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author:("bushman, Mary")
1.  C-reactive protein level and the incidence of eligibility for statin therapy: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Clinical cardiology  2012;36(1):15-20.
Given the results of the JUPITER trial, statin initiation may be considered for individuals with elevated high sensitivity C-reactive protein (CRP). However, if followed prospectively, many individuals with elevated CRP may become statin-eligible, limiting the impact of elevated CRP as a treatment indication. This analysis estimates the proportion of people with elevated CRP that become statin eligible over time.
We followed 2,153 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of cardiovascular disease (CVD) and diabetes with LDL-cholesterol (LDL-C) <130 mg/dL at baseline to determine the proportion who become eligible for statins over 4.5 years. The proportion eligible for statin therapy, defined by the National Cholesterol Education Program (NCEP) 2004 updated guidelines, was calculated at baseline and during follow-up stratified by baseline CRP level (≥2 mg/L).
At baseline, 47% of the 2,153 participants had elevated CRP. Among participants with elevated CRP, 29% met NCEP criteria for statins, compared to 28% without elevated CRP at baseline. By 1.5 years later, 26% and 22% (p=0.09) of those with and without elevated CRP at baseline reached NCEP LDL-C criteria and/or had started statins, respectively. These increased to 42% and 39% (p=0.24) at 3 years and 59% and 52% (p=0.01) at 4.5 years following baseline.
A substantial proportion of those with elevated CRP did not achieve NCEP based statin eligibility over 4.5 years of follow-up. These findings suggest that many patients with elevated CRP may not receive the benefits of statins if CRP is not incorporated into the NCEP screening strategy.
PMCID: PMC3953418  PMID: 22886783
2.  Geographic Variation in CKD Prevalence and ESRD Incidence in the United States: Results From the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
It is not known whether geographic differences in the prevalence of chronic kidney disease (CKD) exist and are associated with end-stage renal disease (ESRD) incidence rates across the US.
Study Design
Cross-sectional and ecologic.
Setting & Participants
White (n=16,410) and black (n=11,109) participants from across the continental US in the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.
Geographic region, defined by the 18 Networks of the US ESRD Network Program.
Outcomes & Measurements
Albuminuria, defined as an albumin-creatinine ratio ≥30 mg/g and reduced estimated glomerular filtration rate (eGFR), defined as levels <60 ml/min/1.73m2, were measured in the REGARDS study. ESRD incidence rates were obtained from the US Renal Data System.
For whites, the Network-specific prevalence of albuminuria ranged from 8.4% (95% CI, 3.3%–13.5%) in Network 15 to 14.8% (95% CI, 8.0%–21.6%) in Network 3, and reduced eGFR ranged from 4.3% (95% CI, 2.0%–6.6%) in Network 4 to 16.7% (95% CI, 12.7%–20.7%) in Network 7. For blacks, the prevalence of albuminuria ranged from 12.1% (95% CI, 8.7%–15.5%) in Network 5 to 26.5% (95% CI, 16.7%–36.3%) in Network 4, and reduced eGFR ranged from 6.7% (95% CI, 5.0%–8.4%) in Network 17/18 to 13.4% (95% CI, 7.8%–19.1%) in Network 12. The Spearman correlation coefficients for the prevalence of albuminuria and reduced eGFR with Network-specific ESRD incidence rates were 0.49 and 0.24, respectively, for whites and 0.29 and 0.25, respectively, for blacks.
There were few cases of albuminuria and reduced eGFR in some geographic regions.
In the US, substantial geographic variations in the prevalence of albuminuria and reduced eGFR exist but were only modestly correlated with ESRD incidence, suggesting the CKD burden may not explain the geographic variation in ESRD incidence.
PMCID: PMC3659181  PMID: 23228944
3.  Hepatocyte Growth Factor and the Risk of Developing Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke.
Methods and Results
We conducted a nested case-control study (972 incident stroke cases and 1:1 age- and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women’s Health Initiative Observational Study, a cohort of postmenopausal women aged 50–79 years. Baseline HGF levels were correlated positively with body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P-values <0.05). Baseline HGF levels were higher among cases than controls (geometric means 601.8 vs. 523.2 pg/mL, p = 0.003). Furthermore, the risk of incident ischemic stroke was significantly greater amongst women in the highest versus lowest quartile of plasma HGF levels (odds ratio [OR] = 1.46; 95% confidence interval [CI]: 1.12–1.91; Ptrend = 0.003), in a conditional logistic regression model that adjusted for BMI. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR=1.39; 95% CI=1.04–1.85, Ptrend=0.023).
Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease among postmenopausal women aged 50–79 years.
PMCID: PMC3903044  PMID: 20203323
Hepatocyte growth factor; ischemic stroke; women
4.  Self-report of stroke, transient ischemic attack, or stroke symptoms and risk of future stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background and Purpose
History of stroke and Transient Ischemic Attack (TIA) are documented risk factors for subsequent stroke and all-cause mortality. Recent reports suggest increased risk among those reporting stroke symptoms absent stroke or TIA. However, the relative magnitude of increased stroke risk has not been described across the symptomatic spectrum: 1) asymptomatic (Asx), 2) stroke symptoms only (SS), 3) TIA, 4) stroke in the distant past (DS), and 5) recent stroke (RS).
Between 2003–2007 the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 black and white Americans aged 45+. DS and RS were defined as self-report of physician diagnosis of stroke >5 or <5 years before baseline, respectively. SS was defined as a history of any of six sudden onset stroke symptoms absent TIA/stroke diagnosis. Kaplan-Meier and proportional hazards analysis were used to contrast stroke risk differences.
Over 5.0 ± 1.72 years of follow up, 737 strokes were validated. Compared to Asx persons, those with SS, TIA, DS and RS all had increased risk of future stroke. After adjustment for age, race, sex, income, education, alcohol intake, current smoking, and a history of diabetes, hypertension, myocardial infarction, atrial fibrillation, and dyslipidemia, there was 1.20-fold (not statistically significant) increased stroke risk for SS (95% CI 0.96, 1.51), 1.73-fold for TIA (95% CI 1.27, 2.36), 2.23-fold for DS (95% CI 1.61, 3.09) and 2.85-fold for RS (95% CI 2.16, 3.76).
Results suggest a spectrum of risk from stroke symptoms to TIA, distant stroke, and recent stroke, and imply a need for establishing these categories in health screenings to manage risk for future stroke, reinforcing the clinical importance of stroke history including the presence of stroke symptoms.
PMCID: PMC3558975  PMID: 23233382
stroke; TIA; stroke symptoms; mortality
5.  Soluble CD14: genome-wide association analysis and relationship to cardiovascular risk and mortality in the older adults 
Arteriosclerosis, thrombosis, and vascular biology  2012;33(1):10.1161/ATVBAHA.112.300421.
CD14 is a glycosylphosphotidylinositol-(GPI)-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.
Methods and Results
We measured baseline levels of sCD14 in over 5,000 European-American (EA) and African-American (AA) adults 65 years and older from the Cardiovascular Health Study, who were well-characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease (CVD), and who have been followed for clinical CVD and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional CVD risk factors), and was also inversely correlated with body mass index. In genome-wide association analyses of sCD14, we (a) confirmed the importance of the CD14 locus on chromosome 5q21 in EA; (b) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in AA; (c) identified a putative novel association in EA of a non-synonymous variant of PIGC, which encodes an enzyme required for the first step in GPI anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident CVD, and strongly and independently predicts all-cause mortality in older adults.
CD14 independently predicts risk mortality in older adults.
PMCID: PMC3826541  PMID: 23162014
CD14; glycosylphosphotidylinositol; coronary heart disease; mortality
6.  Assessing Risk Prediction Models Using Individual Participant Data From Multiple Studies 
Pennells, Lisa | Kaptoge, Stephen | White, Ian R. | Thompson, Simon G. | Wood, Angela M. | Tipping, Robert W. | Folsom, Aaron R. | Couper, David J. | Ballantyne, Christie M. | Coresh, Josef | Goya Wannamethee, S. | Morris, Richard W. | Kiechl, Stefan | Willeit, Johann | Willeit, Peter | Schett, Georg | Ebrahim, Shah | Lawlor, Debbie A. | Yarnell, John W. | Gallacher, John | Cushman, Mary | Psaty, Bruce M. | Tracy, Russ | Tybjærg-Hansen, Anne | Price, Jackie F. | Lee, Amanda J. | McLachlan, Stela | Khaw, Kay-Tee | Wareham, Nicholas J. | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Jansson, Jan-Håkan | Wennberg, Patrik | Salomaa, Veikko | Harald, Kennet | Jousilahti, Pekka | Vartiainen, Erkki | Woodward, Mark | D'Agostino, Ralph B. | Bladbjerg, Else-Marie | Jørgensen, Torben | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Dekker, Jacqueline