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1.  KDDN: an open-source Cytoscape app for constructing differential dependency networks with significant rewiring 
Bioinformatics  2014;31(2):287-289.
Summary: We have developed an integrated molecular network learning method, within a well-grounded mathematical framework, to construct differential dependency networks with significant rewiring. This knowledge-fused differential dependency networks (KDDN) method, implemented as a Java Cytoscape app, can be used to optimally integrate prior biological knowledge with measured data to simultaneously construct both common and differential networks, to quantitatively assign model parameters and significant rewiring p-values and to provide user-friendly graphical results. The KDDN algorithm is computationally efficient and provides users with parallel computing capability using ubiquitous multi-core machines. We demonstrate the performance of KDDN on various simulations and real gene expression datasets, and further compare the results with those obtained by the most relevant peer methods. The acquired biologically plausible results provide new insights into network rewiring as a mechanistic principle and illustrate KDDN’s ability to detect them efficiently and correctly. Although the principal application here involves microarray gene expressions, our methodology can be readily applied to other types of quantitative molecular profiling data.
Availability: Source code and compiled package are freely available for download at http://apps.cytoscape.org/apps/kddn
Contact: yuewang@vt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu632
PMCID: PMC4287948  PMID: 25273109
2.  Mathematical modelling of transcriptional heterogeneity identifies novel markers and subpopulations in complex tissues 
Scientific Reports  2016;6:18909.
Tissue heterogeneity is both a major confounding factor and an underexploited information source. While a handful of reports have demonstrated the potential of supervised computational methods to deconvolute tissue heterogeneity, these approaches require a priori information on the marker genes or composition of known subpopulations. To address the critical problem of the absence of validated marker genes for many (including novel) subpopulations, we describe convex analysis of mixtures (CAM), a fully unsupervised in silico method, for identifying subpopulation marker genes directly from the original mixed gene expressions in scatter space that can improve molecular analyses in many biological contexts. Validated with predesigned mixtures, CAM on the gene expression data from peripheral leukocytes, brain tissue, and yeast cell cycle, revealed novel marker genes that were otherwise undetectable using existing methods. Importantly, CAM requires no a priori information on the number, identity, or composition of the subpopulations present in mixed samples, and does not require the presence of pure subpopulations in sample space. This advantage is significant in that CAM can achieve all of its goals using only a small number of heterogeneous samples, and is more powerful to distinguish between phenotypically similar subpopulations.
doi:10.1038/srep18909
PMCID: PMC4703969  PMID: 26739359
3.  Heart failure risk prediction in the Multi-Ethnic Study of Atherosclerosis 
Heart (British Cardiac Society)  2014;101(1):58-64.
Objective
Heart failure (HF) is a leading cause of mortality especially in older populations. Early detection of high-risk individuals is imperative for primary prevention. The purpose of this study was to develop a HF risk model from a population without clinical cardiac disease.
Methods
The Multi-Ethnic Study of Atherosclerosis is a multicentre observational cohort study following 6814 subjects (mean age 62±10 years; 47% men) who were free of clinical cardiovascular disease at baseline. Median follow-up was 4.7 years. HF events developed in 176 participants. Cox proportional hazards models and regression coefficients were used to determine independent risk factors and generate a 5-year risk score for incident HF. Bootstrapping with bias correction was used for internal validation.
Results
Independent predictors for HF (HR, p value) were age (1.30 (1.10 to 1.50) per 10 years), male gender (2.27 (1.53 to 3.36)), current smoking (1.97 (1.15 to 3.36)), body mass index (1.40 (1.10 to 1.80) per 5 kg/m2), systolic blood pressure (1.10 (1.00 to 1.10) per 10 mm Hg), heart rate (1.30) (1.10 to 1.40) per 10 bpm), diabetes (2.27 (1.48 to 3.47)), N-terminal pro-B-type natriuretic peptide (NT proBNP) (2.48 (2.16 to 2.84) per unit log increment) and left ventricular mass index (1.40 (1.30 to 1.40) per 10 g/m2). A parsimonious model based on age, gender, body mass index, smoking status, systolic blood pressure, heart rate, diabetes and NT proBNP natriuretic peptide predicted incident HF risk with a c-statistic of 0.87.
Conclusions
A clinical algorithm based on risk factors readily available in the primary care setting can used to identify individuals with high likelihood of developing HF without pre-existing cardiac disease.
doi:10.1136/heartjnl-2014-305697
PMCID: PMC4685458  PMID: 25381326
4.  Left Ventricular Dilation and Incident Congestive Heart Failure in Asymptomatic Adults without Cardiovascular Disease. MESA 
Journal of cardiac failure  2014;20(12):905-911.
