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1.  Percentile Ranking and Citation Impact of a Large Cohort of NHLBI-funded Cardiovascular R01 Grants 
Circulation research  2014;114(4):600-606.
Rationale
Funding decisions for cardiovascular R01 grant applications at NHLBI largely hinge on percentile rankings. It is not known whether this approach enables the highest impact science.
Objective
To conduct an observational analysis of percentile rankings and bibliometric outcomes for a contemporary set of funded NHLBI cardiovascular R01 grants.
Methods and results
We identified 1492 investigator-initiated de novo R01 grant applications that were funded between 2001 and 2008, and followed their progress for linked publications and citations to those publications. Our co-primary endpoints were citations received per million dollars of funding, citations obtained within 2-years of publication, and 2-year citations for each grant’s maximally cited paper. In 7654 grant-years of funding that generated $3004 million of total NIH awards, the portfolio yielded 16,793 publications that appeared between 2001 and 2012 (median per grant 8, 25th and 75th percentiles 4 and 14, range 0 – 123), which received 2,224,255 citations (median per grant 1048, 25th and 75th percentiles 492 and 1,932, range 0 – 16,295). We found no association between percentile ranking and citation metrics; the absence of association persisted even after accounting for calendar time, grant duration, number of grants acknowledged per paper, number of authors per paper, early investigator status, human versus non-human focus, and institutional funding. An exploratory machine-learning analysis suggested that grants with the very best percentile rankings did yield more maximally cited papers.
Conclusions
In a large cohort of NHLBI-funded cardiovascular R01 grants, we were unable to find a monotonic association between better percentile ranking and higher scientific impact as assessed by citation metrics.
doi:10.1161/CIRCRESAHA.114.302656
PMCID: PMC3959724  PMID: 24406983
Research funding; bibliometrics; scientific impact; NHLBI
2.  Importance of Treadmill Exercise Time as an Initial Prognostic Screening Tool in Patients with Systolic Left Ventricular Dysfunction 
Circulation  2009;119(25):3189-3197.
Background
We sought to determine if treadmill exercise time may be of value as an initial prognostic screening tool in ambulatory patients with impaired systolic function referred for cardiopulmonary exercise testing.
Methods and Results
We studied 2,231 adult systolic heart failure patients (27% women) who underwent cardiopulmonary stress testing using a modified Naughton protocol. We assessed the value of treadmill exercise time for prediction of all-cause death and a composite of death or UNOS status 1 heart transplantation. During a mean follow up of 5 years, 742 (33%) patients died. There were 249 (11%) UNOS status 1 heart transplants. Treadmill exercise time was predictive of death and the composite outcome in both women and men, even after accounting for peak oxygen consumption and other clinical covariates (adjusted hazard ratio of lowest versus high sex-specific quartile for prediction of death 1.70, 95% CI 1.05–2.75, P=0.03, and for prediction of the composite outcome 1.75, 95% CI 1.15–2.66, P=0.009). For a one minute change in exercise time there was a 7% increased hazard of death (e.g. comparing 480 to 540 seconds HR 1.07, 95% CI 1.02–1.12, P=0.004).
Conclusions
Since cardiopulmonary stress testing is not available in every hospital, treadmill exercise time using a modified Naughton protocol may be of value as an initial prognostic screening tool.
doi:10.1161/CIRCULATIONAHA.109.848382
PMCID: PMC4205105  PMID: 19528334
Heart failure; exercise; sex; prognosis
3.  Epidemiology, Comparative Effectiveness Research, and the NIH: Forces for Health 
Epidemiology (Cambridge, Mass.)  2011;22(5):625-628.
doi:10.1097/EDE.0b013e3182262ac6
PMCID: PMC4196319  PMID: 21811109
4.  Publication of Trials Funded by the National Heart, Lung, and Blood Institute 
The New England journal of medicine  2013;369(20):1926-1934.
BACKGROUND
Rapid publication of clinical trials is essential in order for the findings to yield maximal benefits for public health and scientific progress. Factors affecting the speed of publication of the main results of government-funded trials have not been well characterized.
