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1.  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
2.  Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits 
Pankratz, Nathan | Schick, Ursula M | Zhou, Yi | Zhou, Wei | Ahluwalia, Tarunveer Singh | Allende, Maria Laura | Auer, Paul L | Bork-Jensen, Jette | Brody, Jennifer A | Chen, Ming-Huei | Clavo, Vinna | Eicher, John D | Grarup, Niels | Hagedorn, Elliott J | Hu, Bella | Hunker, Kristina | Johnson, Andrew D | Leusink, Maarten | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Manichaikul, Ani | Marioni, Riccardo E | Nalls, Mike A | Pazoki, Raha | Smith, Albert Vernon | van Rooij, Frank J A | Yang, Min-Lee | Zhang, Xiaoling | Zhang, Yan | Asselbergs, Folkert W | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Cushman, Mary | de Bakker, Paul I W | Deary, Ian J | Dong, Liguang | Feitosa, Mary F | Floyd, James S | Franceschini, Nora | Franco, Oscar H | Garcia, Melissa E | Grove, Megan L | Gudnason, Vilmundur | Hansen, Torben | Harris, Tamara B | Hofman, Albert | Jackson, Rebecca D | Jia, Jia | Kähönen, Mika | Launer, Lenore J | Lehtimäki, Terho | Liewald, David C | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J F | Nguyen, Vy M | Numans, Mattijs E | Pedersen, Oluf | Psaty, Bruce M | Raitakari, Olli T | Rich, Stephen S | Rivadeneira, Fernando | Di Sant, Amanda M Rosa | Rotter, Jerome I | Starr, John M | Taylor, Kent D | Thuesen, Betina Heinsbæk | Tracy, Russell P | Uitterlinden, Andre G | Wang, Jiansong | Wang, Judy | Dehghan, Abbas | Huo, Yong | Cupples, L Adrienne | Wilson, James G | Proia, Richard L | Zon, Leonard I | O’Donnell, Christopher J | Reiner, Alex P | Ganesh, Santhi K
Nature genetics  2016;48(8):867-876.
Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. Erythrocyte and WBC phenotypes were analyzed with Illumina HumanExome BeadChip genotypes in 52,531 individuals (37,775 of European ancestry; 11,589 African Americans; 3,167 Hispanic Americans) from 16 population-based cohorts. We then performed replication analyses of novel discoveries in 18,018 European American women and 5,261 Han Chinese. We identified and replicated four novel erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six novel WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC (MYB). The novel association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments of S1pr4 in mouse and zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
doi:10.1038/ng.3607
PMCID: PMC5145000  PMID: 27399967
3.  Replication of a genetic risk score for venous thromboembolism in whites but not in African Americans 
Summary
Background
Case-control studies have created genetic risk scores of single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) and documented their ability to predict VTE, but prospective data are lacking.
Objective
To test the ability of a genetic risk score to predict VTE incidence in a prospective study, particularly in African Americans.
Methods
We computed a previously proposed genetic risk score, based on five established VTE SNPs in the F5, F2, ABO, FGG, and F11 genes, in 9,520 whites and 3,049 African Americans initially free of VTE. We followed them a median of 22.6 years for VTE occurrence (n=380 events in whites and n=187 in African Americans).
Results
In whites, the 5-SNP weighted genetic risk score ranged from 0 to 5.8, and VTE risk increased 1.41 fold (95% CI 1.27, 1.56) per allele increment. In African Americans, the weighted genetic risk score ranged 0 to 4.6 and the hazard ratio per risk allele was 1.14 (95% CI 0.94, 1.38), with adjustment for 10 principal components of ancestry. The area under the receiver operating characteristic curve (AUC) for 20-year prediction of VTE from the weighted genetic risk score was 0.59 (95% CI 0.56, 0.63) in whites and 0.56 (95% CI 0.51, 0.61) in African Americans. Adding nongenetic factors increased the AUC to 0.67 in whites and to 0.66 in African Americans.
Conclusions
Higher values for a 5-SNP genetic risk score helped identify white adults at risk of VTE. The genetic risk score did not identify future VTE occurrence in African Americans.
doi:10.1111/jth.13193
PMCID: PMC4715510  PMID: 26565658
deep vein thrombosis; pulmonary embolism; prospective studies; genetics; risk factors
4.  Diabetes mellitus and venous thromboembolism: A systematic review and meta-analysis 
Diabetes mellitus (DM) may be a risk factor for venous thromboembolism (VTE) but results are inconsistent.