Background
Limited data exist on the association between LV dilation/remodeling and incident heart failure (HF), especially in adults without prior myocardial infarction and valvular heart disease. We assessed the association between left ventricular (LV) dilation and remodeling, and incident heart failure in a multi ethnic cohort
Methods
4974 of 6814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) had cardiac magnetic resonance imaging and complete data. Kaplan-Meier (KM) and Cox proportional hazard analyses were used to assess the association between LV end diastolic diameter (LVEDD) and adjudicated HF.
Results
During the 12 years of follow up (mean 9.4 years), 177(3.6%) HF events occurred, 126(71.2%) HFref and 51(28.8%) HFpef. LV dilation (LVEDD >52mm or >95th percentile) was associated with HF in univariate [HR (95%CI): 1.21(1.08 – 1.46) p=0.007] and multivariable Cox models [HR (95%CI): 1.28(1.09–1.57) p=0.01] adjusting traditional risk factors, medication use, LV ejection fraction (LVEF) and interim MI. We found a significant multiplicative interaction between LVEDD and LV ejection fraction in our full multivariable models. Participants with dilated LV and normal ejection fraction had increase risk [HR (95%CI):2.22(1.46–3.37), p=0.006) and those with dilated LV and decreased ejection fraction having the worse prognosis [HR (95%CI): 7.35(2.36 – 22.85), p=0.0006] compared with normal size LV and normal ejection fraction. High proportion of participants with LV dilation had eccentric remodeling; a risk factor for HF. Concentric hypertrophy also a risk factor for HF was common in normal LV group.
Conclusion
LV dilation predicts incident HF independent of risk factors, LV EF and interim MI
doi:10.1016/j.cardfail.2014.09.002
PMCID: PMC4250423  PMID: 25225112
left ventricular dilation; left ventricular remodeling; heart failure; risk factors; left ventricular ejection fraction
5.  Prevalence and Determinants of Electrocardiographic Abnormalities in African Americans with Type 2 Diabetes 
Background
Electrocardiographic (ECG) abnormalities are independently associated with poor outcomes in the general population. Their prevalence and determinants were assessed in the understudied African American population with type 2 diabetes.
Methods
Standard 12-lead ECGs were digitally recorded in 635 unrelated African American-Diabetes Heart Study (AA-DHS) participants, automatically processed at a central lab, read, and coded using standard Minnesota ECG Classification. Age- and sex-specific prevalence rates of ECG abnormalities were calculated and logistic regression models were fitted to examine cross-sectional associations between participant characteristics and ECG abnormalities.
Results
Participants were 56% women with a mean age of 56 years; 60% had at least one minor or major ECG abnormality [23% ≥1 major (or major plus minor), and 37% ≥1 minor (with no major)]. Men had a higher prevalence of ≥1 minor or major ECG abnormality (66.1% men vs. 55.6% women, p=0.0089). In univariate analyses, age, past history of cardiovascular disease, diabetes duration, systolic blood pressure, sex and statin use were associated with the presence of any (major or minor) ECG abnormalities. In a multivariate model including variables, female sex (OR [95% CI] 0.79 [0.67,0.93]), statin use (0.79 [0.67,0.93]) and diabetes duration (1.03 [1.0,1.05]) remained statistically significant.
Conclusions
Nearly three out of five African Americans with diabetes had at least one ECG abnormality. Female sex and statin use were significantly associated with lower odds of any ECG abnormality and diabetes duration was significantly associated with higher odds of any ECG abnormality in the multivariable model.
doi:10.1016/j.jegh.2014.04.003
PMCID: PMC4254487  PMID: 25455646
Electrocardiogram; Diabetes; African Americans; Heart; Hypertension; Cardiovascular Disease
6.  Coronary Artery Calcium and Incident Cerebrovascular Events in an Asymptomatic Multi Ethnic Cohort. MESA 
JACC. Cardiovascular imaging  2014;7(11):1108-1115.
Objective
We assessed the predictive value of coronary artery calcium (CAC) score for CVA events in an asymptomatic multi-ethnic cohort.
Background
The coronary artery calcium (CAC) score, a measure of atherosclerotic burden, has been shown to improve prediction of coronary heart disease events. However, the predictive value of CAC for cerebrovascular (CVA) events is unclear.
Methods
CAC was measured at baseline exam of participants (N=6779) of the Multi Ethnic Study of atherosclerosis (MESA) and then followed for an average of 9.5(2.4) years for the diagnosis of incident CVA defined as all strokes or TIAs.
