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1.  Risk Factors for Lymphedema In Breast Cancer Survivors, the Iowa Women’s Health Study 
Background
Risk factors for lymphedema and related arm symptoms in breast cancer (BC) survivors have not been examined using a large prospective population-based cohort.
Methods
The Iowa Women’s Health Study (IWHS) collected self-reported data for diagnosed lymphedema in 2004, and data for cancer diagnosis, treatment, behavioral and health characteristics between 1986–2003. We studied 1,287 women, ages 55–69 at baseline, who developed unilateral BC: n=104 (8%) with diagnosed lymphedema, n=475 (37%) with arm symptoms but without diagnosed lymphedema, and n=708 without lymphedema. Age- and multivariate-adjusted logistic regression models examined risk factors for lymphedema and related arm symptoms (OR [95% confidence interval]).
Results
The mean time between BC and the 2004 survey was 8.1±5.0 (mean±SD) years. After multivariate adjustment (not including time since BC diagnosis), the following cancer characteristics were positively associated with lymphedema: tumor stage (regional vs. in situ: 3.92[1.61–9.54]), number of excised nodes (highest vs. lowest quintile: 3.52[1.32–9.34], Ptrend=0.003), tumor-positive nodes (yes vs. no 2.12 [1.19, 3.79]) and adjuvant chemotherapy (yes vs. no: 3.05[1.75–5.30]). Several health characteristics were positively associated with lymphedema: baseline body mass index (highest vs. lowest tertile: 3.24[1.70–6.21]), waist and hip circumference, and general health (fair/poor vs. excellent: 3.44[1.30–9.06]). Positive associations with arm symptoms were: number of excised nodes (highest vs. lowest quintile: 2.38[1.41–4.03], Ptrend=0.007), axillary radiation (yes vs. no: 1.72 [1.15–2.57]) and baseline general health (fair/poor vs. excellent: 4.27 [2.60–7.00]).
Conclusions
In the IWHS, obesity, poorer general health, and markers of more advanced cancer were risk factors for lymphedema and related arm symptoms in BC survivors.
doi:10.1007/s10549-011-1667-z
PMCID: PMC4091732  PMID: 21761159
2.  Lipoprotein-associated phospholipase A2 and venous thromboembolism: a prospective study 
Thrombosis research  2013;132(1):44-46.
Introduction
Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied.
Methods
We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3 years (from 1996–98 through 2005) for VTE occurrence (n = 226).
Results
There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol ≥ 130 mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14).
Conclusion
Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk.
doi:10.1016/j.thromres.2013.05.014
PMCID: PMC3742644  PMID: 23746626
lipoprotein-associated phospholipase A2; prospective study; pulmonary embolism; venous thromboembolism
3.  Competing Cardiovascular Outcomes Associated with Subclinical Atherosclerosis (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;111(11):1541-1546.
Subclinical atherosclerosis measured by coronary artery calcium (CAC) is associated with increased risk for multiple cardiovascular disease (CVD) outcomes and non-CVD death simultaneously, and we sought to determine the competing risks of specific cardiovascular disease (CVD) events and non-CVD death associated with varying burdens of subclinical atherosclerosis. We included 3095 men and 3486 women from the Multi-Ethnic Study of Atherosclerosis, aged 45–84 years, and from 4 ethnic groups. Participants were stratified by CAC scores: 0, 1–99, and ≥ 100. We used competing Cox models to determine competing cumulative incidences and hazards ratios within a group (e.g., among those with CAC ≥ 100) and hazards ratios for specific events between groups (e.g., CAC ≥ 100 vs. CAC = 0). We compared risks for specific CVD events and also compared against non-CVD death. In women, during a mean follow up of 7.1 years, the hazards ratios (HR) for any CVD event compared with a non-CVD death occurring first for CAC = 0 and CAC ≥ 100 were 1.40 (95% CI, 0.97–2.04) and 3.07 (2.02–4.67), respectively. CHD was the most common first CVD event type at all levels of CAC, and CHD rates were 9.5% vs. 1.6% (HR 6.24; 3.99–9.75) for women with CAC ≥100 compared with CAC = 0. We observed similar results in men. In conclusion, at all levels of CAC, CHD was the most common first CVD event and this analysis represents a novel approach to understanding the temporal sequence of cardiovascular events associated with atherosclerosis.
doi:10.1016/j.amjcard.2013.02.003
PMCID: PMC3657323  PMID: 23499272
coronary artery calcium; competing risks
4.  Statin Therapy and Levels of Hemostatic Factors in a Healthy Population: the Multi-Ethnic Study of Atherosclerosis 
Background
HMG CoA reductase inhibitors (statins) reduce risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for reduction in VTE risk is unknown. In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk.
