Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Human Genome Research Institute (NHGRI), (http://www.nhgri.nih.gov)

Title: Revolutionary Genome Sequencing Technologies The $1000 Genome (R01)

Announcement Type
This Funding Opportunity Announcement (FOA) is a reissue of RFA-HG-08-008

Request for Applications (RFA) Number: RFA-HG-09-011

Update: The following update relating to this announcement has been issued:

• August 27, 2010 - This RFA has been reissued as (RFA-HG-10-012).

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four (4) weeks prior to the grant submission date. See Section IV.

Catalog of Federal Domestic Assistance Number(s)
93.172

Key Dates
Release/Posted Date: July 17, 2009
Opening Date: September 19, 2009 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): September 21, 2009
NOTE: On-time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization). Application Due Date(s): October 19, 2009
AIDS Application Due Date(s): Optional. Not applicable
Peer Review Date(s): January-February 2010
Council Review Date(s): May 2010
Earliest Anticipated Start Date(s): July 1, 2010
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: October 20, 2009

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose. The National Human Genome Research Institute (NHGRI) solicits R01 grant applications to develop novel technologies that will enable extremely low-cost, high quality DNA sequencing. The goal of this initiative is to reduce the cost of sequencing a mammalian-sized genome to approximately $1000. Applicants may propose to develop full-scale sequencing systems or to investigate challenges underlying key system components. Exploration of methods other than those currently being pursued as potential $1,000 genome technologies are encouraged. High-risk/high-payoff proposals are appropriate to achieve the goals of this FOA by approximately 2014.
• Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) grant mechanism and runs in parallel with FOAs of identical scientific scope, RFA-HG-09-012 and RFA-HG-09-013 that solicit applications under the R21 and R43/R44 mechanisms.
• Funds Available and Anticipated Number of Awards. Contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications, the NHGRI may make 2-7 awards and may award $5 million total costs in FY2010 in response to this FOA.
• Budget and Project Period. An applicant may request a project period of up to 4 years and a budget for direct costs up to $1.5 million per year.
• Application Research Plan Component Length: The R01 application Research Plan component of the PHS398 may not exceed 25 pages, including tables, graphs, figures, diagrams, and charts.
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/ 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.
• Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs) may be designated on the application.
• Number of Applications. Applicants may submit more than one application, provided each application is scientifically distinct.
• Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016).
• Renewals. Renewal applications will be permitted for this FOA.
• Special Date(s). This FOA uses non-standard due dates. See Receipt, Review and Anticipated Start Dates.
• Application Materials. See Section IV.1 for application materials.
• General Information. For general information on SF424 (R&R) Application and Electronic Submission, see these Web sites:
  • SF424 (R&R) Application and Electronic Submission Information: http://grants.nih.gov/grants/funding/424/index.htm
  • General information on Electronic Submission of Grant Applications: http://era.nih.gov/ElectronicReceipt/
• Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: (301) 451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt, Review, and Anticipated Start Dates
1. Letter of Intent
B. Submitting an Application Electronically to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contacts
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

The National Human Genome Research Institute (NHGRI) solicits R01 grant applications to develop novel technologies that will enable extremely low-cost DNA sequencing. This FOA continues a program that began in 2004, when the cost to produce a high quality draft mammalian genome sequence was estimated at $5 to $10 million, and the goal of was to reduce costs by four orders of magnitude to approximately $1,000 in ten years.

While substantial progress toward the $1,000 genome has been made, daunting scientific and technical challenges remain. This program will continue to support both fundamental scientific investigation underlying the technologies, and their engineering, to achieve this goal. The program supports development of key system components and of full systems. In this context, key components refers to the method for determining the linear order of nucleotides, in contrast to upstream or downstream steps in sequencing. Exploration of methods other than those currently being pursued as potential $1,000 genome technologies are encouraged. High-risk/high-payoff proposals are appropriate to achieve the goals of this FOA by approximately 2014.

Parallel FOAs of identical scientific scope (RFA-HG-09-012 and RFA-HG-09-013) solicit applications under the R21 and Small Business Innovation Research (SBIR) grant programs.

