Part I Overview Information

Department of Health and Human Services

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

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

Title: The Electronic Medical Records and Genomics (eMERGE) Network, Phase II Study Investigators (U01)

Announcement Type
New

Update: The following updates relating to this announcement have been issued:

• July 6, 2011 - See Companion RFA-HG-11-022 The Electronic Medical Records and Genomics (eMERGE) Network, Phase II Pediatric Study Investigators (U01).
• June 14, 2011 - Notice of Intent to Publish a Request for Applications for The Electronic Medical Records and Genomics (eMERGE) Network - Pediatric Study Investigators (U01). See NOT-HG-11-023.
• August 25, 2010 - See Notice NOT-HG-10-020 Notice of Frequently Asked Questions for this FOA.

Request For Applications (RFA) Number: RFA-HG-10-009

Catalog of Federal Domestic Assistance Number(s)
93.172

Key Dates
Release Date: July 15, 2010
Letters of Intent Receipt Date: October 17, 2010
Application Receipt Date: November 17, 2010
Peer Review Date(s): February/March 2011
Council Review Date: May 2011
Earliest Anticipated Start Date: July 01, 2011
Additional Information To Be Available Date (Url Activation Date): N/A
Expiration Date: November 18, 2010

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose. The purpose of this funding opportunity announcement (FOA) is to provide support for the most competitive existing eMERGE phase I sites and new sites with existing biorepositories and genome-wide genotyping data to incorporate state-of-the-art methods generated in eMERGE Phase I into clinical research and ongoing clinical care in a Phase II eMERGE expansion.
• Mechanism of Support. This FOA will utilize the U01 Cooperative Agreement award mechanism.
• Funds Available and Anticipated Number of Awards. The total amount to be awarded over the 4-year period of this FOA is approximately $22 million. It is anticipated that up to 8 awards will be made under this FOA.
• Budget and Project Period. This is a four-year project. The expected direct costs for each individual research group award are not to exceed $500,000 per year for each of the four years.
• Application Research Strategy Length: The U01 Research Strategy section may not exceed 12 pages, including tables, graphs, figures, diagrams, and charts. See Table of Page Limits.
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
• Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application.
• Number of Applications. Applicants may submit more than one application, provided they are scientifically distinct.
• Resubmissions. Resubmission applications are not permitted in response to this FOA.
• Renewals. Renewal applications are not permitted in response to this FOA.
• Special Date(s). This FOA uses non-standard due dates. See Receipt, Review and Anticipated Start Dates.
• Application Materials. See Section IV.1 for application materials.
  Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: (301) 451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

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

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

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

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
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. Dispute Resolution Process
3. Reporting

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

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Nature of the Research Opportunity

The purpose of this funding opportunity announcement (FOA) is to provide support for the most competitive existing eMERGE Phase I sites and new sites with existing biorepositories and genome-wide genotyping data to compete to become part of the eMERGE Network, Phase II. NHGRI initiated the eMERGE Network in 2007 to support investigative groups with existing biorepositories to develop necessary methods and procedures, and then to perform genome-wide studies in participants with phenotypes and environmental exposures derived from electronic medical records (EMR). Phase I of the Electronic Medical Records and Genomics (eMERGE) Network will now be expanded to incorporate this knowledge into clinical research and ongoing clinical care in eMERGE Phase II. This competitive solicitation is open to investigators supported in eMERGE Phase I and to new research groups meeting the qualifications described below.

eMERGE phase II will begin to incorporate current genomic knowledge combined with available genotyping data and state-of-the-art electronic phenotyping and privacy protection methods into clinical research and ongoing clinical care. To ensure that the maximal scientific benefit is derived from this significant public investment and is consistent with the goals of proposed NIH policy on data sharing (NIH Guide NOT-OD-07-088), this funding opportunity aims to support rapid sharing of the resulting data with the broad scientific community for research use, through community resource databases such as dbGaP (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gap). No funding should be requested for genome-wide genotyping or other genomic technologies, as the costs for these assays, if awarded, will be supported separately.

