News from NHLBI: Nutrition Research at the National Heart, Lung, and Blood Institute and Future Opportunities.

BACKGROUND: Nutrition plays a major role in the prevention and treatment of cardiovascular and other chronic diseases; hence, nutrition research is a priority for the National Heart, Lung, and Blood Institute (NHLBI). The purpose of this analysis is to describe the scope of NHLBI-funded extramural nutrition research grants over the past decade and offer insights into future opportunities for nutrition research relevant to NHLBI's mission. METHODS: Data were extracted using the Research, Condition, and Disease Categorization spending categories from the publicly available NIH Research Portfolio Online Reporting Tool Expenditures and Results. New 2018 and 2019 grants were coded into categories and mapped to the 2016 NHLBI Strategic Vision priorities. RESULTS: Approximately 90% of nutrition research funds supported extramural grants, particularly through investigator-initiated R series grants (69.6%). Of these, 19.8% were classified as clinical trials. Consistent nutrition-related topics, including physical activity, weight loss, fatty acids, metabolic syndrome, childhood obesity, and other topics such as gut microbiota, arterial stiffness, sleep duration, and meal timing, emerged in 2014-2019.  Mapping of the NHLBI Strategic Vision objectives revealed that 32% of newly funded grants focused on pathobiological mechanisms important to the onset and progression of heart, lung, blood, and sleep disorders, with opportunities including developing novel diagnostic and therapeutic strategies and clinical and implementation science research. DISCUSSION: The findings show the breadth of NHLBI-funded nutrition research and highlight potential research opportunities for nutrition scientists.

Portfolio Analysis of Research Grants in Data Science Funded by the National Heart, Lung, and Blood Institute.

Leveraging emerging opportunities in data science to open new frontiers in heart, lung, blood, and sleep research is one of the major strategic objectives of the National Heart, Lung, and Blood Institute (NHLBI), one of the 27 Institutes/Centers within the National Institutes of Health (NIH). To assess NHLBI's recent funding of research grants in data science and to identify its relative areas of focus within data science, a portfolio analysis from fiscal year 2008 to fiscal year 2017 was performed. In this portfolio analysis, an efficient and reliable methodology was used to identify data science research grants by utilizing several NIH databases and search technologies (iSearch, Query View Reporting system, and IN-SPIRE [Pacific Northwest National Laboratory, Richland, WA]). Six hundred thirty data science-focused extramural research grants supported by NHLBI were identified using keyword searches based primarily on NIH's working definitions of bioinformatics and computational biology. Further analysis characterized the distribution of these grants among the heart, lung, blood, and sleep disease areas as well as the subtypes of data science projects funded by NHLBI. Information was also collected for data science research grants funded by other NIH institutes/centers using the same search and analysis methodology. The funding comparison among different NIH institutes/centers highlighted relative data science areas of emphasis and further identified opportunities for potential data science areas in which NHLBI could foster research advances.

The National MDS Natural History Study: design of an integrated data and sample biorepository to promote research studies in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS), a spectrum of heterogeneous hematopoietic stem cell diseases, vary in clinical severity, response to therapy, and propensity toward progression to acute myeloid leukemia. These are acquired clonal disorders resulting from somatic mutations within the hematopoietic stem or progenitor cell population. Understanding the natural history and the risk of developing leukemia and other adverse outcomes is dependent on access to well-annotated biospecimens linked to robust clinical and molecular data. To facilitate the acquisition and distribution of MDS biospecimens to the wider scientific community and support scientific discovery in this disease, the National MDS Natural History study was initiated by the National Heart, Lung, and Blood Institute (NHLBI) and is being conducted in collaboration with community hospitals and academic medical centers supported by the National Cancer Institute (NCI). The study will recruit up to 2000 MDS patients or overlapping myeloproliferative neoplasms (MDS/MPN) and up to 500 cases of idiopathic cytopenia of undetermined significance (ICUS). The National MDS Natural History Study (NCT02775383) will offer the world's largest disease-focused tissue biobank linked to longitudinal clinical and molecular data in MDS. Here, we report on the study design features and describe the vanguard phase of 200 cases. The study assembles a comprehensive clinical database, quality of life results, laboratory data, histopathology slides and images, genetic information, hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources will be available to the scientific community for investigator-initiated research.

