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Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
This Funding Opportunity Announcement (FOA) is developed as a Roadmap initiative. All NIH Institutes and Centers participate in Roadmap initiatives. This FOA will be administered by several NIH institutes on behalf of the NIH.

Title: Human Microbiome Demonstration Projects (UH2/UH3)

Announcement Type
New

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

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

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

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

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

Request for Applications (RFA) Number: RFA-RM-08-012

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release/Posted Date: December 4, 2007
Opening Date: April 22, 2008 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): April 22, 2008 (now May 24, 2008, per NOT-RM-08-015)
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Receipt Date: May 22, 2008 (now June 24, 2008, per NOT-RM-08-015)
Peer Review Date(s): October-November 2008
Council Review Date(s): January 2009
Earliest Anticipated Start Date(s): April 1, 2009
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: May 23, 2008 (now June 25, 2008, per NOT-RM-08-015)

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

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

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

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

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. 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 Contacts
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

The purpose of this FOA is to solicit applications to examine, through the use of molecular techniques, the relationship between an individual’s microbiome and health and disease.

The complex and dynamic communities of microbes (the human microbiota) that are present on and within the human body are thought to profoundly influence human health in a variety of ways, through effects on human physiology, nutrition, immunity and development. Disruptions in community composition, structure or dynamics may reflect, trigger, or influence the course of various disease states. Studies on humans and vertebrate animal models have generated evidence that this is the case for some specific diseases and suggest that further studies in this area may be vital for the understanding, prevention and treatment of many human diseases, as well as maintenance of homeostasis. However, studies of the human microbiome are truly in their infancy, and the range and magnitude of the effects of the collective microbiota upon health and disease are not known.

It is currently a challenge to even identify comprehensively the components of the human microbiota, although genomic approaches have greatly improved the feasibility of doing so. The study of the collective DNA (the human microbiome) of community members has been spurred by recent advances in DNA sequencing and other technologies; such technologies have created the new field of metagenomics (determining the DNA sequence of genomes from a mixed community of organisms). The feasibility of taking a metagenomic approach to the study of the human microbiota has been shown in studies of both model vertebrates and humans. This FOA seeks to stimulate the application of the metagenomic approach to the analysis of the human microbiota and its role in both normal and pathological human conditions by developing a set of resources and reference material that can be used by the entire scientific community.

The NIH Human Microbiome Project is a component of the NIH Roadmap program, which is a trans-NIH effort to accelerate the discovery and translation of scientific knowledge into public health benefits. It is designed to provide a five to ten-year incubator space for new NIH initiatives that promise to transform 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. 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 and started in 2008 (http://nihroadmap.nih.gov/hmp/). 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 in relation to any of a number of relevant variables (e.g., 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 monitor health status, improve understanding of the etiology of disease, and stimulate the 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. Briefly, the HMP is designed as a five-year effort with several components: (1) generation of a reference set of complete genome sequences from cultivable members of the microbial communities from specific anatomical sites of the human body; (2) metagenomic studies that will allow estimation of the complexity of the microbial community at each site in healthy individuals and determination whether there is a core microbiome at each site; (3) demonstration projects to determine whether variation in the microbiome at a particular site can be related to human health or disease states; (4) development of new technologies, informatic 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 must be considered in the study and application of the metagenomic analysis of the human microbiome. The purpose of this announcement is to solicit applications to support component (3) of the initiative.

Recent estimates of the number of microbes that reside in, and upon, the human organism suggest that they outnumber their host’s cells by 10:1 and that the number of genes in the microbiome could outnumber human genes by 100:1. The beneficial symbiotic relationship with microbes has been recognized in plants and animals. The study of the relationship of the human microbiome to human health has begun to be recognized as an important aspect of overall human health, and several preliminary studies in the area are already underway. For example, evidence from recent studies indicates that colonization of the neonatal intestine serves to educate the immune system such that the adult becomes tolerant to a wide variety of food and environmental antigens which otherwise would trigger inappropriate immune responses. Other studies have implicated alterations in the microbiota with obesity and insulin resistance, periodontal disease, cardiovascular disease, urinary tract infections, and autoimmune, inflammatory and hyperallergic responses. Widespread and often inappropriate use of antibiotics has heightened concerns that, under selective pressure, the human microbial population structure has been altered in ways that have unappreciated impacts on health. Similarly, changes in diet and other hygienic practices also may have unexpected and undesirable - effects. Attempts to manipulate the human gut and vaginal microflora with pure or mixed cultures of beneficial bacteria (probiotics) have shown promising results in treating or preventing some diseases. Although these are promising developments that suggest that manipulation of the human microflora may be possible, a scientific, mechanistic basis for these empirical formulations is lacking, preventing rational design of such approaches. In order to assess these and many other possible approaches to the management of human health, it would be valuable to determine the population structure of the microbes that are present in the healthy individual, and how that structure changes in pathological states.