Methods
Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women), and major cardiovascular risk factors.
Results
Participants using statins had lower adjusted levels of D-dimer (−9%), C-reactive protein (−21%) and factor VIII (−3%) than non-users (p<0.05). Homocysteine and von Willebrand factor were non-significantly lower with statin use. Higher fibrinogen (2%) and PAI-1 (22%) levels were observed among statin users than nonusers (p<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors by statin use.
Conclusions
Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and nonusers is warranted.
doi:10.1111/jth.12223
PMCID: PMC3702638  PMID: 23565981
statins; thrombosis; risk factor; blood coagulation; inflammation; fibrinolysis
5.  Classical and Novel Biomarkers for Cardiovascular Risk Prediction in the United States 
Journal of Epidemiology  2013;23(3):158-162.
Cardiovascular risk prediction models based on classical risk factors identified in epidemiologic cohort studies are useful in primary prevention of cardiovascular disease in individuals. This article briefly reviews aspects of cardiovascular risk prediction in the United States and efforts to evaluate novel risk factors. Even though many novel risk markers have been found to be associated with cardiovascular disease, few appear to improve risk prediction beyond the powerful, classical risk factors. A recent US consensus panel concluded that clinical measurement of certain novel markers for risk prediction was reasonable, namely, hemoglobin A1c (in all adults), microalbuminuria (in patients with hypertension or diabetes), and C-reactive protein, lipoprotein-associated phospholipase, coronary calcium, carotid intima-media thickness, and ankle/brachial index (in patients deemed to be at intermediate cardiovascular risk, based on traditional risk factors).
doi:10.2188/jea.JE20120157
PMCID: PMC3700256  PMID: 23604062
risk factors; coronary disease; cardiovascular disease; epidemiology
6.  Height and Risk of Incident Intraparenchymal Hemorrhage: Atherosclerosis Risk in Communities and Cardiovascular Health Study Cohorts 
Background
Height is inversely associated with incident coronary disease and total stroke, but few studies have examined the association between height and intraparenchymal hemorrhage. We hypothesized height would be inversely associated with incident intraparenchymal hemorrhage in the combined cohorts of the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study.
Methods
Data on Caucasian and African American participants were used to estimate the association of height at baseline with incident intraparenchymal hemorrhage verified by MD review of medical records and imaging reports. Sex-specific Cox proportional hazards regression models were used to calculate hazard ratios.
Results
A total of 20,983 participants initially free of stroke (11,788 women, 9,195 men) were followed for an average of 15.9 years (SD = 5.1 years). Incident intraparenchymal hemorrhage occurred in 115 women and 73 men. Sex, but not age, race, study or blood pressure, modified the association, p = 0.03. After adjustment for risk factors (age, systolic blood pressure, triglycerides, LDL-cholesterol, fibrinogen and race), among women, height was significantly inversely associated with incident intraparenchymal hemorrhage [hazard ratio per standard deviation (6.3 cm) = 0.81, 95% CI (0.66 – 0.99)], p = 0.04. The hazard ratio (95% CI) for tertile 3 versus 1 in women was 0.63 (0.37–1.08). Among men, height was not linearly associated with incident intraparenchymal hemorrhage [hazard ratio per standard deviation (6.7 cm) = 1.09, 95% CI (0.84 – 1.40)], p = 0.52.
Conclusions
This large prospective study provides evidence that shorter height may be a risk factor for incident intraparenchymal hemorrhage in women.
doi:10.1016/j.jstrokecerebrovasdis.2011.09.004
PMCID: PMC3310942  PMID: 22177930
7.  Physical Activity and Cardiovascular Disease in African Americans in ARIC 
Purpose
Although there is substantial evidence that physical activity reduces a person's risk of cardiovascular disease (CVD), few of these studies have included African Americans. The studies that have included African Americans offer inconclusive evidence on the association and none studied heart failure separately. We used data from the Atherosclerosis Risk in Communities study cohort to examine, in African Americans, the association of physical activity with the incidence of CVD and its major components – stroke, heart failure, and coronary heart disease.