M. | Nijpels, Giel | Stehouwer, Coen D. A. | Kauhanen, Jussi | Salonen, Jukka T. | Meade, Tom W. | Cooper, Jackie A. | Cushman, Mary | Folsom, Aaron R. | Psaty, Bruce M. | Shea, Steven | Döring, Angela | Kuller, Lewis H. | Grandits, Greg | Gillum, Richard F. | Mussolino, Michael | Rimm, Eric B. | Hankinson, Sue E. | Manson, JoAnn E. | Pai, Jennifer K. | Kirkland, Susan | Shaffer, Jonathan A. | Shimbo, Daichi | Bakker, Stephan J. L. | Gansevoort, Ron T. | Hillege, Hans L. | Amouyel, Philippe | Arveiler, Dominique | Evans, Alun | Ferrières, Jean | Sattar, Naveed | Westendorp, Rudi G. | Buckley, Brendan M. | Cantin, Bernard | Lamarche, Benoît | Barrett-Connor, Elizabeth | Wingard, Deborah L. | Bettencourt, Richele | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Kavousi, Maryam | Witteman, Jacqueline C. | Hofman, Albert | Franco, Oscar H. | Howard, Barbara V. | Zhang, Ying | Best, Lyle | Umans, Jason G. | Onat, Altan | Sundström, Johan | Michael Gaziano, J. | Stampfer, Meir | Ridker, Paul M. | Michael Gaziano, J. | Ridker, Paul M. | Marmot, Michael | Clarke, Robert | Collins, Rory | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimäki, Mika | Ridker, Paul M. | Buring, Julie | Cook, Nancy | Ford, Ian | Shepherd, James | Cobbe, Stuart M. | Robertson, Michele | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S. | Angelantonio, Emanuele Di | Gao, Pei | Haycock, Philip | Kaptoge, Stephen | Pennells, Lisa | Thompson, Simon G. | Walker, Matthew | Watson, Sarah | White, Ian R. | Wood, Angela M. | Wormser, David | Danesh, John
American Journal of Epidemiology  2013;179(5):621-632.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
PMCID: PMC3927974  PMID: 24366051
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
7.  Hemoglobin Decline, Function and Mortality in the Elderly: The Cardiovascular Health Study 
American journal of hematology  2012;88(1):10.1002/ajh.23336.
While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied.
We evaluated the determinants and consequences of hemoglobin decline in 3.758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly ≥65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: 1) per each 1g/dL decrease in hemoglobin and 2) development of anemia by the WHO criteria.
Among participants without baseline anemia, hemoglobin decreased by 0.4g/dL and 9% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95% CI 1.04, 1.18 per 1g/dL decrease) predicted subsequent mortality in men and women.
Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life.
PMCID: PMC3860593  PMID: 23044913
Anemia; Hemoglobin; Elderly; Mortality; Function; Epidemiology
8.  Higher soluble P-selectin is associated with chronic venous insufficiency: the San Diego Population Study 
Thrombosis research  2012;130(5):716-719.
P-selectin is a cell adhesion molecule shown to play a role in venous thromboembolism. We evaluated whether higher P-selectin is associated with chronic venous insufficiency (CVI).
Materials and Methods
In a cohort of 2408 participants, the San Diego Population Study, peripheral venous disease was established by symptoms, clinical examination, and ultrasound. We measured P-selectin in a subsample of 352 CVI cases frequency matched to controls. Cases included four hierarchical groups of increasing severity of CVI.
The association of P-selectin with CVI considering all cases was weak, with an age, race and sex-adjusted odds ratio (OR) of 1.3 (95% CI 1.0-2.2) for values in the 3rd versus 1st tertile. The OR for cases in the two most severe groups was 2.3 (95% CI 1.2-4.2). Addition of body mass index to the model reduced this OR to 1.9 (95% CI 1.0-3.6).
Higher circulating P-selectin was associated with more severe CVI, but not CVI overall. Results support that platelet and endothelial cell activation may be involved in the pathogenesis of CVI.
PMCID: PMC3474873  PMID: 22892384
P-selectin; chronic venous insufficiency; risk factor; blood coagulation
9.  Racial differences in albuminuria, kidney function, and risk of stroke 
Neurology  2012;79(16):1686-1692.
The objective of this study was to examine the joint associations of estimated glomerular filtration rate (eGFR) and urinary albumin excretion with incident stroke in a large national cohort study.
Associations of urinary albumin to creatinine ratio (ACR) and eGFR with incident stroke were examined in 25,310 participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective study of black and white US adults ≥45 years of age.
