Expired RFA-RM-08-001: Construction of a Reference Sequence Data Set for the Human Microbiome Project (U54)

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (www.nih.gov)

Components of Participating Organizations
This RFA is developed as a Roadmap initiative. All NIH Institutes and Centers participate in Roadmap initiatives. This RFA will be administered by the National Human Genome Research Institute ( www.genome.gov) and the National Institute of Allergy and Infectious Diseases (www.niaid.nih.gov) on behalf of the NIH.

Title: Limited Competition: Construction of a Reference Sequence Data Set for the Human Microbiome Project (U54)

Announcement Type
New

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

May 23, 2008 - See Notice (NOT-RM-08-019) which supercedes NOT-RM-08-018, Change in Application Receipt Date.
May 15, 2008 - See Notice (NOT-RM-08-018) Change in Application Receipt Date.

Request For Applications (RFA) Number: RFA-RM-08-001

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release Date: November 21, 2007
Letters of Intent Receipt Date: April 22, 2008
Application Receipt Date: May 22, 2008 - (Changed to June 19, 2008 per NOT-RM-08-019)
(New Date June 3, 2008 per NOT-RM-08-018)
Peer Review Date(s): October/November, 2008
Council Review Date: January 2009
Earliest Anticipated Start Date: April 1, 2009
Expiration Date: May 23, 2008 - (New Expiration Date June 20, 2008 per NOT-RM-08-019)
(New Expiration Date June 4, 2008 per NOT-RM-08-018)
Applicant information meeting: December 10, 2007 (see http://www.scgcorp.com/Microbiome)

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

This RFA invites applications for a limited competition Request for Applications (RFA) for the continued support of sequencing efforts to complete the generation of a reference set of DNA sequence-based data for the Human Microbiome Project (HMP).
The overall objective of this limited competition RFA is to support continued generation of sequenced microbial genomes isolated from the human body and exploration, through metagenomic sequencing, of the microbial flora at a set of designated anatomical sites of the human body.
This limited competition RFA will use the U54 cooperative agreement mechanism to continue the effort of supporting human microbiome sequencing that was begun in FY07 through funds provided to NHGRI- and NIAID-funded large-scale sequencing centers.
The total funds available for up to five awards are approximately $30,542,500 total costs for four years.
Up to 5 awards are anticipated from this FOA.
Public/State Controlled Institution of Higher Education; Private Institution of Higher Education; Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education); Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education); Small Business; For-Profit Organization (Other than Small Business); Eligible Agencies of the Federal Government.
Only NHGRI and NIAID awardees of large-scale sequencing centers (both extramural and intramural; e.g. those Institutions currently funded under RFA-06-001) are invited to apply.
Eligible principal investigators include the current principal investigator and/or any other designated/approved individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research.
See Section IV.1 for application materials.
Telecommunications for the hearing impaired is available at: TTY 301-451-5936.
Special Receipt Date May 22, 2008

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(s) 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. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application 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. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
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 purpose of this limited competition RFA is to solicit applications for projects for continued large-scale, state-of-the-art production of genomic sequence to generate sequenced, assembled and annotated microbial genomes isolated from the human body and to explore, through metagenomic sequencing of the microbial flora at a set of designated body sites, the complexity of the human microbiome.

BACKGROUND: The complex and dynamic communities of microbes (the human microbiota) that are present on and within the human body are thought to be able to profoundly influence human physiology, nutrition, immunity and development. Furthermore, disruption of community dynamics may play a role in triggering, or be affected by, disease or it may promote or interfere with normal development. However, the full range and magnitude of any such effects are not known. Understanding the human microbiota is an untapped area of knowledge that may be vital for the prevention and treatment of human diseases. Genomic approaches to the study of the collective DNA (the human microbiome) of community members have been spurred by recent advances in DNA sequencing and other technologies, and have created the new field of metagenomics (determining the DNA sequence of genomes from a mixed community of organisms), allowing genomic and other -omic analysis of the human microbiome to begin.

The NIH Roadmap program is a trans-NIH effort to accelerate the discovery and translation of scientific knowledge into public health benefits. The Roadmap is designed to provide a five to ten-year incubator space for new NIH initiatives that promise to be transforming of biomedical research, address the missions of a number of the NIH Institutes, and provide a public health benefit by having the data available in the public domain. The NIH Roadmap began in 2004 with an initial set of efforts (http://nihroadmap.nih.gov/). This year, a second round of Roadmap projects was chosen following a public nomination and NIH review process. The Human Microbiome Project (HMP) was chosen as one of these, to start in 2007/2008. The goal of the HMP is to extensively characterize the human microbiome and create a technological and data research resource that will enable in-depth study of its variation (with e.g., population, genotype, disease, age, nutrition, medication and environment) and its influence on health and disease. It is anticipated that exploration of this new and different approach to human health will provide insights that will enable the development of new approaches to monitoring health status, improved understanding of the etiology of disease, and development of new therapeutic and preventive strategies through the maintainance or re-establishment of a healthy microbiota.

The HMP is being implemented in a phased manner (see HMP website at http://nihroadmap.nih.gov/hmp/). Briefly, the HMP has been designed as a five-year effort with several components: (1) generation of a reference set of genome sequences from isolated members of the microbial communities at different anatomical sites on the human body; (2) initial metagenomic studies that will generate an initial estimate of the complexity of the microbial community at each site, providing initial answers to the questions of whether there is a core microbiome at each site and whether variation in the microbiome can be systematically studied; (3) demonstration projects to determine whether variation in the microbiome at a site can be related to human phenotypes, notably disease; (4) development of new technologies, informatics capabilities and resources that are needed for the development of the field of metagenomics; and (5) analysis of potential ethical, legal, and social issues (ELSI) that will need to be considered in the study and application of the metagenomic analysis of the human microbiota. The purpose of this announcement is to solicit applications to support the first two of these components.

