Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Heart, Lung, and Blood Institute (NHLBI)
Funding Opportunity Title	Functional Assays to Screen Genomic Hits (R21/R33)
Activity Code	R21/R33 Phased Innovation Award
Announcement Type	New
Related Notices	October 18, 2013 - See Notice NOT-OD-14-003. Guidance on Resumption of NIH Extramural Activities Following the Recent Lapse in Appropriations. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
Funding Opportunity Announcement (FOA) Number	RFA-HL-13-027
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.233; 93.837; 93.838; 93.839
Funding Opportunity Purpose	This funding opportunity announcement (FOA) issued by National Heart, Lung, and Blood Institute (NHLBI) invites applications to conduct functional analyses of identified genetic variations related to heart, lung, blood and sleep phenotypes, using amenable in vitro or animal model systems. Exploratory/Developmental Phased Innovation (R21/R33) grant applications should identify and justify the genetic variants that they propose to test for functionality, the phenotype(s) the variants are associated with, and the functional measures that will be used to validate them. This FOA provides support for two years (R21 phase) for research planning activities and feasibility studies, followed by possible transition of up to three years of expanded research support (R33 phase). The total project period for an application submitted in response to this FOA may not exceed five years. This FOA requires measurable R21 milestones.

Posted Date	October 2, 2012
Open Date (Earliest Submission Date)	December 23, 2012
Letter of Intent Due Date	30 days prior to the application due date
Application Due Date(s)	January 23, 2013, and (Extended to November 1, 2013 per NOT-OD-14-003), Originally October 23, 2013, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	May/June 2013 and February/March 2014
Advisory Council Review	August 2013 and May 2014
Earliest Start Date(s)	September 2013 and July 2014
Expiration Date	(Extended to November 2, 2013 per NOT-OD-14-003), Originally October 24, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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

Background:

The NHLBI has significantly invested in genomic studies and technologies to identify DNA sequence variations associated with heart, lung, blood, and sleep (HLBS) diseases and related clinical traits. Genome-wide association studies (GWAS), whole exome sequencing (WES), and exome genotyping of NHLBI epidemiological and clinical case-control studies are identifying a large number of genetic variants associated with HLBS phenotypes. These genotype-phenotype data are available to the research community through the database of Genotypes and Phenotypes (dbGaP). However, researchers face a challenging gap between identifying many sequence variations of potential interest and recognizing which of these variations have a direct functional effect on the physiological system of interest, as opposed to merely being associated with the actual causal variant through linkage disequilibrium. Before in-depth mechanistic studies of how specific genetic variants affect the physiology and phenotype can be implemented, researchers must have more effective and inexpensive methods to screen potential variants for an impact on physiological function. Improved genes-to-function screens are critical to accelerating the translation of genomic findings, by making screens of genes and variants for altered physiological function faster, cheaper, and more accurate.

This FOA calls for development and implementation of functional analyses of identified genetic variations using inexpensive in vitro or animal model systems. The proposed model systems and functional assays, whether in vivo animal models or in vitro systems, should have proven relevance to the corresponding disease in humans. Approaches that are generalizable to multiple variants and diseases, as well as those that are customized for studying a particular variant and its associated phenotype, will be considered responsive to this FOA.

Genetic variants:

The application should clearly identify the genetic variants that would be tested for functionality and the basis for their association with specific HLBS phenotypes. Investigators are encouraged to use in silico approaches for predicting deleterious effects of either coding or noncoding variants, animal model databases, or gene expression databases to help identify and prioritize candidate genetic variants for further study, and to provide the basis for the selection of genes/variants and their association with the HLBS phenotypes of interest.

Assays:

Investigators should provide details of the functional assay system(s) that will test the genes/genetic variants that they select. Justification of how the proposed assay system recapitulates or is otherwise informative to the phenotype of interest must be provided. Assays should allow for direct functional measures of normal and altered physiological function or anatomic structure. The assays may range from the molecular to imaging of tissue/organ function and may be in vitro (in cell- or tissue-based assays) or in vivo in relevant animal-model based systems. Cell-free biochemical assays would be responsive. For example cell-free extracts could be used to measure the activity of a mutant vs. wild-type protein or protein-protein interaction (PPI) assays could test for predicted disruptions resulting from variations in coding sequences. However, such cell-free assays should be verified in a cellular, tissue, or whole-organism model as well. Providing multiple lines of convergent evidence supporting functionality using a combination of in silico, in vitro, and in vivo models is expected.