METHODS
We analyzed 244 extramural randomized clinical trials of cardiovascular interventions that were supported by the National Heart, Lung, and Blood Institute (NHLBI). We selected trials for which data collection had been completed between January 1, 2000, and December 31, 2011. Our primary outcome measure was the time between completion of the trial and publication of the main results in a peer-reviewed journal.
RESULTS
As of March 31, 2012, the main results of 156 trials (64%) had been published (Kaplan–Meier median time to publication, 25 months, with 57% published within 30 months). Trials that focused on clinical events were published more rapidly than those that focused on surrogate measures (median, 9 months vs. 31 months; P<0.001). The only independent predictors of more rapid publication were a focus on clinical events rather than surrogate end points (adjusted publication rate ratio, 2.11; 95% confidence interval, 1.26 to 3.53; P = 0.004) and higher costs of conducting the trial, up to a threshold of approximately $5 million (P<0.001). The 37 trials that focused on clinical events and cost at least $5 million accounted for 67% of the funds spent on clinical trials but received 82% of the citations. After adjustment of the analysis for a focus on clinical events and for cost, trial results that were classified as positive were published more quickly than those classified as negative.
CONCLUSIONS
Results of less than two thirds of NHLBI-funded randomized clinical trials of cardiovascular interventions were published within 30 months after completion of the trial. Trials that focused on clinical events were published more quickly than those that focused on surrogate end points. (Funded by the National Heart, Lung, and Blood Institute.)
doi:10.1056/NEJMsa1300237
PMCID: PMC3928673  PMID: 24224625
6.  Translational Research for Cardiovascular Diseases at the NHLBI: Moving from Bench to Bedside and From Bedside to Community 
Circulation  2010;121(7):929-933.
doi:10.1161/CIRCULATIONAHA.109.917948
PMCID: PMC4001816  PMID: 20177007
translational research; research funding
7.  Microvolt T-Wave Alternans, Peak Oxygen Consumption, and Outcome in Patients with Severely Impaired Left Ventricular Systolic Function 
Background
Both abnormal microvolt T-wave alternans (MTWA) and low peak VO2 predict poor outcome in heart failure. However, their independent predictive properties have not been assessed in large scale cohorts.
Methods
We performed an observational prospective cohort study of 303 consecutive patients referred for metabolic stress testing. All had an ejection fraction fl40% and were considered candidates for transplantation. Patients with defibrillators did not have MTWA collected by our exercise laboratory and therefore were not included in the analysis. The primary endpoint was a composite of all-cause death or UNOS 1 transplantation.
Results
During 2.8 years there were 34 deaths and 17 transplantations. Patients with abnormal MTWA had a higher event rate (31/136, 23%, vs. 20/167, 12%, unadjusted HR 1.90, 95% CI 1.90-3.33, P=.03). The association remained significant after adjustment for 3 clinical variables (1.89, 95% CI 1.05-3.39, P=.03). After adding peak VO2 to the model the association was no longer significant (adjusted HR 1.18, 95% CI 0.64-2.17, p=.60). After accounting for peak VO2 and 28 other confounders in a matched propensity analysis, MTWA was not predictive (propensity-matched HR 0.79, 95% CI 0.37-1.66, P=.53).
Conclusions
We confirm the association of abnormal MTWA with poor outcome amongst patients with impaired left ventricular systolic function. However, this association is markedly attenuated after accounting for peak VO2.
doi:10.1016/j.healun.2009.04.009
PMCID: PMC4001817  PMID: 19560697
9.  Identifying Important Risk Factors for Survival in Systolic Heart Failure Patients Using Random Survival Forests 
Background
Heart failure survival models are typically constructed using Cox-proportional hazards regression. Regression modeling suffers from a number of limitations, including bias introduced by commonly used variable selection methods. We illustrate the value of an intuitive, robust approach to variable selection, random survival forests (RSF), in a large clinical cohort. RSF is a potentially powerful extension of Classification and Regression Trees (CART), with lower variance and bias.