Portfolio analysis on preeclampsia and pregnancy-associated hypertension research funded by the National Heart, Lung, and Blood Institute.

Chronic hypertension and preeclampsia are the most common complications of pregnancy. To clarify the contributions of the National Heart, Lung, and Blood Institute (NHLBI) to the field and identify potential research gaps, we performed portfolio analysis of awards related to preeclampsia and pregnancy-associated hypertension. A list of National Institutes of Health (NIH)-funded awards between fiscal years 2008-present was obtained through an NIH RePORTER search using the following terms: "preeclampsia" and "pregnancy-associated hypertension." More in-depth analyses were performed on currently active awards supported by the NHLBI. The NHLBI is the lead institute at the NIH in funding research related to pregnancy-associated hypertension and second leading in funding research related to preeclampsia. The NHLBI currently supports 38 awards related to preeclampsia and six awards related to pregnancy-associated hypertension, with a combined total dollar investment of $21 million. Of the currently active, NHLBI-supported awards on preeclampsia and pregnancy-associated hypertension combined, 47% are related to basic science research, 30% to clinical, 14% to clinical trials, and 9% to early translational research. The focus of NHLBI-funded awards is primarily on vascular mechanisms and short and long-term cardiovascular complications of preeclampsia and pregnancy-associated hypertension. Despite steady funding for research on preeclampsia and pregnancy-associated hypertension, several gaps in knowledge exist. NHLBI held a workshop entitled Predicting, Preventing and Treating Preeclampsia to address some of these gaps and inform future research directions for the institute.

Reducing Cardiovascular Disparities Through Community-Engaged Implementation Research: A National Heart, Lung, and Blood Institute Workshop Report.

Cardiovascular disparities remain pervasive in the United States. Unequal disease burden is evident among population groups based on sex, race, ethnicity, socioeconomic status, educational attainment, nativity, or geography. Despite the significant declines in cardiovascular disease mortality rates in all demographic groups during the last 50 years, large disparities remain by sex, race, ethnicity, and geography. Recent data from modeling studies, linked micromap plots, and small-area analyses also demonstrate prominent variation in cardiovascular disease mortality rates across states and counties, with an especially high disease burden in the southeastern United States and Appalachia. Despite these continued disparities, few large-scale intervention studies have been conducted in these high-burden populations to examine the feasibility of reducing or eliminating cardiovascular disparities. To address this challenge, on June 22 and 23, 2017, the National Heart, Lung, and Blood Institute convened experts from a broad range of biomedical, behavioral, environmental, implementation, and social science backgrounds to summarize the current state of knowledge of cardiovascular disease disparities and propose intervention strategies aligned with the National Heart, Lung, and Blood Institute mission. This report presents the themes, challenges, opportunities, available resources, and recommended actions discussed at the workshop.

Cardiothoracic surgery training grants provide protected research time vital to the development of academic surgeons.

BACKGROUND: The Ruth L. Kirschstein Institutional National Research Service Award (T32) provides institutions with financial support to prepare trainees for careers in academic medicine. In 1990, the Cardiac Surgery Branch of the National Heart, Lung and Blood Institute (NHLBI) was replaced by T32 training grants, which became crucial sources of funding for cardiothoracic (CT) surgical research. We hypothesized that T32 grants would be valuable for CT surgery training and yield significant publications and subsequent funding. METHODS: Data on all trainees (past and present) supported by CT T32 grants at two institutions were obtained (T32), along with information on trainees from two similarly sized programs without CT T32 funding (Non-T32). Data collected were publicly available and included publications, funding, degrees, fellowships, and academic rank. Non-surgery residents and residents who did not pursue CT surgery were excluded. RESULTS: Out of 76 T32 trainees and 294 Non-T32 trainees, data on 62 current trainees or current CT surgeons (T32: 42 vs Control: 20) were included. Trainees who were supported by a CT T32 grant were more likely to pursue CT surgery after residency (T32: 40% [30/76] vs Non-T32: 7% [20/294], P < .0001), publish manuscripts during residency years (P < .0001), obtain subsequent NIH funding (T32: 33% [7/21] vs Non-T32: 5% [1/20], P = .02), and pursue advanced fellowships (T32: 41% [9/22] vs Non-T32: 10% [2/20], P = .02). CONCLUSIONS: T32 training grants supporting CT surgery research are vital to develop academic surgeons. These results support continued funding by the NHLBI to effectively develop and train the next generation of academic CT surgeons.