RESEARCH OBJECTIVES: Applications are being sought from the NHGRI- and NIAID-supported large-scale sequencing centers to (a) continue their work on the sequencing, assemblying and annotation of the genomes of isolated microorganisms that will constitute an HMP reference set, including the genomes of culturable (and potentially uncultivatable) bacteria, archaea, fungi, parasites and viruses from all of the selected anatomical sites (the oral cavity, GI tract, skin and urogenital tract) and (b) to perform metagenomic sequencing to preliminarily characterize the human microbiome at each site. Initial sequencing efforts supported by NIH Roadmap to start the project are underway in the NHGRI- and NIAID-supported sequencing centers, which are currently producing the genomic sequences of 200 cultured microbes isolated from sites on the human body. At the same time, the HMP Roadmap project is recruiting donors and collecting samples that will be used for this initiative, according to recommendations made at a recent workshop on Sample Collection for the Human Microbiome Project (see summary at http://nihroadmap.nih.gov/hmp/meetings.asp). Applications for this solicitation should propose to use these samples or the set of HMP donors already consented for this purpose if more sampling is needed for the initial 16S survey sequencing and metagenomic analyses. The successful awardees will be expected to work together in order for the output of their combined efforts to generate metagenomic analyses of samples from all the body regions recommended by the Workshop on Sample Collections for the Human Microbiome Project and the subsequent expert protol working groups (protocol recommendations will be posted at http://nihroadmap.nih.gov/hmp/).

This solicitation calls for applications to continue this initial work by:

Completion of high quality draft sequencing, assembly and automated annotation of 400 additional microbial genomes (including those of uncultured organisms if the technology becomes available for doing so), including finishing of 15% of those genomes;
Metagenomic sequence analysis of the composition of the microbiota at the body sites that have been chosen for this analysis (see workshop report for July 25^th Workshop on Sample Collection for the Human Microbiome Project recommendations for this part of the initiative);
Genomic sequencing of viruses and eukaryotic microbes isolated from the same anatomical sites;
Additional characterization of the microbiome samples using sequencing-based methods (e.g., expression analysis).

Completion of 400 additional microbial genomes: Funding agencies and sequencing groups in the U.S. and Europe have discussed coordinating their efforts to produce an initial set of the genome sequences of prokaryotic microbes isolated from the human body. The completed data are being deposited in the public sequence archives as a reference data set that will be needed for future studies of changes of the human microbiome. It is estimated that at least 1000 completed genomes are needed for the data resource. To date, funding has been committed to sequence approximately 600 human microbial genomes, some of which have already been completed. A list of microbial genomes that have been sequenced or are planned for sequencing under current funding can be found at (http://nihroadmap.nih.gov/hmp/initiatives.asp). Applicants for RFA RM-08-001 should provide a strategy for completing high quality draft assemblies of the 400 additional bacterial genomes (with 15% finished) as well as additional viral genomes needed to complete the reference set, including how they will choose the organisms to sequence, where they will procure those organisms and which genome assemblies will be finished. In developing such a strategy, applicants should note that it is of interest to include the genomic sequences of uncultivable organisms, if possible. The technology development component of the HMP will include a call for technologies for the isolation and characterization of uncultivable organisms, but such methods are not now available for widespread use.

Cultures of all organisms for which sequence is generated under RFA RM-08-001 must be deposited in the HMP archive (see http://www.beiresources.org/) with no restrictions for further distribution of the culture to the scientific community. Organisms must be deposited in the HMP repository as soon as any sequence information is deposited in the public database. The sequencing of the reference bacterial genomes and deposition of the data and organisms in repositories is to be accomplished by the end of 2010. It is expected that approximately 200 bacterial genomes will be complete per year during 2009 and 2010. The applicant should propose a timetable for completion of viral and eukaryotic microbial genomes.

Genomic sequencing of viruses and eukaryotic microbes: The human microbiome includes not only bacteria and archaea, but also viruses and eukaryotic organisms. The viral and eukaryotic microbial content of the human microbiome is even less well-characterized than the prokaryotic content. In recognition of the difficulty in obtaining isolated organisms, funding for this part of the initiative is provided in FY2011 and 2012. Applicants should propose a strategy through which viral and eukaryotic organisms can be obtained and sequenced beginning in FY2011. Work developing and implementing a pipeline for sequencing these organisms can be proposed in FY 2009 and 2010.

Metagenomic sequencing: There is a great deal of information about the human microbiome that would be very useful, even necessary, for designing a metagenomic research program, but which is not yet available. The complexity of the microbial communities at specific anatomic sites on the human body is not known. It is not clear whether there is a core microbiome that is consistent from individual to individual or at different ages in the same individual. Nor is it known whether variation in the microbiome at each site can be systematically analyzed. Another goal of RFA RM-08-001 is to obtain preliminary information pertinent to these questions. Applicants should propose an approach to the metagenomic sequencing of microbes from a set of anatomical sites on the human body that will address these questions. The metagenomic sequencing under these awards will utilize the samples that are being collected during the initial phase of this project; if additional samples are required, they should be obtained from the set of HMP donors already consented as part of this project. It is anticipated that such samples will start to become available by late 2008; a description of the samples that are expected to be collected and how they will be obtained will be posted at http://nihroadmap.nih.gov/hmp/. Metagenomic sequencing strategies are evolving as the new sequencing technologies are implemented (see section below on utilization of new sequencing technologies). Successful applicants will be those who present creative and effective approaches to metagenomic sequencing in order to produce the most useful data set at the most competitive cost. This part of the initiative is to be undertaken in FY 2009 and 2010.