Applications are being sought for demonstration projects that will investigate the potential relationship of changes in the human microbiota to human health and disease. This FOA will use the Phased Innovation (Cooperative Agreement) mechanism, UH2/UH3. This mechanism has recently been established to support both a feasibility/pilot phase (UH2) and an expanded development phase (UH3). In the UH2/UH3 application for an HMP demonstration project, the applicant must address the following specific objectives:

A more detailed description of each objective follows. In the application, the applicant must describe how all three specific objectives will be met over the course of the proposed four-year effort. The applicant must also describe the activities that will be carried out during the first year feasibility phase of the project to obtain a sufficient number of samples, data, and analysis to allow an assessment of the potential of the expanded phase period to meet the goal of determining whether the microbiota in a specific region on/in the human body plays a role in contributing to health status. The two key components of the application are emphasized below the importance of the biological system and its potential to allow assessment of the relationship between the human microbiome and human health, and the applicant’s ability (based on track record) to utilize high throughput genomics technologies in the study. Both are considered critical for the studies to be funded under this FOA and applicants should carefully address both as indicated below. Cross-disciplinary collaborations are encouraged to ensure development of a high quality plan that addresses both of these elements.

1. Identification of an important biological system that holds the potential to demonstrate whether there is a relationship between the human microbiome and health or disease. Included in this objective is identification of an existing or readily accessible set or collection of donors/samples, consented in a way consistent with HMP guidelines (will be posted at http://nihroadmap.nih.gov/hmp/RFA-RM-08-012/), that can be utilized in the study of the microbiota in the chosen anatomical region or regions in the specific health condition to be studied. Applicants need to carefully describe the human microbiome system(s) which they propose to investigate in their study. A clear definition of the disease state, health condition or phenotype to be examined must be given and a detailed description of how the phenotype(s) will be measured must be presented. Additionally, a rationale for choosing to study the proposed body region(s) with respect to the proposed health condition must be given. Importantly, applicants must identify and carefully describe a set of donors or samples to be used in the proposed study. Standard Operating Procedures (SOPs) for sample collection from the designated region(s) must be described, including a design for collection of metadata (e.g., host characteristics, relevant environmental measurements), and a plan to ensure correct sample tracking. A strategy for obtaining informed consent that addresses all of the issues in the HMP consent form found at http://nihroadmap.nih.gov/hmp/RFA-RM-08-012/ must be described; all consent forms for prospective or retrospective sample collections in funded projects must be approved by the HMP project team before the application can be funded. The application must set out clear recruitment and/or sampling plans with a timetable for implementation of the plan. If not all of the sample collection will be done during the UH2 feasibility phase, the applicant must indicate how much sampling will be done in that time. Power analyses for both the first-year feasibility effort and the overall demonstration project must be presented.

2. Use of high-throughput, cost-effective technologies to study the human microbiome in the selected body region(s) under specified conditions and to make those data publicly available. The applicant should describe how currently available, robust, high-throughput technology platforms will be used to create data sets of sufficient quality and depth to allow analysis under objective 3 to study how changes in the microbiota relate to changes in human health or disease. Molecular characterization technologies should include16S rRNA gene sequencing and metagenomic shotgun sequencing. If appropriate, expression analysis by high throughput methods, proteomic analysis or other approaches for the further characterization of the microbiota at the site of investigation may be proposed.

