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1.  Epidemiologic and Statistical Methods for Comparative Effectiveness Research 
Heart failure clinics  2012;9(1):29-36.
PMCID: PMC3589582  PMID: 23168315
Comparative effectiveness research; Randomized trials; Observational data; Statistical methods; Epidemiologic methods
Circulation  2012;126(19):2293-2301.
One sixth of U.S. dialysis patients older than 65 years have been diagnosed with atrial fibrillation/flutter (AF) and the prevalence is increasing. Little is known, however, about the incidence of AF in this population.
Methods and Results
From the U.S. Renal Data System, we identified 258,605 older patients (≥67 years) with fee-for-service Medicare initiating dialysis between 1995 and 2007, who had not been diagnosed with AF within the previous 2 years. Patients were followed for newly diagnosed AF, which was ascertained from 1 inpatient or 2 outpatient claims containing an AF code. Multivariable proportional hazards regression was used to examine temporal trends and associations of race and ethnicity with incident AF. We also studied temporal trends in the mortality and risk of ischemic stroke after new AF. Over 514,395 person years of follow-up, 76,252 patients experienced incident AF for a crude AF incidence rate of 148/1,000 person years. Incidence of AF increased by 11% (95%CI: 5%-16%) from 1995-2007. Compared with non-Hispanic whites, African Americans (−30%), Asians (−19%), Native Americans (−42%), and Hispanics (−29%) all had lower rates of incident AF. Mortality after incident AF decreased by 22% from 1995-2008. Even more pronounced reductions were seen for incident ischemic stroke during these years.
The incidence of AF is high in older patients initiating dialysis in the U.S. and has been increasing over the 13 years of study. Mortality declined during that time, but remained >50% during the first year after newly diagnosed AF. Since data on warfarin use were not available, we were unable to understand whether trends towards better outcomes could be explained by higher rates of oral anticoagulation in more recent years.
PMCID: PMC3640842  PMID: 23032326
end-stage renal disease; atrial fibrillation; disparities; outcomes; cardiovascular; mortality
4.  Future Directions for Cardiovascular Disease Comparative Effectiveness Research 
Comparative effectiveness research (CER) aims to provide decision-makers the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart Lung and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address eight clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.
PMCID: PMC3416944  PMID: 22796257
comparative effectiveness; research methods; clinical trials
5.  Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden 
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.
Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.
We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.
We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.
The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
PMCID: PMC3653306  PMID: 23352782
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
6.  Chronic Kidney Disease and Risk of Presenting with Acute Myocardial Infarction versus Stable Exertional Angina in Adults with Coronary Heart Disease 
To examine whether kidney dysfunction is associated with the type of clinical presentation of coronary heart disease (CHD).
Reduced kidney function increases risk of developing CHD, but it is not known whether it also influences the acuity of clinical presentation, which has important prognostic implications.
We conducted a case-control study of subjects whose first clinical presentation of CHD was either acute myocardial infarction or stable exertional angina between October 2001-December 2003. Glomerular filtration rate (eGFR) before the incident event was estimated using calibrated serum creatinine and the abbreviated MDRD equation. Patient characteristics and use of medications were ascertained from self-report and health plan databases. We used multivariable logistic regression to examine the association of reduced eGFR and CHD presentation.
We studied 803 adults with incident acute myocardial infarction and 419 adults with incident stable exertional angina who had a baseline eGFR ≤130 ml/min/1.73 m2. Mean eGFR was lower among subjects with acute myocardial infarction compared with stable angina. Compared with eGFR 90–130 ml/min/1.73 m2, we found a strong, graded independent association between reduced eGFR and presenting with acute myocardial infarction: adjusted odds ratio (OR) 1.36 (95% CI: 0.99 to 1.86) for eGFR 60–89 ml/min/1.73 m2, OR 1.55 (0.92 to 2.62) for eGFR 45–59 ml/min/1.73 m2 and OR 3.82 (1.55 to 9.46) for eGFR <45 ml/min/1.73 m2 (P<0.001 for trend).
eGFR less than 45 ml/min/1.73 m2 is a strong, independent predictor of presenting with acute myocardial infarction versus stable angina as the initial manifestation of CHD.