A total of 548 incident strokes were observed over a median of 4.7 years of follow-up. Higher ACR values were associated with lower stroke-free survival in both black and white participants. Among black participants, as compared to an ACR <10 mg/g, the hazard ratios of stroke associated with an ACR of 10–29.99, 30–300, and >300 mg/g were 1.41 (95% confidence interval [CI] 1.01–1.98), 2.10 (95% CI 1.48–2.99), and 2.70 (95% CI 1.58–4.61), respectively, in analyses adjusted for traditional stroke risk factors and eGFR. In contrast, the hazard ratios among white subjects were only modestly elevated and not statistically significant after adjustment for established stroke risk factors. eGFR <60 mL/min/1.73 m2 was not associated with incident stroke in black or white participants after adjustment for established stroke risk factors.
Higher ACR was independently associated with higher risk of stroke in black but not white participants from a national cohort. Elucidating the reasons for these findings may uncover novel mechanisms for persistent racial disparities in stroke.
PMCID: PMC3468778  PMID: 22993285
10.  Association of Mild to Moderate Chronic Kidney Disease with Venous Thromboembolism: Pooled Analysis of Five Prospective General Population Cohorts 
Circulation  2012;126(16):1964-1971.
Recent findings suggest that chronic kidney disease (CKD) may be associated with increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.
Methods and Results
We pooled individual participant data from five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m2, HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m2. Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m2 or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE.
Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.
PMCID: PMC3520022  PMID: 22977129
chronic kidney disease; deep vein thrombosis; epidemiology; pulmonary embolism; thromboembolism
11.  Adipokines Linking Obesity with Colorectal Cancer Risk in Postmenopausal Women 
Cancer research  2012;72(12):3029-3037.
Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case–cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines—adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of antiinflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HRQ4–Q1), 1.84; 95% CI, 1.17–2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.
PMCID: PMC3790260  PMID: 22511581
12.  Associations of BMI and insulin resistance with leptin, adiponectin, and the leptin to adiponectin ratio across ethnic groups: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Annals of epidemiology  2012;22(10):705-709.
Associations of adiponectin and leptin and their ratio with BMI and HOMA-IR have been investigated in different ethnic groups but variability in both assays and statistical methods have made cross-study comparisons difficult. We examined associations among these variables across four ethnic groups in a single study.
Adiponectin and leptin were measured in a subset of MESA participants. We calculated associations (using both partial correlations and adjusted linear regression) in each ethnic group and then compared the magnitude of these associations across groups.
After excluding individuals with type 2 diabetes there were 714 White, 219 Chinese, 332 African American, and 405 Hispanic individuals, in the study sample. Associations of BMI with adiponectin and leptin differed significantly (P < 0.05) across the ethnic groups in regression analyses, while associations of HOMA-IR with adiponectin and leptin did not differ across ethnic groups. The leptin to adiponectin ratio was not associated with a greater amount of adiposity or HOMA-IR variance than leptin or adiponectin in any ethnic group.
Given the consistency of HOMA-IR and adipokine associations, the differing means of adiponectin and leptin across ethnic groups may help to explain ethnic differences in mean insulin resistance.
PMCID: PMC3459265  PMID: 22929534
13.  Association of Race and Sex With Risk of Incident Acute Coronary Heart Disease Events 
It is unknown whether long-standing disparities in incidence of coronary heart disease (CHD) among US blacks and whites persist.
To examine incident CHD by black and white race and by sex.
Prospective cohort study of 24 443 participants without CHD at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, who resided in the continental United States and were enrolled between 2003 and 2007 with follow-up through December 31, 2009.
Expert-adjudicated total (fatal and nonfatal) CHD, fatal CHD, and nonfatal CHD (definite or probable myocardial infarction [MI]; very small non–ST-elevation MI [NSTEMI] had peak troponin level <0.5 µg/L).