Effect Sizes and Primary Outcomes in Large-Budget, Cardiovascular-Related Behavioral Randomized Controlled Trials Funded by NIH Since 1980.

PURPOSE: We reviewed large-budget, National Institutes of Health (NIH)-supported randomized controlled trials (RCTs) with behavioral interventions to assess (1) publication rates, (2) trial registration, (3) use of objective measures, (4) significant behavior and physiological change, and (5) effect sizes. METHODS: We identified large-budget grants (>$500,000/year) funded by NIH (National Heart Lung and Blood Institute (NHLBI) or National Institute of Diabetes & Digestive and Kidney Diseases (NIDDK)) for cardiovascular disease (dates January 1, 1980 to December 31, 2012). Among 106 grants that potentially met inclusion criteria, 20 studies were not published and 48 publications were excluded, leaving 38 publications for analysis. ClinicalTrials.gov abstracts were used to determine whether outcome measures had been pre-specified. RESULTS: Three fourths of trials were registered in ClinicalTrials.gov and all published pre-specified outcomes. Twenty-six trials reported a behavioral outcome with 81 % reporting significant improvements for the target behavior. Thirty-two trials reported a physiological outcome. All were objectively measured, and 81 % reported significant benefit. Seventeen trials reported morbidity outcomes, and seven reported a significant benefit. Nine trials assessed mortality, and all were null for this outcome. CONCLUSIONS: Behavioral trials complied with trial registration standards. Most reported a physiological benefit, but few documented morbidity or mortality benefits.

Toward Independence: Resubmission Rate of Unfunded National Heart, Lung, and Blood Institute R01 Research Grant Applications Among Early Stage Investigators.

PURPOSE: The current, budget-driven low rate of National Institutes of Health (NIH) funding for biomedical research has raised concerns about new investigators' ability to become independent scientists and their willingness to persist in efforts to secure funding. The authors sought to determine resubmission rates for unfunded National Heart, Lung, and Blood Institute (NHLBI) early stage investigator (ESI) independent research grant (R01) applications and to identify resubmission predictors. METHOD: The authors used a retrospective cohort study design and retrieved applications submitted in fiscal years 2010-2012 from NIH electronic research administrative sources. They defined ESI applicants as those who have received no prior R01 (or equivalent) funding and are within 10 years of completion of their terminal research degree or medical residency training. ESI applications at the NHLBI were eligible for special funding consideration if they scored above, but within 10 points of, the payline. The primary outcome was application resubmission after failing to secure funding with the first R01 submission. RESULTS: Over half of the unfunded applications were resubmitted. Some of these were discussed and "percentiled." Among percentiled applications, the only significant predictor of resubmission was the percentile score. Over half (59%) of the ESI R01 grants funded by NHLBI in fiscal years 2010-2012 had percentile scores above but within 10 points of the NHLBI payline, and benefited from the special funding considerations. CONCLUSIONS: The only independent predictor of resubmission of NHLBI ESI R01 grant applications was percentile score; applicant demographics and institutional factors were not predictive of resubmission.

Paediatric heart failure research: role of the National Heart, Lung, and Blood Institute.

The National Heart, Lung, and Blood Institute, of the National Institutes of Health, is committed to supporting research in paediatric heart failure. The Institute's support of paediatric heart failure research includes both investigator-initiated grants and Institute initiatives. There were 107 funded grants in paediatric heart failure over the past 20 years in basic, translational and clinical research, technology development, and support of registries. Such research includes a broad diversity of scientific topics and approaches. The Institute also supports several initiatives for paediatric heart failure, including the Pediatric Circulatory Support Program, the Pumps for Kids, Infants, and Neonates (PumpKIN) Program, PediMACS, and the Pediatric Heart Network. This review article describes the National Heart, Lung, and Blood Institute's past, present, and future efforts to promote a better understanding of paediatric heart failure, with the ultimate goal of improving outcomes.