PMCID: PMC3184235  PMID: 21958887
angina; myocardial infarction; renal failure; chronic kidney disease; risk factor
7.  The effect of age on clinical outcomes and health status in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial (BARI 2D) 
The objective was to determine the extent to which effectiveness of cardiac and diabetes treatment strategies varies by patient age.
The impact of age on the effectiveness of revascularization and hyperglycemia treatments has not been thoroughly investigated.
In BARI 2D, 2368 patients with documented stable heart disease and type 2 diabetes were randomized to receive prompt revascularization versus initial medical therapy with deferred revascularization and insulin-sensitization versus insulin-provision for hyperglycemia treatment. Patients were followed for an average of 5.3 years. Cox regression and mixed models were used to investigate the effect of age and randomized treatment assignment on clinical and health status outcomes.
The effect of prompt revascularization versus medical therapy did not differ by age for death (interaction p=0.99), major cardiovascular events (interaction p=0.081), angina (interaction p=0.98) or health status outcomes. After intervention, participants of all ages had significant angina and health status improvement. Younger participants experienced a smaller decline in health status during follow-up than older participants (age by time interaction p<0.01). The effect of the randomized glycemia treatment on clinical and health status outcomes was similar for patients of different ages.
Among patients with stable heart disease and type 2 diabetes, relative beneficial effects of a strategy of prompt revascularization versus initial medical therapy, and insulin-sensitizing versus insulin-providing therapy on clinical endpoints, symptom relief, and perceived health status outcomes do not vary by age. Health status improved significantly after treatment for all ages, and this improvement was sustained longer among younger patients.
PMCID: PMC3164969  PMID: 21835316
age; coronary heart disease; diabetes mellitus; revascularization; health status
8.  Economic Outcomes of Treatment Strategies for Type 2 Diabetes and Coronary Artery Disease in the BARI 2D Trial 
Circulation  2009;120(25):2550-2558.
The economic outcomes of clinical management strategies are important in assessing their value to patients.
Methods and Results
BARI 2D randomized patients with Type 2 diabetes and angiographically documented, stable coronary disease to strategies of 1) prompt revascularization vs. medical therapy with delayed revascularization as needed to relieve symptoms, and 2) insulin sensitization vs. insulin provision. Prior to randomization, the physician declared whether CABG or PCI would be used if the patient were assigned to revascularization. We followed 2005 patients for medical utilization and costs, and assessed the cost-effectiveness of these management strategies.
Medical costs were higher for revascularization than medical therapy, with a significant interaction with the intended method of revascularization (p<0.0001). In the CABG stratum, four-year costs were $80,900 for revascularization vs. $60,600 for medical therapy (p<0.0001). In the PCI stratum, costs were $73,400 for revascularization vs. $67,800 for medical therapy (p<0.02). Costs also were higher for insulin sensitization ($71,300) vs. insulin provision ($70,200). Other factors that significantly (p<0.05) and independently increased cost included insulin use and dose at baseline, female sex, white race, body mass index ≥30, and albuminuria.
Cost-effectiveness based on four-year data favored the strategy of medical therapy over prompt revascularization and the strategy of insulin provision over insulin sensitization. Lifetime projections of cost-effectiveness showed that medical therapy was cost-effective compared with revascularization in the PCI stratum ($600 per life-year added) with high confidence. Lifetime projections suggest revascularization may be cost-effective in the CABG stratum ($47,000 per life-year added), but with lower confidence.
Prompt coronary revascularization significantly increases costs among patients with Type 2 diabetes and stable coronary disease. The strategy of medical therapy (with delayed revascularization as needed) appears to be cost-effective compared with the strategy of prompt coronary revascularization among patients identified a priori as suitable for PCI.
PMCID: PMC3403834  PMID: 19920002
cost-benefit analysis; revascularization; angioplasty; surgery; diabetes mellitus
10.  BMI and Health Status in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial (BARI 2D) 
American heart journal  2011;162(1):184-192.e3.
The longitudinal association between obesity, weight variability and health status outcomes is important for patients with coronary disease and diabetes.
The Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (BARI 2D) was a multi-center randomized clinical trial to evaluate the best treatment strategy for patients with both documented stable ischemic heart disease and type 2 diabetes. We examined BARI 2D participants for four years to study how BMI was associated with health status outcomes. Health status was evaluated by the Duke Activity Status Index (DASI), RAND Energy/fatigue, Health Distress, and Self-rated health. BMI was measured quarterly throughout follow-up years, and health status was assessed at each annual follow-up visit. Variation in BMI measures was separated into between-person and within-person change in longitudinal analysis.
Higher mean BMI over follow-up years (the between-person BMI) was associated with poorer health status outcomes. Decreasing BMI (the within-person BMI change) was associated with better Self-rated health. The relationships between BMI variability and DASI or Energy appeared to be curvilinear, and differed by baseline obesity status. Decreasing BMI was associated with better outcomes if patients were obese at baseline, but was associated with poorer DASI and Energy outcomes if patients were non-obese at baseline.
For patients with stable ischemic heart disease and diabetes, weight gain was associated with poorer health status outcomes, independent of obesity-related comobidities. Weight reduction is associated with better functional capacity and perceived energy for obese patients but not for non-obese patients at baseline.
PMCID: PMC3141323  PMID: 21742107
BMI; obesity; coronary disease; diabetes mellitus; health status
11.  Persistent racial disparities in survival following heart transplantation 
Circulation  2011;123(15):1642-1649.
Racial and ethnic disparities are well-documented in many areas of health care but have not been comprehensively evaluated among recipients of heart transplantation.
Methods and results
We performed a retrospective cohort study of 39,075 adult primary heart transplant recipients from 1987-2009 using national data from the United Network of Organ Sharing, and compared mortality for non-white and white patients using the Cox proportional hazards model. During the study period, 8,082 non-white and 30,993 white patients underwent heart transplantation. Non-white heart transplant recipients increased over time, comprising nearly 30% of transplants since 2005. Non-white recipients had a higher clinical risk profile than white recipients at the time of transplantation but had significantly higher post-transplant mortality even after adjustment for baseline risk. Among the non-white group, only black recipients had an increased risk of death when compared with white recipients after multivariable adjustment for recipient, transplant, and socioeconomic factors (hazard ratio [HR] 1.34; 95% confidence interval [CI], 1.21-1.47; p<0.001). Five-year mortality was 35.7% (CI, 35.2%-38.3%) among black and 26.5% (CI, 26.0%-27.0%) among white recipients. Black patients were more likely to die from graft failure or a cardiovascular cause than white patients, but less likely to die from infection or malignancy. Although mortality decreased over time for all transplant recipients, the disparity in mortality between blacks and whites remained essentially unchanged.
Black heart transplant recipients have had persistently higher mortality than whites recipients over the past two decades, perhaps due to a higher rate of graft failure.
PMCID: PMC3125110  PMID: 21464049
Transplantation; Survival; Race; Treatment disparities; Trends
12.  Strengthening the Reporting of Genetic Risk Prediction Studies (GRIPS): Explanation and Elaboration 
European journal of epidemiology  2011;26(4):313-337.
The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice.The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality.Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction.A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines.These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.