Over a mean (SD) of 4.2 (1.5) years of follow-up, 659 incident CHD events occurred (153 in black men, 138 in black women, 254 in white men, and 114 in white women). Among men, the age-standardized incidence rate per 1000 person-years for total CHD was 9.0 (95% CI, 7.5–10.8) for blacks vs 8.1 (95% CI, 6.9–9.4) for whites; fatal CHD: 4.0 (95% CI, 2.9–5.3) vs 1.9 (95% CI, 1.4–2.6), respectively; and nonfatal CHD: 4.9 (95% CI, 3.8–6.2) vs 6.2 (95% CI, 5.2–7.4). Among women, the age-standardized incidence rate per 1000 person-years for total CHD was 5.0 (95% CI, 4.2–6.1) for blacks vs 3.4 (95% CI, 2.8–4.2) for whites; fatal CHD: 2.0 (95% CI, 1.5–2.7) vs 1.0 (95% CI, 0.7–1.5), respectively; and nonfatal CHD: 2.8 (95% CI, 2.2–3.7) vs 2.2 (95% CI, 1.7–2.9). Age- and region-adjusted hazard ratios for fatal CHD among blacks vs whites was near 2.0 for both men and women and became statistically nonsignificant after multivariable adjustment. The multivariable-adjusted hazard ratio for incident nonfatal CHD for blacks vs whites was 0.68 (95% CI, 0.51–0.91) for men and 0.81 (95% CI, 0.58–1.15) for women. Of the 444 nonfatal CHD events, 139 participants (31.3%) had very small NSTEMIs.
The higher risk of fatal CHD among blacks compared with whites was associated with cardiovascular disease risk factor burden. These relationships may differ by sex.
PMCID: PMC3772637  PMID: 23117777
coronary heart disease; epidemiology; racial disparities; disease incidence; cohort study
14.  Association between cardiovascular disease risk factors and occurrence of venous thromboembolism 
Thrombosis and haemostasis  2012;108(3):508-515.
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.
PMCID: PMC3482827  PMID: 22782466
Deep-vein thrombosis; pulmonary embolism; risk factors
15.  Racial Differences in the Impact of Elevated Systolic Blood Pressure on Stroke Risk 
JAMA internal medicine  2013;173(1):46-51.
Between the ages 45 and 65 years, incident stroke is 2 to 3 times more common in blacks than in whites, a difference not explained by traditional stroke risk factors.
Stroke risk was assessed in 27 748 black and white participants recruited between 2003 and 2007, who were followed up through 2011, in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Racial differences in the impact of systolic blood pressure (SBP) was assessed using proportional hazards models. Racial differences in stroke risk were assessed in strata defined by age (<65 years, 65–74 years, and ≥75 years) and SBP (<120 mm Hg, 120–139 mm Hg, and 140–159 mm Hg).
Over 4.5 years of follow-up, 715 incident strokes occurred. A 10–mm Hg difference in SBP was associated with an 8% (95% CI, 0%-16%) increase in stroke risk for whites, but a 24% (95% CI, 14%-35%) increase for blacks (P value for interaction, .02). For participants aged 45 to 64 years (where disparities are greatest), the black to white hazard ratio was 0.87 (95% CI, 0.48–1.57) for normotensive participants, 1.38 (95% CI, 0.94–2.02) for those with prehypertension, and 2.38 (95% CI, 1.19–4.72) for those with stage 1 hypertension.
These findings suggest racial differences in the impact of elevated blood pressure on stroke risk. When these racial differences are coupled with the previously documented higher prevalence of hypertension and poorer control of hypertension in blacks, they may account for much of the racial disparity in stroke risk.
PMCID: PMC3759226  PMID: 23229778
16.  Long-term Assessment of Inflammation and Healthy Aging in Late Life: The Cardiovascular Health Study All Stars 
Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996–1997 and 2005–2006.
In 2005–2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996–1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005–2006 level, only level was associated with CVD events and mortality.
Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
PMCID: PMC3436091  PMID: 22367431
Inflammation; Aging; Physical function; Cognitive function
17.  Inflammation and Coagulation Markers and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis 
The strength and direction of the associations between inflammation and coagulation biomarkers with kidney disease onset and progression remains unclear, especially in a population-based setting.
Study Design
Prospective observational study.
Setting & Participants
4,966 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with a cystatin C-based estimate of glomerular filtration rate (eGFRcys) > 60 ml/min/1.73m2 and least one follow-up measure of kidney function. All participants were free of cardiovascular disease (CVD) at entry.
We evaluated the associations of C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, factor VIII, and D-dimer with kidney function decline.
Outcomes and Measurements
Kidney function decline was assessed primarily by repeated measures of eGFRcys over 5 years. Rapid decline of kidney function was defined as an eGFR decrease of more than 3 ml/min/1.73m2 per year. Incident low eGFR was defined as the onset of eGFRcys<60 ml/min/1.73m2 at any follow up exam and eGFRcys decline ≥1 ml/min/1.73m2 per year.