Background

The ability to sequence complete genomes and the free dissemination of sequence data have dramatically changed the nature of biological and biomedical research. Sequence and other genomic data have the potential to lead to remarkable improvement in many facets of human life and society, including the understanding, diagnosis, treatment and prevention of disease; advances in agriculture, environmental science and remediation; and our understanding of evolution and ecological systems.

The ability to sequence many genomes completely has been made possible by the enormous reduction of the cost of sequencing in the past 30 years, from tens of dollars per base in the 1980s to a fraction of a cent per base today. We have progressed from the early Human Genome Project goals to sequence the genomes of the human and mouse and a few additional model organisms (E. coli, C. elegans and D. melanogaster), through programs to sequence at varying pre-determined quality levels numerous genomes across the evolutionary tree including multiple species and variants for some of those, to current programs to sequence portions or the entire genomes of increasing numbers of tumors and human individuals. Technology advances, and in particular the recent emergence of a new generation of sequencing systems, have enabled the launch of several such projects that are producing stunning insights into biology and disease. Nevertheless, the cost to completely sequence large numbers of entire genomes remains too high to allow complete genome sequencing to be used routinely, and we remain far from achieving the low costs needed to enable the use of comprehensive genomic sequence information in individual health care.

The many areas of high priority research to which genomic sequencing at dramatically reduced cost would make vital contributions include:

• Comparative genomic analyses across species to yield insights into the structure and function of the human genome and, consequently, the genetics of human health and disease;
• Studies of human genetic variation and its relationship to health and disease, in large numbers of individuals, that capture not only common single nucleotide variation but also rare, copy number, and structural variants that are increasingly thought to play an important role in complex disease;
• Characterization of somatic changes in the genome that contribute to cancer, revealing information from large numbers of matched tumor/normal samples on a genome-wide basis rather than restricting analysis to suspect genomic regions that are based on incomplete knowledge;
• Additional genome sequences of agriculturally important animals and plants that are needed to study individual variation, different domesticated breeds and wild variants of each species; and
• Sequence analysis of microbial communities, many members of which cannot be cultured. This will provide a rich source of medically and environmentally useful information. Accurate, rapid sequencing may also be the best approach to microbial monitoring of food and the environment, including rapid detection and mitigation of bioterrorism threats.

The broad utility and high importance of dramatically reducing DNA sequencing costs prompted the NHGRI, in 2004, to embark on two parallel technology development programs (Nature Biotech. 26:1113, 2008). The first had the objective of reducing the cost of producing a high quality sequence of a mammalian-sized genome by two orders of magnitude, to about $100,000. Substantial progress has been made toward this goal so no additional grant applications are being solicited at this time. Rather, the NHGRI is focusing its efforts on attaining the goal of the second program, which, as described in this FOA and parallel FOAs for other grant mechanisms, is the development of technology to sequence a genome for about $1,000 (a four order of magnitude cost reduction). Implicit in this goal is the quality of the expected sequence product, as sequencing cost targets are meaningless without associated quality standards as described below.

Sequencing Strategy and Quality

The sequencing technology that was used to produce the reference human genome sequence (Nature 431:931, 2004; Nature 409:860, 2001; Science 291:1304, 2001) was fluorescence detection of dideoxynucleotide-terminated DNA extension reactions resolved by capillary array electrophoresis (CAE). Individual sequence read segments can be as long as 1000 nucleotides. If all of the DNA in a 3 Gb genome were unique, it would be possible to determine the sequence of the entire genome by generating a sufficient number (tens of millions) of randomly-overlapping 1000-base reads and aligning their overlaps. However, the human and the majority of other interesting genomes contain a substantial amount of repetitive DNA. To cope with the complexities of repetitive DNA elements and to assemble the thousand-base reads in the correct long-range order across the genome, genomic sequencing methods involve a variety of additional strategies, such as the sequencing of both ends of cloned DNA fragments, use of libraries of cloned fragments of specified lengths, incorporation of map information, achievement of substantial redundancy (multiple reads of each nucleotide from overlapping fragments) and application of sophisticated assembly algorithms to filter and align the reads. As new sequencing technologies are developed, they must incorporate means to deal with these features of the structure of the genome.