The applicant must describe his/her current technical capabilities for each approach proposed, the amount of data that can be anticipated and the nature of the analysis that will address the hypothesis proposed. The applicant must also describe a baseline quality standard and provide an estimate of the unit cost of the technology (with the appropriate unit to be defined by the applicant). Several different techniques may be proposed but each must be well described, with presentation of power calculations, quality control measures, and projected cost per sample. These calculations and estimates should be based on prior experience, and projections of throughput expectations. If large-scale sequencing is to be used, either with existing Sanger sequencing methods or utilizing new sequencing technologies, the applicant must provide evidence that the sequencing facility is capable of the throughput, quality and cost needed for the project. Further information about how to report information on throughput and costs is presented in Section IV 6, Other Submission Requirements .

It should be noted that the budget for the three years of the UH3 phase of the initiative (see below) decreases by 10% per year because NIH expects that the cost of data production will drop by at least that much per year. The applicant should address how data production costs will be reduced by at least that factor, and ideally more, during the grant period. If new technologies, particularly sequencing technologies, are to be utilized, the applicant’s track record in using the technologies must be provided; this will be an important review criterion.

All data supported through this initiative will be released rapidly. The applicant must discuss tools and plans for rapid data release. The development of new genomic analysis technologies is beyond the scope of this FOA, but will be supported by two other FOAs from the HMP that will be released in Fall 2007. However, the overall plan of an application in response to RM-08-012 should include a strategy for adopting improvements and technologies that could emerge during the course of the program that would offer advantages over the currently available technologies used in the demonstration projects. As indicated below, applicants should propose a policy for the data from each of the technologies being used. These plans will be reviewed by NIH staff, and agreed upon before the application is funded.

3. Present a cohesive analysis plan that will allow conclusions to be drawn about the role of human microbiota in health and disease. The objective of the demonstration projects is to produce deep data sets that can help answer questions about the human microbiota s relationship to human health. Applicants must describe their plans to utilize existing analysis tools, including their experience using them, to generate useful biological conclusions and the strengths and weaknesses of those tools.

Applicants may, in addition, propose experiments with model organisms to establish causal relationships between changes in the microbiota and health or disease states, which may be difficult to infer from observational studies on humans (see section 6.II.1, Biological Goals of the Proposal, below).

As noted above the program will be funded in two phases:

Initial Pilot Phase: The initial year should be devoted to pilot studies, such as 16S rRNA gene sequences, that will indicate the value of the chosen system and the applicant’s ability to demonstrate how changes in the human microbiota in one or more body regions relate to specific human health conditions or diseases. Applicants may choose to study any body region for which they want to analyze the role of microbiota in determining or maintaining health status and disease. During the first year, awardees will be expected to recruit sample donors (if necessary) or utilize an existing set of donors and/or samples to generate the pilot data. As indicated above, applicants must provide a clear description of the sample acquisition strategy and logistics (if needed), phenotype description(s), reconsenting procedures (if needed) and sampling SOPs for the region(s) to be studied. Quantitative milestones for six months and 1 year of the pilot phase must be provided.

At the end of the first year of the UH2 awards, there will be an administrative review to determine which of the cooperative agreements will continue to the UH3 phase. The administrative review will be conducted by the Roadmap HMP staff, outside experts and NIH Advisory Councils, who will consider several factors, including both the progress made toward and potential for achieving the goals of the program, i.e. whether the chosen system will demonstrate how changes in the microbiome relate to human health. Beyond attaining or exceeding the stated milestones, the successful projects will be those that are judged to have the most significant impact on understanding the relationship between the human microbiome and human health. Other factors that will be considered include significance of the health problem being addressed and program balance. Thus, along with milestones, applicants should propose, where possible, other approaches to determining progress and significance.

Expanded development phase: Applicants should describe how the expanded development phase will build on the data generated in the pilot phase. If new data types are to be collected during the expanded phase, what questions will be addressed? If new technologies are proposed for implementation in the expanded demonstration phase, information about the applicant’s track record with the technologies, as outlined above, must be provided. A well formulated analysis plan describing how the data will be used to demonstrate the significance of any correlation found must be presented. Clear milestones must be set for each year, although the applicant will have an opportunity to revise them as the work progresses.

In sum, applications submitted in response to RFA RM-08-012 must:

The criteria that will be used to determine which of the UH2 projects will make the transition to the UH3 phase will include:

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 FOA are invited to attend the meeting at their own expense. An applicant information meeting will be held on the afternoon of December 10th, following the conclusion of the international meeting. Anyone intending to attend the international meeting must email [email protected] for further information. Only one attendee per application will be allowed. Call-in information for the applicant information meeting will be available through a request email to ([email protected]).