Mean age was 60 years, 39% were white, 52% were women, and 11% had diabetes. Mean eGFRcys was 96 mL/min/1.73 m2 and 7% had albuminuria. Median follow up time was 4.77 years. Higher Factor VIII levels (per 1-standard deviation [SD] of biomarker) had the strongest association with kidney function decline (β= −0.25; 95% CI, −0.38 to −0.12; p<0.001), followed by IL-6 (β= −0.16; 95% CI, −0.29 to −0.03; p=0.01), CRP (β= −0.09; 95% CI, −0.22 to 0.03; p=0.1), and fibrinogen (β= −0.09; 95% CI, −0.22 to 0.04; p=0.2). Each 1-SD higher concentration of IL-6 (OR, 1.15; 95% CI, 1.07–1.23), Factor VIII (OR, 1.11; 95% CI, 1.03–1.18), and CRP (OR, 1.09; 95% CI, 1.02–1.16) at baseline was significantly associated with rapid kidney function decline. Only IL-6 was significantly associated with incident low eGFR (OR, 1.09; 95% CI, 1.00–1.19).
Observational study design and absence of measured GFR.
Inflammation and coagulation biomarkers are associated with declining kidney function in ambulatory adults without established CVD or CKD.
PMCID: PMC3745301  PMID: 22560844
18.  The association between self-reported tooth loss and cognitive function in the REasons for Geographic And Racial Differences in Stroke study 
Several mechanisms may associate tooth loss and related oral inflammation with cognitive impairment. The authors studied the relationship between tooth loss and cognitive function.
The REasons for Geographic And Racial Differences in Stroke study is a national longitudinal study of more than 30,000 African American and white adults 45 years or older. Data for tooth loss, cognitive function and potential confounding variables were available for 9,853 participants at the time of analysis. The authors used incremental linear regression modeling to investigate the cross-sectional association between self-reported tooth loss and cognitive function.
In unadjusted analysis (mean learning followed by recall; α level of significance of .05), the loss of six to 16 teeth and the loss of more than 16 teeth were associated with poorer cognitive function compared with the loss of no teeth. Attenuated associations persisted after the authors adjusted for demographic and systemic risk factors. The full model, which was adjusted for socioeconomic status (SES), revealed no association between tooth loss and cognitive function.
Tooth loss may be associated with cognitive function; however, this association is mediated by age and SES.
Clinical Implications
Tooth loss due to periodontal disease may be a marker for low SES, and the interplay of these factors with advanced age may confer risk of having poorer cognitive function. Further studies are needed to clarify these associations.
PMCID: PMC3744362  PMID: 21454843
Cognitive function; tooth loss
19.  Detectability and reproducibility of plasma levels of chemokines and soluble receptors☆ 
Results in Immunology  2013;3:79-84.
Background: Multiplex assays are available to measure an array of circulating chemokines, soluble cytokine receptors and growth factors. However, there is limited information regarding whether these analytes are suitable for large-scale epidemiological studies to assess their relationships with chronic diseases, including cancer.
Methods: We examined detectability, assay repeatability, and 3-year within-subject reproducibility of plasma levels of 25 chemokines and 11 soluble receptors of cytokines and growth factors selected from the Human Millipore Panels. Plasma samples were obtained from 36 men (average age 62 years) and 17 women (average age 32 years) who participated in two epidemiological studies. Inter-assay and within-subject reproducibility were assessed by intraclass correlation coefficients (ICC).
Results: All analytes, except lymphotactin (47% detectability), were detectable in >90% of plasma samples. Inter-assay reproducibility for all analytes in 36 men tested three times on separate days were good to excellent (ICCs: 0.71–1.00). Within-subject reproducibility in 17 women sampled three times in three years were excellent (ICC ≥ 0.75) for five chemokines (eotaxin, fractalkine, 6Ckine, eotaxin 3, and SDF-1α+β) and three soluble receptors (sIL-1R2, sIL-4R and sVEGFR2); ICCs were fair to good (0.4 ≤ ICC < 0.75) for 15 chemokines and eight soluble receptors. However, five chemokines (GRO, IP-10, MIP-1β, BCA-1, and MIP-3α) had ICC < 0.4, suggesting biological variability.
Conclusion: Multiplex assays for plasma levels of selected chemokines and soluble receptors showed good to excellent assay detectability and repeatability. Most analytes also had good 3-year within-subject reproducibility, indicating that a single measurement of these analytes may be used to assess biomarker-disease associations.
