It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Program Overview

Congenital heart disease (CHD) affects approximately 40,000 infants in the United States each year and is one of the leading causes of infant mortality. Improved medical and surgical management over the past 20 years has produced a growing number of adults living with CHD. It is estimated that there are as many as 2 million adults and 800,000 children in the US living with CHD. Outcomes have improved significantly for patients with CHD, but mortality and morbidity for some lesions remain unacceptably high. Many genetic contributions to the pathogenesis of CHD have been well-established by animal models and human studies. However, the influence of genetics on clinical outcomes remains largely unexplored, and finding new targets for therapy or novel approaches for prevention and risk stratification requires a deeper understanding of CHD genetics. Major barriers to genetic/genomic studies in CHD include the heterogeneity of conditions, the complexity of the involved molecular pathways and networks, the small numbers of subjects with a particular malformation at any one institution, the large number of possible causative genes, and the low frequency of causative variants.

Since its creation in 2009, the PCGC has provided a flexible and collaborative framework in which multi-disciplinary teams have explored the genetic underpinnings of CHD. The multi-center approach has enabled robust patient recruitment such that the PCGC has accumulated the largest collection, to date, of data and DNA from patients with CHD (>12,000 probands enrolled). The PCGC has discovered the etiology, by various genetic mechanisms, of approximately 25% of unexplained CHD and identified many new CHD-associated genes.

The Bench to Bassinet Program (B2B) was launched by the NHLBI as a novel approach to break through the major barriers, identify the causes of human congenital heart disease, and ultimately improve outcomes for individuals with congenital heart disease. The B2B strategy is to accelerate the translation of scientific discovery into clinical practice through collaborations of basic, translational, and clinical researchers. Recognizing that many research institutions excel in one or two of these areas, but not necessarily all three, the B2B is structured into three consortia. The PCGC comprises human genetics and genomics researchers; Cardiovascular Developmental Biology Data Resource Center (CDDRC) basic and computational scientists; and the Pediatric Heart Network (PHN) clinical trial and observational study experts. Although each component is free-standing, the close communication among the groups means that the findings of one consortium are readily shared with and acted on by the others, thereby driving the science forward in a more comprehensive, translational manner. An Administrative Coordinating Center (ACC) supports the PCGC’s clinical protocols and performs administrative tasks for the PCGC and CDDRC. The ACC also subcontracts to core facilities that support the scientific work of the PCGC. The NHLBI intends to publish a FOA for an ACC at a later date.

Consortium Objectives

The overall objective of the PCGC is to improve the outcomes of patients with CHD by translating discoveries of the genetic architecture of CHD into optimized diagnosis, management, and therapeutic strategies. To date, this objective has been met by identifying genetic and epigenetic causes of human CHD. In this renewal of the PCGC, the focus will shift to exploring how these genetic discoveries may be relevant to clinical applications.

Another important goal of the PCGC is to increase the human capital and resources to sustain multidisciplinary, integrated research in CHD pathogenesis. Equipping junior scientists with the skills and experience of conducting genomic research in CHD is central to accomplishing this mission. Increasing resources for the broader CHD research community to advance research through robust data sharing is also a critical goal and involves timely public releases of datasets (i.e., submission to dbGaP) and access to PCGC data and specimens.

The PCGC accomplishes its goals by establishing a consortium of collaborative, multidisciplinary research teams supported by appropriate scientific cores and infrastructure. The Research Centers are the scientific units of the PCGC. As such, the Research Centers will:

• Collaborate to determine the scientific direction of the PCGC
• Actively implement each consortium-wide protocol approved by the PCGC Steering Committee
• Enroll research subjects, as needed
• Collect and report highly detailed phenotypic data
• Conduct the scientific analysis on genotype, phenotype, and other data
• Interpret the results in the context of disease significance

Specific areas of research interest

The PCGC conducts clinical genomic research with multiple studies potentially active at any given time. Applications are expected to propose research that addresses critical knowledge gaps and areas of high priority to children and adults with CHD. NHLBI expects that projects will be hypothesis-driven and will focus on enabling genotype-phenotype association, with the eventual goal of translating discoveries of the genetic architecture of CHD into optimized diagnosis, management, and therapeutic strategies. Proposed studies will be expected to leverage state-of-the-art and emerging genetic and genomic techniques as needed. Also, projects may involve leading approaches to phenotyping, including linkage to registry data and/or extraction of electronic health data. Studies should fit within the collaborative, multi-center infrastructure of the PCGC and should be able to be completed in a three-to-five-year time frame. NHLBI expects that where possible, proposed projects will leverage the existing PCGC patient cohort.