Publication Speed, Reporting Metrics, and Citation Impact of Cardiovascular Trials Supported by the National Heart, Lung, and Blood Institute.

BACKGROUND: We previously demonstrated that cardiovascular (CV) trials funded by the National Heart, Lung, and Blood Institute (NHLBI) were more likely to be published in a timely manner and receive high raw citation counts if they focused on clinical endpoints. We did not examine the metrics of trial reports, and our citation measures were limited by failure to account for topic-related citation behaviors. METHODS AND RESULTS: Of 244 CV trials completed between 2000 and 2011, we identified 184 whose main results were published by August 20, 2014. One investigator who was blinded to rapidity of publication and citation data read each publication and characterized it according to modified Delphi criteria. There were 46 trials (25%) that had Delphi scores of 8 or 9 (of a possible 9); these trials published faster (median time from trial completion to publication, 12.6 [interquartile range {IQR}, 6.7 to 23.3] vs. 21.8 [IQR, 12.1 to 34.9] months; P<0.01). They also had better normalized citation impact (median citation percentile for topic and date of publication, with 0 best and 100 worst, 1.92 [IQR, 0.64 to 7.83] vs. 8.41 [IQR, 1.80 to 24.75]; P=0.002). By random forest regression, we found that the 3 most important predictors of normalized citation percentile values were total costs, intention-to-treat analyses (as a modified Delphi quality measure), and focus on clinical (not surrogate) endpoints. CONCLUSIONS: NHLBI CV trials were more likely to publish results quickly and yield higher topic-normalized citation impact if they reported results according to well-defined metrics, along with focus on clinical endpoints.

Predicting Productivity Returns on Investment: Thirty Years of Peer Review, Grant Funding, and Publication of Highly Cited Papers at the National Heart, Lung, and Blood Institute.

There are conflicting data about the ability of peer review percentile rankings to predict grant productivity, as measured through publications and citations. To understand the nature of these apparent conflicting findings, we analyzed bibliometric outcomes of 6873 de novo cardiovascular R01 grants funded by the National Heart, Lung, and Blood Institute (NHLBI) between 1980 and 2011. Our outcomes focus on top-10% articles, meaning articles that were cited more often than 90% of other articles on the same topic, of the same type (eg, article, editorial), and published in the same year. The 6873 grants yielded 62 468 articles, of which 13 507 (or 22%) were top-10% articles. There was a modest association between better grant percentile ranking and number of top-10% articles. However, discrimination was poor (area under receiver operating characteristic curve [ROC], 0.52; 95% confidence interval, 0.51-0.53). Furthermore, better percentile ranking was also associated with higher annual and total inflation-adjusted grant budgets. There was no association between grant percentile ranking and grant outcome as assessed by number of top-10% articles per $million spent. Hence, the seemingly conflicting findings on peer review percentile ranking of grants and subsequent productivity largely reflect differing questions and outcomes. Taken together, these findings raise questions about how best National Institutes of Health (NIH) should use peer review assessments to make complex funding decisions.

The vascular surgeon-scientist: a 15-year report of the Society for Vascular Surgery Foundation/National Heart, Lung, and Blood Institute-mentored Career Development Award Program.

The Society for Vascular Surgery (SVS) Foundation partnered with the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) in 1999 to initiate a competitive career development program that provides a financial supplement to surgeon-scientists receiving NIH K08 or K23 career development awards. Because the program has been in existence for 15 years, a review of the program's success has been performed. Between 1999 and 2013, 41 faculty members applied to the SVS Foundation program, and 29 from 21 different institutions were selected as awardees, resulting in a 71% success rate. Three women (10%) were among the 29 awardees. Nine awardees (31%) were supported by prior NIH F32 or T32 training grants. Awardees received their K award at an average of 3.5 years from the start of their faculty position, at the average age of 39.8 years. Thirteen awardees (45%) have subsequently received NIH R01 awards and five (17%) have received Veterans Affairs Merit Awards. Awardees received their first R01 at an average of 5.8 years after the start of their K award at the average age of 45.2 years. The SVS Foundation committed $9,350,000 to the Career Development Award Program. Awardees subsequently secured $45,108,174 in NIH and Veterans Affairs funds, resulting in a 4.8-fold financial return on investment for the SVS Foundation program. Overall, 23 awardees (79%) were promoted from assistant to associate professor in an average of 5.9 years, and 10 (34%) were promoted from associate professor to professor in an average of 5.2 years. Six awardees (21%) hold endowed professorships and four (14%) have secured tenure. Many of the awardees hold positions of leadership, including 12 (41%) as division chief and two (7%) as vice chair within a department of surgery. Eight (28%) awardees have served as president of a regional or national society. Lastly, 47 postdoctoral trainees have been mentored by recipients of the SVS Foundation Career Development Program on training grants or postdoctoral research fellowships. The SVS Foundation Career Development Program has been an effective vehicle to promote the development and independence of vascular surgeon-scientists in the field of academic vascular surgery.