Model Systems:

The proposed model systems for the functional assays may either be based on a model organism (including but not limited to model organisms such as Drosophila, C. elegans, zebrafish, chick, mouse, or rat), or may be based on a cell or tissue-based culture system, including organoids and patient-derived or genome engineered induced pluripotent stem cells and their differentiated derivatives of defined genotype. Investigators are encouraged to use existing resources for animal or in vitro systems, such as the knockout mouse project (KOMP) or the NIH Center for Regenerative Medicine (NIH CRM).

As these projects will be generating new resources of interest to the research community, applications must provide detailed dissemination plans for timely sharing of resultant animal models, assays, data, and results with the community.

Examples of research topics relevant to this FOA include but are not limited to the following areas:

1. Known genetic variants in coding sequences: screening for known exonic variants that may cause functional changes due to alterations in expression, structure, binding, transport, or reactivity of resultant RNA or proteins. The potential detrimental or protective genetic variants may be assessed for the loss/alteration/gain of function at a molecular, cellular, tissue, or whole-organism levels. For instance, using knock-out/knock-in/siRNA technologies in relevant human cells or model organisms (e.g., mice or Drosophila) to screen for cardiac dysfunction or airway remodeling. The functional assays could be designed to monitor heart rate, lung function, blood pressure, and response to environmental perturbations (e.g., smoking, allergen, and diet).

2. Genetic variants in putative regulatory regions: A given noncoding variant with suspected deleterious consequences on cellular or organ function may be identified by direct DNA sequencing or by GWAS, but additional validation of the variant affecting the heart/lung/blood trait of interest is expected to justify the selection of that variant for further analyses. This additional information might include: (1) eQTL data that demonstrate that the variant is associated with alterations in restricted or more global gene expression patterns in relevant tissue and cell types that could plausibly be connected to the normal biology and disease state in question, (2) evidence that the variant alters the binding of a critical transcription factor in a known or putative cis- or trans-regulatory element that could adversely affect the function of that element, and/or (3) association of the variant with epigenomic changes such as DNA methylation, histone modifications or DNase I hypersensitivity occurring in relevant cell types and potentially influencing regulatory effects involved in the trait of interest. However, applications should go beyond simple associations with such regulatory changes by including detailed plans for identifying the molecular mechanism by which a variant actually causes abnormalities.

• In the control of gene expression or other pertinent cis-regulatory effects, research plans should definitively establish how these mechanisms alter normal biological functions in vitro or in a relevant human cell-based or animal model system in order to explain the origin of the given pathological state. For example, merely identifying that specific DNA variants change the sequences of putative transcription factor binding sites would be insufficient for this program. Rather, it would be expected that applications focusing on genomic regulatory regions would characterize the normal activity of a particular cis-regulatory element in controlling the associated gene(s) whose functions are involved in a given phenotype, how the variant found within that element alters this normal function at a molecular level, and how this abnormality explains the pathophysiological state in question.
• Characterizing alterations in gene regulatory effects that act in trans would also be considered responsive to this FOA. Such studies might include mechanistic experiments documenting how specific variants alter the DNA binding characteristics of specific transcription factors, protein-protein interactions between transcription factors and their co-factors, or chromatin modifying enzymes that could produce global epigenomic changes. However, as with the requirement outlined for studies of cis-acting defects, it is essential that experimental evidence be sought for how trans-acting molecular mechanisms cause the pathophysiological changes associated with the phenotype of interest using appropriate cell-based or model organism systems.

3. Multi-variant analysis: where identified variants affecting heart/lung/blood/sleep trait constitute part of a haplotype block or certain biological pathways, investigators will propose computational and experimental methods to identify critical elements and test the role of specific group variants in causing the phenotype of interest. For instance, investigators may narrow the focus to variants associated with specific gene pathways or networks previously indicated to be essential in that cellular or tissue function.

Criteria for non-responsive applications:

• Studies that propose to solely measure gene expression to assess gene function are not considered responsive.
• Applications that propose purely in silico or cell-free testing of variants are not responsive.
• Applications that do not propose functional assays to test the impact of the genetic variants, whether they are in coding or non-coding DNA regions are not responsive.
• Applications designed mainly to find new genetic variants through performing new GWAS studies, additional genotyping, or new or additional sequencing to confirm genetic findings or identify new genes of interest for functional studies are not responsive.
• Investigators who have already demonstrated the functional importance of their gene/region should use the normal R01 mechanism for their follow-up work.

Phased Innovation Awards

This funding opportunity will utilize the R21/R33 phased innovation award mechanism. Applications for R21 support alone will not be accepted under this FOA and will not be reviewed. Applications should propose milestone-driven exploratory/feasibility studies for the initial 2-year R21 phase and describe how the concept will be further developed in proof-of-concept studies during the R33 phase. Clearly defined, quantifiable milestones should be listed in the application, along with a timeline or Gantt chart to delineate the projects and milestones that make up the R21 and R33 phases.