Aim
We conducted a systematic review and meta-analysis of epidemiologic studies to quantify the association between DM and VTE.
Methods and results
We included studies identified in PubMed, Web of Science, and CINAHL through 07/31/2014. We identified 19 studies that met our selection criteria. We pooled RRs using a random-effects model: the pooled RR for the association of DM with VTE was 1.10 (95% CI: 0.94–1.29). Between-study heterogeneity was explored with a forest plot, funnel plot, meta-regression, and a stratified analysis. Between-study heterogeneity was observed and not explained by study design, method of DM assessment, or degree of adjustment for confounding. Sensitivity analyses omitted one study at a time to assess the influence of any single study on the pooled estimate. These analyses indicated that one large study was highly influential; when this study was excluded, the pooled estimate increased and just reached statistical significance: 1.16 (95% CI: 1.01–1.34)].
Conclusions
This meta-analysis suggests either no association or a modest positive one between DM and VTE in the general population. DM is unlikely to play a major role in VTE development.
doi:10.1016/j.diabres.2015.10.019
PMCID: PMC4752919  PMID: 26612139
diabetes mellitus; venous thromboembolism; systematic review; meta-analysis
5.  Secondhand Smoke Exposure and Stroke 
Introduction
Stroke is a major public health concern worldwide given the associated morbidity and mortality. Smoking is a risk factor for stroke, but the relationship between secondhand smoke (SHS) exposure and stroke has been inconsistent to date. The aim of the current study was to examine the association of SHS exposure and risk of stroke and its subtypes (ischemic and hemorrhagic stroke) among nonsmokers.
Methods
Demographic and clinical characteristics were compared by SHS exposure status for black and white nonsmokers aged ≥45 years in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study in 2014. Hazard ratios (HRs) and corresponding 95% CIs were calculated by Cox proportional hazards models to assess the relationship between SHS exposure and stroke risk.
Results
Of the 21,743 participants (38% African American, 45% male), SHS exposure in the past year was reported by 23%. Compared with those without SHS exposure, exposed participants were more likely to be female, white, younger, and reside with a smoker (all p<0.001). A total of 428 incident strokes were observed from April 2003 to March 2012 during a mean follow-up of 5.6 years. The risk of overall stroke was increased 30% among those with SHS exposure after adjustment for other stroke risk factors (95% CI=2%, 67%). This relationship appeared to be driven by ischemic strokes.
Conclusions
SHS exposure is independently associated with an increased risk of stroke. Future studies are needed to confirm these findings and examine the role of long-term effects of SHS exposure on stroke outcomes.
doi:10.1016/j.amepre.2015.04.014
PMCID: PMC4656115  PMID: 26117341
6.  Serial measurement of N-terminal pro-B-type natriuretic peptide and cardiac troponin T for cardiovascular disease risk assessment in the Multi-Ethnic Study of Atherosclerosis (MESA) 
American heart journal  2015;170(6):1170-1183.
Background
N-terminal-pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (TnT) predict cardiovascular disease (CVD) risk in a variety of populations. Whether their predictive value varies by ethnicity is unknown. We sought to determine: whether NT-proBNP and TnT improve prediction of incident coronary heart disease (CHD) and CVD, independent of CVD risk factors, in a multi-ethnic population; whether NT-proBNP improves prediction compared to the Framingham Risk Score (FRS) or the Pooled Cohort Risk Equation (PCRE); and whether a second NT-proBNP further improves prediction.
Methods
NT-proBNP and TnT were measured in 5592 Multi-Ethnic Study of Atherosclerosis white, black, Hispanic and Chinese participants (60% nonwhite, mean age 62.3±10.3) in 2000–2002 and 2004–2005. We evaluated adjusted risk of incident CHD and CVD based on baseline and change in biomarker concentration.
Results
Participants were followed through 2011 and incurred 370 CVD events (232 CHD). NT-proBNP and TnT concentrations varied by ethnicity. NT-proBNP and TnT were associated with an increased risk of events (adjusted HR for CHD [95% CI] for 5th versus other 4 quintiles of NT-proBNP, 2.03[1.50–2.76]; HR for CHD for detectable versus undetectable TnT, 3.95[2.29–6.81]). NT-proBNP improved risk prediction and classification compared to the FRS and the PCRE. Change in NT-proBNP was independently associated with events (HR for CHD per unit increase in ΔlogNT-proBNP, 1.95[1.16–3.26]). None of the observed associations varied by ethnicity.