The PCGC patient cohort is currently being recruited under the CHD GENES protocol.. The current patient cohort consists of over 12,000 patients with all types of CHD except isolated patent foramen ovale or isolated, prematurity-associated patent ductus arteriosus. The patients are of all ages (approximately 30% recruited at less than 1 year of age and 20% recruited as adults). More information about the PCGC patient cohort and CHD GENES protocol can be found at the Bench to Bassinet website (www.benchtobassinet.com) or by contacting the Scientific/Research Contact listed below).

Each application is expected to focus on a clinical protocol, or group of related clinical protocols, designed to explore how PCGC’s genetic discoveries may eventually be applied to clinical management of patients with CHD. It is expected that the proposed projects will generate data that can be used to provide preliminary support for approaches to clinical management that can be tested in future trials outside of the PCGC. Therefore, expertise in clinical translation of genetics will be required of the investigative team for each application. Current centers that re-compete may need to adjust study personnel to meet this evaluation criterion.

The PCGC Steering Committee (see below) will evaluate the proposed protocols. The exact number of protocols supported will depend on the nature and extent of the investigations. Protocols may be selected from the studies proposed by successful applicants in response to this FOA, but a decision to fund a particular Research Center will not commit the PCGC to develop that applicant’s proposed protocol. All Research Centers are expected to participate in all protocols.

This FOA is intended to support only human studies. Studies may focus on children with CHD, adults with CHD, or both.

Examples of research topics

Some examples of research topic areas appropriate for this FOA include, but are not limited to, those listed below:

• What genetic factors are associated with a high risk of surgical mortality for patients with CHD?
• What are the genetic factors that convey resiliency in patients with CHD who are high risk for arrhythmia/post-bypass pulmonary edema/post-bypass low cardiac output?
• Can genetic risk factors predict long term outcome, such as survival/need for transplant, chronic arrhythmia, heart failure, neurodevelopmental outcome?
• What are the genetic risk factors for late complications, such as arrhythmia, heart failure, protein-losing enteropathy, or liver dysfunction, in adults with CHD?
• How do placental factors interact with genetic variants to influence clinical outcomes?
• How do environmental factors and other social determinants of health interact with genetic variants to influence clinical outcomes?

These topics are examples only. Applicants should not feel limited to the topics mentioned above and are encouraged to submit other topics pertinent to the objectives of the FOA.

The following topics would NOT be responsive to this FOA:

• Applications that include animal studies
• Applications that propose patient registries without concomitant genetic or genomic scientific aims
• Applications that propose clinical trials

Consortium Organization

The B2B Program is a consortium that includes the cooperative PCGC Research Centers, the CDDRC, an Administrative Coordinating Center (ACC), the PHN, and NHLBI Project Scientists.

PCGC Research Centers are responsible for proposing and developing human genomics studies, recruiting study subjects, entering data into the web-based data collection system, performing other aspects related to conducting the research, training junior investigators, and disseminating research findings. All individual Research Centers are expected to participate in a cooperative and interactive manner with one another and with the ACC and NHLBI.

The CDDRC will be responsible for assembling data relevant to cardiovascular developmental biology into a queryable data repository complete with computational tools. The CDDRC will establish an educational program and collaborate with the ACC to stimulate use of the data through Challenge prizes. The CDDRC will collaborate with the PCGC Steering Committee to use the CDDRC data resource to relate genes and variants identified by the PCGC to cardiovascular developmental biology and gene regulatory networks. The CDDRC will collaborate with the PCGC Data Hub to assure interoperability between the CDDRC data resource and human genomics data collected by the PCGC.

The Administrative Coordinating Center (ACC) issues subcontracts to core facilities that support the scientific work of the consortium, organizes meetings, and coordinates activities of the External Advisory Committee (EAC). The ACC also provides a PCGC Data Hub that serves as PCGC data repository and internal data portal, supports the PCGC’s clinical protocols, and performs administrative tasks for the entire B2B program. Cores necessary to support the science and to provide resources and services to multiple Research Centers are established by the ACC. The NHLBI will determine the Core configuration with input from the Steering Committee and the EAC (see below). Cores can be located at Research Centers or at institutions outside of the PCGC, depending upon expertise, performance, and cost. The ACC and NHLBI will oversee the process of Core selection, and the ACC will administer the budget for the Cores. Cores may be phased in and out based on scientific need during the course of the funding cycle.