Methods
Participants aged 45 to 64 years (3,707 African Americans and, for comparison, 10,018 Caucasians) had physical activity assessed via questionnaire in 1987 and were followed for incident CVD (n=1,039) through 2008.
Results
After adjustment for potential confounders, physical activity was inversely related to CVD, heart failure, and coronary heart disease incidence in both races (p-values for trend <.0001), and with stroke in African Americans. Hazard ratios (95% confidence intervals) for CVD for each higher physical activity category were similar by race: 1.0, 0.65 (0.56, 0.75), and 0.59 (0.49, 0.71) for African Americans and 1.0, 0.74 (0.66, 0.83), and 0.67 (0.59, 0.75) for Caucasians (p-value for interaction = 0.38).
Conclusions
Our findings reinforce recommendations that regular physical activity is important for CVD risk reduction in African Americans as well as Caucasians and support the idea that some physical activity is better than none.
doi:10.1249/MSS.0b013e31827d87ec
PMCID: PMC3622814  PMID: 23247714
exercise; stroke; coronary heart disease; heart failure; race
8.  Troponin T, NT-pro BNP, and Incidence of Stroke: The Atherosclerosis Risk in Communities (ARIC) Study 
Background and Purpose
Increased levels of plasma troponins and natriuretic peptides are associated with increased risk of cardiovascular disease, but only limited information exists on these biomarkers and stroke occurrence. In a prospective epidemiological study, we tested the hypothesis that high-sensitivity troponin T (TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are associated positively with incidence of stroke.
Methods
The Atherosclerosis Risk in Communities (ARIC) Study measured plasma TnT and NT-proBNP in 10,902 men or women initially free of stroke and followed them for a mean of 11.3 years for stroke occurrence (n=507).
Results
Both biomarkers were associated positively with total stroke, nonlacunar ischemic, and especially, cardioembolic stroke, but not with lacunar or hemorrhagic stroke. For example, after adjustment for prevalent risk factors and cardiac diseases, the hazard ratios (95% confidence intervals) for jointly high values of TnT and NT-proBNP (versus neither biomarker high) were 2.70 (1.92, 3.79) for total stroke and 6.26 (3.40, 11.5) for cardioembolic stroke. Associations with stroke appeared somewhat stronger for NT-proBNP than TnT. Strikingly, approximately 58% of cardioembolic strokes occurred in the highest quintile of pre-stroke NT-proBNP, and 32% of cardioembolic strokes occurred in participants who had both NT-proBNP in the highest quintile and were known by ARIC to have atrial fibrillation sometime before their cardioembolic stroke occurrence.
Conclusions
In the general population, elevated plasma TnT and NT-proBNP concentrations are associated with increased risk of cardioembolic and other nonlacunar ischemic strokes.
doi:10.1161/STROKEAHA.111.000173
PMCID: PMC3614093  PMID: 23471272
epidemiology; natriuretic peptides; risk factors; stroke; troponins
9.  Ideal Cardiovascular Health is Inversely Associated with Incident Cancer: The Atherosclerosis Risk in Communities Study 
Circulation  2013;127(12):1270-1275.
Background
The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of their 2020 Strategic Impact Goals. We examined if adherence to ideal levels of the seven AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17-19 years of follow-up.
Methods and Results
After exclusions for missing data and prevalent cancer, 13,253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to seven AHA cardiovascular health metrics. Combined cancer incidence (excluding non-melanoma skin cancers) from 1987-2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant (p-trend< .0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6-7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5-6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics (p-trend = .03).
Conclusions
Adherence to the seven ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence.
doi:10.1161/CIRCULATIONAHA.112.001183
PMCID: PMC3685848  PMID: 23509058
ideal cardiovascular health; cancer; prevention
10.  Diabetes and risk of bladder cancer among postmenopausal women in the Iowa Women's Health Study 
Cancer causes & control : CCC  2013;24(3):603-608.
Purpose
Studies have indicated that diabetes is a risk factor for bladder cancer; however, many failed to adjust for confounding variables. An earlier publication from the Iowa Women's Health Study reported a positive association of baseline diabetes with bladder cancer risk between 1986 and 1998, although the number of cases was small (n=112). We re-examined the diabetes–bladder cancer risk association by accounting for 12 more years of follow-up and assessed whether the association varied by diabetes duration, body mass index or waist-to-hip ratio (WHR).