For the purposes of this FOA, a biorepository is defined as a resource that collects and stores biospecimens from which DNA sufficient for genome-wide studies can be isolated from individuals, and which are (or can be) linked to electronic personal health information on these individuals. The biospecimens may have been collected in the course of clinical care or as part of a research resource. Electronic medical records are defined as computerized data obtained in the course of clinical care or research that can be electronically accessed, manipulated, shared, and analyzed, with appropriate consent and patient protections, for research purposes and ongoing clinical care. Affiliation with a biorepository means documented ongoing or future access to data and samples in a highly-effective collaborative relationship, and ability to commit the biorepository data and samples, in consultation with appropriate decision-makers, to participate in this FOA.

The goals of this initiative are to build upon the eMERGE Phase I experience in defining phenotypes from electronic medical records (EMRs), conducting genome-wide association (GWA) studies, reducing risks to patient privacy from the sharing of EMR data, and developing consent and community consultation procedures for conducting such research to begin to incorporate genomic research results into clinical care. It will achieve these goals by: 1) expanding and validating the eMERGE electronic phenotyping library from 14 phenotypes to at least 40; 2) expanding the number and diversity of participating eMERGE sites to include under-represented populations such as racial/ethnic minorities and children; and 3) incorporating GWA genotyping information into EMRs, where feasible, for improving genetic risk assessment, prevention, diagnosis, treatment, and/or accessibility of genomic medicine.

Background

eMERGE Phase I is a 4-year program awarded in September 2007 through RFA-HG-07-005, Genome-Wide Studies in Biorepositories with Electronic Medical Record Data. Biorepositories in eMERGE are conducting GWA studies of six site-specific phenotypes in roughly 18,000 subjects and a network-wide phenotype of resistant hypertension in an additional ~1,800 subjects. These approximately 20,000 subjects are also electronically phenotyped and analyzed for hypothyroidism. Six additional network-wide EMR phenotypes have been assessed in genotyped subjects through support made possible by the American Recovery and Reinvestment Act (ARRA). Detailed information on the eMERGE network can be found at the eMERGE website (www.gwas.org) and the website of the Office of Population Genomics (OPG), NHGRI, NIH (http://www.genome.gov/27530162).

Each of the eMERGE Phase I sites is working to transport and validate its primary phenotyping algorithms in at least two additional eMERGE sites, and then to implement them within the diverse EMR systems at all five sites, thus increasing sample sizes at minimal extra cost. The external validity of these algorithms will also be assessed in settings outside eMERGE. An EMR-based phenotyping library containing the pseudocode (syntactical description outlining the general steps of an algorithm rather than the actual computer code) for these algorithms is available through the eMERGE website (www.gwas.org). Using diagnostic codes extracted from EMRs, already-genotyped patients in eMERGE can be classified on several hundred additional preliminary phenotypes in a phenome-wide scan, or PheWAS . Phenotypes showing suggestive SNP-trait associations can then be refined through the eMERGE algorithm development process for more reliable GWA-based discovery studies. Software tools for analyzing privacy risk (VDART) and harmonizing data dictionaries (eleMAP) are available though the eMERGE website (www.gwas.org), as is model consent language for genomic research in biobanks, which is also posted on the NHGRI consent website (http://www.genome.gov/Pages/PolicyEthics/InformedConsent/eMERGEModelLanguage2009-12-15.pdf).

While mining the vastness of EMR data greatly expands the potential for conducting GWA studies and related genomic research, it also expands the possible risks to patients privacy as well as concerns about widespread data sharing. eMERGE Phase I is addressing the potential for re-identifiability in EMR data through bioinformatics research to determine the potential for linking large amounts of standardized clinical information, such as ICD-9 codes, back to a patient’s identifying information in their EMR. Methods to extract potentially linkable clinical characteristics and modify them (by grouping or suppression) to minimize threats to the confidentiality of a patient’s genomic information, while maximizing the EMR information preserved, have been developed and disseminated in eMERGE Phase I.
Concerns about genomic research linked to EMRs and widespread data sharing are being addressed by eMERGE’s Consent and Community Consultation group, which explores consent and privacy concerns with participants and community advisory groups. Participant surveys have demonstrated: 1) generally favorable views of sharing; 2) support for sharing where it enhances the research value of the biorepository; and 3) some uneasiness over sharing with commercial entities. Participants have also expressed interest in receiving results of their genomic studies, even if findings are not actionable, but strong preferences and even expectations are expressed for receiving information that could affect clinical care.