Conclusions
NT-proBNP and TnT are predictors of incident CHD, independent of established risk factors and ethnicity, in a multi-ethnic population without known CVD. Change in NT-proBNP may add additional prognostic information.
doi:10.1016/j.ahj.2015.09.010
PMCID: PMC4684596  PMID: 26678639
cardiovascular disease; coronary heart disease; ethnicity; race; natriuretic peptides; risk classification; biomarkers
7.  Prospective study of circulating factor XI and incident venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) 
American journal of hematology  2015;90(11):1047-1051.
Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (p<0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African Americans.
doi:10.1002/ajh.24168
PMCID: PMC4618026  PMID: 26260105
deep vein thrombosis; factor XI; prospective study; pulmonary embolism
8.  Inflammation and Hemostasis in Atrial Fibrillation and Coronary Heart Disease: The REasons for Geographic And Racial Differences in Stroke Study 
Atherosclerosis  2015;243(1):192-197.
Background
Recent studies suggest atrial fibrillation (AF) is an independent risk factor for coronary heart disease (CHD).
Aims
To determine if alterations in hemostasis or inflammation explain the association between AF and CHD.
Methods
C-reactive protein (CRP), D-dimer, factor VIII, and fibrinogen were measured in incident CHD cases (n=647) and a stratified cohort random sample (CRS, n=1,104) between 2003 and 2007 from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Using a case-cohort approach, Cox models examined whether inflammation or hemostasis biomarkers explained the association between AF and CHD.
Results
In participants free of CHD at baseline, 12.2% of CHD cases and 7.1% of the CRS had AF. Over a median follow-up of 4.4 years, all biomarkers were associated with an increased risk of CHD in those with and those without AF after adjusting for CHD risk factors. The association of D-dimer with CHD was greater in those with AF (HR 2.52, 95% CI=1.49, 4.26) than those without AF (HR 1.34, 95% CI=1.12, 1.61) (p-interaction=0.02). Similar interactions were not observed for the other biomarkers.
Conclusions
Our results suggest that alterations in D-dimer, a marker of hemostasis, explain the association between AF and CHD. Potentially, D-dimer is a useful biomarker to assess CHD risk in persons with AF.
doi:10.1016/j.atherosclerosis.2015.09.009
PMCID: PMC4634936  PMID: 26398291
atrial fibrillation; coronary disease; biological markers
9.  Environmental Tobacco Smoke and Atrial Fibrillation: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Objective
To examine the association between environmental tobacco smoke (ETS) exposure and atrial fibrillation.
Methods
We examined the cross-sectional association between ETS exposure and atrial fibrillation in 12,021 participants (mean age: 65 ± 9.9 years; 60% women; 40% blacks) from the REasons for Geographic And Racial Differences in Stroke study who self-identified as never smokers between 2003 and 2007.
Results
A total of 2,503 (21%) participants reported ETS exposure. In a multivariate logistic regression model adjusted for socio-demographics and potential confounders, ETS exposure was significantly associated with atrial fibrillation (OR=1.27, 95%CI=1.08, 1.50).
Conclusions
Our findings suggest that the harmful effects of ETS exposure extend to sustained arrhythmias such as atrial fibrillation.
doi:10.1097/JOM.0000000000000565
PMCID: PMC4636018  PMID: 26539762
environmental tobacco smoke; arrhythmia; epidemiology
10.  A Genetic Risk Score Comprising Known Venous Thromboembolism Loci is Associated with Chronic Venous Disease in a Multi-Ethnic Cohort 
Thrombosis research  2015;136(5):966-973.
Background
Chronic venous disease is common and shares some risk factors with venous thromboembolism (VTE). Several genetic loci have been discovered and well-replicated for VTE in European descent populations. We examined associations of a genetic risk score (GRS), comprising known VTE loci, with chronic venous disease.
Methods
The San Diego Population Study (SDPS) is a multi-ethnic cohort that evaluated 2404 men and women aged 29–91 from 1994 – 1998 for chronic venous disease. The current study includes 1447 participants genotyped for 33 variants in 22 established VTE risk loci. Using these variants, unweighted and weighted GRS were constructed. Logistic regression was used to examine associations with venous disease.
Results
In non-Hispanic Whites, African-Americans, Hispanics, and Asians, each standard deviation increment higher of the unweighted 33-SNP GRS was associated with a 1.45-fold (95% CI (1.26, 1.67)), 1.74-fold (1.18, 2.55), a 1.80-fold (1.30, 2.51), and 1.88-fold (1.30, 2.73) greater odds, respectively, for moderate plus severe disease. The difference in c-statistics was significant between a known venous risk factor model and a model adding the 33-SNP GRS for Whites (p=0.008), African-Americans (0.03), and Hispanics (p=0.04), with marginal significance in Asians (p=0.06).