PMCID: PMC3088812  PMID: 21424820
13.  Lack of association between the Trp719Arg polymorphism in kinesin-like protein 6 and coronary artery disease in 19 case-control studies 
Assimes, Themistocles L | Hólm, Hilma | Kathiresan, Sekar | Reilly, Muredach P | Thorleifsson, Gudmar | Voight, Benjamin F | Erdmann, Jeanette | Willenborg, Christina | Vaidya, Dhananjay | Xie, Changchun | Patterson, Chris C | Morgan, Thomas M | Burnett, Mary Susan | Li, Mingyao | Hlatky, Mark A | Knowles, Joshua W | Thompson, John R | Absher, Devin | Iribarren, Carlos | Go, Alan | Fortmann, Stephen P | Sidney, Stephen | Risch, Neil | Tang, Hua | Myers, Richard M | Berger, Klaus | Stoll, Monika | Shah, Svati H. | Thorgeirsson, Gudmundur | Andersen, Karl | Havulinna, Aki S | Herrera, J. Enrique | Faraday, Nauder | Kim, Yoonhee | Kral, Brian G. | Mathias, Rasika | Ruczinski, Ingo | Suktitipat, Bhoom | Wilson, Alexander F | Yanek, Lisa R. | Becker, Lewis C | Linsel-Nitschke, Patrick | Lieb, Wolfgang | König, Inke R | Hengstenberg, Christian | Fischer, Marcus | Stark, Klaus | Reinhard, Wibke | Winogradow, Janina | Grassl, Martina | Grosshennig, Anika | Preuss, Michael | Eifert, Sandra | Schreiber, Stefan | Wichmann, H-Erich | Meisinger, Christa | Yee, Jean | Friedlander, Yechiel | Do, Ron | Meigs, James B | Williams, Gordon | Nathan, David M | MacRae, Calum A | Qu, Liming | Wilensky, Robert L | Matthai, William H. | Qasim, Atif N | Hakonarson, Hakon | Pichard, Augusto D | Kent, Kenneth M | Satler, Lowell | Lindsay, Joseph M | Waksman, Ron | Knouff, Christopher W | Waterworth, Dawn M | Walker, Max C | Mooser, Vincent | Marrugat, Jaume | Lucas, Gavin | Subirana, Isaac | Sala, Joan | Ramos, Rafael | Martinelli, Nicola | Olivieri, Oliviero | Trabetti, Elisabetta | Malerba, Giovanni | Pignatti, Pier Franco | Guiducci, Candace | Mirel, Daniel | Parkin, Melissa | Hirschhorn, Joel N | Asselta, Rosanna | Duga, Stefano | Musunuru, Kiran | Daly, Mark J | Purcell, Shaun | Braund, Peter S | Wright, Benjamin J | Balmforth, Anthony J | Ball, Stephen G | Ouwehand, Willem H | Deloukas, Panos | Scholz, Michael | Cambien, Francois | Huge, Andreas | Scheffold, Thomas | Salomaa, Veikko | Girelli, Domenico | Granger, Christopher B. | Peltonen, Leena | McKeown, Pascal P | Altshuler, David | Melander, Olle | Devaney, Joseph M | Epstein, Stephen E | Rader, Daniel J | Elosua, Roberto | Engert, James C | Anand, Sonia S | Hall, Alistair S | Ziegler, Andreas | O’Donnell, Christopher J | Spertus, John A | Siscovick, David | Schwartz, Stephen M | Becker, Diane | Thorsteinsdottir, Unnur | Stefansson, Kari | Schunkert, Heribert | Samani, Nilesh J | Quertermous, Thomas
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455) and clinical coronary artery disease (CAD).
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with non-carriers.
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in nineteen case-control studies of non-fatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Over 17 000 cases and 39 000 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the nineteen studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with non-carriers. Regression analyses and fixed effect meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early onset disease (<50 years of age for males and <60 years for females) compared with similarly aged controls as well as all non-European subgroups.
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
PMCID: PMC3084526  PMID: 20933357
kinesin-like protein 6; KIF6; coronary artery disease; myocardial infarction; polymorphism
14.  Health Status after Treatment for Coronary Artery Disease and Type 2 Diabetes in the BARI 2D Trial 
Circulation  2010;122(17):1690-1699.
Health status is a key outcome for comparing treatments, particularly when mortality does not differ significantly.
Methods and Results
BARI 2D randomized 2368 patients with type 2 diabetes and stable ischemic heart disease to 1) prompt revascularization versus medical therapy and 2) insulin sensitization versus insulin provision. Randomization was stratified by the intended method of revascularization, coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI). The Duke Activity Status Index (DASI) and RAND Energy, Health Distress and Self-rated Health were assessed at study entry and annually thereafter; linear mixed models were used to evaluate the effect of randomized treatment on these measures. Health status improved significantly from baseline to one-year (p<0.001) in each randomized treatment group. Compared with medical therapy, prompt revascularization was associated with significantly greater improvements in DASI (1.32 points, p<0.001), Energy (1.36 points, p=0.02) and Self-rated Health (1.77 points, p=0.007) but not Health Distress (−0.47, p=0.46). These treatment effects were largely maintained over four years of follow-up. The effect of revascularization on DASI was significantly larger in the subgroup of patients intended for CABG compared with the subgroup intended for PCI. Health status did not differ significantly on any of the four measures between the insulin provision and insulin sensitization strategies.