The Steering Committee is the main governing body of the PCGC. The Steering Committee is composed of the PDs/PIs of each Research Center and the ACC, NHLBI Program Scientists, and Core Directors. The Steering Committee has primary responsibility for the general organization of the PCGC, approval of clinical protocols and genetic/genomic studies, conduct and monitoring of studies, allocation of core resources, and expeditious reporting of study results. All major scientific and administrative decisions are determined by majority vote of the Steering Committee, which meets at least monthly by teleconference.

The NHLBI is responsible for organizing and providing overall support for the B2B Program. The NHLBI Program Office and Office of Grants Management are responsible for the overall management. In addition to regular grant stewardship, the NHLBI Project Scientists will be involved substantially with the awardees as a scientific partner, consistent with the Cooperative Agreement mechanism.

An independent External Advisory Committee (EAC), appointed by the NIH and funded through the ACC, reviews the progress of the program every 6 - 12 months and provides advice to the PCGC and CDDRC grantees about scientific direction. Members of the EAC and ad hoc external experts review all applications for potential cores and provide advice to the ACC about core selection.

An Observational Safety and Monitoring Board (OSMB), also appointed by the NIH and funded through the ACC, monitors patient safety and data integrity and reviews the performance of each study. The OSMB also reviews proposed ancillary study projects for issues of patient burden. As a part of

its monitoring responsibility, the OSMB submits recommendations to the NIH regarding the conduct and continuation of each protocol.

Interaction with CDDRC and PHN

An important aspect of the B2B program is the interaction of scientists along the translational spectrum. Therefore, PCGC investigators will meet regularly with investigators from the CDDRC, through teleconferences and in-person meetings, to share data and discuss and implement collaborative projects. PCGC investigators will also interact with investigators from the PHN to advise the PHN on genomics aims of PHN clinical studies and trials and to implement collaborative projects.

Data sharing

A critical mission and goal of the PCGC and B2B program is to expand resources to the broader scientific community to advance research. The PCGC strives to meet or exceed expectations in NIH data sharing policies. Data generated by the PCGC are expected to be made available to the broader research community through open, shared databases such as dbGaP and ClinVar, consistent with achieving the goals of the program. A goal of the PCGC will be to achieve real-time data sharing with the broader scientific community through the ancillary study process or other bioinformatics solutions. Appropriate controls will be implemented to ensure patient privacy and regulatory compliance.

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Not Applicable

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

In addition, applications should address the following three elements:

Facilities and Other Resources

Table of Study Population: Applicants should have access to sufficient patients to support recruitment in a variety of studies in the PCGC. Include a table providing annual estimates of the number of open heart surgical cases, cardiac catheterizations performed, and outpatient visits for infants, children, and adults with CHD. An approximate breakdown of the types of CHD present in the potential subjects should also be included.

Clinical and Translational Science Award (CTSA) Resources (if applicable): Applicants at sites that have a CTSA award funded by the NIH National Center for Advancing Translational Sciences should identify the resources that could be available to support the proposed PCGC Research Center. Include a description of aspects of those resources that will enhance programmatic and scientific efficiency. In such cases, a description of how the applicant proposes to interact with CTSA resources should be included.

All instructions in the SF424 (R&R) Application Guide must be followed.

Research Center Budgets should reflect support for personnel and infrastructure costs of the center. The budget must include support for a 9 person months effort for the clinical study coordinator; a minimum of 2.4 calendar months effort for the PD/PI or a minimum of 2.4 person months combined effort for all PDs/PIs, and other investigators and staff as required. Travel costs for 2 Steering Committee meetings per year in Bethesda, MD should be included ?for 2-3 members of the Research Center, including at least one PD/PI and the coordinator. If CTSA resources are to be used, and a fee is charged, please note this in the budget.

Enter the estimated costs for the protocol as a line item in Section F. Other Direct Costs:

Line 8 should be identified as Main Research Project, and the corresponding protocol costs should be entered under Funds Requested ($) in this line.

As part of the budget justification section, applications ?must support the protocol budget request by estimating relevant patient care, phenotyping, and genetic testing costs. The protocol budget should include all costs associated with the conduct of the protocol such as identification, screening, and recruitment of subjects and, if indicated, controls; per-patient costs for sequencing, genotyping or other genomic activities, if applicable; per-patient costs for phenotyping, if applicable; and other costs associated with the analyses required for the aims of the research. The costs of obtaining, processing, and storage of DNA derived from blood do not need to be included.