Conclusions
GRS comprising variants primarily from VTE findings in European descent populations were associated with chronic venous disease across all race/ethnic groups, and contributed significantly to prediction, indicating some level of generalizability to other race/ethnic groups. Future work should focus on more in depth examination of racial/ethnic group genetic architecture in relation to chronic venous disease.
doi:10.1016/j.thromres.2015.09.016
PMCID: PMC4718662  PMID: 26442836
chronic venous disease; venous thromboembolism; race/ethnicity; genetic risk score; single nucleotide polymorphisms
11.  Prospective study of plasma D-dimer and incident venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) Study 
Thrombosis research  2015;136(4):781-785.
Introduction
Plasma D-dimer is a useful clinical test for acute venous thromboembolism (VTE), and concentrations remain higher in VTE patients after treatment than in controls. Yet, evidence is limited on whether higher basal D-dimer concentrations in the general population are associated with greater risk of first VTE.
Objective
To assess the prospective association between D-dimer and incident VTE over a long follow-up.
Methods
We measured plasma D-dimer in 12,097 participants, initially free of VTE, in the Atherosclerosis Risk in Communities Study. Over a median follow-up of 17 years, we identified 521 VTEs. We calculated hazard ratios of VTE using proportional hazards regression.
Results
The age, race, and sex adjusted hazard ratios of VTE across quintiles of D-dimer were 1, 1.5, 1.8, 2.1, and 3.2 (p for trend <0.0001). For the first 10 years of follow-up, the hazard ratio for the highest versus lowest quintile was 3.5, and was 2.9 after 10 years. In both whites and African Americans, VTE risk remained strongly associated with D-dimer after further adjustment for diabetes, body mass index, kidney function, and several thrombophilia genetic markers. D-dimer was associated with both unprovoked and provoked VTE, but more strongly with unprovoked.
Conclusions
A higher basal level of plasma D-dimer in the general population, presumably reflecting a predisposition to thrombosis, is a strong, long-term risk factor for a first VTE.
doi:10.1016/j.thromres.2015.08.013
PMCID: PMC4577468  PMID: 26337932
Deep vein thrombosis; D-dimer; Prospective studies; Pulmonary embolism; risk factors
12.  Association Between Life's Simple 7 and Noncardiovascular Disease: The Multi‐Ethnic Study of Atherosclerosis 
Background
The American Heart Association introduced the Life's Simple 7 (LS7) metrics to assess and promote cardiovascular health. We examined the association between the LS7 metrics and noncardiovascular disease.
Methods and Results
We studied 6506 men and women aged between 45 and 84 years, enrolled in the Multi‐Ethnic Study of Atherosclerosis. Median follow‐up time was 10.2 years. Each component of the LS7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and blood glucose) was assigned points, 0 indicates “poor” category; 1, “intermediate,” and 2, “ideal.” The LS7 score, ranged from 0 to 14, was created from the points and categorized as optimal (11–14), average (9–10), and inadequate (0–8). Hazard ratios and event rates per 1000 person‐years were calculated for outcomes based on self‐reported hospitalizations with the International Classification of Diseases, 9th Revision, diagnoses of cancer, chronic kidney disease, pneumonia, deep venous thromboembolism/pulmonary embolism, chronic obstructive pulmonary disease, dementia, and hip fracture. Analyses were adjusted for age, sex, race/ethnicity, income, and education. Overall, noncardiovascular disease event rates were lower with increasing LS7 scores. With the inadequate LS7 score as reference, an optimal score was associated with a decreased risk for noncardiovascular disease events. The hazard ratio for cancer was, 0.80 (0.64–0.98); chronic kidney disease, 0.38 (0.27–0.54); pneumonia, 0.57 (0.40–0.80); deep venous thromboembolism/pulmonary embolism, 0.52 (0.33–0.82), and chronic obstructive pulmonary disease, 0.51 (0.31–0.83).
Conclusions
The American Heart Association's LS7 score identified individuals who were vulnerable to multiple chronic nonvascular conditions. These results suggest that improving cardiovascular health will also reduce the burden of cancer and other chronic diseases.
doi:10.1161/JAHA.116.003954
PMCID: PMC5121499  PMID: 27792654
epidemiology; Life's Simple 7; prevention; risk factor; Race and Ethnicity; Lifestyle; Exercise; Diet and Nutrition; Obesity
13.  Validating laboratory results in a national observational cohort study without field centers: The Reasons for Geographic and Racial Differences in Stroke cohort 
Clinical biochemistry  2014;47(16-17):243-246.