Methods
Proportional hazards regression was used to estimate the hazard ratio (HR) of bladder cancer (n=277) in relation to diabetes (before enrollment and during follow-up) and diabetes duration using a time-dependent approach.
Results
In a multivariate time-dependent analysis, the HR for bladder cancer was 1.69 (95% CI, 1.40-2.41) in relation to diabetes among 37,327 postmenopausal women initially free of cancer. There was an interaction between diabetes and WHR (p =0.01). Bladder cancer HR in diabetic women with WHR>0.9 was 2.5 times higher than expected. There was no dose-response relation of bladder cancer risk with diabetes duration. Compared to no diabetes, HR were 1.77. 2.03, and 1.55 for diabetes durations of ≤5, 6-10, and >10 years, respectively.
Conclusions
We confirmed a positive association between diabetes and bladder cancer risk among white post-menopausal women. We also observed a synergistic interaction between diabetes and high WHR in bladder cancer development that might be explained by increased insulin resistance and inflammation related to abdominal obesity.
doi:10.1007/s10552-012-0143-3
PMCID: PMC3574198  PMID: 23296458
Bladder cancer; diabetes; prospective study
11.  Troponin T, B type natriuretic peptide, C-reactive protein and cause-specific mortality 
Annals of epidemiology  2012;23(2):66-73.
Purpose
To evaluate the associations of high sensitivity Troponin T (Hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high sensitivity C-reactive protein (Hs-CRP) with mortality from any cause, cardiovascular disease (CVD), coronary heart disease (CHD), stroke, cancer, and respiratory disease in the Atherosclerosis Risk in Communities (ARIC) cohort.
Methods
11193 participants aged 54-74 years, initially free of the conditions being studied, had biomarkers measured and were followed for a mean of 9.9 years.
Results
Hazard ratios (HR), adjusted for multiple risk factors, for mortality in participants in the highest Hs-TnT category compared to those with undetectable levels were: total 3.42 (95% Confidence Interval: 2.75-4.26), CVD 7.34 (4.64-11.6), CHD 6.06 (2.91-12.6), stroke 3.31 (1.26-8.66), cancer 1.60 (1.08-2.38) and respiratory 3.85 (1.39-10.7). Comparing the highest NT-proBNP quintile to those in the lowest quintile, the adjusted HRs for mortality were: total 3.05 (2.46-3.77), CVD 7.48 (4.67-12.0), CHD 4.07 (2.07-7.98) and stroke 10.4 (2.26-47.7). Comparing extreme Hs-CRP quintiles, the adjusted HRs for mortality were: total 1.61 (1.32-1.97), CVD 1.76 (1.19-2.62) and respiratory 3.36 (1.34-8.45). Having multiple markers elevated simultaneously greatly increased cause-specific mortality risks.
Conclusions
Greater levels of Hs-TnT, NT-proBNP and Hs-CRP are associated with increased risk of death, not just from cardiovascular disease but also from some non-cardiovascular causes.
doi:10.1016/j.annepidem.2012.11.004
PMCID: PMC3543509  PMID: 23228375
biomarkers; troponin T; B natriuretic peptide; C- reactive protein; mortality
12.  Glycated Hemoglobin and Cancer Incidence and Mortality in the Atherosclerosis in Communities (ARIC) Study, 1990–2006 
Diabetes is a risk factor for many cancers; chronic hyperglycemia is hypothesized to be, in part, explanatory. We evaluated the association between glycated hemoglobin, a time-integrated glycemia measure, and cancer incidence and mortality in non-diabetic and diabetic men and women. We conducted a prospective study of 12,792 cancer-free participants attending the second visit (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) Study. We measured glycated hemoglobin in whole-blood samples using HPLC. Incident cancers were ascertained from registries and hospital records through 2006. We estimated multivariable-adjusted hazard ratios (HR) of cancer incidence and mortality for non-diabetic participants with values ≥5.7% (elevated), non-diabetic participants with <5.0% (low), and diabetic participants all compared with non-diabetic participants with 5.0–5.6% (normal). We ascertained 2,349 incident cancer cases and 887 cancer deaths. Compared with non-diabetic women with normal glycated hemoglobin, non-diabetic women with elevated values had an increased risk of cancer incidence (HR:1.24; 95% CI:1.07,1.44) and mortality (HR:1.58; 95% CI:1.23,2.05) as did diabetic women (incidence, HR:1.30; 95% CI:1.06,1.60, mortality, HR:1.96; 95% CI:1.40,2.76). Non-diabetic women with low values also had increased risk. Diabetic women with good glycemic control (<7.0%) had a lower cancer risk than those with higher values. Glycated hemoglobin in non-diabetic and diabetic men, and diabetes were not statistically significantly associated with total cancer risk. Our findings support the hypothesis that chronic hyperglycemia, even in the non-diabetic range, increases cancer risk in women. Maintaining normal glycated hemoglobin overall, and good glycemic control among diabetic adults, may reduce the burden of cancer, especially in women.