eMERGE Phase II studies are expected to expand the phenotype library and ensure its transferability outside eMERGE; increase the diversity of patients and settings; and incorporate GWA results in these patients into their EMRs for clinical use. The key goal of eMERGE Phase II is to begin to explore the value of GWA genotyping information and its demonstrated associations in clinical decision-making, such as to warn clinicians of pharmacogenetically important variants at time of drug prescription or, conceivably, beforehand, or to identify persons at very high (e.g., >99th percentile) genetic risk for a given condition for increased surveillance when/if appropriate. In addition, the advent of federally incentivized meaningful use of EMRs in clinical care through the Health Information Technology for Economic and Clinical Health (HITECH) Act will drive harmonization of EMR data as they are generated and recorded, thus positioning eMERGE to promote use of standardized EMR data for genomic research.

Scientific Knowledge to be Achieved

This funding opportunity and the related RFA-HG-10-010, The Electronic Medical Records and Genomics (eMERGE) Network, Phase II Coordinating Center, will continue to define important potential sources of bias and error in phenotypic and exposure data derived from EMRs, identify approaches for improving phenotyping accuracy for genomic research and to conduct GWA studies of EMR-derived phenotypes. It will also continue to define needs for additional consent and/or community consultation, especially in returning genetic results to EMRs, and using this information in diagnostic and treatment decisions. Most importantly, it will combine available genotyping data with EMR-defined phenotypes and state-of-the-art knowledge of clinically relevant associations to determine how best to improve assessment of disease risk, specificity of diagnosis, opportunities for prevention, and individualization of treatment through decision tools and algorithms incorporated into EMRs used in ongoing clinical care.

Objectives of this Research Program

This FOA will support investigative groups affiliated with existing biorepositories to incorporate current genomic knowledge combined with available genotyping data and state-of-the-art electronic phenotyping and privacy protection methods into clinical research and ongoing clinical care in a Phase II eMERGE expansion. The barriers to incorporating genomic results into clinical practice and approaches for addressing those barriers will be investigated in terms of: 1) technical challenges in extracting and combining valid phenotypic and exposure information from EMR systems; 2) sociocultural challenges in ensuring adequate human subject protections and addressing patients concerns regarding such research; 3) regulatory challenges in requirements for CLIA certification, IRB approvals, and data sharing; 4) scientific challenges in identifying clinically relevant genomic information, linking it to appropriate clinical activities (such as counseling, prevention, diagnosis, and treatment), and continually updating this information as knowledge accrues; 5) informatic challenges in providing effective EMR-linked clinical decision-making tools that provide only the genomic information relevant to clinical care and only when it is needed; and 6) educational challenges in promoting appropriate understanding, interpretation, and action by patients and their practitioners. These complex issues will be pursued in a closely integrated research program in which their interdependence is recognized, fostered, and fully taken advantage of to provide the most comprehensive and effective approaches for incorporating genomic research results into clinical care.

An eMERGE Phase II site will be expected to conduct a comprehensive program of research to promote incorporation of genomic findings into clinical care. Components of such a program might include, but are not limited to:

• Development and/or innovative application or adaptation of approaches to identify persons at very high (e.g. >99th percentile) genetic risk for a given condition to their clinician for increased surveillance or preventive efforts when appropriate, followed by assessment of disease-centered, patient-centered, and/or cost-related outcomes.
• Development and/or innovative application or adaptation of approaches to identify patients carrying pharmacogenetically important variants for modification of treatment strategies when appropriate, followed by assessment of disease-centered, patient-centered, and/or cost-related outcomes.
• Definition and testing of approaches for return of incidental or clinically relevant genetic research results directly to patients, including assessment of impact on relevant outcomes.
• Expansion of the electronic phenotyping library with valid and transportable algorithms followed by wide dissemination to the scientific community.
• Improvements in analytic methods or tools to deal with heterogeneities of genotyping platforms across multiple study sites and phenotype heterogeneity in populations with different demographics, such as race, gender, age, and geographic locations.