The gold standard for genomic sequencing is based on the above-described methods and remains =99.99% accuracy (not more than one error per 10,000 nucleotides) with essentially no gaps (http://www.genome.gov/10000923). The finishing steps needed to achieve that very high quality have not been automated and thus require substantial hand-crafting. However, experience shows that much comparative and medically useful sequence information can be obtained from automatically generated sequence assemblies that are known as high-quality draft or comparative grade. Therefore, the cost targets for NHGRI’s sequencing technology development programs were originally defined in terms of a mammalian-sized genome with a sequence quality equivalent to or better than that of the mouse draft assembly published in December 2002 (Nature 420:520, 2002). Producing such a product for $1,000 is still not possible, so this remains a useful and challenging technology target. However, it is critical to note that the ultimate need, for medical research and individualized medicine, will be for higher quality sequence of the 3 Gb diploid human genome

Subsequent to dideoxy/CAE sequencing, a second generation of sequencing technologies has been developed and implemented. These are broadly described as array-based methods in which large numbers of templates are extended one base at a time, the extensions are detected, and that cycle is repeated (reviewed in Nature Biotechnology October 2008). These technologies enable the sequencing of larger numbers of genomes for $50,000 - $100,000 dollars each, or less for targeted sequencing of particular genomic regions. While challenges remain related to producing and interpreting sequence information using these technologies, they are proving invaluable to the biomedical research enterprise and they validate the impetus toward further substantial decreases in cost with increases in quality, throughput and speed of genomic sequencing.

The eventual goal of these programs is to obtain technologies that can produce assembled sequence of genomes that had not been previously sequenced (i.e., de novo sequencing). However, an accompanying goal is to obtain highly accurate sequence data at the single base level that can be overlain on a reference sequence of the organism (i.e., re-sequencing). This could be achieved, for example, with short reads that lack information linking them to other reads. In spite of shortcomings (some of which are described below), re-sequencing would potentially be available sooner and of considerable value for certain studies on disease etiology and individualized medicine. Therefore, technology development for re-sequencing will be supported under this FOA. As the cost goal for the more difficult challenge, de novo assembly sequencing, is $1,000, the goal for re-sequencing is to develop technologies that will provide a genome’s worth of less-well-mapped sequence for well below $1,000.

For re-sequencing, the per-base accuracy must be sufficient to distinguish between sequencing errors and real polymorphism. Additional challenges include assigning reads to gene families with very similar sequence, the identification of copy number changes and genomic rearrangements, and the identification of haplotypes (i.e., linear juxtapositioning of particular single nucleotide polymorphism [SNP] alleles along a single chromosome) in diploid organisms. Thus, in proposing the development of re-sequencing technologies, it is essential that the applicant clearly address the extent to which the proposed technology will meet or fall short of these various challenges, and the cost tradeoffs that justify developing the technology to produce data of high value for particular biomedical studies.

Research and Scope

The goal of research supported under this FOA is to develop new or improved technology to enable rapid, efficient DNA sequencing of mammalian-sized genomes. The target cost for a 3 Gb diploid genome sequence determined at reasonably high quality is about $1,000 because the ability to generate routinely complete genomic sequences at that cost would revolutionize biological research and medicine.

Both fundamental scientific discovery and cutting edge engineering will likely be needed to achieve these goals. For example, new sensing and detection modalities and fabrication methods may be required, and the physics of systems operating at nm length scales will need to be better understood. It is therefore anticipated that proposals responding to this FOA will involve fundamental and engineering research conducted by multidisciplinary teams of investigators. The guidance for budget requests accommodates the formation of groups having investigators at several institutions, in cases where that is needed to assemble a team of the appropriate balance, breadth and experience.

The scientific and technical challenges inherent in achieving the cost goals are significant. Achieving these goals may require research projects that entail substantial risk. That risk should be balanced by an outstanding scientific and management plan designed to achieve the very high payoff goals of this solicitation. High-risk/high-payoff projects may fail for legitimate reasons, so applicants proposing such projects should identify them as such, elaborate key quantitative milestones to be achieved, and describe the consequences of not achieving those milestones in a reasonable period of time.

Applicants may propose to develop full-scale sequencing systems or investigate key components of such systems. For the latter, applicants must describe how the knowledge gained as a result of the proposed project would be incorporated into a full system that they or others might subsequently propose to develop. Such independent proposals are an important path for pursuing novel, high-risk/high-payoff ideas, short of developing a full system.