Methods and Results
We studied 2231 adult systolic heart failure patients who underwent cardiopulmonary stress testing. During a mean follow-up of 5 years, 742 patients died. Thirty-nine demographic, cardiac and noncardiac co-morbidity, and stress testing variables were analyzed as potential predictors of all-cause mortality. A RSF of 2000 trees was constructed, with each tree constructed on a bootstrap sample from the original cohort. The most predictive variables were defined as those near the tree trunks (averaged over the forest). The RSF identified peak VO2, serum BUN, and treadmill exercise time as the three most important predictors of survival. The RSF predicted survival similarly to a conventional Cox-proportional hazards model (out-of-bag C-index of 0.705 for RSF vs 0.698 for Cox-proportional hazards model).
Conclusions
A random survival forests model in a cohort of heart failure patients performed as well as a traditional Cox-proportional hazard model, and may serve as a more intuitive approach for clinicians to identify important risk factors for all-cause mortality.
doi:10.1161/CIRCOUTCOMES.110.939371
PMCID: PMC3991475  PMID: 21098782
Heart failure; prognosis; statistical modeling; survival analyses
10.  Transforming Epidemiology for 21st Century Medicine and Public Health 
In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving towards more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating “big data” science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.
doi:10.1158/1055-9965.EPI-13-0146
PMCID: PMC3625652  PMID: 23462917
big data; clinical trials; cohort studies; epidemiology; genomics; medicine; public health; technologies; training; translational research
11.  Use of Hundreds of Electrocardiograhpic Biomarkers for Prediction of Mortality in Post-Menopausal Women: The Women’s Health Initiative 
Background
Simultaneous contribution of hundreds of electrocardiographic biomarkers to prediction of long-term mortality in post-menopausal women with clinically normal resting electrocardiograms (ECGs) is unknown.
Methods and Results
We analyzed ECGs and all-cause mortality in 33,144 women enrolled in Women’s Health Initiative trials, who were without baseline cardiovascular disease or cancer, and had normal ECGs by Minnesota and Novacode criteria. Four hundred and seventy seven ECG biomarkers, encompassing global and individual ECG findings, were measured using computer algorithms. During a median follow-up of 8.1 years (range for survivors 0.5–11.2 years), 1,229 women died. For analyses cohort was randomly split into derivation (n=22,096, deaths=819) and validation (n=11,048, deaths=410) subsets. ECG biomarkers, demographic, and clinical characteristics were simultaneously analyzed using both traditional Cox regression and Random Survival Forest (RSF), a novel algorithmic machine-learning approach. Regression modeling failed to converge. RSF variable selection yielded 20 variables that were independently predictive of long-term mortality, 14 of which were ECG biomarkers related to autonomic tone, atrial conduction, and ventricular depolarization and repolarization.
Conclusions
We identified 14 ECG biomarkers from amongst hundreds that were associated with long-term prognosis using a novel random forest variable selection methodology. These were related to autonomic tone, atrial conduction, ventricular depolarization, and ventricular repolarization. Quantitative ECG biomarkers have prognostic importance, and may be markers of subclinical disease in apparently healthy post-menopausal women.
doi:10.1161/CIRCOUTCOMES.110.959023
PMCID: PMC3893688  PMID: 21862719
Electrocardiography; epidemiology; women; prognosis
12.  The Longitudinal Study of Implantable Cardioverter Defibrillators: Methods and Clinical Characteristics of Patients Receiving Implantable Cardioverter Defibrillators for Primary Prevention in Contemporary Practice 
Background
Implantable cardioverter defibrillators (ICDs) are increasingly used for primary prevention followingrandomized controlled trials (RCTs) demonstrating that they reduce the risk of death in patients with left ventricular systolic dysfunction (LVSD). The extent to which the clinical characteristics and long-term outcomes of unselected, community-based patients with LVSD undergoing primary prevention ICD implantation in a real-world setting compare with those enrolled in the RCTs is not well characterized. The Longitudinal Study of ICDs is being conducted to address these questions.