In eMERGE Phase II, biorepositories will be supported to expand and validate the eMERGE electronic phenotyping library from 14 phenotypes to at least 40; conduct GWA analyses for phenotypes newly derived from EMRs in Phase II; expand the number and diversity of patients and sites; incorporate GWA genotyping information into EMRs, where feasible, for improving clinical care; and work within the collaborative infrastructure developed in eMERGE Phase I. Sharing of expertise and experience within and outside eMERGE will continue to be a key goal, with the intent of raising the standards for genomic research in biorepositories and its incorporation into medical care in general.

Within the first year of eMERGE phase II, an initial set of GWA-defined variants potentially useful in clinical practice for purposes such as assessment of very high genetic risk for complex disorders or selection or dosing of drugs, along with the levels of evidence supporting them, will be agreed upon by the Steering Committee. Informatics procedures for linking genotyping data on these variants to a patient’s clinical EMR and appropriate decision-support tools (such as warning of an SLCO1B1 variant when prescribing a statin, and recommending lower doses and more frequent monitoring), as well as policy decisions regarding need for CLIA-certification and potential re-consent, will also be developed within this period, so that use of genotyping data in clinical care can be initiated by the beginning of year 2. Consent and certification constraints may limit the number of variants that can be returned to those that can be efficiently re-genotyped in accordance with accepted processes. Approaches for CLIA-certified re-genotyping should consider the potential for limiting assays to the small subset of SNPs identified as having clinical relevance to an individual patient by linking their GWA research results to their EMR and applying appropriate decision-support and education tools. Limited funding for genotyping a subset of variants and/or patients will be made available and the costs for genotyping will be supported separately by NHGRI. The process of defining clinically useful variants, the evidence supporting them, the approvals necessary to implement them in clinical care, and the impact on outcomes will continue in years 2-4. Initial experience from year 2 will be used to inform the approval process and streamline, where possible, the need for repeat genotyping.

eMERGE Phase II will be open to the most competitive existing eMERGE Phase I groups and new groups, and weight will be given to distribution and balance of proposed studies across the fields of EMR and genomics. To be considered for inclusion in eMERGE phase II, all applicants must demonstrate the comprehensiveness of their EMR systems, ideally capturing all or nearly all inpatient and outpatient visits and medications for the past several years. They must also demonstrate their ability to utilize available EMR data for phenotyping, including phenotypes developed in eMERGE Phase I, and to access existing high-quality GWA genotyping data that are linked to these EMR data in patients with sufficient consent for sharing individual-level data through dbGaP and incorporating them into clinical care.

Each application should clearly define the source population, consent process, and numbers and demographics of patients who have genome-wide genotyping data available for further research and integration into clinical care. Numbers and methods of ascertainment of confirmed or possible cases of complex diseases proposed for genomic research should be described, along with definitions of primary and secondary phenotypes and exposures or covariates from EMRs.

Applicants should describe their current EMR system, including data standards (such as SNOMED, HL-7, LOINC, or other Unified Medical Language Systems) used for recording, formatting, and retrieving this information from the EMR, as well as attempts at mapping existing EMR to such standard formats. Data security measures should also be described, including precautions taken to ensure removal of individual identifiers and to prevent inadvertent release of data or identification of participating individuals or groups.

Applicants should describe their existing genotyping data, including genotyping platform(s) and genome-wide technologies used, quality control methods, CLIA certification, and imputation methods, if any. Proposed approaches for incorporating genotyping information, especially incidental genetic findings and findings of potential clinical relevance, into EMRs for use in clinical care should be described. This should include current status of relevant consent and approvals; ability to conduct appropriate consultations with patients, the communities from which they come, and other relevant stakeholders on issues related to incorporating genomic data into individual patients EMR; and plans for obtaining additional consent and approvals as needed. In addition, approaches should be described for identifying clinically relevant genomic information, linking it to appropriate clinical activities, and continually updating it as knowledge accrues, as well as development and implementation of clinical decision tools and education efforts for patients and clinicians.

Adequacy of current informed consent for GWA studies, integration into clinical care, and sharing of individual-level data in databases such as dbGaP, should be clearly described along with any restrictions on research use of the data. Processes and outcomes of consultation with participants, their families, communities, physicians or other care providers, and IRBs specifically related to participation in this FOA should be described. Each application should also clearly describe possible approaches or best practices for re-consent for returning of incidental genetic findings and findings of potential clinical relevance for use in clinical care. Obtaining additional consent, if necessary, will be an allowable cost under the awards to be made, to the extent that resources permit.