While the major focus of this program is on the development of new technologies for detection of nucleotide sequence, any successful technology will have to address matters related to the practical implementation of the technologies so that the technology can form the basis of, or be incorporated into, an efficient, high quality, high-throughput DNA sequencing scheme. Any new technology will eventually need to be incorporated effectively into a sequencing workflow, starting with a biological sample and ending with sequence data of the desired quality. Sample preparation requirements can depend upon the detection method which, in turn, can affect the way in which output data are handled. If a full system development is proposed, these issues should be addressed on an appropriate schedule in the research plan; applicants should focus as early as possible in the research plan on the most critical and highest-risk aspects of the project related to determining the sequence of nucleotides, on which the rest of the project depends. Projects to address key components must address the fundamental method of determining the base sequence (that is, a proposal addressing only sample prep would not be considered responsive to this FOA).

Most technology developers lack practical experience in high-throughput sequencing and in testing of methods and instruments for robust, routine sequencing operation. Applicants may therefore wish to include such expertise as they develop their teams. Academic investigators may wish to consider collaborating with commercial entities that have the experience and capabilities to bring practical systems into the hands of users.

The quality of sequence to be generated by the technology is of paramount importance for this solicitation. Two major factors contributing to genomic sequence quality are per-base accuracy and contiguity of the assembly. Much of the utility of comparative sequence information will derive from characterization of sequence variation between species, and between individuals of a species. Therefore, per-base accuracy must be high enough to discern polymorphism at the single-nucleotide level (substitutions, insertions, deletions) and distinguish polymorphism from sequencing errors. Experience and resulting policy have established a target accuracy of not more than one error per 10,000 bases. All applications in response to this FOA, whether to develop re-sequencing or de novo sequencing technologies, must propose to achieve at least this standard.

Assembly information is needed for determining sequence of new genomes and ultimately also for genomes for which a reference sequence exists, to detect rearrangements, insertions, deletions, and copy number changes. All of these are genomic changes have been shown to be associated with disease, and knowledge of rearrangements can reveal new biological mechanisms. The phase of single nucleotide polymorphisms to define haplotypes is important in understanding and diagnosing disease. Achieving a high level of sequence contiguity may be essential to achieve the full benefit from the use of sequencing for individualized medicine, e.g., to evaluate genomic contributions to risk for specific diseases and syndromes, and drug responsiveness. Nevertheless, it is recognized that perfect sequence assembly from end to end of each chromosome is unlikely to be achievable with most technologies in a fully automated fashion and without adding considerable cost. Therefore, for the purpose of this solicitation, grant applications proposing technology development for de novo sequencing shall describe how they will achieve, for about $1,000, a draft-quality assembly that is at least comparable to that represented by the mouse draft sequence produced by December 2002: 7.7-fold coverage, 6.5-fold coverage in Q20 bases, assembled into 225,000 sequence contigs connected by at least two read-pair links into supercontigs [total of 7,418 supercontigs at least 2 kb long], with N50 length for contigs equal to 24.8 kb and for supercontigs equal to 16.9 Mb (Nature 420:520, 2002). Grant applications that propose technology development for re-sequencing should fully describe the qualities and characteristics of the genomic sequence information that the technology would produce, and the projected cost. That cost should be about four orders of magnitude lower than was the cost to produce comparable quality data in 2004, when this program was initiated.

Grant applications will be evaluated, and funding decisions made, in such a way as to develop a balanced portfolio that has strong potential to develop both robust de novo and re-sequencing technologies, exploring a variety of technology approaches. If the estimate is correct, that achieving the goal of $1,000 de novo genome sequencing incorporating substantial assembly information will be achieved by about 2014, then low-cost re-sequencing technologies for even lower cost might be expected in a shorter time. Projects with a plan to achieve re-sequencing while on the path to de novo sequencing will receive priority.

Research conducted under this FOA may include development of the computational tools associated with the technology, e.g., to extract sequence information, including image analysis and signal processing, and to evaluate sequence quality and assign confidence scores. It may also address strategies to assemble the sequence from the information being obtained from the technology or by merging the sequence data with information from parallel technology. However, this FOA will not support development of sequence assembly or sequence analysis software independent of technology development to obtain the linear nucleotide sequence.