Additional characterization of the human microbiome samples: Another open question is whether the HMP data set could be enriched by data from other approaches to characterization of the HMP samples, such as gene expression studies. While the accomplishment of the goals set out above will be the priority for this initiative, NIH anticipates that as the new sequencing technologies are implemented in the HMP the costs of completing the reference resource and initial metagenomic sequencing will fall, so that additional characterization of the HMP samples can be undertaken. Applicants may, therefore, propose other sequence based methods of characterizing the samples; proposals that use creative approaches in utilizing the new sequencing technologies for purposes in addition to genomic and metagenomic sequencing will be of interest to NIH.

Utilization of new sequencing technologies: It is expected that the most competitive proposals will involve both conventional and new sequencing technologies. All sequencing strategies must be well described and the applicant must provide a description of the center’s track record in using the technology or technologies proposed and the current status of implementation (including likely issues with the new technologies). A discussion of software that will be used or is being developed to manipulate and analyze the data must also be provided. A set of milestones and a timetable for implementation of technology or software that is not yet in production must be provided. The amount of sequence to be produced and cost goals must be given for all technologies that will be used.

As indicated above, the majority of the funding for this initiative is provided in FY2009 and FY2010 in order to achieve sequencing of 400 prokaryotic genomes and the metagenomic sequencing of samples from selected sites in order to provide the data resource needed to enable the research being conducted by other initiatives in the HMP. Reduced funding levels are available in the last two years of the initiative, at which time the sequencing of eukaryotic microbes and viruses is expected to be completed. Some limited technology development may be undertaken within these awards to address the problem of isolating uncultivable organisms; any such proposed efforts must be well-described and justified.

The primary characteristic of the NHGRI- and NIAID-supported sequencing centers being invited to compete in RFA RM-08-001 is their long track record of maintaining and improving state-of-the art sequence production facilities that emphasize the generation of high quality microbial sequence at a low cost. The most competitive applications for this solicitation will be those that are able to demonstrate a past record of high quality, low-cost production and innovative approaches that promise to continue to provide state-of-the-art capabilities to this project, and that are actively implementing new technologies and strategies that can be utilized in the HMP. A production and cost history must be provided; it is suggested that applicants utilize the format that can be found at http://nihroadmap.nih.gov/hmp/referencedataset/ to present this information. The research objectives given above are considered a minimum for success in this project, and the most competitive applications will be those that can demonstrate the likelihood that they will far exceed those objectives with the funds available over the four years of the award.

The features of a state-of-the-art large-scale sequencing center are:

An automated production pipeline for Sanger-based sequencing technology with a minimum throughput of 20 million attempted reads per year and a success rate of at least 80% successful reads, defined as having a minimum of 100 high quality bases (bases with quality scores of 20 using the phred base-calling program or an equivalent system);
An overall average read length for successful Sanger-based reads of at least 550 high quality bases;
A high read pairing rate, if a strategy using paired end reads is employed. For new technologies, significant progress toward or planned implementation of paired end sequencing protocols;
A cost per attempted Sanger production read of $1.50 or less. (Production read costs considered here are inclusive of amortized equipment, technology development, informatics, and indirect costs, as detailed below);
A demonstrated capacity to finish at least 15Mb of sequence per month;
Significant progress toward a planned or implemented production pipeline utilizing one or more of the new, single-molecule technologies;
The ability to use multiple genome sequencing strategies, including clone-based and whole genome shotgun approaches, or even more effective strategies; and the demonstrated ability to adapt and modify approaches as the technology and demands on the center change;
The demonstrated ability to produce both high quality draft microbial genome assemblies and finished microbial genome sequences;
Expertise in efficiently cloning and finishing microbial genomes with a total cost per finished base of $0.05 or less above the cost of draft sequence;
Integrated bioinformatics capabilities to support production, including systems and database administration, laboratory information management, and data handling and deposition;
Ability to perform primary automated annotation of genomic sequence to maximize its utility for the biological community;
A technology development capability focused on developing and integrating technology improvements (e.g., robotics, chemistries, protocols) that lead to increased efficiency and decreased sequencing cost;
A proven track record in rapidly and efficiently releasing both sequence and trace data to public repositories;
A high degree of flexibility and ability to interact with other publicly funded large-scale sequencing centers, public databases, other Human Microbiome Project researchers, genome analysis experts and other entities with whom it may be necessary to integrate to be maximally productive.

The NIH Roadmap HMP effort will, in all likelihood, be complemented by other human microbiome metagenomic sequencing efforts supported by international funding agencies. Applicants must describe their demonstrated ability to work productively in an international sequencing consortium to achieve common goals.

In sum, applications submitted in response to RFA RM-08-001 must:

provide a strategy for completing by 2010 a high quality draft assembly of 400 additional genomes (with 15% finished) needed to complete the reference set;
provide a description/plan of how they will choose the organisms to sequence and where they will procure those organisms;
propose an approach to the metagenomic sequencing of microbes from a set of anatomical sites on the human body that will address the goals of the RFA using samples that will be provided;
may propose other methods of characterizing the samples, including the use of creative approaches in utilizing the new sequencing technologies for purposes in addition to genomic and metagenomic sequencing;
propose a strategy for obtaining and sequencing a set of reference viral and eukaryotic microbes from the relevant anatomical sites beginning in FY2011;
describe their ability to work productively with other NIH and international sequencing efforts in a consortium approach to achieving the goals described;
present information demonstrating experience and the ability to achieve the goals of this RFA (see http://nihroadmap.nih.gov/hmp/referencedataset/ for guidance).