Applicants to become new eMERGE sites in Phase II, as well as current Phase I sites, should clearly describe the diversity of their study populations, particularly in regard to children and to minority populations with important health disparities; availability of high-quality GWA genotyping data in 3,000-4,000 patients from platforms testing at least 550,000 SNPs; and public health importance of the traits to be studied. Existing eMERGE sites applying for inclusion in Phase II must also demonstrate their ongoing productivity and contributions to eMERGE collaborative efforts, and describe any additional genotyped and phenotyped samples to contribute to eMERGE Phase II, if available. All applicants should demonstrate their ability to implement existing eMERGE phenotypes reliably and to develop new electronic phenotypes and disseminate them within and outside eMERGE.

No patient recruitment or direct data collection for use in genome-wide studies (such as questionnaires, examinations, or laboratory measures), or sample acquisition will be supported by this FOA. NHGRI will support the genotyping activities of the program, if any are needed, separately; no funding should be requested for genotyping or other genomic technologies.

Program Formation and Governance

The awards funded under this FOA will be cooperative agreements (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award). Close interaction among awardees and the NIH will be required to develop appropriate strategies and tools to carry out this program.

The eMERGE Steering Committee, which will include the Principal Investigators from each Phase II investigative group and Coordinating Center (CC) and the NIH Project Scientist, will continue to define, validate, and disseminate EMR phenotypes; develop informatics tools for enhancing genomic research in biorepositories; and address consent and community concerns related to this research. A key component of eMERGE phase II will be examination of concerns related to return of genotyping data to patients, their physicians, and their EMRs for use in clinical care. Such concerns might include constraints in existing consent documents, potential benefits and harms, lack of CLIA certification, and need to repeat some or all genotyping through CLIA-approved processes.

Early after funding, the eMERGE Phase II Steering Committee will meet to set goals and proposed milestones for Phase II. The Steering Committee will meet three times per year and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as preliminary results. Key co-investigators, and pre- and postdoctoral trainees, in addition to the PIs, will be eligible to attend Steering Committee meetings. PIs are encouraged to include investigators and trainees who are members of under-represented minority groups and those from related disciplines such as bioinformatics, computational biology, public health, social sciences, health services and outcomes research, and translational research where appropriate. The cost of 3-4 persons to attend these meetings, as well as the costs associated with monthly conference calls, should be included in the proposed research budget.

eMERGE will continue to have working groups in areas of interest to the awardees and the funding institute(s). Currently eMERGE has 4 such groups, addressing: Consent and Community Consultation, Informatics, Genomics, and Return of Results. In eMERGE Phase II, a Publications Workgroup may be formed. The tasks of the working groups will include, among other responsibilities: identifying common scientific areas and adjusting projects to accommodate shared interests, identifying novel projects that may result from synergy among the awarded groups, and identifying ways to interact with external ongoing networks and initiatives. Working groups may propose new research collaborations with non-network investigators and organizations, as long as the most or all eMERGE sites have the opportunity to participate, according to criteria established by the eMERGE Steering Committee.

A separate FOA (RFA-HG-10-010) will be issued to support a Coordinating Center (CC) This CC will serve as a centralized resource to facilitate and support eMERGE Phase II.

External Input to the Network

eMERGE will continue to have an External Scientific Panel (ESP). The ESP will be convened to advise NHGRI and the network on how best to incorporate genomic research into clinical care and accelerate the contributions to the field of EMR and genomic research. The eMERGE Steering Committee members will meet with members of the ESP once a year in-person and once a year through teleconference, will receive and consider a report of the ESP’s comments, and will respond with a written letter each time through NHGRI.

Data Sharing under this Initiative

NIH has issued a policy on data sharing in genome-wide association studies (GWAS) (NIH Guide NOT-OD-07-088) and NHGRI expects awardees to follow this policy. Data from this FOA are expected to be handled so as to increase the value of the significant public investment in conducting genome-wide studies on samples from the participating biorepositories. NHGRI intends that Project Datasets (including phenotypic, environmental, covariate and other relevant data) and associated genotyping data from the participating biorepositories be widely shared with the scientific community for research uses through NIH-supported databases such as dbGaP, which contains both an open and controlled access section. Although NHGRI expects all Project Datasets and genetic data from genome-wide studies selected as part of this FOA to be available through a database such as dbGaP, the NHGRI does not intend dbGaP, or any single database, to become the exclusive source of this program’s data. Information such as study protocols, descriptions, and publications are expected to be made available through an open access section of a database such as dbGaP, other public web sites, and/or publication in the scientific literature.