Citation impact of NHLBI R01 grants funded through the American Recovery and Reinvestment Act as compared to R01 grants funded through a standard payline.

RATIONALE: The American Recovery and Reinvestment Act (ARRA) allowed National Heart, Lung, and Blood Institute to fund R01 grants that fared less well on peer review than those funded by meeting a payline threshold. It is not clear whether the sudden availability of additional funding enabled research of similar or lesser citation impact than already funded work. OBJECTIVE: To compare the citation impact of ARRA-funded de novo National Heart, Lung, and Blood Institute R01 grants with concurrent de novo National Heart, Lung, and Blood Institute R01 grants funded by standard payline mechanisms. METHODS AND RESULTS: We identified de novo (type 1) R01 grants funded by National Heart, Lung, and Blood Institute in fiscal year 2009: these included 458 funded by meeting Institute's published payline and 165 funded only because of ARRA funding. Compared with payline grants, ARRA grants received fewer total funds (median values, $1.03 versus $1.87 million; P<0.001) for a shorter duration (median values including no-cost extensions, 3.0 versus 4.9 years; P<0.001). Through May 2014, the payline R01 grants generated 3895 publications, whereas the ARRA R01 grants generated 996. Using the InCites database from Thomson-Reuters, we calculated a normalized citation impact for each grant by weighting each article for the number of citations it received normalizing for subject, article type, and year of publication. The ARRA R01 grants had a similar normalized citation impact per $1 million spent as the payline grants (median values [interquartile range], 2.15 [0.73-4.68] versus 2.03 [0.75-4.10]; P=0.61). The similar impact of the ARRA grants persisted even after accounting for potential confounders. CONCLUSIONS: Despite shorter durations and lower budgets, ARRA R01 grants had comparable citation outcomes per $million spent to that of contemporaneously funded payline R01 grants.

An analysis of the NIH-supported sickle cell disease research portfolio.

Sickle cell disease (SCD), an inherited blood disorder is due to a single amino acid substitution on the beta chain of hemoglobin, and is characterized by anemia, severe infections, acute and chronic pain, and multi-organ damage. The National Institutes of Health (NIH) is dedicated to support basic, translational and clinical science research to improve care and ultimately, to find a cure for SCD that causes such suffering. This report provides a detailed analysis of grants funded by the NIH for SCD research in Fiscal Years 2007 through 2013. During this period, the NIH supported 247 de novo grants totaling $272,210,367 that address various aspects of SCD. 83% of these funds supported research project grants investigating the following 5 scientific themes: Pathology of Sickle Red Blood Cells; Globin Gene Expression; Adhesion and Vascular Dysfunction; Neurological Complications and Organ-specific Dysfunction; and Pain Management and Intervention. The remaining 17% of total funds supported career development and training grants; Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) grants; large Center grants; and Conference grants. Further analysis showed that the National Heart, Lung, and Blood Institute (NHLBI) is the largest funder of SCD research within NIH with 67% of total grants, contributing 77% of total funds; followed by the National Institute for Digestive Diseases and Kidney (NIDDK) that is funding 19% of grants, contributing 13% of total funds. The remaining 14% of grants totaling 10% of the funds were supported by all other NIH Institutes/Centers (ICs) combined. In summary, the NIH is using multiple funding mechanisms to support a sickle cell disease research agenda that is intended to advance the detection, treatment, and cure of this debilitating genetic disease.