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

International Human Microbiome Meeting (http://www.scgcorp.com/Microbiome): December 9-10, 2007

Applicant information meeting: December 10, 7:00 to 9:00 PM (Further information will be available online at http://www.scgcorp.com/Microbiome/agenda.asp)

The NIH Human Microbiome Project is only one of several international efforts designed to take advantage of metagenomic analysis to study human health. The NIH and European Union plan to convene a meeting with representatives from the international projects to discuss formation of an international Human Microbiome Consortium. The meeting will be held on December 9-10 2007 in the Washington, DC area. Researchers who intend to apply to this RFA are invited to attend the meeting at their own expense. An applicant information meeting will be held on the evening of December 10^th, following the conclusion of the international meeting. Anyone intending to attend the international meeting must register for it at http://www.scgcorp.com/Microbiome. Call-in information for the applicant information meeting will be available through a request email to (hmpRFAinformation@mail.nih.gov).

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the cooperative agreement U54 award mechanism.

The NIH U54 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award". Plans for support of the funded grants beyond the five year Roadmap funding are indefinite. It is anticipated that the goals of this RFA will be completed (or exceeded) during the term of the project.

2. Funds Available

The total funds available for these awards are $30,542,500 (total costs) for four years.
Up to 5 awards will be made from this solicitation with an anticipated start date of April 1, 2009.
The expected amount of each award is $1 to 9.5 million (direct costs) for the first year (FY 2009).
Through Roadmap funding, total costs of approximately $13,840,000 dollars in FY 2009, $12,522,500 in FY 2010, $2,200,000 in FY 2011 and $1,980,000 in FY 2012 will be available for applications funded under this RFA.
An applicant may request a project period of up to 4 years and a budget for direct costs up to $9.5 million (direct costs) per year for the first two years and $1.5 million (direct costs) per year for the last two years.

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 NIH Roadmap provides support for this program, awards pursuant to this funding opportunity are contingent upon the availability of NIH Roadmap funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

Public/State Controlled Institution of Higher Education; Private Institution of Higher Education; Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education); Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education); Small Business; For-Profit Organization (Other than Small Business); Eligible Agencies of the Federal Government.
Only NHGRI and NIAID awardees of large-scale sequencing centers (both extramural and intramural; e.g. those Institutions currently funded under RFA-06-001) NHGRI are invited to apply.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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.

Only the Principal Investigators or key personnel within the large-scale sequencing centers eligible for this FOA may apply.

2. Cost Sharing or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing

3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

The applicants are asked to submit information regarding track record and past performance in production sequencing or any other sequence based technology that may be proposed for use in the application. Additionally, the applicant must supply credible information about projected production and cost for the initiative. The information should be added to the appendix. Formats for submitting that information may be found at http://nihroadmap.nih.gov/hmp/referencedataset/.

Applications Involving Federal Agencies

The requests from federal agencies, including the NIH intramural program, will not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs).

In general, the budget requests will be limited to the incremental costs required for carrying out the proposed work. These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. While support for extramural collaborators may be requested in a separate grant application, funds can be requested for services by an external investigator or contractor as a subcontract/consortium including the applicable indirect (F&A costs) of the contractor/collaborating institution.

Justification must be provided for all requested support and for the Federal employees who will be committed to the project although no funds are requested in the application.

Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: April 22, 2008
Application Receipt Date: May 22, 2008 - (Changed to June 19, 2008 per NOT-RM-08-019)
Peer Review Date(s): October/November, 2008
Council Review Date: January 2009
Earliest Anticipated Start Date: April 1, 2009

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 Principal Investigator
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 NIH staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Jane L. Peterson, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane
Room Number 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: 301 480 2770
Email: jane_peterson@nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHGRI and NIAID. Incomplete and non-responsive applications will not be reviewed and will be returned.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

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. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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 competing continuation award if such costs: are necessary to conduct the project, and 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 competing continuation 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 NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Special Guidance for Applicants

The NHGRI and the NIAID have engaged in several competitions for large-scale projects and it has been our experience that there are specific information items and specific presentation formats that the reviewers have found to be critical for their ability to assess proposals for such efforts effectively. The following guidance summarizes that experience in a format the applicant may use to provide that information. If there is additional information beyond what is addressed in this Guidance that the applicant wishes to present, s/he is encouraged to provide it in a concise form, in addition to the information requested here.

Applications should contain both a Progress Report (not to exceed 10 pages), containing an introduction and rationale with retrospective information about the investigator’s track record in large-scale sequencing, and also a Research Proposal (not to exceed 30 pages) containing detailed plans addressing the goals of this RFA. As one component of both the Progress Report and the Research Proposal, applicants are asked to provide detailed information about throughput, quality, and cost, addressing both past performance (Progress Report) and projected performance (Research Plan).

Note: Costs and throughput of non-directed sequencing using new technology. It is anticipated that some applicants will propose to include the use of new, next generation sequencing technologies for the work outlined in this RFA. In the spreadsheet provided at http://nihroadmap.nih.gov/hmp/referencedataset/ are instructions and a template for providing throughput and cost information for those platforms. Because the new platforms are still in the implementation phase, it may be difficult to provide this information. Nonetheless, the applicant is asked to provide as much information as possible on these topics so that the reviewers can assess the applicant s experience and progress in implementing them. Since costs may fluctuate widely at the current stage of implementation, the applicant should provide a range of current or expected costs. Finally, it is important for the applicant to provide a timetable in which s/he describes the expectation for being able to report more accurate costs and provides anticipated costs for years 2 through 4.

6.I. Progress Report. The progress report should represent the applicant's past accomplishments, rather than future plans. Brief, concise summaries are encouraged, and the total length of this section must not exceed 10 pages. The Progress Report should address each of the factors discussed in the RESEARCH OBJECTIVES section above and should adequately describe the applicant's past experience in large-scale genomic sequencing. In presenting the information requested in this section, the applicant may choose, but is not required, to use the suggested production throughput and cost reporting format entitled Report of Past Sequencing Activities available at http://nihroadmap.nih.gov/hmp/referencedataset/ to report retrospective cost and production data. This suggested format may be used for the convenience of the applicant and is not included in the 10 page limit; its purpose is to facilitate a uniform summary of the information from applicants to ensure equitable review.