Methods and Results
The study cohort includes consecutive patients undergoing primary prevention ICD placement between 1/1/2006 and 12/31/2009 in seven health plans. Baseline clinical characteristics were acquired from the NCDRICD Registry. Longitudinal data collection is underway and will include hospitalization, mortality, and resource utilization from the Virtual Data Warehouse. Data regarding ICD therapies will be obtained through chart abstraction and adjudicated by a panel of experts in device therapy. Compared with the populations of primary prevention ICD therapy RCTs, the cohort (n=2,621) is on average significantly older (by 2.5-6.5 years); more often female, more often from racial and ethnic minority groups, and has a significantly higher burden of coexisting conditions. The cohort is similar, however, to a national population undergoing primary prevention ICD placement.
Conclusions
Patients undergoing primary prevention ICD implantation in the Longitudinal Study of ICDs differ from those enrolled in the RCTs that established the efficacy of ICDs. Understanding a broad range of health outcomes, including ICD therapies, in this cohort will provide patients, clinicians, and policy-makers with contemporary data to inform decision-making.
doi:10.1161/CIRCOUTCOMES.112.965368
PMCID: PMC3526187  PMID: 23170006
arrhythmia; electrophysiology; epidemiology
14.  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.
doi:10.1016/j.jacc.2011.12.057
PMCID: PMC3416944  PMID: 22796257
comparative effectiveness; research methods; clinical trials
15.  Rigorous science as the road to better public health 
In the current issue of Population Health Metrics, two reports paint a bleak picture of American public health. Both physical inactivity and obesity remain highly prevalent; yet, it is not clear that increased physical activity will reduce the burden of obesity. There continue to be widespread disparities in life expectancy across United States counties. These reports appear against a backdrop of debate regarding how we should allocate our scarce resources for improving health: should we focus more on improving access to high-quality medical care, or should we instead focus on more and better public health interventions? While optimal solutions remain obscure, a look at prior successes suggests that ultimately they will come from the conduct and implementation of rigorous science, and in particular event-driven trials.
doi:10.1186/1478-7954-11-10
PMCID: PMC3710508  PMID: 23842137
Public health; Population science; Obesity; Physical activity; Life-expectancy; Randomized trials
16.  Cardiovascular Epidemiology in a Changing World—Challenges to Investigators and the National Heart, Lung, and Blood Institute 
American Journal of Epidemiology  2012;175(7):597-601.
Over the past 60 years, revolutionary discoveries made by epidemiologists have contributed to marked declines in cardiovascular disease morbidity and mortality. Now, in an era of increasingly constrained resources, researchers in cardiovascular epidemiology face a number of challenges that call for novel, paradigm-shifting approaches. In this paper, the authors pose to the community 4 critical questions: 1) How can we avoid wasting resources on studies that provide little incremental knowledge? 2) How can we assure that we direct our resources as economically as possible towards innovative science? 3) How can we be nimble, responding quickly to new opportunities? 4) How can we identify prospectively the most meritorious research questions? Senior program staff at the National Heart, Lung, and Blood Institute invite the epidemiology community to join them in an ongoing Web-based blog conversation so that together we might develop novel approaches that will facilitate the next generation of high-impact discoveries.
doi:10.1093/aje/kws138
PMCID: PMC3390031  PMID: 22415032
cardiovascular diseases; epidemiology; National Institutes of Health (U.S.); research
17.  Quantitative Electrocardiography for Predicting Postoperative Atrial Fibrillation after Cardiac Surgery 
Journal of electrocardiology  2011;44(6):761-767.
Background
Atrial fibrillation (AF) after cardiac surgery is a common marker of poor outcomes. Quantitative electrocardiographic (ECG) measurements may be valuable predictors of postoperative AF.
Methods
We evaluated clinical and ECG predictors of postoperative AF in 13,356 patients who underwent cardiac surgery in sinus rhythm.
Results
4,724 patients (35%) developed postoperative AF. P-wave amplitude in lead aVR and V1 were the strongest ECG predictors. A less negative P-wave amplitude in lead aVR was associated with increased risk for postoperative AF (OR 1.46, CI 1.32–1.61), as was a more positive or a more negative P-wave amplitude in lead V1 (OR 1.25, CI 1.16–1.36) after adjusting for clinical and procedural predictors of postoperative AF. Reclassification analysis showed a 7% discrimination improvement (p<0.0001).