Personnel costs should only be included if special personnel are needed for the successful completion of the study who are not already listed in Sections A and B of the SF424 R&R Budget form. Protocol budgets will be understood to be estimated budgets until the Steering Committee selects and develops common protocols. Patient-related costs and sequencing/genotyping costs will be distributed from the ACC budget.

Specific Aims: Applicants should list the overall Specific Aims of the proposed research center.

Research Strategy: The Research Strategy must consist of two subsections: Research Center Overview and Research Project. The Research Center Overview may be up to 2 pages and the entire Research Strategy section should be up to 12 pages.

A. Research Center Overview

Provide a research center overview to discuss the Research Center's overall research goals and the strategic plan to achieve those goals. The research goals should be put into the context of the current state of knowledge of CHD genetics, its application to clinical management, and current technologic capabilities. This subsection should include a statement of assurance that the applicant will (1) comply with all PCGC policies and procedures, including those specified in the Resource Sharing Plan instructions and (2) provide timely responses to all communications from the PCGC Steering Committee Chair, ACC, and NHLBI Project Scientists. In addition, the Overview subsection should address the following areas:

Qualification and experience

Applications for Research Centers must demonstrate experience and expertise in the collaborative conduct of complex genomic clinical studies in congenital cardiac disease. Describe Research Center's established research program in the scientific areas of interest, appropriate expertise, the established infrastructure that supports multi-center studies, the track record of successful collaborative research, and access to a sufficient number of patients to accomplish the Research Center's portion of the proposed protocols. Application to participate in the PCGC should not be undertaken lightly, as participation entails a significant commitment in terms of time, organizational skills, and administrative ability. Applications should indicate willingness to attend all Steering Committee meetings, which may include conference calls at least monthly and in-person meetings at least twice a year, as well as participation in other aspects of the PCGC (study, writing, protocol development, ancillary studies, and other committees).

Collaboration

Applications should describe support of proposed collaborative research and interaction with other Research Centers, the NHLBI, the ACC, and the companion consortia, the CDDRC, and the PHN.

Provide a clear and concise description of the interrelationships among the members of the proposed team, and the contribution of each member to fulfilling the objectives of this FOA. In addition, the application should provide a plan to ensure the maintenance of close cooperation and effective communication among members of the proposed team and evidence of the capability of the applicant’s organization to participate and interact effectively in cooperative multi-center research.

Applications may propose to participate as a Research Center made up of two or more sites. For Research Centers with more than one site, plans for collaboration and interaction among institutions should be clearly documented in the application, and the responsible investigator(s) at the collaborating site(s) should be named. Centers with more than one clinical site should provide management plans that include descriptions of supervision, skills development, certification, data handling, quality assurance, cost effective management, and communication.

Applicants must agree, if awarded, to accept the Cooperative Agreement Terms and Conditions of Award in Section VI. 2. A.

Research Team

The PD/PI or another member of the physician investigative team is expected to be readily available to respond directly to questions about PCGC matters on a daily basis, preferably through e-mail and this should be indicated in the application. The PDs/PIs must have a demonstrated track record of successful leadership of a multi-disciplinary team, including the ability to communicate promptly with and ensure collaboration among pediatric cardiologists, geneticists, nurses, and other related subspecialists. While the multiple PD/PI leadership strategy is highly encouraged, in the case of a single PD/PI, an alternate PD/PI must be designated to serve in the absence of the PD/PI.

Plans for availability of staff, including study coordinators, must also be included in the application. The level of training and experience of individual staff, as well as qualifications and prior involvement in clinical research, should be described in the Personal Statement section of the Biosketch.

Skills Development

Applications should include a description of skills development plans for junior investigators and/or how junior investigators will be included in the research teams. Specific examples of how junior investigators have been included in past efforts and specific plans for inclusion in PCGC activities should be provided.

B. Research Project

The Research Project subsection should discuss a project or group of related projects, consistent with the objectives of the FOA that can be completed in 5 years by the Research Center within the context of the Consortium.

This subsection should focus on a clinical protocol, or group of related clinical protocols, designed to explore how genetic discoveries may be relevant to clinical applications. Describe the protocol rationale, research aims, study design and timetable, a description of the study population with sample size calculations, and a description of the statistical analysis plan. Although all Research Centers will contribute to fulfilling the recruitment requirements, please indicate how many study participants are available at your Research Center. Also, comment on approaches for recruitment. The research plan should also propose specific milestones that could be used to evaluate the success of the project throughout the duration of funding. Milestone examples include, but are not limited to development of an approved protocol; enrollment of the first patient; enrollment of 25, 50, 75 and 100% of the proposed cohort, etc.