Results
During the follow up 234(3.5%) adjudicated CVA events occurred. In Kaplan Meier analysis the presence of CAC was associated with a lower CVA event - free survival versus CAC absent (Log rank χ2 = 59.8, p<0.0001). Log transformed CAC was associated with increased risk for CVA after adjusting for age, gender, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL-C, cigarette smoking status, blood pressure medication use, statin use and interim atrial fibrillation[hazard ratio(95% CI): 1.13(1.07 – 1.20),p<0.0001]. The ACC/AHA recommended CAC cut off was also an independent predictor of CVA and strokes [HR (95%CI): 1.70(1.24–2.35),p=0.001 and 1.59(1.11–2.27), p=0.01 respectively]. CAC was an independent predictor of CVA when analysis was stratified by gender or race/ethnicity, and improved discrimination for CVA when added to the full model (c statistic: 0.744 vs. 0.755). CAC also improved the discriminative ability of the Framingham stroke risk score for CVA.
Conclusion
CAC is an independent predictor of CVA events, and improves the discrimination afforded by current stroke risk factors or the Framingham stroke risk score for incident CVA in an initially asymptomatic multi-ethnic adult cohort.
doi:10.1016/j.jcmg.2014.07.009
PMCID: PMC4254694  PMID: 25459592
Coronary artery calcium score; cerebrovascular disease; risk prediction; prevention
7.  Risk Factors for Atrial Fibrillation in Patients with Normal versus Dilated Left Atria (from the Atherosclerosis Risk in Communities [ARIC] Study) 
The American journal of cardiology  2014;114(9):1368-1372.
Epidemiological data are limited regarding risk factors of atrial fibrillation (AF) in patients with normal-sized left atria (LA). We evaluated whether traditional risk factors of AF differ between patients with normal-sized and dilated LA. This is a cross sectional study of community-dwelling participants of Atherosclerosis Risk in Communities Study. LA volume index (LAVI) was measured by 2-dimensional echocardiography. LAVI ≥29mm3/m2 defined dilated LA. Prevalent AF was defined by electrocardiogram and hospital discharge international classification of diseases - 9 codes. Multivariable adjusted logistic regression analysis was used to examine whether magnitude of association of risk factors with AF differ by LA cavity size. Interaction of risk factors by LA cavity size was evaluated to determine significance of these differential associations. Of 5496 participants (mean age 75±5 years, women 58%), 1230 (22%) had dilated LA. The prevalence of AF was 11% in individuals with normal-sized LA and 15% in individuals with dilated LA. Age >75 years [Odds Ratio (OR) 1.87; 95% confidence interval (CI) 1.49 – 2.35, interaction p=0.12] and heart failure (OR 5.43; 95% CI 3.77 – 7.87, interaction p=0.10) were stronger risk factors for AF in normal-sized LA than dilated-LA. Female sex (OR 1.67; 95% CI 1.01 – 2.77, interaction p=0.09), weight (OR 1.32; 95% CI 1.02 – 1.71, interaction p=0.19) and alcohol-use (OR 1.61; 95% CI 1.08 – 2.41, interaction p=0.004) were stronger risk factors for AF in individuals with dilated LA than normal-sized LA. In conclusion, risk factors of AF may differ by left ventricular cavity size.
doi:10.1016/j.amjcard.2014.07.073
PMCID: PMC4195803  PMID: 25245413
Atrial fibrillation; normal size left atrium; left atrium; risk factors; epidemiology
8.  Contributors to Mortality in High-Risk Diabetic Patients in the Diabetes Heart Study 
Diabetes Care  2014;37(10):2798-2803.
OBJECTIVE
Not all individuals with type 2 diabetes and high coronary artery calcified plaque (CAC) experience the same risk for adverse outcomes. This study examined a subset of high-risk individuals based on CAC >1,000 mg (using a total mass score) and evaluated whether differences in a range of modifiable cardiovascular disease (CVD) risk factors provided further insights into risk for mortality.
RESEARCH DESIGN AND METHODS
We assessed contributors to all-cause mortality among 371 European American individuals with type 2 diabetes and CAC >1,000 from the Diabetes Heart Study (DHS) after 8.2 ± 3.0 years (mean ± SD) of follow-up. Differences in known CVD risk factors, including modifiable CVD risk factors, were compared between living (n = 218) and deceased (n = 153) participants. Cox proportional hazards regression models were used to quantify risk for all-cause mortality.
RESULTS
Deceased participants had a longer duration of type 2 diabetes (P = 0.02) and reduced use of cholesterol-lowering medications (P = 0.004). Adjusted analyses revealed that vascular calcified plaque scores were associated with increased risk for mortality (hazard ratio 1.31–1.63; 3.89 × 10−5 < P < 0.03). Higher HbA1c, lipids, and C-reactive protein and reduced kidney function also were associated with a 1.1- to 1.5-fold increased risk for mortality (3.45 × 10−6 < P < 0.03) after adjusting for confounding factors.