The progress report should include the following:

6.I.1. General introduction and justification. Applicants should present information about the sequencing centers and their track records in contributing to past and current sequencing initiatives. The track record in outreach to the community using the sequence information generated should be discussed. If the applicant has participated as part of a collaborative research group, efforts to facilitate the success of that larger group should be described.

6.I.2. Genome sequence production. The applicant should include a concise description of past experience in large-scale genome sequencing and describe relevant sequencing products that relate to the goals of this RFA, including whole genome shotgun data sets, whole genome shotgun assemblies, metagenomic sequencing, refined or finished genome sequence data sets, and other similar relevant information. Past experience should be described in relation to state of the art in large-scale sequencing as discussed in the Research Objectives section.

Each of the following factors should be addressed:

1. Throughput and costs. Cost and throughput information for non-directed sequencing using Sanger-based capillary or next generation sequencing platforms (if proposed) is requested.

Major equipment costs should be amortized over three years. A template is provided at http://nihroadmap.nih.gov/hmp/referencedataset/ that should help the applicant in providing this information in a tabular format, which has proved useful for reviewers of large-scale sequencing applications in the past.

All throughput and cost information should be provided for the most recent three-month period or quarter for the total center’s capacity and for the most recent three-month period or quarter for microbial sequencing activity.

A. Costs and throughput for clone-based or whole genome shotgun sequencing.

i. Throughput and pass rate: provide total number of Q20 bp produced; number of Q20 bases deposited in a public database; pass rate (successful reads/attempted reads success for Sanger-based capillary sequencers is =100 Q20kbp of nonvector sequence). For Sanger-based capillary sequencing provide information separately for 1. small insert plasmids; 2. large-insert plasmids; 3. WGS fosmids; 4. BAC-ends. For next generation technologies provide information for 1. whole genome, 2. BAC-based and 3. all other approaches.

ii. Provide costs broken down into the following categories a-f. Within each category, costs should include management, administrative support, personnel, supplies, reagents, informatics support, and indirect costs.

a. Base production costs. State as total costs and as cost per Q20 kbp. This includes, in addition to the above: management LIMS, informatics support and costs associated with coordination on shared projects, amortized equipment costs (amortized over three years) associated with shotgun sequencing, incremental bioinformatics improvements, incremental technology development, (i.e., improvements to technologies already incorporated into production), routine automated BAC assembly, data submission. Provide information separately for 1. small insert plasmids; 2. large-insert plasmids; 3. WGS fosmids; 4. BAC-ends.

b. Library construction costs.

c. Quality assessment

d. Whole genome assembly costs.

e. Assembly assessment and validation costs. This includes assembly assessment and validation, and assembly quality assessment, map and sequence integration.

f. Manual annotation costs.

B. Costs and throughput for Finished sequence production: Provide the total number of finished bases produced, and the total costs associated with finishing (over and above those associated with production of the unfinished data).

C. Costs and throughput for Additional activities not part of the above. Please list other activities and associated costs. This may include:

i. Genome analysis biological analysis of data

ii. Other for example, finding SNPs, EST sequencing, SAGE tag sequencing, publication preparation, outreach, interaction with scientific communities

2. Assessment of quality of previous sequencing products. The applicant should describe how the quality of sequencing products related to this RFA have been measured or assessed.

3. Prior experience in attaining production milestones. The applicant should describe and document his/her track record in attaining production milestones.

6.I.3. Informatics. The applicant should discuss his/her experience with all aspects of informatics related to the production aspects of large-scale sequencing, including basic IT infrastructure, laboratory information management (LIMS), and data handling and deposition. Applicants should also discuss experience with informatics and software development related to analysis of sequence data, including genome assembly, automated annotation, analysis of medical sequencing data, etc.

6.I.4. Technology implementation. If the applicant proposes to utilize next generation technology in this project he/she should address any experience that s/he has had in improving technology for large-scale sequencing and in integrating new sequencing platforms. The discussion should describe, in quantitative terms, the effect that such technology improvements have had in process improvement and decreased production costs.

6.I.5. Outreach and dissemination. The applicant should address past experience in collaborating with individual research communities on specific genome projects. Of particular interest is experience in dissemination of knowledge about how to use the genome sequence, and the scientific outcomes of those collaborative relationships.

6.II. The Research Proposal. This section (a maximum of 30 pages) comprises the applicant's proposed plan for meeting the objectives of this RFA. The organization suggested below is optional and the applicant is free to use an alternative presentation but, in so doing, must address all of the issues raised below.

6.II.1. Sequence production. The application should describe the sequence production component proposed, the strategy or strategies that will be used to generate various sequencing products required for the RFA, the projected throughput, the expected or needed read characteristics and quality (for all platforms), the assembly strategy and all other pertinent factors.

The applicant should present a clear plan, including concrete milestones, for meeting and exceeding the current state of the art in all areas of production sequencing discussed in this RFA. All phases of the production process must be addressed, as well as:

A. the overall projected cost and throughput proposed for each year of requested funding. Costs, success rates, and throughput must be discussed using the definitions given above in the description of the Progress Report.

B. potential bottlenecks or other problems that can be anticipated, as well as proposed solutions;

C. timelines and quantitative milestones where appropriate, especially for throughput, cost, quality, and adoption of new technologies;

6.II.2. Informatics. Applicants should discuss the informatics that will be used to support sequence production, including routine IT/systems administration, LIMS, etc. Applicants should discuss any proposed sequence assembly informatics that will be used in genome assembly. Applicants to this RFA may propose appropriate automated annotation and, if so, should provide details in the application about the extent of annotation to be done, justifying choices based on the utility of the annotated sequence to the user community, and defining the point at which primary annotation (of projects, genome assemblies, finished genomes, etc.) will be considered to be complete enough for hand-off to the community.