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

Section II. Award Information

1. Mechanism of Support

This Funding Opportunity Announcement (FOA) will use the NIH Research Project Grant cooperative agreement UH2/UH3 award mechanism.

The applicant will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm).

The NIH UH2/UH3 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 FOA will be completed (or exceeded) during the term of the project.

2. Funds Available

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

The NIH intends to commit approximately $28.3 million dollars total costs to this initiative over its term of fiscal year 2009-12. Up to 10 UH2 pilot awards will be made and up to 5 UH3 scaled up projects will be awarded following administrative review of the results from the pilot phase. The anticipated start date of the pilot phase is April 2009. The expected amount of each UH2 award is $300,000 to $700,000 (direct costs) and the expected amount of each UH3 award is $1 million to $4 million (direct costs), depending upon the number of awards made. Through Roadmap funding, approximately $4 million in FY 2009, $8.7 million in FY 2010, $8.1 million in FY 2011 and $7.5 million in FY 2012 will be available for applications funded under this FOA.

An applicant may request a project period of up to 4 years and a budget for direct costs up to $700,000 (direct costs) for the UH2 and $4 million (direct costs) per year for the UH3.

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

F&A costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, November 2, 2004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

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

1.B. Eligible Individuals

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

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

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

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

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

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/applicants/apply_for_grants.jsp and follow the directions provided on that Web site.

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

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

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

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

2) Organizational/Institutional Registration in the eRA Commons

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

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

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

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

1. Request Application Information

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

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

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

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

2. Content and Form of Application Submission

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

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

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

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
Research & Related Budget

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

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

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

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

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

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

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

Applications Involving a Single Institution

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

Applications Involving Multiple Institutions

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

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

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates
Opening Date: April 22, 2008 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date: April 22, 2008
Application Receipt Date: May 22, 2008
Peer Review Date(s): October-November, 2008
Council Review Date(s): January 2009
Earliest Anticipated Start Date(s): April 1, 2009

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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

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

The letter of intent should be sent to the following or by email to the address listed. These letters will be directed to the HMP working group member (http://nihroadmap.nih.gov/hmp/members.asp) representing the NIH Institute/center most appropriate for the health condition/disease proposed for study. Applicants may contact any of the HMP working group members listed at http://nihroadmap.nih.gov/hmp/members.asp.

Human Microbiome Working Group (http://nihroadmap.nih.gov/hmp/members.asp)

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: [email protected]

3.B. Submitting an Application Electronically to the NIH

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

3.C. Application Processing

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

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the National Human Genome Research Institute and the HMP working group. Incomplete and non-responsive applications will not be reviewed

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

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

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal (formerly 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 renewal award.

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

6. Other Submission Requirements

The applications sought in this FOA will propose high throughput, cost effective technologies to study the human microbiome. In addition to the applicant’s track record in the biological system proposed for study, it is important for the reviewers to be able to critically evaluate the applicant’s track record in the use of the technologies proposed. In order to do so, the applicant needs to provide specific information items. The following guidance summarizes the elements that must be addressed for all approaches proposed. If there is additional information, not 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.

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 FOA. In the spreadsheet provided at (http://nihroadmap.nih.gov/hmp/RFA-RM-08-012/) are instructions and a template for providing throughput and cost information for those platforms. This format may be converted to a .pdf and included as an attachment to either the Preliminary Studies/Progress Report Section (for throughput and cost information in past performance) or Research Design and Methods (for anticipated throughput and costs in future plans proposed). Because the new platforms are still in the implementation phase, it is understood that 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 are able to assess the applicant’s experience and progress in implementing them. At the current stage of implementation, costs may fluctuate widely during a set period of time, and in that case 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 1 through 4.

Applications should contain the following sections as Attachments 2-5: Specific aims, Background and Significance, Preliminary Studies/Progress Report and Research Design and Methods.

6.I.Specific Aims. This section may not exceed 1 page.

6.II.1 Background and Significance This section should be limited to 4 pages and should concisely present the scientific background and potential significance of the proposed study for the HMP.