CONCLUSIONS
Even in this high-risk group, vascular calcification and known CVD risk factors provide useful information for ongoing assessment. The use of cholesterol-lowering medication seemed to be protective for mortality.
doi:10.2337/dc14-0081
PMCID: PMC4392938  PMID: 24989706
9.  Development of a New Diabetes Risk Prediction Tool for Incident Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study 
Atherosclerosis  2014;236(2):411-417.
Objective
We develop a new diabetes CHD risk estimator using traditional risk factors plus coronary artery calcium (CAC), ankle-brachial index (ABI), high sensitivity C-reactive protein, family history of CHD, and carotid intima-media thickness and compared it with United Kingdom Prospective Diabetes study (UKPDS), Framingham risk and the NCEP/ATP III risk scores in type 2 diabetes mellitus (T2DM).
Methods and Results
We combined data from T2DM without clinical CVD in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (N=1343). After a mean follow-up of 8.5 years, 85(6.3%) participants had incident CHD. Among the novel risk markers, CAC best predicted CHD independent of the FRS [hazard ratio: HR (95% CI): log (CAC +25):1.69(1.45 – 1.97), p<0.0001; CAC categories: CAC ≤ 25 as reference, >25 and ≤ 125:2.29(0.87 – 5.95), >125 and ≤ 400: 3.87(1.57– 9.57), >400: 5.97(2.57– 13.84), respectively). The MESA-HNR diabetes CHD risk score has better accuracy for the main outcome versus the FRS or UKPDS [area under curve (AUC) of 0.76 vs. 0.70 and 0.69, respectively; all p<0.05]. The MESA-HNR risk score improved risk classification versus the FRS (net reclassification improvement (NRI) = 0.19 and integrated discrimination improvement (IDI) =0.046, p<0.05) and UKPDS (NRI=0.215 and IDI = 0.046, p<0.05). Compared with the ATP III guidelines, the MESA-HNR score has an NRI of 0.74 for the main outcome.
Conclusions
This new CHD risk estimator has better discriminative ability for incident CHD than the FRS, UKPDS, and the ATP III/NCEP recommendations in a multi-ethnic cohort with T2DM.
doi:10.1016/j.atherosclerosis.2014.07.035
PMCID: PMC4170005  PMID: 25150939
Diabetes mellitus; coronary calcium score; risk assessment; coronary heart disease
10.  Multiple rare alleles at LDLR and APOA5 confer risk for early-onset myocardial infarction 
Do, Ron | Stitziel, Nathan O. | Won, Hong-Hee | Jørgensen, Anders Berg | Duga, Stefano | Merlini, Pier Angelica | Kiezun, Adam | Farrall, Martin | Goel, Anuj | Zuk, Or | Guella, Illaria | Asselta, Rosanna | Lange, Leslie A. | Peloso, Gina M. | Auer, Paul L. | Girelli, Domenico | Martinelli, Nicola | Farlow, Deborah N. | DePristo, Mark A. | Roberts, Robert | Stewart, Alexander F.R. | Saleheen, Danish | Danesh, John | Epstein, Stephen E. | Sivapalaratnam, Suthesh | Hovingh, G. Kees | Kastelein, John J. | Samani, Nilesh J. | Schunkert, Heribert | Erdmann, Jeanette | Shah, Svati H. | Kraus, William E. | Davies, Robert | Nikpay, Majid | Johansen, Christopher T. | Wang, Jian | Hegele, Robert A. | Hechter, Eliana | Marz, Winfried | Kleber, Marcus E. | Huang, Jie | Johnson, Andrew D. | Li, Mingyao | Burke, Greg L. | Gross, Myron | Liu, Yongmei | Assimes, Themistocles L. | Heiss, Gerardo | Lange, Ethan M. | Folsom, Aaron R. | Taylor, Herman A. | Olivieri, Oliviero | Hamsten, Anders | Clarke, Robert | Reilly, Dermot F. | Yin, Wu | Rivas, Manuel A. | Donnelly, Peter | Rossouw, Jacques E. | Psaty, Bruce M. | Herrington, David M. | Wilson, James G. | Rich, Stephen S. | Bamshad, Michael J. | Tracy, Russell P. | Cupples, L. Adrienne | Rader, Daniel J. | Reilly, Muredach P. | Spertus, John A. | Cresci, Sharon | Hartiala, Jaana | Tang, W.H. Wilson | Hazen, Stanley L. | Allayee, Hooman | Reiner, Alex P. | Carlson, Christopher S. | Kooperberg, Charles | Jackson, Rebecca D. | Boerwinkle, Eric | Lander, Eric S. | Schwartz, Stephen M. | Siscovick, David S. | McPherson, Ruth | Tybjaerg-Hansen, Anne | Abecasis, Goncalo R. | Watkins, Hugh | Nickerson, Deborah A. | Ardissino, Diego | Sunyaev, Shamil R. | O’Donnell, Christopher J. | Altshuler, David | Gabriel, Stacey | Kathiresan, Sekar
Nature  2014;518(7537):102-106.