doi:10.1002/ijc.27394
PMCID: PMC3906204  PMID: 22161730
glycated hemoglobin; diabetes; cancer incidence; cancer mortality
13.  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.
doi:10.1093/aje/kwt298
PMCID: PMC3927974  PMID: 24366051
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
14.  Serum albumin and risk of venous thromboembolism 
Thrombosis and haemostasis  2010;104(1):100-104.
Summary
The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n=462 in ARIC and n=174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated GFR, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% CI = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (versus above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
doi:10.1160/TH09-12-0856
PMCID: PMC2902783  PMID: 20390234
albumin; prospective study; pulmonary embolism; venous thrombosis
15.  Association of Ideal Cardiovascular Health Metrics and Retinal Microvascular Findings: The Atherosclerosis Risk in Communities Study 
Background
This study evaluated the prevalence of ideal cardiovascular (CV) health in the Atherosclerosis Risk in Communities Study and determined its relationship with prevalent retinopathy, wider retinal venular diameters, and narrower arteriolar diameters, which are risk markers for subclinical cerebrovascular disease and are associated with increased stroke and coronary heart disease (CHD) morbidity and mortality.
Methods and Results
We used gradings of fundus photography measurements from the Atherosclerosis Risk in Communities Study to examine the association of retinopathy and retinal arteriolar and venular calibers to the number of ideal CV health metrics. Prevalent retinopathy showed a graded relationship with the CV health categories and number of ideal CV health metrics present: retinopathy prevalence was 2.1% among those with ≥5 ideal CV health metrics compared with 13.1% among those with zero ideal CV health metrics (odds ratio [CI]), 4.8 [2.5 to 8.9]). Central retinal venule equivalent and central retinal arteriolar equivalent diameters also showed graded relationships with CV health categories and number of ideal CV health metrics: after adjustment for age, race, sex, and education, mean central retinal venular equivalent was 187.8 μm (95% CI, 186.9 to 188.6 μm) among those with ≥5 ideal CV health metrics compared with 201.1 μm (95% CI, 199.1 to 203.1 μm) among those with zero ideal CV health metrics. Mean central retinal arteriolar equivalent was 163.8 μm (95% CI, 163.0 to 164.5 μm) among those with ≥5 ideal CV health metrics compared with 157.9 μm (95% CI, 156.1 to 159.7 μm) among those with zero ideal CV health metrics.
Conclusions
Few adults had ideal cardiovascular health. Those with the best level of health were less likely to have retinopathy signs, wide retinal venules, and narrow retinal arterioles, which are associated with increased stroke and coronary heart disease risk.
doi:10.1161/JAHA.113.000430
PMCID: PMC3886782  PMID: 24252843
cardiovascular diseases; cardiovascular health metrics; cerebrovascular circulation; epidemiology; risk factors
16.  Coagulation factors II, V, IX, X, XI, XII, plasminogen, and α-2 antiplasmin and risk of coronary heart disease 
Aim
Since few studies have examined the associations of plasma levels of coagulation factors II, V, IX, X, XI, XII, plasminogen, or α-2 antiplasmin with coronary heart disease (CHD), we sought to examine the associations of these factors with incident CHD in a prospective case-cohort study.
Methods
This case-cohort sample consisted of 368 African-American or white incident CHD cases that occurred between 1990–92 and 1998 in the Atherosclerosis Risk in Communities (ARIC) study, and a cohort random sample of n=412. Hemostatic factors were measured in the case-cohort sample using plasma stored at −70°C since 1990–92.
