Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

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 approximately 1 to 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 CHD pathogenesis 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, including possibly newborn genetic screening, and risk stratification requires a deeper understanding of CHD genetics. In particular, the NICHD and NHLBI have a shared interest in understanding how genetic variants influence neurodevelopmental outcomes in the context of CHD. Neurodevelopment is a critical mediator of quality of life and of school success in patients with CHD. Up to half of surviving children with complex CHD will have neurodevelopmental abnormalities.

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.

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; the Cardiovascular Development Consortium (CvDC) basic scientists; and the Pediatric Heart Network (PHN) clinical 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 entire B2B program. The ACC also subcontracts to core facilities that support the scientific work of the consortium PCGC. The NHLBI intends to publish an FOA for an ACC at a later date.

The primary goals of the PCGC are to identify genetic and epigenetic causes of human CHD and to relate genetic variants present in patients with CHD to clinical outcomes with the hopes of ultimately translating these findings to improved therapies, prevention strategies, or risk stratification schemes. The objectives of the PCGC are to establish a consortium of collaborative, multidisciplinary research teams supported by appropriate scientific cores and infrastructure.

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, such as through robust data sharing, is also a critical goal and would involve timely public releases of datasets (i.e., submission to dbGaP) and access to PCGC data and specimens, consistent with achieving the goals of the program.

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
• Collect and report highly detailed phenotype 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 active at any given time. Applicants should propose research to address critical knowledge gaps and areas of high priority to the community. Projects should be hypothesis-driven and focused on CHD pathogenesis or genetic determinants of clinical outcome. Studies should leverage state-of-the-art and emerging genetic and genomic techniques. 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. Where possible, proposed projects should leverage the existing PCGC patient cohort.

The PCGC patient cohort is being recruited under the CHD GENES protocol. The current patient cohort consists of over 7,500 patients with all types of CHD except isolated patent foramen ovale or isolated, prematurity-associated patent ductus arteriosus. The patients are of all ages with 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 must propose two research projects. The first research project should focus on a clinical protocol, or group of related clinical protocols, designed to advance understanding of genetic and genomic influences on congenital cardiovascular conditions and their outcomes. Applicants should also propose a second research project exploring how genetic variants influence neurodevelopmental outcomes in patients with CHD.

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:

• Determine if specific genetic variants are associated with relevant clinical outcomes, such as abnormal neurodevelopment, arrhythmia, pulmonary vascular disease, or thrombotic complications.
• Test the hypothesis that variants in cis-regulatory regions or modifier genes contribute to CHD pathogenesis.
• Explore the extent to which gene-environment interactions contribute to CHD pathogenesis.
• Determine the mechanistic steps of translating genetic variants into CHD using human iPSCs derived from subjects with CHD.

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.

The PCGC is a consortium of cooperative Research Centers, an ACC, and NHLBI Project Scientists.

Research Centers are responsible for proposing and developing 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.

The Administrative Coordinating Center (ACC) supports the PCGC’s clinical protocols, and performs administrative tasks for the entire B2B program. The ACC also issues subcontracts to core facilities that support the scientific work of the consortium, organizes meetings, and coordinates activities of the Observational Safety and Monitoring Board (OSMB) and External Advisory Committee (EAC).

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.

Subcommittees are established as necessary, and membership includes appropriate representation from the Research Centers, the ACC, and the NIH.

Cores are necessary to support the science and to provide resources and services to multiple Research Centers. A centralized biorepository stores all blood and DNA samples and a centralized data hub manages all clinical and genomic data. Other core facilities are used in an ad hoc fashion, as driven by the science, to perform sequencing, genotyping, and other scientific tasks. Once the PCGC is convened, requirements for Cores across the Consortium will be evaluated. 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 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. In addition to regular grant stewardship, the NHLBI and NICHD 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 months and provides advice to the Bench to Bassinet 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 CvDC 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 CvDC, 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. 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.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

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

Other

• 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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924
Bethesda, MD 20817 (express/courier service)
Telephone: (301) 435-0270
Fax: (301) 480-0730
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements.

The Research Strategy should consist of the following subsections with the indicated page limits:

A. Research Center Overview: required; 6 pages

B. Main Research Project: required; 12 pages

C. Neurodevelopment Project: required; 12 pages

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

All instructions in the SF424 (R&R) Application Guide must be followed. In addition, applicants 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. Applicants should include a table providing the number of open heart surgical cases, number of cardiac catheterizations performed, and number of out-patient visits for patients with CHD each year. 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 Clinical and Translational Science Award (CTSA) 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, commenting particularly on those aspects that will enhance their programmatic and scientific efficiency. In such cases, a description of how the applicant proposes interacting with CTSA resources should be included.