Phenotypic, exposure and genomic data proposed for use in eMERGE Phase II are expected to be deposited to dbGaP prior to award (aside from newly-defined or refined phenotypes developed in the course of Phase II). These data must pass appropriate data quality assessments, conducted in collaboration with NCBI and NHGRI. Simple, unadjusted genomic- or genotype-phenotype associations ( pre-computes ) may be calculated and made available through these resources. Data on newly-defined or revised phenotypes or exposures should be deposited in dbGaP as soon as they are available.

Applicants should indicate their willingness to cooperate with other awardees in the development and design of research and consultation methods, procedures, policies and strategies to be applied in this program. Applicants should also describe prior experience in working as part of a research consortium or other collaborative activities to meet individual study and collaborative goals.

This initiative will not support additional recruiting of human subjects for genome-wide studies, collecting human samples, or for collecting medical or phenotype data to develop or broaden the biorepository. It will not support studies using animal models. Applications that include recruiting human subjects for genome-wide studies, collecting human samples, collecting medical or phenotype data (other than eMERGE-defined EMR-phenotypes) to develop or broaden the repository, support additional genotyping (other than that needed to meet CLIA certification standards, if required) and applications using animal models will be considered non-responsive and returned to the applicant.

Proof of appropriate informed consent and/or IRB approval for using the EMR and previously collected data for genomic research and incorporation into clinical care, or a plan for re-consent, should be provided at the time of application submission. Only applications describing protection of patients privacy and confidentiality will be considered.

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 will use the U01 award mechanism(s).
The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) 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".

2. Funds Available

• The NHGRI expects to award approximately $22 million (total costs) over a four-year period through this announcement;
• An applicant may request a project period of up to four years;
• The NHGRI anticipates funding up to 8 awards in response to this announcement;
• The expected direct costs for each individual research group award are not to exceed $500,000 per year;
• The anticipated start date is July 01, 2011 and the period of performance is August 01, 2011 to July 31, 2015.

The estimated amount of funds available for support of up to 8 projects awarded as a result of this announcement is $5.0 million for fiscal year 2011. Future year amounts will depend on annual appropriations.

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

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

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

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education
• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Small Businesses
• For-Profit Organizations (Other than Small Businesses)
• State Governments
• Other(s):
  • Eligible Agencies of the Federal Government
  • Faith-based or Community-based Organizations.

1.B. Eligible Individuals

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

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, 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://grants.nih.gov/grants/ElectronicReceipt/preparing.htm for instructions).

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

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit more than one application, provided they are scientifically distinct.

Resubmissions. Resubmission applications are not permitted in response to this FOA.

Renewals. Renewal applications are not permitted in response to this FOA.

Section IV. Application and Submission Information

1. Address to Request Application Information

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

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

2. Content and Form of Application Submission

Prepare all applications using the PHS 398 application forms and in accordance with the PHS 398 Application Guide (http://grants.nih.gov/grants/funding/phs398/phs398.html).

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

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a 3h for all PD/PIs. NIH requires one PD/PI be designated as the contact PD/PI for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the Contact PD/PI, et. al. The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

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

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

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

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

3.A. Receipt, Review and Anticipated Start Dates
Letter of Intent Receipt Date: October 17, 2010
Application Receipt Date: November 17, 2010
Peer Review Date(s): February/March 2011
Council Review Date: May 2011
Earliest Anticipated Start Date: July 01, 2011

3.A.1. Letter of Intent

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

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows 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:

Rongling Li, MD, PhD
Office of Population Genomics
National Human Genome Research Institute
5635 Fishers Lane
Suite 3058, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail
Rockville, MD 20852 (FedEx/UPS/courier service; non-USPS service)
Telephone: 301-594-6524
FAX: 301-480-8811
Email: [email protected]

3.B. Sending an Application to the NIH

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

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

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

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Rudy Pozzatti, PhD
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-496-7531
FAX: 301-435-1580
Email: [email protected]

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute. Incomplete and/or non-responsive applications will not be reviewed.