Prior to the end of the second year, awardees will submit the R33 transition package, which includes the R21 progress report that describes progress towards the initial milestones and a clear description of how research during the R33 phase will be impacted by attainment of the R21 milestones. Transition to the R33 is not automatic, and not all R21s are expected to result in an R33 award. These materials will be reviewed by NHLBI Program staff and then, if selected, will be transitioned to an R33 award without the need to submit a new grant application. For R21s awarded in September 2013 council, this transition package will be accepted no later than June 30, 2015; for R21s awarded in the June 2014 council, the transition package will be accepted no later than April 30, 2016 . R33 funding decisions will be based on the original R21/R33 peer review recommendations, successful completion of milestones, program priorities, and availability of funds. If an R33 award is not approved, the grantee may invoke their right to a 12 month no cost extension to the R21 award.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications. The National Heart, Lung, and Blood Institute intends to commit $2,500,000 in FY 2013 and FY 2014 to fund up to 10 R21s in each year.
Award Budget	Direct costs will vary with the scope of the project. Support for the R21 phase will be for two years. Direct costs are limited to $275,000 over an R21 two-year period, with no more than $150,000 in direct costs in any single year of the R21 phase. The R33 phase may not exceed three years and direct costs are limited to $1,000,000 with no more than $375,000 in direct cost in any single year of the R33 phase. Transition to the R33 phase is not automatic and, NHLBI anticipates that a maximum of sixty percent (60%) of the funded R21 phase awards will progress to the R33 award.
Award Project Period	The total project period for an application submitted in response to this FOA cannot exceed five years. Awards will support milestone-driven exploratory/feasibility proof-of-concept studies (two-year R21 phase), with possible rapid transition to expanded development (three-year R33 phase). Conversion to the R33 phase is not automatic and is contingent upon satisfactory progress towards meeting and achieving the R21 milestones, programmatic review, and the availability of funds.

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

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 must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• System for Award Management (SAM) must maintain an active entity registration (formerly CCR registration), to be renewed at least annually. Use the SAM.gov Manage Entity function to manage your entity registrations. See the Grants Registration User Guide at SAM.gov for additional information.
• Grants.gov
• eRA Commons

All Program Directors/Principal Investigators (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 6 weeks prior to the application due date.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director/Principal Investigator (PD/PI) 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 SF 424 (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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for 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 research
• Name, address, and telephone number of the PD(s)/PI(s)
• Names of other key personnel
• Participating institutions
• 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, MSC 7924
Bethesda, MD 20892-7924 (express/courier service 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

The forms package associated with this FOA includes all applicable components, mandatory 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.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

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

Specific Aims

The Specific Aims for the R21 and R33 Phases should both be contained in the Specific Aims section, but should be clearly demarcated.

Research Strategy

The Research Strategy will contain both the R21 and R33 research plans, as well as the Milestones. Within the Research Strategy, applicants should include a brief justification statement addressing the relevance of the aims to screen genetic variants associated with given phenotypes for functionality using inexpensive and relevant model systems. The Research Strategy section should have a clear demarcation of the R21 and R33 portions of the application. There should be separate research design and methods for the R21 and R33 phases.

The first section of the Research Strategy will be the R21 Phase. This section will include the background, evidence of feasibility of the proposed approach, and the research plan and methods for the R21 Phase. This section must also include milestones, specific estimates of expected progress during the R21 phase that includes a timeline, a discussion of the suitability of the milestones for assessing success in the R21 Phase, and a discussion of the implications of successful completion of these milestones for the proposed R33 Phase. Milestones should be specific, quantifiable, and scientifically justified; they should not be simply a restatement of the R21 specific aims.

The second section of the Research Strategy will be the R33 Phase. It is not necessary to repeat background information or details of methods in the R33 section that were provided in the R21 section. The R33 Phase must be described in sufficient detail to permit reviewers to assess the significance and innovation of the proposed work and the strength of the experimental design.

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 modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Resource Sharing Plan.

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.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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 SF 424 (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 SF 424(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.

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 Central Contractor Registration (CCR). 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.

The R21 component of an R21/R33 application will be considered exploratory, so that extensive preliminary data from the applicant s own laboratory are not required. However, the project must be based on a strong rationale, and the applicant should provide evidence that the proposed approach and methods are feasible. The R21 Phase provides time for necessary preliminary work, for example, the substantial modification of approaches, methods, or technology. Although preliminary data are not required for an R21/R33 application, they may be included.