Conclusions
P-wave amplitude in lead aVR and lead V1 are powerful predictors of postoperative AF and in combination with other clinical predictors can guide application of prophylactic interventions.
doi:10.1016/j.jelectrocard.2010.12.005
PMCID: PMC3096700  PMID: 21276589
18.  And What About Exercise? Fitness and Risk of Death in “Low-Risk” Adults 
doi:10.1161/JAHA.112.003228
PMCID: PMC3487347  PMID: 23130175
editorials; exercise; risk, low; Framingham Risk Score; cardiovascular diseases
19.  Emerging Cardiovascular Risk Factors That Account for a Significant Portion of Attributable Mortality Risk in Chronic Kidney Disease 
The American Journal of Cardiology  2008;101(12):1741-1746.
Chronic kidney disease (CKD) increases cardiovascular risk and mortality. However, traditional cardiovascular risk factors do not adequately account for the substantial increase in mortality observed in CKD. The aim of this study was to examine the relative contributions of novel cardiovascular risk factors to the risk between CKD and mortality. The study population included 4,680 consecutive new patients from a tertiary care preventive cardiology program from 1996 to 2005. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) method. Baseline levels of traditional (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, hypertension, triglycerides, total cholesterol, and fasting glucose) and emerging (apolipoproteins A-I and B, lipoprotein[a], fibrinogen, homocysteine, and high-sensitivity C-reactive protein) risk factors were examined. All-cause mortality was obtained from the Social Security Death Index. There were 278 deaths over a median follow-up period of 22 months. CKD (estimated glomerular filtration rate ≤60 ml/min/1.73 m2) was strongly associated with mortality after adjusting for traditional cardiovascular risk factors (hazard ratio 2.31, 95% confidence interval 1.77 to 3.11, p <0.001) and with the addition of propensity score (hazard ratio 2.33, 95% confidence interval 1.75 to 3.10, p <0.001). Of all the traditional and emerging risk factors monitored, only the addition of homocysteine and fibrinogen significantly attenuated the association between CKD and mortality (adjusted hazard ratio 1.73, 95% confidence interval 1.23 to 2.34, p <0.001), explaining 38% of the attributable mortality risk from CKD. A significant interaction (p = 0.004) between homocysteine and estimated glomerular filtration rate was observed whereby the annual mortality rate in subjects with CKD with homocysteine <10 μmol/L (the bottom tertile) was similar to those with normal renal function (1% per year), whereas homocysteine levels ≥12.5 μmol/L (the top tertile) were associated with a sevenfold greater mortality risk. In conclusion, homocysteine and fibrinogen levels explain nearly 40% of the attributable mortality risk from CKD.
doi:10.1016/j.amjcard.2008.02.060
PMCID: PMC3354958  PMID: 18549850
20.  The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health–Centers for Disease Control and Prevention Multidisciplinary Workshop 
The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.
doi:10.1097/GIM.0b013e3181b13a6c
PMCID: PMC2936269  PMID: 19617843
behavioral sciences; epidemiologic methods; evidence-based medicine; genetics; genetic testing; genomics; medicine; public health
21.  Outcomes Research in Cardiovascular Imaging 
In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.
doi:10.1016/j.echo.2009.05.026
PMCID: PMC2739093  PMID: 19560655
cardiovascular imaging; chest pain diagnosis; clinical trials
22.  Outcomes Research in Cardiovascular Imaging: Report of a Workshop sponsored by the National Heart Lung and Blood Institute 
JACC. Cardiovascular imaging  2009;2(7):897-907.
doi:10.1016/j.jcmg.2009.01.018
PMCID: PMC2790271  PMID: 19608141
cardiovascular imaging; chest pain diagnosis; clinical trials
23.  How One Division at NHLBI Establishes Its Scientific Priorities 
doi:10.1016/j.jacc.2009.03.024
PMCID: PMC2758646  PMID: 19520248
25.  Comparative Effectiveness Research: The View from NHLBI 
doi:10.1016/j.jacc.2008.11.047
PMCID: PMC2692180  PMID: 19298925

Results 1-25 (26)