Summary
Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
doi:10.1038/nature13917
PMCID: PMC4319990  PMID: 25487149
11.  Mediation of Cardiovascular Risk Factor Effects Through Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objective
It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT) and brachial flow mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT and FMD.
Approach and Results
6355 out of 6814 MESA participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) were used to assess whether CAC, CIMT or FMD are mediators of the association between traditional risk factors and incident CVD event.
Mean age of 62, with 47% males, 12% diabetics and 13% current smokers. Mean follow up of 7.5 years, 539 CVD events were adjudicated. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes while current cigarette smoking had the least percent of total effect mediated via CAC [percent (95%CI: 80.2(58.8, 126.7) % vs. 10.6(6.1, 38.5) % respectively). BMI showed the highest percent of total effect mediated via CIMT [17.7(11.6, 38.9) %], only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD.
Conclusion
Many of the risk factors for incident CVD (other than age, sex and BMI) showed a modest level of mediation via CAC, CIMT and FMD suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification
doi:10.1161/ATVBAHA.114.303753
PMCID: PMC4329880  PMID: 24876350
12.  Association of Parity with Carotid Diameter and Distensibility: Multi-Ethnic Study of Atherosclerosis 
Hypertension  2014;64(2):253-258.
Pregnancy and childbirth are associated with hemodynamic changes and vascular remodeling. It is not known whether parity is associated with later adverse vascular properties such as larger arterial diameter, wall thickness and lower distensibility.
We used baseline data from 3283 women free of cardiovascular disease aged 45-84 years enrolled in the population based Multi-Ethnic Study of Atherosclerosis. Participants self-reported parity status. Ultrasound derived carotid artery lumen diameters and brachial artery blood pressures were measured at peak-systole and end-diastole. Common carotid intima media thickness (cIMT) was also measured. Regression models to determine the association of carotid distensibility coefficient, lumen diameter, and cIMT with parity were adjusted for age, race, height, weight, diabetes, current smoking, BP medication use, total and high density lipoprotein cholesterol levels.
The prevalence of nulliparity was 18%. In adjusted models, carotid distensibility coefficient was 0.09 × 10−5Pa−1 lower (p = 0.009) in parous vs. nulliparous women. Among parous women, there was a nonlinear association with the greatest carotid DC seen in women with 2 live births, and significantly lower distensibility seen in primiparas (p=0.04) or with higher parity > 2 (p=0.005). No such pattern of association with parity was found for lumen diameter or cIMT.
Parity is associated with lower carotid artery distensibility, suggesting arterial remodeling that lasts beyond childbirth. These long-term effects on the vasculature may explain the association of parity with cardiovascular events later in life.
doi:10.1161/HYPERTENSIONAHA.114.03285
PMCID: PMC4184976  PMID: 24842921
common carotid artery; arterial stiffness; carotid intima-media thickness; women; pregnancy
13.  The HEART Pathway Randomized Trial 
Background
The HEART Pathway is a decision aid designed to identify emergency department patients with acute chest pain for early discharge. No randomized trials have compared the HEART Pathway with usual care.
Methods and Results
Adult emergency department patients with symptoms related to acute coronary syndrome without ST-elevation on ECG (n=282) were randomized to the HEART Pathway or usual care. In the HEART Pathway arm, emergency department providers used the HEART score, a validated decision aid, and troponin measures at 0 and 3 hours to identify patients for early discharge. Usual care was based on American College of Cardiology/American Heart Association guidelines. The primary outcome, objective cardiac testing (stress testing or angiography), and secondary outcomes, index length of stay, early discharge, and major adverse cardiac events (death, myocardial infarction, or coronary revascularization), were assessed at 30 days by phone interview and record review. Participants had a mean age of 53 years, 16% had previous myocardial infarction, and 6% (95% confidence interval, 3.6%–9.5%) had major adverse cardiac events within 30 days of randomization. Compared with usual care, use of the HEART Pathway decreased objective cardiac testing at 30 days by 12.1% (68.8% versus 56.7%; P=0.048) and length of stay by 12 hours (9.9 versus 21.9 hours; P=0.013) and increased early discharges by 21.3% (39.7% versus 18.4%; P<0.001). No patients identified for early discharge had major adverse cardiac events within 30 days.