6.III.1 Preliminary Studies/Progress Report. This section 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 section should adequately describe the applicant's past experience in microbial studies related to the goals of this FOA as well as the use of high throughput technologies.

This section should include the following:

6.III.2. General introduction and justification. Applicants should present information about past work related to the goals of this FOA. 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.III.3 Data production using high throughput technologies including microbial sequence production. The applicant should include a concise description of past experience in high throughput microbial sequencing and describe relevant sequencing products that relate to the goals of this FOA, such as whole genome shotgun data sets, whole genome shotgun assemblies, metagenomic sequencing, expression analysis and so on.

For high throughput sequencing each of the following factors should be addressed. If sequence data production will be done by an existing NIH-funded large-scale sequencing center that regularly reports its throughput, quality metrics and costs to NIAID or NHGRI, a sequencing report for the most recent quarter may be submitted as an attachment to the Preliminary Studies/Progress Report Section of the application. In that case, progress with microbial sequencing must be highlighted.

6.III.3.1. 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/RFA-RM-08-012/) 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. This template may be converted to a .pdf and attached to the Preliminary Studies/Progress Report section.

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

A. Costs and throughput for 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; 3. all other.

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

a. Base production costs. State as total costs and 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. Other analysis costs.

For other high throughput technologies proposed in the application the applicant should describe his/her experience with the technology for the past quarter as well as for the effort proposed in the application (by year). In order to assess experience with the high throughput technology proposed, the following should be described:

1. Number of attempted experiments using the technology and how much data were produced (define the unit of data and define an experiment as it relates to the proposed method[s]).

2. Number of verified experiments and the method(s) used for verification.

3. The quality of the data produced and how data quality was assessed. 4. Cost per experiment (total cost per experiment including management, administrative support, personnel, equipment (amortized over three years, supplies, reagents, informatics support, and indirect costs associated with each as defined above).

6.III.3.2. Prior experience in attaining production milestones. The applicant should discuss his/her track record in attaining production milestones.

6.III.3.3. Informatics. The applicant should discuss his/her experience with all aspects of informatics related to the proposal and the goals of this FOA.

6.III.3.4. 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 the purpose proposed and in integrating new platforms into laboratory practice. The discussion should describe, in quantitative terms, the effect that such technology improvements have had in process improvement and decreased production costs.

6.IV. The Research Design and Methods. This section (a maximum of 35 pages) comprises the applicant's proposed plan for meeting the objectives of this FOA. 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.

This section should include the following:

6.IV.1. Biological goals of the proposal. The application should describe the biological system in which the relationship between the microbiome and health/disease will be studied. Specifically, the following must be described: the applicant s track record working in this or a related system; the set of existing samples or prospectively collected samples to be studied along with a timetable to obtain those samples; the strategy to be used, including technological approaches, to study the relationship of the microbiome in the system to health/disease. Appropriate animal models, particularly those with relevant disease models, can be proposed to complement the human studies where critical data would not be easily obtained from humans, where animal studies would be necessary to confirm indications from human studies, or when development of advanced techniques would be more efficiently piloted, or validated. Examples would be invasive sampling techniques, use of genetically modified or genetically uniform organisms to study host genotype/phenotype interactions, or use of gnotobiotic organisms. The primary emphasis of the application must be in studying samples derived from the human body.

6.IV.2. Data production milestones: The applicant should present a clear plan, including concrete milestones, for producing data that will be used to address the goals laid out above. Milestones are needed for each quarter of the pilot project year (UH2) and yearly for years 2 through 5. These include, for all technologies:

A. the overall projected cost and throughput proposed for data production for each technology in each year of requested funding. The description given above in preliminary studies/progress report may be used to project cost and throughput of sequencing and other technologies.

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. A description of how quality will be measured must be given for all technologies;

6.IV.3. Informatics plans: Applicants should discuss the informatics that will be used to support the data production and analysis, including routine IT/systems administration, LIMS, quality assessment, annotation, etc.

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

Additionally, the applicant may use the suggested format cost spreadsheet available at http://nihroadmap.nih.gov/hmp/RFA-RM-08-012/ to provide sequencing costs for year 1. This format may be converted to a .pdf and attached to this section (the Research Design and Methods). The 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 that provide this information may be used, but sequencing costs and categories must be reported as defined in the Progress Report section above.