This program is aimed at technology to sequence entire genomes. Projects are under way to determine sequence from selected important regions (e.g., all of the genes). Grant applications that propose to meet the cost targets by sequencing only selected regions of a genome will be considered unresponsive to this FOA. However, applications that propose novel ways to sequence selected genomic regions, cost-effectively, while on a path to whole-genome sequencing, will be considered to be responsive.

NHGRI is interested in supporting diverse approaches to achieving the goals of this FOA. To assist the research community, investigators who are pursuing one set of technology paths that involve the use of nanopores and nanogaps published an overview of the challenges they face (Nature Biotech. 26:1146, 2008). Proposals to meet these and related challenges, and proposals to pursue alternative technologies, are welcome under this FOA. Information on projects funded under earlier versions of this and related FOAs and a program bibliography are available at http://www.genome.gov/10000368#6.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism of Support

This FOA will use the NIH Research Project Grant (R01) award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts (see SF424 (R&R) Application Guide). It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, a U.S. organization submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) must use the PHS398 Modular Budget component.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.

2. Funds Available

NHGRI intends to commit approximately $5 million total costs in fiscal year 2010 to fund 2-7 applications. An applicant may request a project period of up to 4 years and a budget for direct costs up to $1.5 million per year.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004.

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.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education
• Private 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)
• Small Businesses
• For-Profit Organizations (Other than Small Businesses)
• State Governments
• Non-domestic (non-U.S.) Entities (Foreign Organizations)
• Eligible Agencies of the Federal Government

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the 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.

More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH electronic Research Administration (eRA) Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering the multiple PD/PI option, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit more than one application, provided each application is scientifically distinct.

Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). Beginning with applications intended for the January 25, 2009 official submission due date, all original new applications (i.e., never submitted) and competing renewal applications will be permitted only a single amendment (A1). See new NIH policy on resubmission (amended) applications (NOT-OD-09-003, NOT-OD-09-016). Original new and competing renewal applications that were submitted prior to January 25, 2009 will be permitted two amendments (A1 and A2). For these grandfathered applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.

Renewals. Renewal applications will be permitted for this FOA.

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, use the Apply for Grant Electronically button in this FOA or link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

• Grants.gov (http://www.grants.gov/applicants/get_registered.jsp) and
• eRA Commons (http://era.nih.gov/ElectronicReceipt/preparing.htm)

PDs/PIs should work with their institutions/organizations to make sure they are registered in the NIH eRA Commons.

Several additional separate actions are required before an applicant can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Registered

• Your organization will need to obtain a Data Universal Number System (DUNS) number and register with the Central Contractor Registration (CCR) as part of the Grants.gov registration process.
• If your organization does not have a Taxpayer Identification Number (TIN) or Employer Identification Number (EIN), allow for extra time. A valid TIN or EIN is necessary for CCR registration.
• The CCR also validates the EIN against Internal Revenue Service records, a step that will take an additional one to two business days.
• Direct questions regarding Grants.gov registration to:
  Grants.gov Customer Support
  Contact Center Phone: 800-518-4726
  Business Hours: M-F 7:00 a.m. - 9:00 p.m. Eastern Time
  Email [email protected]

2) Organizational/Institutional Registration in the eRA Commons

• To find out if an organization is already Commons-registered, see the "List of Grantee Organizations Registered in NIH eRA Commons.
• Direct questions regarding the Commons registration to:
  eRA Commons Help Desk
  Phone: 301-402-7469 or 866-504-9552 (Toll Free)
  TTY: 301-451-5939
  Business hours M-F 7:00 a.m. 8:00 p.m. Eastern Time
  Email [email protected]

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

• The individual(s) designated as PDs/PIs on the application must be registered also in the NIH eRA Commons. In the case of multiple PDs/PIs, all PDs/PIs must be registered and be assigned the PI role in the eRA Commons prior to the submission of the application.
• Each PD/PI must hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a PD/PI role and an NIH Internet Assisted Review (IAR) role, both roles should exist under one Commons account.
• When multiple PDs/PIs are proposed, all PDs/PIs at the applicant organization must be affiliated with that organization. PDs/PIs located at another institution need not be affiliated with the applicant organization, but must be affiliated with their own organization to be able to access the Commons.
• This registration/affiliation must be done by the AOR/SO or his/her designee who is already registered in the Commons.