PMCID: PMC3908322  PMID: 24600562
Chemokines; Soluble receptors; Within-subject variability; Biomarker; Limit of detection
20.  Regional Differences in Diabetes as a Possible Contributor to the Geographic Disparity in Stroke Mortality 
Background and Purpose
Diabetes and hypertension impart approximately the same increased relative risk for stroke, although hypertension has a larger population-attributable risk because of its higher population prevalence. With a growing epidemic of obesity and associated increasing prevalence of diabetes that disproportionately impacts the southeastern Stroke Belt states, any potential contribution of diabetes to the geographic disparity in stroke mortality will only increase.
Racial and geographic differences in diabetes prevalence and diabetes awareness, treatment, and control were assessed in the REasons for Geographic And Racial Differences in Stroke study, a national population-based cohort of black and white participants older than 45 years of age. At the time of this report, 21 959 had been enrolled.
The odds of diabetes were significantly increased in both white and black residents of the stroke buckle (OR, 1.26; [1.10, 1.44]; OR, 1.45 [1.26, 1.66], respectively) and Stroke Belt (OR, 1.22; [1.09, 1.36]; OR, 1.13 [1.02, 1.26]) compared to the rest of the United States. In the buckle, regional differences were not fully mediated and remained significant when controlling for socioeconomic status and risk factors. Addition of hypertension to the models did not reduce the magnitude of the associations. There were no significant differences by region with regard to awareness, treatment, or control for either race.
These analyses support a possible role of regional variation in the prevalence of diabetes as, in part, an explanation for the regional variation in stroke mortality but fail to support the potential for a contribution of regional differences in diabetes management.
PMCID: PMC3725822  PMID: 18388336
diabetes; geography; racial differences
21.  High-Sensitivity C-Reactive Protein and Risk of Sepsis 
PLoS ONE  2013;8(7):e69232.
Conventional C-reactive protein assays have been used to detect or guide the treatment of acute sepsis. The objective of this study was to determine the association between elevated baseline high-sensitivity C-reactive protein (hsCRP) and the risk of future sepsis events.
We studied data from 30,239 community dwelling, black and white individuals, age ≥45 years old enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Baseline hsCRP and participant characteristics were determined at the start of the study. We identified sepsis events through review of hospital records. Elevated hsCRP was defined as values >3.0 mg/L. Using Cox regression, we determined the association between elevated hsCRP and first sepsis event, adjusting for sociodemographic factors (age, sex, race, region, education, income), health behaviors (tobacco and alcohol use), chronic medical conditions (coronary artery disease, diabetes, dyslipidemia, hypertension, chronic kidney disease, chronic lung disease) and statin use.
Over the mean observation time of 5.7 years (IQR 4.5–7.1), 974 individuals experienced a sepsis event, and 11,447 (37.9%) had elevated baseline hsCRP (>3.0 mg/L). Elevated baseline hsCRP was independently associated with subsequent sepsis (adjusted HR 1.56; 95% CI 1.36–1.79), adjusted for sociodemographics, health behaviors, chronic medical conditions and statin use.
Elevated baseline hsCRP was associated with increased risk of future sepsis events. hsCRP may help to identify individuals at increased risk for sepsis.
PMCID: PMC3720576  PMID: 23935961
22.  Moderate Waist Circumference and Hypertension Prevalence: The REGARDS Study 
American journal of hypertension  2011;24(4):482-488.
High waist circumference (WC) (women: >88 cm; men: >102 cm) increases cardiovascular risk. Less is known about moderate WC (women: 80–88 cm; men: 94–102 cm). Therefore, we examined the association between moderate WC and hypertension prevalence, independent of body mass index (BMI).
Among 24,247 eligible adults 45–84 years old, when recruited from January 2003 to October 2007 in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, we examined hypertension prevalence (systolic blood pressure (BP) ≥140 mm Hg, or diastolic BP ≥90 mm Hg, or self-reported antihypertensive medication use) by WC before and after stratification by BMI (normal: 18.5–24.9; overweight: 25–29.9; obese class I: 30–34.9). Logistic regression adjusted associations between WC, BMI, and hypertension prevalence for age, race, sex, region, income, education, cigarette smoking, glomerular filtration rate, alcohol use, and physical activity.
Overall, hypertension prevalence was 44% among those with low WC (n = 8,068), 55% with moderate WC (n = 6,488), and 66% with high WC (n = 9,691). After full adjustment, moderate WC was independently associated with hypertension prevalence among persons with normal BMI, (adjusted odds ratio (aOR), 1.49; 95% confidence interval (CI), 1.31–1.70), overweight BMI (aOR, 1.80; 95% CI, 1.64–1.98), and obese class I BMI (aOR, 2.28; 95%CI, 1.96–2.65) (referent: low WC-normal BMI). The moderate WC–hypertension association was observed in blacks and whites and in men and women.