Conclusions
The HEART Pathway reduces objective cardiac testing during 30 days, shortens length of stay, and increases early discharges. These important efficiency gains occurred without any patients identified for early discharge suffering MACE at 30 days.
doi:10.1161/CIRCOUTCOMES.114.001384
PMCID: PMC4413911  PMID: 25737484
acute coronary syndrome; chest pain; clinical trial; decision support techniques
14.  Understanding the High Prevalence of Diabetes in U.S. South Asians Compared With Four Racial/Ethnic Groups: The MASALA and MESA Studies 
Diabetes Care  2014;37(6):1621-1628.
OBJECTIVE
We compared South Asians with four other racial/ethnic groups in the U.S. to determine whether sociodemographic, lifestyle, or metabolic factors could explain the higher diabetes prevalence and whether insulin resistance and β-cell dysfunction occurred at younger ages and/or lower adiposity levels compared with other groups.
RESEARCH DESIGN AND METHODS
We performed a cross-sectional analysis of two community-based cohorts, the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study and the Multi-Ethnic Study of Atherosclerosis (MESA); all participants had no known cardiovascular disease and were between 44 and 84 years of age. We compared 799 South Asians with 2,611 whites, 1,879 African Americans, 1,493 Latinos, and 801 Chinese Americans. Type 2 diabetes was classified by fasting plasma glucose ≥126 mg/dL or use of a diabetes medication. Insulin resistance was estimated by the homeostasis model assessment (HOMA) and β-cell function was measured by the HOMA-β model.
RESULTS
South Asians had significantly higher age-adjusted prevalence of diabetes (23%) than the MESA ethnic groups (6% in whites, 18% in African Americans, 17% in Latinos, and 13% in Chinese Americans). This difference increased further after adjustment for potential confounders. HOMA of insulin resistance (HOMA-IR) levels were significantly higher and HOMA-β levels were lower among South Asians compared with all other racial/ethnic groups after adjustment for age and adiposity.
CONCLUSIONS
The higher prevalence of diabetes in South Asians is not explained by traditionally measured risk factors. South Asians may have lower β-cell function and an inability to compensate adequately for higher glucose levels from insulin resistance.
doi:10.2337/dc13-2656
PMCID: PMC4030091  PMID: 24705613
15.  Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease 
PLoS ONE  2015;10(5):e0125497.
Background
Previous studies in mice and humans have implicated the lipoprotein receptor SCARB1 in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP) rs4238001 with incident coronary heart disease (CHD).
Methods and Results
Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR]=1.49, 95% CI [1.04, 2.14], P = 0.028). Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events) and African Americans (total n = 5,962 with 355 CHD events) and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], P = 0.013), in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], P = 0.019), in males (HR of 1.29 with 95% CI [1.08, 1.54], P = 4.91x10-3) and in White males (HR of 1.24 with 95% CI [1.03, 1.51], P = 0.026).
Conclusion
SCARB1 missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.
doi:10.1371/journal.pone.0125497
PMCID: PMC4439156  PMID: 25993026
16.  Age-related variations in the methylome associated with gene expression in human monocytes and T cells 
Nature communications  2014;5:5366.
Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age- and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55–94 years). None of the age-eMS detected in 227 T cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers, and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may play in the aging process.
doi:10.1038/ncomms6366
PMCID: PMC4280798  PMID: 25404168
17.  Comparing Coronary Artery Calcium among U.S. South Asians with Four Racial/Ethnic Groups: The MASALA and MESA studies 
Atherosclerosis  2014;234(1):102-107.
Objectives
South Asians (individuals from India, Pakistan, Bangladesh, Nepal, and Sri Lanka) have high rates of cardiovascular disease which cannot be explained by traditional risk factors. Few studies have examined coronary artery calcium (CAC) in South Asians.
Methods
We created a community-based cohort of South Asians in the United States and compared the prevalence and distribution of CAC to four racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA). We compared 803 asymptomatic South Asians free of cardiovascular disease to the four MESA racial/ethnic groups (2,622 Whites, 1,893 African Americans, 1,496 Latinos and 803 Chinese Americans).
Results
The age-adjusted prevalence of any CAC was similar between White and South Asian men, but was lower in South Asian women compared to White women. After adjusting for all covariates associated with CAC, South Asian men were similar to White men and had higher CAC scores compared to African Americans, Latinos and Chinese Americans. In fully adjusted models, CAC scores were similar for South Asian women compared to all women enrolled in MESA. However, South Asian women ≥70 years had a higher prevalence of any CAC than most other racial/ethnic groups.