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

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

Organizational DUNS

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

PHS398 Research Plan Component Sections

Attachments 2-5 of the PHS398 Research Plan component are limited to 50 pages as noted above. While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following additional requirements:

424 RR Detailed Budget Component

Applications must present the detailed SF424 (R&R) Budget forms for all years. In the budget justification, it must be indicated whether the budget year is for the UH2 or the UH3 phase.

Appendix Materials

NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.

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

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

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 FOA is to fund large-scale analysis of the human microbiome in order to demonstrate the value of studying the relationship between the microbiome and human health and disease, the utility of such data to the community is largely dependent on how quickly it can be deposited into public databases. The NIH considers this FOA to be funding community resource projects 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 for each technology proposed.

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


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.

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). The IP and data management plan may be included with the Plan for Sharing Research Data.

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.

The Government may, at its discretion, provide Authorization and Consent and/or Patent Indemnity clauses (see below) to the grantee at the time of the award.

Authorization and Consent".

(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.

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_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 sharing research resources plan 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). See Section VI.3., Reporting.

Applicants should discuss the following:

Section V. Application Review Information

1. Criteria

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

2. Review and Selection Process

Applications that are complete and responsive to the FOA 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:

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

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? Will the donor recruitment or sampling plan presented provide the needed resource for this study? Is there a high likelihood that the proposed effort can produce high-quality metagenomic data and that analysis of those data will provide important information pertinent to the question of the relationship of changes in the microbiota to human health and disease?

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? For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs?

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 PD/PI(s) and other key personnel 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 PD/PI(s) and investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Do(es) the scientific environment(s) 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 Human Subjects Sections of the PHS398 Research Plan component of the SF424 (R&R).

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 Human Subjects Sections of the PHS398 Research Plan component of the SF424 (R&R)

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the adequacy of the plans for their care and use will be assessed. See the Other Research Plan Sections of the PHS398 Research Plan component of the SF424 (R&R).

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 and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. The priority score should not be affected by the evaluation of the budget.

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

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a 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_2003/NIHGPS_Part7.htm#_Toc54600131). 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 the plan for sharing research resources.

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), See Section VI.3., Reporting.

Model Organism Sharing Plan: Reviewers are asked to assess the sharing plan in an administrative note. The sharing plan itself should be discussed after the application is scored. Whether a sharing plan is reasonable can be determined by the reviewers on a case-by-case basis, taking into consideration the organism, the timeline, the applicant's decision to distribute the resource or deposit it in a repository, and other relevant considerations.

3. Anticipated Announcement and Award Dates

Applicants can expect to learn about the outcome of their applications, whether successful or unsuccessful, by February 28, 2009.

Section VI. Award Administration Information

1. Award Notices

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

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

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

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5., Funding Restrictions.

2. Administrative and National Policy Requirements

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 (UH2/UH3), 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 demonstration project within the guidelines of this FOA 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 HMP demonstration project will:

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

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

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:

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 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 ESC is composed of four to six senior scientists with relevant expertise who are not Principal Investigators 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 Human Microbiome Research Network and present advice about changes, if any, which may be necessary in the Human Microbiome Research Network program to the Directors, NHGRI, NIAID, NIDCR, NIDDK and 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.

Awardees will also be required to submit periodic (at least biannually) progress reports in a standard format, as agreed upon by the Steering Committee and the ESC. As part of good program management, the NIH may request information essential to an assessment of the effectiveness of this Program. Accordingly, recipients are hereby notified that grantees may be asked to provide information for program evaluation purposes, both locally and at the national level.

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.

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

3. Reporting

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

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 Contact(s):

Jane L. Peterson, Ph.D. for the Human Microbiome Working Group (http://nihroadmap.nih.gov/hmp/members.asp)
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: [email protected]

2. Peer Review Contact(s):

Alexander Politis, Ph.D.
Division of Biologic Basis of Disease
Center for Scientific Review
6701 Rockledge Dr., Room 3210
Bethesda, MD 20892-7808
Telephone: (301) 435-1150
FAX: (301) 480-0940
Email: [email protected]

3. Financial/Grants Management Contact(s):

Ms. Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9305
Telephone: (301) 402-0733
Fax: (301) 402-1951
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

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

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

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

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

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

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

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.

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

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

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

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

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 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 Part 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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

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

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