Both the PDs/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo -- Telephone 301-710-0267; Email: [email protected].

Telecommunications for the hearing impaired: TTY: (301) 451-5936

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. Some fields within the SF424 (R&R) application components, although not marked as mandatory, are required by NIH (e.g., the Credential log-in field of the Research & Related Senior/Key Person Profile component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., Special Instructions, regarding appropriate required budget component.)

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Foreign Organizations (Non-Domestic [non-U.S.] Entities)

NIH policies concerning grants to Foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from Foreign organizations must:

• Request budgets in U.S. dollars;
• Prepare detailed budgets for all applications (that is, complete the Research & Related Budget component of the SF424 (R&R) application forms not the PHS398 Modular Budget component)(see NOT-OD-06-096);
• Not include any charge-back of customs and import fees;
• Comply with the format specifications, which are based upon a standard U.S. paper size of 8.5 x 11 within each PDF;
• If appropriate, request funds for up to 8% administrative costs (excluding equipment) ( see NOT-OD-01-028, March 29, 2001);
• Comply with Federal/NIH policies on human subjects, animals, and biohazards; and
• Comply with Federal/NIH biosafety and biosecurity regulations (see Section VI.2., Administrative and National Policy Requirements ).

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of PD/PI. Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the Credential field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan [Section 14 of the Research Plan Component in the SF424 (R&R)], must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates
Opening Date: September 19, 2009 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): September 21, 2009
Application Due Date(s): October 19, 2009
Peer Review Date(s): January-February 2010
Council Review Date(s): May 2010
Earliest Anticipated Start Date(s): July 1, 2010

3.A.1. Letter of Intent

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.

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.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Jeffery A. Schloss, Ph.D.
Division of Extramural Research
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
Email: [email protected]

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/applicants/apply_for_grants.jsp and follow Steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED.

In order to expedite the review, applicants are requested to notify the NHGRI Referral Office by email ([email protected]) when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday Friday, excluding Federal holidays) to view the application image to determine if any further action is necessary.

• If everything is acceptable, no further action is necessary. The application will automatically move forward to the Division of Receipt and Referral in the Center for Scientific Review for processing after two weekdays, excluding Federal holidays.
• Prior to the submission deadline, the AOR/SO can Reject the assembled application and submit a changed/corrected application within the two-day viewing window. This option should be used if it is determined that some part of the application was lost or did not transfer correctly during the submission process, the AOR/SO will have the option to Reject the application and submit a Changed/Corrected application. In these cases, please contact the eRA Help Desk to ensure that the issues are addressed and corrected. Once rejected, applicants should follow the instructions for correcting errors in Section 2.12, including the requirement for cover letters on late applications. The Reject feature should also be used if you determine that warnings are applicable to your application and need to be addressed now. Remember, warnings do not stop further application processing. If an application submission results in warnings (but no errors), it will automatically move forward after two weekdays if no action is taken. Some warnings may need to be addressed later in the process.
• If the two-day window falls after the submission deadline, the AOR/SO will have the option to Reject the application if, due to an eRA Commons or Grants.gov system issue, the application does not correctly reflect the submitted application package (e.g., some part of the application was lost or didn t transfer correctly during the submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.
• If the AOR/SO chooses to Reject the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be submitted, but it will be subject to the NIH late policy guidelines and may not be accepted. The reason for this delay should be explained in the cover letter attachment.
• Both the AOR/SO and PD/PI will receive e-mail notifications when the application is rejected or the application automatically moves forward in the process after two weekdays.

Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the IC. Incomplete and non-responsive applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR/SO receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on the application status in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review...

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see the NIH Grants Policy Statement).

6. Other Submission Requirements

Supplementary Instructions

A detailed research plan must be presented. The application should include a description of the level of risk of key technical challenges, alternative approaches, go/no-go decision points, etc. It should also include a detailed timeline accompanied by quantitative milestones (see below) that address the key scientific and technical challenges central to the approach. The timeline and milestones are essential for use by the grantee and the NHGRI for planning the research project and assessment of progress toward goals, and by the reviewers for evaluating the proposal.