Conclusions
South Asian men have similarly high CAC burden as White men, but higher CAC than other racial/ethnic groups. South Asian women appear to have similar CAC burden compared to other women, but have somewhat higher CAC burden in older age. The high burden of subclinical coronary atherosclerosis in South Asians may partly explain higher rates of cardiovascular disease in South Asians.
doi:10.1016/j.atherosclerosis.2014.02.017
PMCID: PMC4005416  PMID: 24632509
South Asians; ethnic differences; subclinical atherosclerosis; coronary artery calcium
18.  Heart Rate–Corrected QT Interval Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Diabetes Heart Study 
Diabetes Care  2014;37(5):1454-1461.
OBJECTIVE
Heart rate–corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.
RESEARCH DESIGN AND METHODS
We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.
RESULTS
At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03–1.36]) and 29% increased risk for CVD mortality (1.29 [1.05–1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95–3.15]; CVD mortality 2.86 [1.35–6.08]).
CONCLUSIONS
Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.
doi:10.2337/dc13-1257
PMCID: PMC4182905  PMID: 24574343
19.  Transcriptomic profiles of aging in purified human immune cells 
BMC Genomics  2015;16(1):333.
Background
Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.
Results
Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55–94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age.
Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.
Conclusions
An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1522-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1522-4
PMCID: PMC4417516  PMID: 25898983
Aging; Monocyte; T cell; Transcriptome; Mitochondrial ribosome; Translation; Protein synthesis; Ribonucleoprotein complex; Oxidative phosphorylation; Autophagy; Methylation
20.  Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset 
Human Molecular Genetics  2013;23(8):1957-1963.
The study of genetic influences on drug response and efficacy (‘pharmacogenetics’) has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6–11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
doi:10.1093/hmg/ddt588
PMCID: PMC3959810  PMID: 24282029
21.  Validity of the Surface Electrocardiogram Criteria for Right Ventricular Hypertrophy: The MESA - Right Ventricle Study 
Objectives
We aimed to assess the diagnostic properties of ECG criteria for RVH measured by cardiac magnetic resonance imaging (cMRI) in adults without clinical cardiovascular disease.
Background
Current electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) were based on cadaveric dissection in small studies.
Methods
The Multi-Ethnic Study of Atherosclerosis performed cMRIs with complete right ventricle (RV) interpretation on 4,062 participants without clinical cardiovascular disease. Endocardial margins of the RV were manually contoured on diastolic and systolic images. The ECG screening criteria for RVH from the 2009 AHA Recommendations for Standardization and Interpretation of the ECG were examined in participants with and without left ventricular hypertrophy or reduced ejection fraction. RVH was defined using sex-specific normative equations based on age, height, and weight.
Results
The study sample with normal left ventricular morphology and function (n = 3,719) was 61.3 ± 10.0 years old, 53.5% female, 39.6% Caucasian, 25.5% African-American, 21.9% Hispanic, and 13.0% Asian. The mean BMI was 27.9 ± 5.0 kg/m2. Six percent had RVH which was generally mild. Traditional ECG criteria were specific (many > 95%) but had low sensitivity for RVH by cMRI. The positive predictive values were not sufficiently high as to be clinically useful (maximum 12%). The results did not differ based on age, sex, race, smoking status, or with including participants with abnormal LV mass or function. Classification and regression tree analysis revealed that no combination of ECG variables was better than the criteria used singly.
Conclusions
The recommended ECG screening criteria for RVH are not sufficiently sensitive or specific for screening for mild RVH in adults without clinical cardiovascular disease.
doi:10.1016/j.jacc.2013.08.1633
PMCID: PMC3944058  PMID: 24080107
Right Ventricular Hypertrophy; Magnetic Resonance Imaging; Electrocardiogram
22.  Improved Protein Extractionand Protein Identification from Archival Formalin-fixed Paraffin-embedded Human Aortas 
Purpose
Evaluate combination of heat and elevated pressure to enhance protein extraction and quality of formaldehyde-fixed (FF), and FF paraffin-embedded (FFPE) aorta for proteomics.
Experiment design
Proteins were extracted from fresh frozen aorta at RT. FF and FFPE aortas (3 months and 15 years) were extracted at RT, heat alone, or a combination of heat and high pressure. Protein yields were compared, and digested peptides from the extracts were analyzed with mass spectrometry.
Results
Combined heat and elevated pressure increased protein yield from human FF or FFPE aorta compared to matched tissues with heat alone (1.5 fold) or at RT (8.3 fold), resulting in more proteins identified and with more sequence coverage. The length of storage did adversely affect the quality of proteins from FF tissue. For long term storage, aorta was preserved better with FFPE than FF alone. Periostin and MGF-E8 were demonstrated suitable for MRM assays from FFPE aorta.