The Milestone section must include milestones, specific estimates of expected progress during the R21 phase that includes a timeline, a discussion of the suitability of the milestones for assessing success in the R21 Phase, and a discussion of the implications of successful completion of these milestones for the proposed R33 Phase. Milestones should be specific, quantifiable, and scientifically justified; they should not be simply a restatement of the R21 specific aims. Stating well-defined, measurable milestones is critical to the application. These will vary depending on the nature of the proposed research, and should be tailored to the applicant s specific research goals. The clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones are critical. These milestones will be evaluated in the peer review process and any negotiated actions must be mutually agreed upon by the applicant (Authorized Organizational Representative (AOR), the PD/PI, the NHLBI program and grants officer prior to the award of the R21 phase. Funded applicants are solely responsible for planning, directing, and executing the proposed project. The finalized Milestones will be incorporated into the terms and conditions of the award and will be considered in judging the success of the R21 award.

• The R21/R33 Phased Innovation Award application must be submitted as a single application with one PHS398 Cover Page Supplement component and one Research & Related Budget component.
• The Specific Aims page should list the aims of both R21 and R33 Phases.
• In preparing the R21/R33 application, investigators should consider that the application will be assigned a single overall impact score. Thus, clarity and completeness of the application with regard to specific goals and the feasibility of each phase and the Milestones are critical. Milestones that are not sufficiently rigorous scientifically to be valid for assessing progress in the R21 phase will reflect poorly on the scientific merit of the application as a whole.
• Any preliminary data that will support or justify the proposed hypothesis, rationale or development plan may be included. However, preliminary data are not required for an R21/R33 application.

For funded applications, the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) will submit an AOR-approved R33 transition package to the NHLBI Grants and Program Officer. For R21s awarded in September 2013 council, this R33 transition package will be due no later than June 30, 2015, and for R21s awarded in the June 2014 council it will be due no later than March 31, 2016. The R33 transition package should describe progress towards the initial milestones and a clear description of how research during the R33 phase will be impacted by attainment of the R21 milestones. This report should clearly indicate which milestones were or were not completed successfully. In the latter case, an explanation should be provided as to why the milestone was not met. Receipt of this progress report will trigger an administrative program review that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on original R21/R33 peer review recommendations, successful completion of mutually agreed upon negotiated scientific milestones, on program priorities, and on the availability of funds. The applicant is reminded that the budget for the R33 phase is subject to the Budgeting for Genomic Arrays for NIH Grants, Cooperative Agreements and Contracts Policy NOT-OD-10-097 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-10-097.html. For funded applications, peer review is not anticipated between the two phases of the project, but NHLBI reserves the right to conduct a program review with outside opinions.

Funded investigators will be expected to participate in periodic program teleconferences and webinars during the R21 and R33 Phases of the award. In addition, applicants should budget for an annual in-person meeting near Bethesda Maryland during the R33 Phase.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

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:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

Reviewers will provide an overall impact/priority 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? Would successful completion of the aims result in new or improved functional screening assays for genomic variants? Would assays developed in the proposed research be useful to other researchers in the field? How great is the potential significance to the field of better understanding the functional role of these genetic variants in the named disease(s)?

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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

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? Are the choice of genetic variants, model systems, and assays well justified? Is the rationale for the R21 component strong? Are the proposed approaches and methods feasible?

Milestones: Are the proposed milestones appropriate, quantifiable, and achievable within the allotted timeframe? Are the milestones and specific aims of the R21 adequate to evaluate the feasibility of proceeding to the R33 phase of the application?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion 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/priority 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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

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/priority score.

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).

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 the NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments 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/priority 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. 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 appropriate national Advisory Council or Board. 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.

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, CCR 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

Not Applicable.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually 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.

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Jennie Larkin, Ph.D.
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Rockledge 2, Room 8200
Bethesda, MD 20892-7940
Telephone: 301- 435-0513
FAX: 301-480-1454
Email: LarkinJ2@nhlbi.nih.gov

Pankaj Qasba, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Dr, MSC 7950
Bethesda, MD 20892-7950
Telephone: 301-435-0050
FAX: 301-480-0867
Email: qasbap@nhlbi.nih.gov

Weiniu Gan, Ph.D.
Division of Lung Diseases
National Heart, Lung and Blood Institute
6701 Rockledge Drive
Bethesda, Maryland 20892-7952
Telephone: 301-435-0215
Email: ganw2@nhlbi.nih.gov

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214, MSC 7924
Bethesda, MD 20892-7924
Bethesda, MD 20817 (express/courier service 20817)
Telephone: 301-425-0270
Fax: 301-480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

Amy Connolly
Office of Grants Management
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7152, MSC 7926
Bethesda, MD 20892-7926
Telephone: 301-435-0169
Email:connolla@mail.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.

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.