Timelines and quantitative milestones are essential for development of a realistic research plan; they provide a basis for project leaders to make decisions, assess their own progress, set priorities, and redistribute resources when needed. It will be particularly important to establish quantitative milestones in cases where subsequent steps in technology development depend upon threshold performance characteristics of earlier developments. Elaboration of timelines and milestones is primarily the responsibility of the applicant, and the quality and utility of the proposed timelines and milestones will be a review criterion, because they reflect the insights and judgment of the applicant concerning key challenges and how best to conduct the research. The NHGRI appreciates that these projects will require research, not just engineering; progress toward milestones will be evaluated accordingly. If the proposed timeline and milestones are not adequate in the case of an otherwise meritorious proposal, reviewers of the application may make recommendations to NHGRI regarding improved timelines and milestones.

Projects that propose to build sequencing systems (in contrast to developing components) that will be assembled by the end of the project period may wish to present a strong case for that system’s capabilities by proposing to demonstrate the sequencing of a substantial amount of DNA (e.g., mega- to gigabases) at the target cost and quality; other measures may be proposed by the applicant.

To accelerate progress in the field of advanced DNA sequencing technology development, grantees will be required to participate actively and openly in at least one grantee meeting per year. Substantial information sharing will be required and is a condition of the award; failure to openly share information will be grounds for discontinuation of funding. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the technology. Applicants should describe their plans for participating in the grantee meetings and for managing the intellectual property concerns in the context of those meetings and other opportunities for information sharing. Other investigators in the field (i.e., not supported under this program) may be invited to participate in these workshops; their agreement to share information substantially will be a prerequisite to participation. Applicants should request travel funds in their budgets for the Principal Investigator and two additional lead investigators to attend the annual meetings.

Applicants must describe their plan for providing access to the technology developed under this grant support, and information about that technology. For example, the technology might be made available as a fee-for-service, through sale of instruments and/or reagents, through collaboration, through publication and posting of results, plans and methods, or by other means. If any quantity of sequence data will be collected under grant support, a plan to disseminate those data must be described.

Applicants may include funds for an internally appointed advisory board. However, they should not contact potential advisors, nor should potential advisors be named in the grant application, to avoid conflicts of interest in the review process.

In summary, applicants must incorporate into application section 5 (Research Design and Methods):

• A detailed timeline for the period of requested funding; and
• Quantitative milestones against which progress toward the timeline will be measured.

After the Research Design and Methods section, applicants must include a management plan (not to exceed 4 pages) incorporating:

• Plans to manage collaborations, including geographic separation, if any;
• Plans to manage key project decision points, e.g., use of milestones for determining resource re-allocation, project re-direction, etc.;
• A plan for sharing data at grantee meetings, consistent with the goals described above;
• Plans for data and technology dissemination (see below, Plan for Sharing Research Data);
• Institutional commitment, if any (see Section III.2., Cost Sharing or Matching); and
• Plans for an internal advisory board, if desired.

Page limits for the management plan (4 pages) are in addition to the page limits for the research plan (25 pages).

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD(s)/PI(s) to fill in his/her Commons User ID in the PROFILE Project Director/Principal Investigator section, Credential log-in field of the Research & Related Senior/Key Person Profile component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

PHS398 Research Plan Component Sections

Page limitations of the PHS398 Research Plan component must be followed as outlined in the SF424 (R&R) Application Guide. While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts.

Appendix Materials

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not comply with the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.)

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact (see Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.)

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources or state appropriate reasons why such sharing is restricted or not possible (see Sharing Model Organisms Policy, and NOT-OD-04-042.)

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (go to NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.)

Foreign Applications (Non-Domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to this FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHGRI and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

• 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;
• Receive a written critique; and
• Receive a second level of review by National Advisory Council for Human Genome Research.

Applications submitted in response to this FOA will compete for available funds with all other recommended applications submitted in response to this FOA. The following will be considered in making funding decisions:

• Scientific merit of the proposed project as determined by peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact. 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 five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical 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 study directly address the problems outlined in this FOA?
• Are the plans sufficiently bold to constitute a substantial advance, if they can be achieved, toward the demanding goals of the FOA?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, 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?

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?
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?