Objectives
The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is a prospective cohort of 30,239 Americans in the contiguous United States; the first of this scale to use home visits to obtain, process, and ship biologic samples to a core laboratory. Pre-analytical factors resulting from this study design may affect the results of some laboratory assays. We investigated the impact of REGARDS processing on a variety of analytes.
Design and methods
In REGARDS, blood samples were processed in the field by technicians who were trained on standardized methods for phlebotomy and sample processing. Field processing included centrifugation using varying non-uniform equipment and shipping overnight on ice to the University of Vermont, where samples were re-centrifuged for 30,000 ×g-minutes and stored at −80 °C. We assessed the effects of REGARDS sample handling by processing split samples from 20 volunteers using either ideal procedures or simulated REGARDS procedures. Assays for 19 analytes for potential study in REGARDS were then run on both samples and results compared.
Results
Spearman correlation coefficients for analytes measured in ideal versus REGARDS processed samples ranged from 0.11 to 1.0. Thirteen of 19 analytes were highly correlated (>0.75), but platelet proteins were more variable.
Conclusions
Simulation of non-optimal field processing and shipment to a central laboratory showed high variability in analytes released by platelets. The majority of other analytes produced valid results, but platelet contamination in REGARDS samples makes measurement of platelet proteins unadvisable in these samples. Future analytes considered by REGARDS or similar studies should undergo similar pilot testing.
doi:10.1016/j.clinbiochem.2014.08.003
PMCID: PMC5038129  PMID: 25130959
Quality control; Blood chemical analysis; Biological markers; Blood specimen collection; Cohort studies
14.  A Risk Algorithm for Assessing Short–Term Mortality for Obese Black and White Men and Women 
Obesity (Silver Spring, Md.)  2013;22(4):1142-1148.
Objective
To develop and validate a mortality risk algorithm for obese black and white men and women to elucidate risk factors prognostic of short-term mortality among obese persons.
Methods
Prospective cohort study. Reasons for geographic and racial differences in stroke (REGARDS) study, is a cohort of black and white men and women aged ≥45 years. Obese (≥30 kg m−2) participants in REGARDS (n = 11 288) were randomly assigned to the derivation data set or an independent validation set.
Results
During the mean follow-up period of 4.9 years, 8.9% (n = 504) in the derivation cohort and 8.7% (n = 492) in the validation cohort died. The best-fitting model based on data from the derivation cohort included demographic (age, sex), coronary heart disease (CHD) conditions (diabetes, systolic blood pressure, history of CHD), health behaviors (smoking, physical activity, alcohol use), and socioeconomic variables (income, use of physician services). The C-statistic when the model was applied to the validation cohort was 0.80. Observed and predicted rates of mortality were similar across deciles of mortality risk by race.
Conclusions
A risk algorithm was established and validated to predict mortality among black and white obese subjects based on CHD risk factors, behavioral risk factors, and socioeconomic status.
doi:10.1002/oby.20622
PMCID: PMC5036400  PMID: 24115735
15.  A Risk Score to Guide Cystatin C Testing to Detect Occult Reduced Estimated Glomerular Filtration Rate 
American journal of nephrology  2015;42(2):141-147.
Background/Aims
Persons with occult reduced eGFR (eGFR <60 ml/min/1.73m2 detected by serum cystatin C but missed by creatinine) have high risk for complications. Among persons with preserved kidney function by creatinine-based estimated glomerular filtration rate ((eGFRcreat) >60 ml/min/1.73m2), tools to guide cystatin C testing are needed.
Methods
We developed a risk score to estimate an individual's probability of reduced eGFR by cystatin C (eGFRcys<60 ml/min/1.73m2) in The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and externally validated in the Third National Health and Nutrition Examination Survey (NHANES III). We used logistic regression with Bayesian model averaging and variables available in practice. We assessed performance characteristics using calibration and discrimination measures.
Results
Among 24,877 adults with preserved kidney function by creatinine, 13.5% had reduced eGFRcys. Older and Black participants, current smokers, and those with higher BMI, lower eGFRcreat, diabetes, hypertension, and history of cardiovascular disease were more likely to have occult reduced eGFR (p <0.001). The final risk function had a c-statistic of 0.87 in REGARDS, and 0.84 in NHANES. By risk score, 72% of occult reduced eGFR cases were detected by screening only 22% of participants.