Results
After adjustment for age, sex and race, coagulation factors IX and XI, and α-2 antiplasmin were associated positively with risk of CHD: The hazard ratio [95% confidence interval] for the highest vs lowest quartiles was 1.52 [1.01–2.27] for factor IX; 2.26 [1.47–3.48] for factor XI; and 1.64 [1.05–2.57] for α-2 antiplasmin. However, these hemostatic factors were correlated with classical risk factors, so that after multivariable adjustment their associations with CHD were attenuated and no longer statistically significant. No associations were observed between CHD and factors II, V, X, XII, or plasminogen.
Conclusions
Positive associations of factors IX and XI, and α-2 antiplasmin with incident CHD were not strong and were accounted for by classical coronary risk factors. (213 words/250 limits)
PMCID: PMC2866762  PMID: 20379055
epidemiology; cardiovascular disease; ischemic disease; fibrinolytic factors; blood clotting
17.  Association of SERPINA9 gene variants with carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.
PMCID: PMC3852645  PMID: 24319541
SERPINA9 gene; carotid atherosclerosis; MRI; genetic association
18.  C-reactive protein and venous thromboembolism: a prospective investigation in the ARIC cohort 
Thrombosis and haemostasis  2009;102(4):615-619.
Summary
The role of inflammation in the causation of venous thromboembolism (VTE) is uncertain. In 10,505 participants of the Atherosclerosis Risk in Communities (ARIC) Study, we assessed the association of the systemic inflammation marker, elevated C-reactive protein (CRP), with incidence of VTE (n=221) over a median of 8.3 years of follow-up. Adjusted for age, race, and sex, the hazard ratios of VTE across quintiles of CRP were 1.0, 1.61, 1.16, 1.56, and 2.31 (p for trend p<0.0007). For CRP above the upper 10 percentile (≥8.55 mg/L), compared with the lowest 90% of CRP values, the hazard ratio of VTE was 2.07 (95% CI 1.47, 2.94). Further adjustment for baseline hormone replacement therapy, diabetes, and body mass index attenuated the hazard ratios only slightly. For example, the adjusted hazard ratio of VTE was 1.76 (95% CI 1.23, 2.52) for CRP above versus below the 90th percentile. In conclusion, this prospective, population-based study suggests elevated CRP is independently associated with increased risk of VTE.
doi:10.1160/TH09-04-0274
PMCID: PMC2810122  PMID: 19806245
C-reactive protein; prospective study; pulmonary embolus; venous thrombosis
19.  Serum and Dietary Magnesium and Risk of Ischemic Stroke 
American Journal of Epidemiology  2009;169(12):1437-1444.
The authors sought to examine the relation between serum or dietary magnesium and the incidence of ischemic stroke among blacks and whites. Between 1987 and 1989, 14,221 men and women aged 45–64 years took part in the first examination of the Atherosclerosis Risk in Communities Study cohort. The incidence of stroke was ascertained from hospital records. Higher serum magnesium levels were associated with lower prevalence of hypertension and diabetes mellitus at baseline. During the 15-year follow-up, 577 ischemic strokes occurred. Serum magnesium was inversely associated with ischemic stroke incidence. The age-, sex-, and race-adjusted rate ratios of ischemic stroke for those with serum magnesium levels of ≤1.5, 1.6, 1.7, and ≥1.8 mEq/L were 1.0, 0.78 (95% confidence interval (CI): 0.62, 0.96), 0.70 (95% CI: 0.56, 0.88), and 0.75 (95% CI: 0.59, 0.95) (Ptrend = 0.005). After adjustment for hypertension and diabetes, the rate ratios were attenuated to nonsignificant levels. Dietary magnesium intake was marginally inversely associated with the incidence of ischemic stroke (Ptrend = 0.09). Low serum magnesium levels could be associated with increased risk of ischemic stroke, in part, via effects on hypertension and diabetes.
doi:10.1093/aje/kwp071
PMCID: PMC2727202  PMID: 19372211
brain infarction; diet; magnesium; risk factors
20.  Variation in PCSK9, Low LDL Cholesterol, and Risk of Peripheral Arterial Disease 
Atherosclerosis  2008;202(1):211-215.
Background
We hypothesized that variants in PCSK9 that lower LDL cholesterol levels are associated with reduced prevalence and incidence of peripheral artery disease (PAD).