Prompt coronary revascularization was associated with small yet statistically significant improvements in health status compared with initial medical therapy among patients with diabetes and stable ischemic heart disease.
PMCID: PMC2964421  PMID: 20937978
coronary disease; diabetes mellitus; revascularization; health status
15.  Potential role of differential medication use in explaining excess risk of cardiovascular events and death associated with chronic kidney disease: A cohort study 
BMC Nephrology  2011;12:44.
Patients with chronic kidney disease (CKD) are less likely to receive cardiovascular medications. It is unclear whether differential cardiovascular drug use explains, in part, the excess risk of cardiovascular events and death in patients with CKD and coronary heart disease (CHD).
The ADVANCE Study enrolled patients with new onset CHD (2001-2003) who did (N = 159) or did not have (N = 1088) CKD at entry. The MDRD equation was used to estimate glomerular filtration rate (eGFR) using calibrated serum creatinine measurements. Patient characteristics, medication use, cardiovascular events and death were ascertained from self-report and health plan electronic databases through December 2008.
Post-CHD event ACE inhibitor use was lower (medication possession ratio 0.50 vs. 0.58, P = 0.03) and calcium channel blocker use higher (0.47 vs. 0.38, P = 0.06) in CKD vs. non-CKD patients, respectively. Incidence of cardiovascular events and death was higher in CKD vs. non-CKD patients (13.9 vs. 11.5 per 100 person-years, P < 0.001, respectively). After adjustment for patient characteristics, the rate of cardiovascular events and death was increased for eGFR 45-59 ml/min/1.73 m2 (hazard ratio [HR] 1.47, 95% CI: 1.10 to 2.02) and eGFR < 45 ml/min/1.73 m2 (HR 1.58, 95% CI: 1.00 to 2.50). After further adjustment for statins, β-blocker, calcium channel blocker, ACE inhibitor/ARB use, the association was no longer significant for eGFR 45-59 ml/min/1.73 m2 (HR 0.82, 95% CI: 0.25 to 2.66) or for eGFR < 45 ml/min/1.73 m2 (HR 1.19, 95% CI: 0.25 to 5.58).
In adults with CHD, differential use of cardiovascular medications may contribute to the higher risk of cardiovascular events and death in patients with CKD.
PMCID: PMC3180367  PMID: 21917174
16.  Racial variation in lipoprotein-associated phospholipase A2 in older adults 
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a predictor of cardiovascular events that has been shown to vary with race. The objective of this study was to examine factors associated with this racial variation.
We measured Lp-PLA2 mass and activity in 714 healthy older adults with no clinical coronary heart disease and not taking dyslipidemia medication. We evaluated the association between race and Lp-PLA2 mass and activity levels after adjustment for various covariates using multivariable linear regression. These covariates included age, sex, diabetes, hypertension, body mass index, lipid measurements, C-reactive protein, smoking status, physical activity, diet, income, and education level. We further examined genetic covariates that included three single nucleotide polymorphisms shown to be associated with Lp-PLA2 activity levels.
The mean age was 66 years. Whites had the highest Lp-PLA2 mass and activity levels, followed by Hispanics and Asians, and then African-Americans; in age and sex adjusted analyses, these differences were significant for each non-White race as compared to Whites (p < 0.0001). For example, African-Americans were predicted to have a 55.0 ng/ml lower Lp-PLA2 mass and 24.7 nmol/ml-min lower activity, compared with Whites, independent of age and sex (p < 0.0001). After adjustment for all covariates, race remained significantly correlated with Lp-PLA2 mass and activity levels (p < 0.001) with African-Americans having 44.8 ng/ml lower Lp-PLA2 mass and 17.3 nmol/ml-min lower activity compared with Whites (p < 0.0001).