Conclusions
A risk score using characteristics readily accessible in clinical practice can identify the majority of persons with reduced eGFRcys that is missed by creatinine.
doi:10.1159/000439231
PMCID: PMC4589276  PMID: 26381887
kidney disease; Serum Cystatin C; Creatinine; Creatinine-based estimated glomerular filtration rate (eGFRcreat); Cystatin C-based estimated glomerular filtration rate (eGFRcys)
16.  Circulating Adipokines and Inflammatory Markers and Postmenopausal Breast Cancer Risk 
Background:
Adipokines and inflammation may provide a mechanistic link between obesity and postmenopausal breast cancer, yet epidemiologic data on their associations with breast cancer risk are limited.
Methods:
In a case-cohort analysis nested within the Women’s Health Initiative Observational Study, a prospective cohort of postmenopausal women, baseline plasma samples from 875 incident breast cancer case patients and 839 subcohort participants were tested for levels of seven adipokines, namely leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α, hepatocyte growth factor, and plasminogen activator inhibitor-1, and for C-reactive protein (CRP), an inflammatory marker. Data were analyzed by multivariable Cox modeling that included established breast cancer risk factors and previously measured estradiol and insulin levels. All statistical tests were two-sided.
Results:
The association between plasma CRP levels and breast cancer risk was dependent on hormone therapy (HT) use at baseline (P interaction = .003). In a model that controlled for multiple breast cancer risk factors including body mass index (BMI), estradiol, and insulin, CRP level was positively associated with breast cancer risk among HT nonusers (hazard ratio for high vs low CRP levels = 1.67, 95% confidence interval = 1.04 to 2.68, P trend = .029). None of the other adipokines were statistically significantly associated with breast cancer risk. Following inclusion of CRP, insulin, and estradiol in a multivariable model, the association of BMI with breast cancer was attenuated by 115%.
Conclusion:
These data indicate that CRP is a risk factor for postmenopausal breast cancer among HT nonusers. Inflammatory mediators, together with insulin and estrogen, may play a role in the obesity–breast cancer relation.
doi:10.1093/jnci/djv169
PMCID: PMC4651104  PMID: 26185195
17.  ADIPONECTIN IS INDEPENDENTLY ASSOCIATED WITH NT-ProBNP: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Background and Aims
To investigate the associations between selected adipokines and the N-terminal prohormone of B-type natriuretic peptide (NT-proBNP).
Methods and Results
1489 individuals enrolled in the Multi-Ethnic Study of Atherosclerosis were evaluated at 4 clinic visits about every 2 years. The evaluation included fasting venous blood, which was analyzed for NT-proBNP (at visits 1 and 3) and the adipokines adiponectin and leptin (at visits 2 and 3). The mean age was 64.8 ± 9.6 years and 48% were female. After multivariable adjustment, a 1-SD increment in adiponectin was associated with a 14 pg/ml higher NT-proBNP level (p < 0.01), while, compared to the 1st quartile of adiponectin, the 2nd, 3rd and 4th quartiles had 28, 45 and 67% higher NT-proBNP levels (p < 0.01 for all). For changes in NT-proBNP over the follow-up period, and after multivariable adjustment including baseline NT-proBNP, a 1-SD increment in adiponectin was associated with a 25 pg/ml absolute increase in NT-proBNP (p < 0.01), while those in the 2nd, 3rd and 4th quartiles of adiponectin were associated with increases of 5, 28 and 65 pg/ml (p = 0.74, 0.09 and < 0.01, respectively). There was a significant interaction between adiponectin and sex for visit 3 NT-proBNP (p-interaction < 0.01), with significantly stronger associations in men. Leptin was not associated with NT-proBNP.
Conclusion
Higher adiponectin, but not leptin, is significantly associated with higher levels of NT-proBNP, as well as with greater longitudinal increases in NT-proBNP. The associations were stronger in men.
doi:10.1016/j.numecd.2015.04.005
PMCID: PMC4515181  PMID: 26026204
18.  A Review of the Relationships Between Endogenous Sex Steroids and Incident Ischemic Stroke and Coronary Heart Disease Events 
Current Cardiology Reviews  2015;11(3):252-260.