Moderate WC is associated with hypertension prevalence independent of BMI and several hypertension risk factors in middle-aged and older adults.
PMCID: PMC3717383  PMID: 21233800
blood pressure; clinical epidemiology; hypertension; obesity; race; waist circumference
23.  What Stroke Symptoms Tell Us: Association of Risk Factors and Individual Stroke Symptoms in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study 
Stroke symptoms are common among people without a history of stroke or transient ischemic attack; however, it is unknown if particular attention should be focused on specific symptoms for subgroups of patients.
Using baseline data from 26,792 REasons for Geographic and Racial Differences in Stroke (REGARDS) participants without a history of transient ischemic attack or stroke, we assessed the association between age, sex, race, current smoking, hypertension and diabetes and the six stroke symptoms in the Questionnaire for Verifying Stroke-Free Status.
The mean age of participants was 64.4 ± 9.4 years, 40.7% were black and 55.2% women. After multivariable adjustment, older persons more often reported an inability to understand (odds ratio [OR] = 1.16 per 10 years older age, 95% confidence interval [CI]: 1.07–1.25) and unilateral vision loss (OR=1.09, 95% CI: 1.01–1.18) and less often reported numbness (OR=0.83, 95% CI: 0.79–0.87) and weakness (OR=0.85, 95% CI: 0.80–0.90). Women reported difficulty communicating more often than men (OR=1.36, 95% CI: 1.19–1.56). The OR for blacks compared to whites for each of the six stroke symptoms was increased, markedly so for unilateral numbness (OR=1.97, 95% CI: 1.81–2.16), unilateral weakness (OR=1.96, 95% CI: 1.76–2.18) and inability to understand (OR=1.87, 95% CI: 1.61–2.18). Current smoking, hypertension, and diabetes were associated with higher ORs for each stroke symptom.
The association of risk factors with six individual stroke symptoms studied was not uniform, suggesting the need to emphasize individual stroke symptoms in stroke awareness campaigns when targeting populations defined by risk.
PMCID: PMC3383611  PMID: 22726606
individual stroke symptoms; stroke symptoms; risk factors
24.  Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality 
A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.
To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.
Design, Setting, and Participants
Prospective cohort study involving 26 643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m2 and ACR of either <30 or ≥30 mg/g.
Main Outcome Measures
All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.
Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26 643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0–5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2–4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9–8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4–1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9–2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4–3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7–40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05–2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6–11.3). Net reclassification improvement for death was 13.3% (P<.001) and for end-stage renal disease was 6.4% (P<.001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.
Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
PMCID: PMC3697771  PMID: 21482744
25.  Association of Baseline Sex Hormone Levels with Baseline and Longitudinal Changes in Waist-to-Hip Ratio : Multi-Ethnic Study of Atherosclerosis 
Waist-to-hip ratio (WHR) is strongly associated with prevalent atherosclerosis. We analyzed the associations of baseline serum levels of testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA) with WHR in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
Baseline data was available for 3144 men and 2038 postmenopausal women, who were non-users of hormone therapy, who were 45–84 years of age, and of White, Chinese, Black or Hispanic racial/ethnic groups. Of these, 2708 men and 1678 women also had longitudinal measurements of WHR measured at the second and/or the third study visits (median follow-up 578 days, and 1135 days, respectively).
In cross-sectional analyses adjusted for age, race, and cardiovascular disease risk factors, T was negatively associated with baseline WHR in men, while in both sexes, E2 was positively associated and SHBG was negatively associated with WHR (all p<0.001). In longitudinal analyses, further adjusted for follow-up time and baseline WHR, baseline T was negatively associated with WHR at follow-up (p=0.001) in men, while in both sexes, E2 was positively associated (p=0.004), and SHBG was negatively associated with WHR (p<0.001). The longitudinal association of E2, but not T, was independent of SHBG. In both cross-sectional or longitudinal analyses, there were no associations between DHEA and WHR in either men or women.
Sex hormones are associated with WHR at baseline and also during follow-up above and beyond their baseline association. Future research is needed to determine if manipulation of hormones is associated with changes in central obesity.
PMCID: PMC3342434  PMID: 22270378
Sex Hormones; epidemiology; waist to hip ratio

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