Intellectual and Developmental Disabilities Research Center (IDDRC) Resources (if applicable): Applicants at sites that have an IDDRC funded by the NICHD may be able to leverage IDDRC core resources to support the proposed PCGC Research Center. In such cases, a description of how the applicant will take advantage of IDDRC resources should be included.

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

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 0.75 FTE clinical study coordinator; a minimum of 2.4 calendar months effort for the PD/PI or a minimum of 2.4 calendar months combined effort for all PDs/PIs, 1.2 calendar months effort for an expert in neurodevelopmental and/or neuropsychological assessment, 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 two protocols as line items 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 ($) in this line.
• Line 9 should be identified as Neurodevelopment Project and the corresponding protocol costs should be entered under Funds Requested ($) in this line.

As part of the budget justification, applicants will support the protocol budget requests by estimating 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; per patient costs for phenotyping, if applicable; and other costs associated with the analyses required for the genetic or genomic 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 (e.g., MRIs, neurodevelopmental testing) and sequencing/genotyping costs will be distributed from the ACC budget.

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

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

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

Research Strategy: The Research Strategy must consist of the following subsections uploaded as a single attachment:

A. Research Center Overview

In this narrative subsection 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 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 and NICHD Project Scientists. In addition, the Overview subsection should address the following areas:

Qualification and experience

Applicants for Research Centers must demonstrate experience and expertise in the collaborative conduct of complex genomic clinical studies in congenital cardiac disease. Research Centers must have an established research program in the scientific areas of interest, appropriate expertise, ability to carry out neuropsychological assessments, an established infrastructure that supports multi-center studies, a track record of successful collaborative research, and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols.

Application to participate in the PCGC should not be undertaken lightly, as it entails a significant commitment in terms of time, organizational skills, and administrative ability. Applicants should indicate their 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, ancillary studies, and other committees).

Collaboration

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

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

Applicants 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, training, in-service, 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

As 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, 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 individual staff training, experience, qualifications, and prior involvement in clinical research should be described in the Personal Statement section of the Biosketch.

Training

Applications should include a description of plans to train junior investigators and/or include junior investigators in their 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. Main Research Project

The Main 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 advance understanding of genetic and genomic influences on CHD and their outcomes. 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. Indicate how many study participants are available in the Research Center, and 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.

C. Neurodevelopment Project

NICHD and NHLBI have a shared interest in understanding how genetic variants influence neurodevelopmental outcomes in the context of CHD. Neurodevelopment is a critical mediator of quality of life and school success in patients with CHD.

In addition to the main research project, applicants should provide a research strategy exploring how genetic variants influence neurodevelopmental outcome in patients with CHD. Describe the importance of this topic and research gaps, the rationale for the proposed project, research aims, study design and timetable, a description of the study population with sample size calculations, and a statistical analysis plan. Indicate how many study participants are available in the Research Center. Discuss how neurodevelopmental phenotyping can be done in a cost-efficient manner, such as using pre-existing data, parent reported surveys, novel information technology platforms, neuropsychological assessments, etc.

Letters of Support: Letters of institutional and departmental support for participation in the PCGC should be included in the application.

If applicant 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.

If applicant proposes to leverage IDDRC core resources to support the proposed PCGC Research Center, provide a letter of agreement from the IDDRC PD/PI.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

• 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 including the goal of real-time data sharing immediately following completion of data quality assessment, consistent with achieving the goals of the program.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

This initiative is not subject to intergovernmental review.

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.

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 Applying Electronically.

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 by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research 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, Main Research Project, and Neurodevelopment 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? 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? Does the application propose to develop data or resources of potentially high value to the scientific community?

Specific for this FOA:

Main Research Project: Does the Main Research Project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?

Neurodevelopment Project: Does the Neurodevelopmental Project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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? Do the investigators have significant experience with multi-center, collaborative research? Are the plans for training new investigators comprehensive and relevant to the goal of increasing investigators in this field of specialization?

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? 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?

Specific for this FOA:

Main Research Project: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Main Project? Does the approach demonstrate a commitment to collaborative research?

Neurodevelopment Project: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Neurodevelopmental Project? Does the approach demonstrate a commitment to collaborative research? Does the main project incorporate cost-efficient approaches to neurodevelopmental phenotyping?

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 children, 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?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six 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 six 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 Children

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 children 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

Not Applicable

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

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

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) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS). Does the applicant acknowledge the goal of achieving real-time data sharing?

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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.

As part of the scientific peer review, all applications:

• 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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications . Following initial peer review, recommended applications will receive a second level of review by the NHLBI Advisory Council and the National Advisory Child Health and Human Development 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.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

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 resides 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 CvDC 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 and NICHD 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 and NICHD 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 composed of three 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.

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html
TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY 301-451-5936
Email: [email protected]

Jonathan Kaltman, MD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0510
Email: [email protected]

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: [email protected]

Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: [email protected]

John Diggs
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-4267
Email: [email protected]

Bryan Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: [email protected]

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.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.