Methods
The Atherosclerosis Risk in Communities (ARIC) Study assessed risk factors and PCSK9 variants Y142X and C679X (relevant to blacks) and R46L (relevant to whites) in a cohort of 45-64 year olds in 1987-89 (n=13,634). Prevalent PAD (n=619 cases) was defined by an ankle-brachial index <0.9 or a history of leg claudication. Incident PAD (n=895) was identified from 1987 through 1998 by the same PAD criteria or a PAD hospitalization.
Results
As expected, greater LDL cholesterol was a risk factor for prevalent and incident PAD. 2.4% of blacks and 3.1% of whites were carriers of one of the race-specific PCSK9 variants. Carriers had lower prevalence of PAD compared with non-carriers (2.3% vs. 4.6%). The corresponding age- and sex-adjusted odds ratio of PAD was 0.47 (95% confidence interval, 0.24-0.92). In contrast with the cross-sectional findings, there was no association between PCSK9 variants and incident PAD [age- and sex-adjusted hazard ratio, 1.09 (95% confidence interval, 0.76-1.57)].
Conclusions
Our study provides mixed evidence that variation in PCSK9 may contribute to genetic risk of PAD.
doi:10.1016/j.atherosclerosis.2008.03.009
PMCID: PMC2607475  PMID: 18436227
Peripheral arterial disease; Prospective study; PCSK9; Total cholesterol; LDL cholesterol
21.  Effect of 9p21 genetic variation on coronary heart disease is not modified by other risk markers. The Atherosclerosis Risk in Communities (ARIC) Study 
Atherosclerosis  2012;224(2):435-439.
Objective
To determine whether the 9p21 SNP association with coronary heart disease is modified by other classical or novel risk markers.
Methods
The 9p21 SNP (rs10757274) and multiple risk markers were measured in the Atherosclerosis Risk in Communities Study, and incident coronary disease events were ascertained. Effect modification (interaction) of the 9p21 SNP with risk markers was tested in Cox proportional hazard regression models.
Results
The incidence rates of coronary heart disease per 1000 person-years were 14.4, 17.0, and 18.7 for AA, AG, and GG genotypes, yielding hazard ratios of 1.0, 1.20 (95% CI = 1.07-1.36), and 1.34 (95% CI = 1.16-1.53). There was no meaningful evidence of an interaction (all p-interaction > 0.04) between 9p21 SNP and any of 14 other risk markers for coronary heart disease. These included novel markers not previously explored for 9p21 interaction (e.g., cardiac troponin T and N-terminal pro-brain natriuretic peptide).
Conclusion
Our study extends evidence that the 9p21 SNP association with coronary heart disease is not modified by classical or novel risk markers. Our findings therefore rule out additional plausible pathways by which 9p21 might have increased coronary heart disease risk.
doi:10.1016/j.atherosclerosis.2012.08.007
PMCID: PMC3459136  PMID: 22935634
coronary disease; prospective study; 9p21 SNP
22.  Associations of Acculturation and Socioeconomic Status with Subclinical CVD in the MultiEthnic Study of Atherosclerosis 
American journal of public health  2008;98(11):1963-1970.
Objective
To assess whether markers of acculturation (birthplace, number of U.S. generations) and socioeconomic status (SES) are associated with carotid artery plaque, internal carotid intima-media thickness (IMT), and albuminuria, in four racial/ethnic groups.
Methods
Using Multi-Ethnic Study of Atherosclerosis data (n = 6,716; age: 45-84) and race-specific binomial regression models, we computed prevalence ratios, adjusted for demographics and traditional cardiovascular risk factors.
Results
The adjusted U.S. to foreign-born prevalence ratio (99% CI) for carotid plaque was 1.20 (0.97, 1.39) in Whites, 1.91 (0.94, 2.94) in Chinese, 1.62 (1.28, 2.06) in Blacks, and 1.23 (1.15, 1.31) in Hispanics. Greater carotid plaque prevalence was also found among Whites, Blacks, and Hispanics with more generations of US residence (p<0.001). Lower educational attainment and/or income were associated with greater carotid plaque prevalence in Whites and Blacks. Similar associations were observed with IMT. There was also some evidence of an inverse association between albuminuria and SES, in Whites and Hispanics.