For decades, it has been recognized that men have a higher age-adjusted risk of ischemic cardiovascular (CVD) events compared to women, thus generating hypotheses that sex steroids contribute to CVD risk. Potential mechanisms include genomic and non-genomic effects of sex steroids as well as mediation through classic CVD risk factors and obesity. However, results from randomized studies suggest that sex steroid supplementation in men and women do not result in improved CVD outcomes and may increase CVD risk. In contrast, prospective observations from endogenous sex steroid studies, i.e. among participants not using sex steroids, have suggested the opposite relationship. We reviewed the findings of prospective observational studies in men (17 studies) and women (8 studies) that examined endogenous sex steroids and CVD risk. These studies suggested a lack of association or that lower levels of testosterone or dihydrotestosterone are associated with higher CVD risk in both men and women. Higher, rather than lower, estradiol levels were associated with higher CVD risk in women. There were several significant gaps in the literature. First, it is unclear whether more sensitive measures of sex steroid levels might detect significant differences. Second, there are few prospective studies in women. Similarly, no studies report outcomes for high-risk groups such as African-Americans and Hispanics. Finally, few studies report upon ischemic coronary disease as opposed to ischemic stroke separately, although relationships between sex steroids and CVD may vary by vascular bed. Future investigations need to examine high risk groups and to distinguish between subtypes of CVD.
doi:10.2174/1573403X1103150515110749
PMCID: PMC4558357  PMID: 25563292
Coronary disease; epidemiology; estradiol; ischemia; stroke; testosterone.
19.  Lipoprotein-Associated Phospholipase A2 and Risk of Incident Cardiovascular Disease in a Multi-Ethnic Cohort: The Multi Ethnic Study of Atherosclerosis 
Atherosclerosis  2015;241(1):176-182.
Objective
Prospective studies reporting a positive association of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with incident cardiovascular disease (CVD) have included primarily white individuals. We evaluated associations of Lp-PLA2 and first-time cardiovascular events in a healthy multi-ethnic cohort characterized by presence or absence of baseline subclinical atherosclerosis.
Methods
Lp-PLA2 mass and activity were measured at baseline in 5456 participants in the Multi-Ethnic Study of Atherosclerosis. Individuals were characterized for presence of baseline subclinical disease (coronary artery calcium score>0 or carotid intima-media thickness value>80th percentile) and followed prospectively for development of CVD events (coronary heart disease, ischemic stroke, and cardiovascular death).
Results
516 incident CVD events occurred over median follow-up of 10.2 years. In adjusted Cox proportional hazards models, each higher standard deviation of both Lp-PLA2 activity and mass was associated with an increased risk of cardiovascular events; hazard ratios (HR; 95% confidence intervals (CI)) 1.12 (1.01–1.26) for Lp-PLA2 activity and 1.10 (1.01–1.21) for mass. Associations did not differ by subclinical disease status (p-value for interaction 0.99 for Lp-PLA2 activity and 0.32 for Lp-PLA2 mass) and there was no confounding by subclinical atherosclerosis measures. Associations of Lp-PLA2 activity but not mass were weaker in Chinese participants but there were relatively few events among Chinese in race-stratified analysis.
Conclusion
In this multi-ethnic cohort, Lp-PLA2 was positively associated with CVD risk, regardless of the presence of coronary artery calcium or a thickened carotid-intimal media.
doi:10.1016/j.atherosclerosis.2015.05.006
PMCID: PMC4504012  PMID: 26004387
Lipoprotein-associated Phospholipase A2; Cardiovascular Disease; Inflammation; Ethnicity; Biomarker
20.  ABO Blood Type and Stroke Risk: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background
ABO blood type is an inherited trait associated with coagulation factor levels and vascular outcomes.
Objectives
To assess the association of blood type with stroke and whether blood type contributes to racial disparities in stroke in the United States.
Patients and Methods
The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study recruited 30,239 participants between 2003-07. Using a case-cohort design, blood type was genotyped in 646 participants with stroke and a 1,104 participant cohort random sample. Cox models adjusting for Framingham stroke risk factors assessed the association of blood type with stroke.
Results
Over 5.8 years of follow-up, blood types A or B versus type O were not associated with stroke. Blood type AB versus O was associated with an increased risk of stroke (adjusted HR 1.83; 95% CI 1.01, 3.30). The association of blood type AB versus O was greater in those without diabetes (adjusted HR 3.33; 95% CI 1.61, 6.88) than those with diabetes (adjusted HR 0.49; 95% CI 0.17, 1.44) (p-interaction = 0.02). Factor VIII levels accounted for 60% (95% CI 11%, 98%) of the association of AB blood type and stroke risk.
Conclusion
Blood type AB is associated with an increased risk of stroke that is not attenuated by conventional stroke risk factors and factor VIII levels were associated with 60% of the association. While blood type AB is rare in the U.S. population, it is a significant stroke risk factor and may play an important role in stroke risk in these individuals.
doi:10.1111/jth.12507
PMCID: PMC4913462  PMID: 24444093
ABO Blood-Group System; Continental Population Groups; Risk Factors; Factor VIII; Stroke
21.  Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans 
American journal of hematology  2015;90(6):534-540.
Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII:C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII:C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, P=5.10 × 10−7 in EAs and P=3.88 × 10−3 in AAs) and VWF rs7962217 (Gly2705Arg, P=6.30 × 10−9 in EAs and P=2.98 × 10−2 in AAs). Significant associations for FVIII:C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P=8.02 × 10−10), with VWF rs1800380 in AAs (P=5.62 × 10−11), and with MAT1A rs2236568 in AAs (P=1.69 × 10−6). We replicated previously reported associations of FVIII:C and VWF:Ag with the ABO blood group, VWF rs1063856 (Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII:C and VWF:Ag in both EAs and AAs.
doi:10.1002/ajh.24005
PMCID: PMC4747096  PMID: 25779970
22.  Atrial Fibrillation and Risk of ST-Segment Elevation versus Non-ST Segment Elevation Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study 
Circulation  2015;131(21):1843-1850.
Background
It has recently been reported that atrial fibrillation [AF] is associated with an increased risk of myocardial infarction [MI]. However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with type of MI [ST elevation MI (STEMI) vs. non-ST elevation MI [NSTEMI] might shed light on the potential mechanisms.
Methods and Results
We examined the association between AF and incident MI in 14,462 participants [mean age 54 years, 56% women, 26% African Americans] from the Atherosclerosis Risk in Communities study who were free of coronary heart disease at baseline [1987–1989] with follow-up through December 31, 2010. AF cases were identified from study visits electrocardiogram and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow up of 21.6 years, 1374 MI events occurred [829 NSTEMI, 249 STEMI, 296 unclassifiable]. In a multivariable adjusted model, AF [n=1545] as a time-varying variable was associated with a 63% increased risk of MI [HR (95% CI):1.63(1.32–2.02)]. However, AF was associated with NSTEMI [HR (95% CI): 1.80(1.39–2.31)] but not STEMI [HR (95% CI): 0.49(0.18–1.34)]; p-value for hazard ratios comparison=0.004. Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men [interaction p-value<0.01 for both].
Conclusions
AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI.
doi:10.1161/CIRCULATIONAHA.114.014145
PMCID: PMC4447576  PMID: 25918127
Atrial Fibrillation; Myocardial Infarction; STEMI; NSTEMI
23.  Correlates of Incident Cognitive Impairment in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
The Clinical neuropsychologist  2015;29(4):466-486.
Objective
To identify approximately 500 cases of incident cognitive impairment (ICI) in a large, national sample adapting an existing cognitive test-based case definition and to examine relationships of vascular risk factors with ICI.
Method
Participants were from the REGARDS study, a national sample of 30,239 African-American and white Americans. Participants included in this analysis had normal cognitive screening and no history of stroke at baseline, and at least one follow-up cognitive assessment with a three test battery (TTB). Regression-based norms were applied to TTB scores to identify cases of ICI. Logistic regression was used to model associations with baseline vascular risk factors.
Results
We identified 495 participants with ICI out of 17,630 eligible participants. In multivariable modeling, income (OR 1.83 CI 1.27,2.62), stroke belt residence (OR 1.45 CI 1.18,1.78), history of transient ischemic attack (OR 1.90 CI 1.29,2.81), coronary artery disease(OR 1.32 CI 1.02,1.70), diabetes (OR 1.48 CI 1.17,1.87), obesity (OR 1.40 CI 1.05,1.86), and incident stroke (OR 2.73 CI 1.52,4.90) were associated with ICI.
Conclusions
We adapted a previously validated cognitive test-based case definition to identify cases of ICI. Many previously identified risk factors were associated with ICI, supporting the criterion-related validity of our definition.
doi:10.1080/13854046.2015.1042524
PMCID: PMC4504009  PMID: 25978342
epidemiology; risk factors; methods; cognitive disorders; mild cognitive impairment; cognitive aging; stroke
24.  Improving Awareness and Outcomes Related to Venous Thromboembolism 
JAMA  2015;314(18):1913-1914.
doi:10.1001/jama.2015.15107
PMCID: PMC4682565  PMID: 26547458
25.  American Heart Association’s Life’s Simple 7 and incidence of venous thromboembolism 
doi:10.1002/ajh.23950
PMCID: PMC4409490  PMID: 25644737
Venous thrombosis; pulmonary embolism; risk factors; prospective study

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