 1000 person-years of follow-up. The corresponding hazard ratios (95% confidence intervals) across inflammation score categories were 1.0, 1.22 (1.00–1.49), 1.32 (1.06–1.65), and 1.59 (1.22–2.06) (P for linear trend 0.0006) after multivariable adjustment.
In this large-scale prospective study among women without a history of cardiovascular disease, markers of systemic inflammation were significantly related to AF even after controlling for traditional risk factors.
Atrial fibrillation; Inflammation; C-reactive protein; Intercellular adhesion molecule-1; Fibrinogen
Several lines of evidence have suggested that female hormones may lower 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).
We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women's Health Study aged 45 years or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs).
There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correction ≥0.25). There was also no association with any of the haplotypes examined (p ≥0.15) and no evidence of joint effects of variants in the 5 genes (p ≥0.51).
Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and risk for developing colorectal cancer.
Rare variants in cardiac ion channel genes are associated with sudden cardiac death (SCD) in rare primary arrhythmic syndromes; however, it is unknown whether common variation in these same genes may contribute to SCD risk at the population level.
Methods and Results
We examined the association between 147 single nucleotide polymorphisms (SNPs) (137 tag, 5 non-coding 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 controls of European ancestry enrolled in six prospective cohort studies. After accounting for multiple testing, two SNPs (rs2283222 located in intron 11 in KCNQ1 and rs11720524 located in intron 1 in SCN5A) remained significantly associated with sudden/arrhythmic death (FDR = 0.01 and 0.03 respectively). Each increasing copy of the major T allele of rs2283222 or the major C allele of rs1172052 was associated with an OR = 1.36 (95% CI 1.16-1.60, P=0.0002) and 1.30 (95% CI 1.12-1.51, P=0.0005) respectively. Control for cardiovascular risk factors and/or limiting the analysis to definite SCDs did not significantly alter these relationships.
In this combined analysis of 6 prospective cohort studies, two common intronic variants in KCNQ1 and SCN5A were associated with SCD in individuals of European ancestry. Further study in other populations and investigation into the functional abnormalities associated with non-coding variation in these genes may lead to important insights into predisposition to lethal arrhythmias.
death; sudden; genetics; ion channels; epidemiology
To characterize the relationship between changes in body mass index (BMI) and incident atrial fibrillation (AF) in a large cohort of women.
Obesity and AF are increasing public health problems. The importance of dynamic obesity-associated AF risk is uncertain, and mediators are not well characterized.
Cases of AF were confirmed by medical record review in 34,309 participants in the Women’s Health Study. Baseline and updated measures of BMI were obtained from periodic questionnaires.
Over 12.9 +/− 1.9 years of follow-up, 834 AF events were confirmed. BMI was linearly associated with AF risk, with a 4.7% (95% CI 3.4, 6.1, p<0.0001) increase in risk with each kg/m2. Adjustment for inflammatory markers minimally attenuated this risk. When updated measures of BMI were utilized to estimate dynamic risk, overweight (HR 1.22 95%CI 1.02, 1.45, p=0.03) and obesity (HR 1.65 95%CI 1.36, 2.00, p<0.0001) were associated with adjusted short term elevations in AF risk. Participants becoming obese during the first 60 months had a 41% adjusted increase in risk of developing AF (p=0.02) compared to those maintaining BMI <30 kg/m2. The prevalence of overweight and obesity increased over time. The adjusted proportion of incident AF attributable to short term elevations in BMI was substantial (18.3%).
In this population of apparently healthy women, BMI was associated with short and long term elevations in AF risk, accounting for a large proportion of incident AF independent of traditional risk factors. A strategy of weight control may reduce the increasing incidence of AF.
Systemic inflammation and endothelial activation are implicated in the development of hypertension. However, epidemiologic studies have yet to compare multiple corresponding biomarkers in relation to risk of hypertension, particularly in multiethnic populations.
We identified 800 cases of incident hypertension and 800 matched controls with equal numbers of White and Black women in a nested case-control study within the Women’s Health Initiative Observational Study. We measured markers of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], interleukin-1β [IL-1β], tumor necrosis factor receptor 2 [TNF-r2]) and endothelial activation (soluble intercellular adhesion molecule-1 [sICAM-1]) in baseline blood samples.
Before adjustment for measures of adiposity, higher hsCRP and IL-6 were associated with increased risk of hypertension in both White and Black women, higher TNF-r2 was associated with increased risk of hypertension only in Black women, and IL-1β and sICAM-1 were unassociated with risk of hypertension. All the positive associations were attenuated after adjustment for body mass index. The resulting multivariable-adjusted relative risks (95% CI) of hypertension comparing the highest versus lowest quartile were 1.52 (0.94–2.48) and 1.23 (0.76–1.97) for hsCRP and IL-6 in White women, and 1.30 (0.81–2.07), 1.58 (0.96–2.59), and 1.49 (0.94–2.36) for hsCRP, IL-6, and TNF-r2 in Black women. The results after adjustment for waist circumference were similar.
After adjustment for measures of adiposity, there was no significant association of hsCRP, IL-6, IL-1β, TNF-r2, and sICAM-1 with incident hypertension in either White or Black women. The interrelationships between inflammation and adiposity in development of hypertension need further investigation.
inflammation; endothelium-derived factors; hypertension; women; epidemiology