Conclusions and clinical relevance
Combination of heat and high pressure is an effective method to extract proteins from FFPE aorta for downstream proteomics. This method opens the possibility for use of archival and often rare FFPE aortas and possibly other tissues available to proteomics for biomarker discovery and quantification.
doi:10.1002/prca.201200064
PMCID: PMC4340701  PMID: 23339088
aorta; FFPE; formalin-fixed paraffin-embedded; heat and high-pressure protein extraction; mass spectrometry
23.  Methylomics of gene expression in human monocytes 
Human Molecular Genetics  2013;22(24):5065-5074.
DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3′ UTR, gene bodies, CpG shores or ‘offshore’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10−308) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.
doi:10.1093/hmg/ddt356
PMCID: PMC3836482  PMID: 23900078
24.  Prediction of mortality using a multi-bed vascular calcification score in the Diabetes Heart Study 
Background
Vascular calcified plaque, a measure of subclinical cardiovascular disease (CVD), is unlikely to be limited to a single vascular bed in patients with multiple risk factors. Consideration of vascular calcified plaque as a global phenomenon may allow for a more accurate assessment of the CVD burden. The aim of this study was to examine the utility of a combined vascular calcified plaque score in the prediction of mortality.
Methods
Vascular calcified plaque scores from the coronary, carotid, and abdominal aortic vascular beds and a derived multi-bed score were examined for associations with all-cause and CVD-mortality in 699 European-American type 2 diabetes (T2D) affected individuals from the Diabetes Heart Study. The ability of calcified plaque to improve prediction beyond Framingham risk factors was assessed.
Results
Over 8.4 ± 2.3 years (mean ± standard deviation) of follow-up, 156 (22.3%) participants were deceased, 74 (10.6%) from CVD causes. All calcified plaque scores were significantly associated with all-cause (HR: 1.4-1.8; p < 1x10−5) and CVD-mortality (HR: 1.5-1.9; p < 1×10−4) following adjustment for Framingham risk factors. Associations were strongest for coronary calcified plaque. Improvement in prediction of outcome beyond Framingham risk factors was greatest using coronary calcified plaque for all-cause mortality (AUC: 0.720 to 0.757, p = 0.004) and the multi-bed score for CVD mortality (AUC: 0.731 to 0.767, p = 0.008).
Conclusions
Although coronary calcified plaque and the multi-bed score were the strongest predictors of all-cause mortality and CVD-mortality respectively in this T2D-affected sample, carotid and abdominal aortic calcified plaque scores also significantly improved prediction of outcome beyond traditional risk factors and should not be discounted as risk stratification tools.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0160-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-014-0160-5
PMCID: PMC4266952  PMID: 25496604
Vascular calcified plaque; Mortality; Computed tomography; Type 2 diabetes
25.  Mediators of Atherosclerosis in South Asians Living in America (MASALA) study: Objectives, Methods, and Cohort Description 
Clinical cardiology  2013;36(12):713-720.
Background
South Asians (individuals from India, Pakistani, Bangladesh, Nepal, and Sri Lanka) have high rates of cardiovascular disease which cannot be explained by traditional risk factors. There are no prospective cohort studies investigating antecedents of cardiovascular disease in South Asians.
Methods
The Mediators of Atherosclerosis in South Asians Living in America (MASALA) study is investigating the prevalence, correlates and outcomes associated with subclinical cardiovascular disease (CVD) in a population-based sample of South Asian men and women between ages 40 – 79 years from two U.S. clinical field centers. This cohort is similar in methods and measures to the Multi-Ethnic Study of Atherosclerosis to allow for efficient cross-ethnic comparisons. Measurements obtained at the baseline examination include sociodemographic information, lifestyle and psychosocial factors, standard CVD risk factors, oral glucose tolerance testing, electrocardiogram, assessment of microalbuminuria, ankle and brachial blood pressures, carotid intima media wall thickness using ultrasonagraphy, coronary artery calcium measurement and abdominal visceral fat using computed tomography. Blood samples will be assayed for biochemical risk factors.
Results
Between October 2010 and March 2013 we enrolled 906 South Asians with mean age of 55±9 years, 46% women, 98% immigrants who have lived 27±11 years in the US.
Conclusions
The sociodemographic characteristics of this cohort are representative of US South Asians. Participants are being followed with annual telephone calls for identification of CVD events including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, therapeutic interventions for CVD, and mortality.
doi:10.1002/clc.22219
PMCID: PMC3947423  PMID: 24194499

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