6.II.3. Outreach and dissemination. The applicant should discuss how s/he would work with the various research communities that are consumers of sequence data, including a description of what the applicants believe is the best product for different research communities, the end-point for particular kinds of projects, and how s/he would propose to increase the ability of those communities to use the sequence data over the short- and long-term.

6.II.4. Management Plan. The application should describe the management plan for the proposed work, and how it will support the goals proposed.

6.III. Budget Request. The budget requested must be described clearly and be well justified. Applicants should submit the Detailed Budget for the Initial Budget Period (page 4 of PHS-398) and the Budget for Entire Proposed Period of Support (page 5 of PHS-398).

For submitting cost projections, the applicant may use the suggested format cost spreadsheets, Year 1 Projection and Years 2-4 Projection, both available at http://nihroadmap.nih.gov/hmp/referencedataset/ . Both of these spreadsheets are provided for the convenience of the applicant and have been found to be very useful by the review committee to assess the applicant's proposed plans regarding sequencing production and costs. Other formats may be used if they provide the necessary information. For year 1, sequencing costs and categories must be provided as defined in the Progress Report section above. For each year 2, 3, and 4, the following information must be provided: base output and cost for each sequencing platform, finishing output and costs, assembly costs, annotation costs, genome analysis costs, and other costs.

Plan for Sharing Research Data

The application for a Human Microbiome funded project must include a plan for sharing research data. The HMP strongly endorses rapid release of HMP-related data and materials. Applicants should refer to specific NHGRI and NIAID policy on release of sequence data at http://www.genome.gov/10506376 and http://www.niaid.nih.gov/dmid/genomes/mscs/data_release.htm. Because the purpose of this RFA is to fund large-scale sequencing of the Human Microbiome, and the utility of such data is largely dependent on how quickly it can be deposited into public databases, NHGRI and NIAID consider this RFA to be funding a community resource project as discussed in the report Sharing Data From Large-Scale Biological Research Projects - 2003: A System of Tripartite Responsibility available at http://www.genome.gov/10506376. The general NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how research data will be shared.

Responses to this RFA should propose a plan for data release, as quality of the data release plan will be considered in the review of the application. Appropriate data release plans will be made a condition of the awards made as a result of this RFA. Each of the following items should be discussed separately:

Release of sequence read and trace data or the equivalent for new technologies;
Release of metadata associated with the trace data;
Release of assembled projects;
Release of whole genome shotgun assemblies;
Release of annotation performed by the center.

All applicants must include a plan for sharing research data and reagents including clones and organisms in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared.

Authorization and Consent".

The government may, at its discretion, provide its Authorization and Consent and/or indemnity to the grantee at the time of the award.

(a) The Government authorizes and consents to all use and manufacture of any invention described in and covered by a United States patent in the performance of this Cooperative Agreement.

Notice and Assistance Regarding Patent and Copyright Infringement.

(a) The Grantee shall report to the Program Director, promptly and in reasonable written detail, each notice or claim of patent or copyright infringement based on the performance of this Cooperative Agreement of which the Grantee has knowledge.

(b) In the event of any claim or suit against the Government on account of any alleged patent or copyright infringement arising out of the performance of this Cooperative Agreement or out of the use of any supplies furnished or work or services performed under this Cooperative Agreement, the Grantee shall furnish to the Government, when requested by the Program Director, all evidence and information in possession of the Grantee pertaining to such suit or claim. Such evidence and information shall be furnished at the expense of the Government except where the Grantee has agreed to indemnify the Government.

(c) The Grantee agrees to include, and require inclusion of, this clause in all subawards and subcontracts at any tier for supplies or services (including construction and architect-engineer subawards and subcontracts and those for material, supplies, models, samples, or design or testing services).

Patent Indemnity

(a) The Grantee shall indemnify the Government and its officers, agents, and employees against liability, including costs, for infringement of any United States patent (except a patent issued upon an application that is now or may hereafter be withheld from issue pursuant to a Secrecy Order under 35 U.S.C. 181) arising out of the manufacture or delivery of supplies or materials or the performance of services under this Cooperative Agreement, or out of the use or disposal by or for the account of the Government of such supplies or materials.

(b) This indemnity shall not apply unless the Grantee shall have been informed as soon as practicable by the Government of the suit or action alleging such infringement and shall have been given such opportunity as is afforded by applicable laws, rules, or regulations to participate in its defense. Further, this indemnity shall not apply to

(1) An infringement resulting from compliance with specific written instructions of the Program Director;

(2) An infringement resulting from addition to or change in supplies or components furnished or construction work performed that was made subsequent to delivery or performance; or

(3) A claimed infringement that is unreasonably settled without the consent of the Grantee, unless required by final decree of a court of competent jurisdiction.

Intellectual property management plan

A primary objective for the Human Microbiome Project is to maximize the public benefit of the data produced. Accordingly, awardees should manage intellectual property (IP) and data in a way that achieves this goal. In the case of the HMP, awardees are expected to generate a large collection of data that will serve as a foundation for the scientific community to develop future diagnostics, therapeutics and other medical applications. To achieve the objective of producing and broadly sharing the resources generated by the HMP, applicants should develop a comprehensive IP and data management strategy that is consistent with the NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf). Examples which applicants may wish to consider include the recommendations cited in NIH’s Best Practices for the Licensing of Genomic Inventions (http://www.ott.nih.gov/policy/genomic_invention.html).