Conclusions
Greater U.S. acculturation and lower SES were associated with a higher prevalence of carotid plaque and IMT, while little association was found with albuminuria.
doi:10.2105/AJPH.2007.123844
PMCID: PMC2575668  PMID: 18511718
23.  Association between cardiovascular disease risk factors and occurrence of venous thromboembolism 
Thrombosis and haemostasis  2012;108(3):508-515.
Summary
Apart from obesity, it remains controversial whether atherosclerosis and its cardiovascular risk disease (CVD) factors are associated with risk of venous thromboembolism (VTE). Using data from the Atherosclerosis Risk in Communities study (ARIC), we evaluated associations between CVD risk factors and incident VTE in a cohort of 15,340 participants who were free a history of VTE and/or anticoagulant use on enrolment. The CVD risk factors were updated during the follow-up period. Over a mean follow-up time of 15.5 years (237,375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk [HR of 1.44 (95% CI: 1.12–1.86)] compared to non-smokers. There was a positive monotonic association between BMI and VTE risk. Individuals with a BMI ≥35 kg/m2 had a HR for VTE of 3.09 (95%CI: 2.26–4.23) compared to those with normal BMI (<25 kg/m2). Greater physical activity was associated with lower VTE risk in a demographic adjusted model; however, this association became non-significant following adjustment for BMI. Alcohol intake, diabetes, hypertension, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were not associated with VTE risk. In conclusion, among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in this large cohort where risk factors were updated serially during follow-up. This finding corroborates that the pathogenesis of venous disease differs from that of atherosclerotic disease.
doi:10.1160/TH11-10-0726
PMCID: PMC3482827  PMID: 22782466
Deep-vein thrombosis; pulmonary embolism; risk factors
24.  Associations Between Lipoprotein(a) Levels and Cardiovascular Outcomes in African Americans and Caucasians: The Atherosclerosis Risk in Communities (ARIC) Study 
Circulation  2011;125(2):241-249.
Background
Based on studies with limited statistical power, lipoprotein(a) [Lp(a)] is not considered a risk factor for cardiovascular disease (CVD) in African Americans. We evaluated associations between Lp(a) and incident CVD events in African Americans and Caucasians in the Atherosclerosis Risk in Communities (ARIC) study.
Methods and Results
Plasma Lp(a) was measured in African Americans (n=3,467) and Caucasians (n=9,851). Hazards ratios (HRs) for incident CVD events (coronary heart disease [CHD] and ischemic strokes) were calculated. Lp(a) levels were higher with wider interindividual variation in African Americans (median [interquartile range]: 12.8 [7.1–21.7] mg/dl) than Caucasians (4.3 [1.7–9.5] mg/dl; p <0.0001). At 20 years of follow-up, 676 CVD events occurred in African Americans and 1,821 events occurred in Caucasians. Adjusted HRs (95% confidence interval [CI]) per race-specific 1-SD–greater log-transformed Lp(a) were 1.13 (1.04–1.23) for incident CVD, 1.11 (1.00–1.22) for incident CHD, and 1.21 (1.06–1.39) for ischemic strokes in African Americans. For Caucasians, the respective HRs (95% CIs) were 1.09 (1.04–1.15), 1.10 (1.05–1.16), and 1.07 (0.97–1.19). Quintile analyses showed that risk for incident CVD was graded but statistically significant only for the highest compared with the lowest quintile (HR [95%CI] 1.35 [1.06–1.74] for African Americans; HR 1.27 [1.10–1.47] for Caucasians). Similar results were obtained using Lp(a) cut-offs of ≤10 mg/dl, >10–≤20 mg/dl, >20–≤30 mg/dl, and >30 mg/dl.
Conclusions
Lp(a) levels were positively associated with CVD events. Associations were at least as strong, with a larger range of Lp(a) concentrations, in African Americans compared with Caucasians.
doi:10.1161/CIRCULATIONAHA.111.045120
PMCID: PMC3760720  PMID: 22128224
lipoproteins; cardiovascular diseases; risk factors; race/ethnicity; cardiovascular disease risk factors
25.  ENDOGENOUS SEX HORMONES, BLOOD PRESSURE CHANGE, AND RISK OF HYPERTENSION IN POSTMENOPAUSAL WOMEN: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Atherosclerosis  2012;224(1):228-234.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.atherosclerosis.2012.07.005
PMCID: PMC3428144  PMID: 22862963
sex steroid hormones; hypertension; blood pressure; postmenopausal women; prospective study; epidemiology

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