Letters of Support: Include letters of institutional and departmental support for participation in the PCGC.

If the application is from a site that has a CTSA funded by the NIH National Center for Advancing Translational Sciences, provide a letter of support from the CTSA PD/PI stating the specific CTSA resources that will be used.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan that is consistent with the NIH Genomic Data Sharing Policy.
• The Resource Sharing Plan are expected to include assurances that the applicant will comply with PCGC data sharing policies (http://www.benchtobassinet.com/DataSharingPlan.asp) including the goal of real-time data sharing immediately following completion of data quality assessment, consistent with achieving the goals of the program.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

A single impact score will reflect the review of the entire application including the Research Center Overview and Research Project.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific for this FOA:

If the specific aims of the research project are completed, how likely are they to advance translation of genetic discoveries into the clinical arena?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA:

How adequate and relevant is the level of investigator experience with multi-center, collaborative research?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project ? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

Not Applicable

Applications from Foreign Organizations

Not Applicable

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

• Will receive a written critique.

Applications will be assigned to the NHLBI. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Heart, Lung, and Blood Advisory Council.

The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Compliance with resource sharing policies as appropriate.

3. Anticipated Announcement and Award Dates

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

1. Award Notices

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

2. Administrative and National Policy Requirements

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility reside with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• The Research Center PDs/PIs will be responsible for all aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee.

• Awardee(s) agree to the governance of the study through a Steering Committee and to accept and implement policies approved by the Steering Committee. The Steering Committee voting member for the Awardee will be the PD/PI. For Centers with multiple PDs/PIs, the contact PD/PI will serve as the voting member.

• Awardee(s) will assure that all members of the research team are aware of PCGC policies and procedures and kept informed of PCGC activities, meetings, and results.

• Awardee(s) agree to publicly release data and other products of the study in a timely manner and publish results in peer-reviewed journals, in accordance with PCGC policies and governance. Genomic data will be shared through dbGaP consistent with the NIH data sharing policies and PCGC policy as described in the PCGC Manual of Operations. The goal for the consortium will be to share data in real time as promptly after quality assessment as feasible.

• The PD/PI will serve as a member of a joint leadership committee with the CDDRC PDs/PIs, and joint committees with the PHN members, as necessary.

• Awardees agree to follow best practice in clinical research and to follow procedures to protect and ensure the privacy of medical and genetic data and records of individuals.

• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NHLBI is responsible for organizing and providing overall support for the PCGC. The NHLBI Program Office and Office of Grants Management are responsible for the overall management.

• The NHLBI Project Scientists will serve on the Steering Committee; he/she or other NIH scientists may serve on other study committees, when appropriate. The NHLBI Project Scientist (and other NIH scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment.

• The NHLBI Project Scientists, on behalf of the NIH, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee.

• The NIH reserves the right to withhold funding or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol; (b) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (c) major breach of the protocol, substantive changes in the agreed-upon protocol, or PCGC policies with which NHLBI cannot concur; or (d) human subject ethical issues that may dictate a premature end of the award.

• The NIH will appoint members of the External Advisory Committee (EAC).

• Support or other involvement of industry or any other third party in the study - e.g., participation by the third party; involvement of study resources or citing the name of the study or NIH support; or special access to study results, data, findings or resources - may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIH.

• Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NHLBI staff other than the Project Scientist. The responsibility for final decision-making may reside with senior Institute management, separate organizational components and/or oversight committees.

Areas of Joint Responsibility include:

• The Steering Committee has primary responsibility for the general organization of the PCGC, approval of clinical protocols and genetic/genomic studies, conduct and monitoring of studies, allocation of core resources, and expeditious reporting of study results. All major scientific and administrative decisions are determined by majority vote of the Steering Committee.

• The Steering Committee voting membership shall consist of the Research Center principal investigators (i.e., PD/PI), the NHLBI Project Scientist, and the ACC PD/PI. Meetings of the Steering Committee will ordinarily be held by telephone conference call or in person. The Steering Committee Chair will be appointed by NHLBI from the Steering Committee membership or other experts and will be funded through the ACC. Additional members may be added by majority vote of the Steering Committee.

• An independent OSMB will be appointed by the Director, NHLBI, to provide overall monitoring of study data and safety issues. An NHLBI scientist, other than the NHLBI Program Scientist, will serve as Executive Secretary to the OSMB.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Jonathan Kaltman, MD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0510
Email: kaltmanj@nhlbi.nih.gov

Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Lynn Rundhaugen
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-480-4546
Email: lynn.rundhaugen@nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.