It is intended that the tools of scientific discovery necessary to rapidly and effectively develop new diagnostics, therapeutics and other medical applications be widely available for research use. Accordingly, awardees will be expected to manage IP in a way that is consistent with the goals of the initiative and in accordance with applicable NIH guidelines and best practices. Applicants should submit an IP Management Plan that assures that data is rapidly released according to approved criteria (see above), that licensing and sharing practices ensure the availability of data and research resources for future use by the scientific community, and that research collaboration or sponsorship agreements are consistent with the requirements of the HMP. IP Management Plans, once approved, will also become Terms and Conditions of award.

Restrictive licensing and sharing practices for HMP data could substantially diminish the value and public benefit provided by this community resource project. Management practices that would prevent or block access to, or use of, HMP data and resources for research use will be considered to be hindering the goals of the HMP Initiative. Applicants are encouraged to clearly demonstrate in their IP Management plan how their strategies will achieve the desired public benefit and programmatic goals through effective sharing of HMP data and tools.

Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Applicants should discuss the following:

Availability of software developed with funds from this award
Availability of biological resources utilized and/or developed (e.g., 10kb libraries, fosmids, microorganisms)
Availability of technologies and protocols developed with funds from this award

Section V. Application Review Information

1. Criteria

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

The following will be considered in making funding decisions:

Scientific merit of the proposed project as determined by peer review;
Availability of funds;
Relevance to overall program priorities related to achieving programmatic balance with respect to the flexibility over the program as a whole to respond to scientific opportunities, and related to achieving the overall goals for the program;
The likelihood that the proposed effort will make a significant contribution to the availability of Human Microbiome sequence data to the community;
The prospect for attaining and improving the state of the art with respect to cost, data quality, and throughput;
The quality of the plan to share data and materials and to make them available to the public and private research community.

This award will entail specific terms and conditions appropriate to the U54 mechanism and the structuring of the HMP program as a research network. See Section VI below.

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by CSR in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific merit will be discussed and assigned a priority score.
Receive a written critique.
Receive a second level of review by the appropriate national advisory council or board.

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is there a high likelihood that the proposed center can produce high-quality microbial sequence, based on the applicant’s past experience and the proposed future plans for generating high quality read data, accurate subassemblies and whole genome assemblies, finished sequence, and other kinds of large-scale sequencing products as discussed in this solicitation? Is there a high likelihood that the applicants can accomplish this at and beyond current state-of-the-art levels of throughput, data quality, and cost?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Does the applicant have adequate plans for increasing throughput while lowering costs? Does the applicant have a successful record in this regard?
If proposed, are plans for technology development related to characterization of the Human Microbiome adequate and solving critical integration problems, and adopting new sequencing platforms to increase efficiency and lower costs? Does the applicant have a successful record in this regard?
Does the applicant have adequate plans for bioinformatics related to Human Microbiome sequencing, including infrastructure/laboratory information management, assembly, and primary annotation? Does the applicant have a successful record in this regard?
Is the proposed approach to sequencing adequate? Does the applicant have a successful record in this regard?
Are the plans adequate for release of sequence data? Is there evidence that the systems are in place to support rapid data release? Are there adequate plans for release or distribution of other resources, software, or technologies developed under this award? Does the applicant have a successful record in this regard?
If collaborations are proposed, for example with other sequencing centers, are the plans adequate to ensure a productive collaboration? Does the applicant have a successful record of coordinating efforts with other Human Microbiome sequencing centers in the U.S. and abroad?
Does the applicant have adequate and forward-looking plans to disseminate information about microbial genomes and to collaborate in effective ways with user communities? Does the applicant have a successful record in this regard?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?
Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?
Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of data sharing plans or the rationale for not sharing research data will be assessed by the reviewers. Adequacy of data release plans will be considered in the review and in making funding decisions and may be negotiated by program staff prior to making an award. . Any approved data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and

http://grants.nih.gov/grants/intell-property_64FR72090.pdf). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of plans for sharing research resources.

The adequacy of resources sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. Accepted data and resource sharing plans will become a condition of the award of the grant. The effectiveness of resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

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 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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

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 (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the 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 Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement (U54), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining the details for the HMP centers within the guidelines of this RFA and for performing the scientific activities. The P.I. will agree to accept close coordination, cooperation, and participation of NIH HMP Program staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities."

The P.I. of a genome sequencing production center will:

Determine experimental approaches, design protocols, set project milestones and conduct experiments;
Provide goals for throughput, quality, and cost to the NIH HMP staff as requested (usually at the outset of the award and annually thereafter, but also at other times as requested by NIH HMP staff);
Ensure that the genomic sequence produced meets the quality standards and costs agreed upon at the time of award or any improved quality standards and costs negotiated during the award period;
Ensure that the sequence data (reads, assemblies, annotations) are deposited in the appropriate public database (e.g., GenBank or other, as specified by NIH HMP staff), that resources developed as part of this project are made publicly available according to NHGRI and NIAID policies, and that results are published in a timely manner;
Adhere to the NIH HMP policies regarding data release and other applicable policies;
Integrate with the HMP s process for donor recruitment and sampling for a supply of metagenomic samples;
Submit data for quality assessment in any manner specified by the Steering Committee or the External Scientific Consultants (ESC);
Submit quarterly progress reports in a standard format, as agreed upon by the Steering Committee and the ESC;
Collaborate with the Data Analysis and Coordination Center and the NIH program official to ensure coordination of data access and analysis;
Accept and implement any other common guidelines and procedures developed for the Human Microbiome Program and approved by the Steering Committee and the ESC;
Accept and participate in the cooperative nature of the Human Microbiome Research Network;
Coordinate and collaborate with other U.S. and international groups engaged in the Human Microbiome Project;
Inform the Program Director of all major interactions of members of the Steering Committee;
Attend Steering Committee meetings;

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

2.A.2. NIH Responsibilities

NIH Project Scientists will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

NIH HMP Project Scientists will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NIH HMP Project Scientists will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the Human Microbiome Research Network and NIH HMP Project staff will be given the opportunity to offer input to this process.