Biological, lifestyle, demographic, and select genetic factors do not appear to explain variations in Lp-PLA2 mass and activity levels between Whites and non-Whites, suggesting that Lp-PLA2 mass and activity levels may need to be interpreted differently for various races.
PMCID: PMC3146402  PMID: 21714927
17.  Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration 
The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.
PMCID: PMC3083630  PMID: 21407270
18.  Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration 
European Journal of Epidemiology  2011;26(4):313-337.
The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.
PMCID: PMC3088812  PMID: 21424820
Genetic; Risk prediction; Methodology; Guidelines; Reporting
19.  Right coronary wall cmr in the older asymptomatic advance cohort: positive remodeling and associations with type 2 diabetes and coronary calcium 
Coronary wall cardiovascular magnetic resonance (CMR) is a promising noninvasive approach to assess subclinical atherosclerosis, but data are limited in subjects over 60 years old, who are at increased risk. The purpose of the study was to evaluate coronary wall CMR in an asymptomatic older cohort.
Cross-sectional images of the proximal right coronary artery (RCA) were acquired using spiral black-blood coronary CMR (0.7 mm resolution) in 223 older, community-based patients without a history of cardiovascular disease (age 60-72 years old, 38% female). Coronary measurements (total vessel area, lumen area, wall area, and wall thickness) had small intra- and inter-observer variabilities (r = 0.93~0.99, all p < 0.0001), though one-third of these older subjects had suboptimal image quality. Increased coronary wall thickness correlated with increased coronary vessel area (p < 0.0001), consistent with positive remodeling. On multivariate analysis, type 2 diabetes was the only risk factor associated with increased coronary wall area and thickness (p = 0.03 and p = 0.007, respectively). Coronary wall CMR measures were also associated with coronary calcification (p = 0.01-0.03).
Right coronary wall CMR in asymptomatic older subjects showed increased coronary atherosclerosis in subjects with type 2 diabetes as well as coronary calcification. Coronary wall CMR may contribute to the noninvasive assessment of subclinical coronary atherosclerosis in older, at-risk patient groups.
PMCID: PMC3022803  PMID: 21192815
20.  Criteria for Evaluation of Novel Markers of Cardiovascular Risk 
Circulation  2009;119(17):2408-2416.
There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.
PMCID: PMC2956982  PMID: 19364974
AHA Scientific Statements; risk assessment; models, statistical; evaluation studies
21.  Cost effectiveness of pre-participation screening for prevention of sudden cardiac death in young athletes 
Annals of internal medicine  2010;152(5):276-286.
Inclusion of a 12-lead electrocardiogram in the preparticipation screening of young athletes is controversial in large part due to concerns over cost-effectiveness.
To evaluate the cost-effectiveness of electrocardiography plus cardiac-focused history and physical and history and physical for preparticipation screening.
Decision analysis cost-effectiveness model.
Data Sources
Published epidemiologic and preparticipation screening data, vital statistics, other publicly available data.
Target Population
High school and college competitive athletes ages 14 to 22
Time Horizon
Non-participation in competitive athletic activity and disease-specific treatment for identified athletes with heart disease.
Outcome Measures
Incremental health care cost per life year gained.
Results of Base-Case Analysis
The addition of electrocardiography to pre-participation screening saves 2.06 life years per 1000 athletes at an incremental total cost of $89 per athlete, yielding a cost-effectiveness ratio of $42,900 per life year saved (95% confidence interval, $21,200–71,300) when compared with cardiac-focused history and physical alone and saves 2.6 life years per 1000 athletes screened and costs $199 per athlete, yielding a cost-effectiveness ratio of $76,100 per life year saved ($62,400–130,000) when compared with no screening.
Results of Sensitivity Analysis
Results are sensitive to the relative risk reduction associated with non-participation and the cost of initial screening.
Effectiveness data is derived from one major European study. Patterns of sudden death etiology may vary among countries.
Screening young athletes with a 12-lead electrocardiogram plus cardiovascular-focused history and physical may be cost effective.
PMCID: PMC2873148  PMID: 20194233
22.  The Effect of Race on the Clinical Outcomes in the Bypass Angioplasty Revascularization Investigation (BARI) Trial 
In observational studies, clinical outcomes for black patients with coronary disease have been worse than for white patients. There are few data from randomized trials comparing the outcomes of coronary revascularization between black patients and white patients.