• Are key scientific and technological issues on which the rest of the approach depends, identified and addressed early in the project?
• Does the proposed technology address sequence quality and the sequencing of entire genomes?
• Does the application clearly state whether the goal is to develop re-sequencing, or de novo sequencing technology, and if the latter, is there an adequate plan for evaluating the achieved long-range contiguity?
• Is the analysis of sequencing costs well developed and well-informed, relative to the state of the technology?
• Are bold plans counterbalanced to manage the inherent risk, for example by firm theoretical basis, reasonable preliminary data (depending on the mechanism), the track record of the lead investigators, and an outstanding scientific and management plan?
• Are the timeline and milestones logical and realistic?
• Are key technical barriers and dependencies identified?
• Are milestones adequately developed and quantitative, to serve as effective guidance for assessment of progress by the investigators and the NHGRI?
• Are plans to participate actively and openly in grantee meetings sufficiently clear and forthcoming so as to contribute substantially to advancement of the field?

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?

Additional Review Criteria. As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, 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.

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.

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.

Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), 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.

Renewal Applications. When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Revision Applications. When reviewing a Revision application (formerly called a competing supplement application), the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

Additional Review Considerations. As applicable for the project proposed, reviewers will address 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.

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

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).

Applications from Foreign Organizations. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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 (http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information

1. Award Notices

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 NIH eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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. See Section IV.5., Funding Restrictions.

2. Administrative and National Policy Requirements

Prior to funding an application, the NHGRI will negotiate the milestones with the applicant, beginning with the applicant ’s stated milestones and incorporating recommendations from the review panel, the National Advisory Council for Human Genome Research, and staff. The negotiated milestones will become a condition of the award, including appropriate language to recognize that the project includes research whose outcomes are unpredictable. In the case of research programs projected to require longer than the initial grant period, the decision to fund beyond the initial period will be based on a competitive renewal process that will take into account overall progress in the field as well as progress on the individual research effort, as compared to the negotiated milestones.

To accelerate progress in the field of advanced DNA sequencing technology development, grantees will be expected to participate actively and openly in at least one grantee meeting per year. Substantial information sharing will be required and is a condition of the award; failure to openly share information will be grounds for discontinuation of funding. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the technology. Applicants should describe their plans for participating in the grantee meetings and for managing the intellectual property concerns in the context of those meetings and other opportunities for information sharing. Other investigators in the field (i.e., not supported under this program) may be invited to participate in these workshops; their agreement to share information substantially will be a prerequisite to their participation. The applicant s participation plan, after negotiation with NHGRI staff, will become the minimum standard for continued funding.

Grantees may be asked to host the annual grantee meetings on a rotating basis. The NHGRI will negotiate a schedule for the grantee meetings and will adjust budgets to accommodate these meetings. Holding these meetings at grantee sites or in association with other meetings will facilitate information sharing and participation of a larger portion of the research staff than would otherwise occur.

The applicant’s plans, as negotiated with staff, for complying with timelines and milestones, participation in grantee meetings, submitting progress reports, and sharing research data will be conditions of the award.

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.

3. Reporting

Applicants must plan to submit two progress reports per year one at the time of the non-competing continuation and one at a time to be determined by NHGRI staff. The latter may coincide with grantee meetings, meetings of advisors to NHGRI, or site visits. The NHGRI will use information from reports, meetings, site visits, etc. to evaluate each grantee progress and the success of the overall program; this information will be used to determine if funding levels should be increased or decreased for future years, for each grant, and for the program.

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 Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research (program), peer review, and financial or grants management issues:

1. Scientific/Research Contact(s):

Jeffery A. Schloss, Ph.D.
Division of Extramural Research
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
Email: [email protected]

2. Peer Review Contact(s):

Ken Nakamura, Ph.D.
Scientific Review Branch
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9306 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service, non-USPS service)
Telephone: (301) 402-0838
E-mail: [email protected]

3. Financial/Grants Management Contact(s):

Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9306
Phone: (301) 435-7858
Fax: (301) 402-1951
E-mail: [email protected]

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants ( NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing). Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (IRB) rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are: (1) first produced in a project that is supported in whole or in part with Federal funds; and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for Federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicine’s PubMed Central (see http://www.pubmedcentral.nih.gov/), an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html). For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. 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. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.