Each NIH HMP Project Scientist shall participate as a member of the Steering Committee where the Project Scientists may vote, but their total votes will count as a maximum of one-third of the total number of votes.

The Project Scientists will:

Participate (with the other Steering Committee members) in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Project Scientists will assist and facilitate the group process and not direct it;
Negotiate throughput, quality, cost goals, and metagenomic sampling needs with the awardees as necessary;
Serve as a liaison between the awardees and the ESC, the Advisory Councils for those Institutes that plan to fund elements of the HMP and the larger scientific community;
Coordinate the efforts of the awardee with others engaged in Human Microbiome research, including other awardees under this RFA and those awardees involved in related NIH programs, with other U.S. large-scale sequencing efforts, and with the international Human Microbiome community;
Attend all Steering Committee meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;
Periodically report progress to the Directors, NHGRI, NIAID, NIDCR, NIDDK and the NIH Roadmap Office;
Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve as External Scientific Consultants and the Steering Committee; serve as liaison between the Steering Committee and the External Scientific Consultants;
Serve on subcommittees of the Steering Committee and the External Scientific Consultants, as appropriate;
Provide advice in the management and technical performance of the investigation;
Assist in promoting the availability of the genome sequence and related resources developed in the course of this project to the scientific community at large;
Participate in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through the Human Microbiome Research Network;
Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
Retain the option to recommend, with the advice of the External Scientific Consultants, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned program director may also serve as the NIH Project Scientist.

2.A.3. Collaborative Responsibilities

A Steering Committee will serve as the main governing board of the Human Microbiome Research Network. The Steering Committee membership will include NIH HMP Project Scientists and the PI of each awarded cooperative agreement. The PI of each center (or designee) will have one vote on the Steering Committee. The Project Scientists may vote, but the total votes will count as a maximum of one-third of the total number of votes. The Steering Committee Chair will not be an NIH staff member. Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions. The Steering Committee will:

Discuss progress in meeting the goals of various Human Microbiome projects;
Develop recommendations for uniform procedures and policies necessary to meet the goals of the Research Network, for example for data quality measures and assessment, conventions for data deposition, or measuring costs and throughput. Adoption of procedures and policies developed by the Steering Committee will require concurrence by the External Scientific Consultants;
Serve as a venue for coordination on the improvement of Human Microbiome scientific methods, for example by disseminating best practices and collectively evaluating new procedures, resources, and technologies.
Schedule the time for, and prepare concise (3 to 4 pages) summaries of, the Steering Committee meetings, which will be delivered to members of the group within 30 days after each meeting.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. External Scientific Consultants

The External Scientific Consultants (ESC) will be responsible for reviewing and evaluating the progress of the members of the Human Microbiome Research Network toward meeting their individual and collective goals. The ESC will be appointed by and provide recommendations to the Directors, NHGRI, NIAID, NIDCR, NIDDK and the NIH Roadmap Office about continued support of the components of the Human Microbiome Research Network. The Advisory Panel is composed of four to six senior scientists with relevant expertise who are not PIs of a cooperative agreement involved in the Human Microbiome Research Network. The membership of the External Scientific Consultants may be enlarged permanently, or on an ad hoc basis, as needed.

The External Scientific Consultants will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the External Scientific Consultants members to interact directly with the awardees. Annually, the External Scientific Consultants will make recommendations regarding progress of the Genome Sequencing Research Network and present advice about changes, if any, which may be necessary in the Genome Sequencing Research Network program to the Directors, NHGRI, NIAID, NIDCR, NIDDK and the NIH Roadmap Office.

2.A.5 Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

The NIH will evaluate this program. Each awardee will be required to define a set of concrete and quantifiable project-specific milestones. Prior to funding the application, program staff will negotiate the milestones with the applicant. The negotiated milestones will become a condition of the award, including appropriate language to recognize that the project includes research the outcomes of which are unpredictable. Each awardee will be required to update these milestones annually at the anniversary date. In addition, each awardee is expected to provide additional information as required to assist the program evaluation.

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, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Jane L. Peterson, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane
Room Number 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 480-2770
Email: jane_peterson@nih.gov

Maria Y. Giovanni, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6610 Rockledge Drive
Room Number 6007
Bethesda, MD 20892
Telephone: (301) 496-1884
FAX: (301) 480-4528
Email: mgiovanni@niaid.nih.gov

2. Peer Review Contacts:

Dr. Richard Panniers
Chief of the Genes, Genomes and Genetics IRG
Center for Scientific Review
6701 Rockledge Drive,
Room Number 2198
Bethesda, MD 20892
Telephone: (301) 435-1741
FAX: (301) 480-2067
Email: pannierr@csr.nih.gov

3. Financial or Grants Management Contacts:

Ms. Cheryl Chick
Division Of Extramural Research
National Human Genome Research Institute
5635 Fishers Ln
Room Number 4061
Bethesda, MD 20892
Telephone: (301) 435-7858
FAX: (301) 402-1951
Email: ChickC@mail.nih.gov

Tina Carlisle
Grants Management Program
National Institute of Allergy and Infectious Diseases
6700 B Rockledge Drive
Room Number 2121
Bethesda, MD 20892
Telephone: (301) 402-6579
FAX: (301) 493-0597
Email: tc48k@nih.gov

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 (45CFR46) 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).

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.

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 http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, 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.

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 new PHS Form 398; 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.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) 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 DHHS 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) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

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 RFA 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 or Health Systems Agency review. 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 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 NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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.