Methods and Results
We analyzed data from the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial. At study entry, the 113 black patients had significantly higher rates of diabetes, hypertension, smoking, heart failure, and abnormal left ventricular function than the 1,653 white patients. Black patients had significantly higher mortality than white patients (hazard ratio 2.16, p=<0.001), which remained significant after statistical adjustment for differences in baseline clinical characteristics (hazard ratio 1.59, p=0.003). In a substudy of economic and quality of life outcomes, the 67 black patients had similar frequency of physician visits and use of evidence-based cardiac medications, but significantly worse physical function scores than the 885 white patients. The effect of random assignment to either surgery or angioplasty on clinical outcomes was not significantly modified by race (interaction p-values ≥0.18).
Clinical outcomes of black patients after coronary revascularization were worse than those of white patients in a clinical trial setting with similar treatment and access to care. The differences in outcome between black and white patients were not completely attributable to the greater levels of co-morbidity among black patients at study entry.
PMCID: PMC2783640  PMID: 20031836
Coronary disease; treatment outcome; randomized controlled trials; health policy
23.  Characterizing the admixed African ancestry of African Americans 
Genome Biology  2009;10(12):R141.
Genome-wide SNP analyses reveal the admixed African genetic ancestry of African Americans.
Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.
From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.
These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.
PMCID: PMC2812948  PMID: 20025784
24.  Peroxisome Proliferator-Activated Receptor Gamma Polymorphisms and Coronary Heart Disease 
PPAR Research  2009;2009:543746.
Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor γ (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96–12.27], P = .058, 3.41 [0.95–12.22], P = .060 and 5.10 [0.99–26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99 [0.92–1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99–1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20–2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed.
PMCID: PMC2792957  PMID: 20016803
25.  Depressive Symptoms and Health-Related Quality of Life: The Heart and Soul Study 
Little is known regarding the extent to which patient-reported health status, including symptom burden, physical limitation, and quality of life, is determined by psychosocial vs physiological factors among patients with chronic disease.
To compare the contributions of depressive symptoms and measures of cardiac function to the health status of patients with coronary artery disease.
Design, Setting, and Participants
Cross-sectional study of 1024 adults with stable coronary artery disease recruited from outpatient clinics in the San Francisco Bay Area between September 2000 and December 2002.
Main Measures
Measurement of depressive symptoms using the Patient Health Questionnaire (PHQ); assessment of cardiac function by measuring left ventricular ejection fraction on echocardiography, exercise capacity on treadmill testing, and ischemia on stress echocardiography; and measurement of a range of health status outcomes, including symptom burden, physical limitation, and quality of life, using the Seattle Angina Questionnaire. Participants were also asked to rate their overall health as excellent, very good, good, fair, or poor.
Of the 1024 participants, 201 (20%) had depressive symptoms (PHQ score ≥10). Participants with depressive symptoms were more likely than those without depressive symptoms to report at least mild symptom burden (60% vs 33%; P<.001), mild physical limitation (73% vs 40%; P<.001), mildly diminished quality of life (67% vs 31%; P<.001), and fair or poor overall health (66% vs 30%; P<.001). In multivariate analyses adjusting for measures of cardiac function and other patient characteristics, depressive symptoms were strongly associated with greater symptom burden (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3-2.7; P=.002), greater physical limitation (OR, 3.1; 95% CI, 2.1-4.6; P<.001), worse quality of life (OR, 3.1; 95% CI, 2.2-4.6; P<.001), and worse overall health (OR, 2.0; 95% CI, 1.3-2.9; P<.001). Although decreased exercise capacity was associated with worse health status, left ventricular ejection fraction and ischemia were not.
Among patients with coronary disease, depressive symptoms are strongly associated with patient-reported health status, including symptom burden, physical limitation, quality of life, and overall health. Conversely, 2 traditional measures of cardiac function—ejection fraction and ischemia—are not. Efforts to improve health status should include assessment and treatment of depressive symptoms.
PMCID: PMC2776689  PMID: 12851276

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