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

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

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at 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 award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information".

Access to and Sharing Data and Specimens

Applicants are expected to document access to DNA specimens, high-quality GWA genotyping data, and phenotypic and exposure data derived from electronic medical records from an existing biorepository. DNA samples should be available for sharing with the program’s genetic facilities at the time of award. For the proposed GWA analyses of EMR-defined phenotypes using available GWA genotyping data, applicants should describe all relevant phenotypic and environmental exposure measures proposed for use in the study, and justify the choice of population and sampling design.

Human Subjects (as part of item E in the application)

The applicant must address human subjects issues, including potential privacy and consent issues to sharing phenotypic/exposure and genetic data from individual patients with the broad scientific community.

Applicants are expected to demonstrate that the proposed uses under this FOA are acceptable to biorepository patients, associated communities, supporting institutions, and other relevant groups. Documentation of any required approvals by the local IRB, (if, for example, one or more participating investigators retain the ability to identify subjects), should also be provided. If additional consent or approval is needed, a plan should be proposed for obtaining re-consent including IRB approval, or an IRB waiver of re-consent for data sharing, and a specific budget for re-consent (if needed) should be provided. Restrictions on data use (such as limitations to a specific disease or condition or to non-commercial investigators) should be clearly described in applications and Institutional Data Use Certifications before award. Investigators are strongly encouraged to provide Project Datasets with the widest possible application and greatest potential value for identifying genetic variants related to complex diseases. Copies of the applicable IRB approvals (if needed) should be included in the grant application.

Applicants are expected to document IRB approval for submitting individual-level phenotype and exposure data and genotyping results to dbGaP or a similar shared data resource as described under Plans for Sharing Research Data, as well as approval for incorporating genomic results into clinical care, or IRB approval for a re-consent process.

PHS398 Research Plan Sections

All application instructions outlined in the PHS398 Application Instructions are to be followed, with the following additional requirements:

• Specific Aims is limited to 1 page.
• Research Strategy, including tables, graphs, figures, diagrams, and charts is limited to 12 pages. See Table of Page Limits.

Budget

This FOA uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

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

Resource Sharing Plan(s)

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

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

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

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

Sharing Research Resources

As this program has been identified as a community resource project, NIH expects that not only data, but also resources generated during the course of the program, such as analytic methods and data standards, will be made rapidly available to the research community and that sharing plans should follow the same principles and spirit as the rapid data release policy. The applicant should provide specific plans for resource sharing and distribution in the application.

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

Review 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 NHGRI and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

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

• Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned an impact/priority score.
• Receive a written critique.
• Receive a second level of review by the National Advisory Council for Human Genome Research.

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

Overall Impact

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five scored review criteria, and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Will the proposed research help to incorporate genomic data into clinical care and evaluate its impact?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation. Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? What advantages does the project offer for investigation of issues and concerns of biorepository patients, investigators, IRBs, and other relevant groups? What is the richness of the biorepository and linked EMR system for future studies that may be based on incorporation of genomic data into clinical care?

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Are the phenotype and exposure measures derived from EMR, and available GWA genotyping data, of sufficient quality and completeness to provide maximal scientific value, or do they have the potential to be such within the project period? Are the biorepository’s EMR and informatics system, consent and governance structure, and educational/outreach efforts capable of incorporating genomic results and decision-making tools into clinical care?

Environment. Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Have the investigators documented their ongoing or future access to data and samples from the biorepository in a highly-effective collaborative relationship, and their ability to commit the biorepository data, EMR, patients and clinicians, in consultation with appropriate decision-makers, to participate in this FOA?

Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Protections for Human Subjects. For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

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

Biohazards. Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmission Applications. Resubmissions are not allowed for this FOA.

Renewal Applications. Renewals are not allowed for this FOA

Revision Applications. Revisions are not allowed for this FOA.

Additional Review Considerations

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

Applications from Foreign Organizations. Foreign applications are not allowed for this FOA.

Select Agents Research. Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

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

Selection Process

The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by peer review
• Availability of funds
• Relevance of the proposed project to program priorities
• Compliance with resource sharing policies
• Complementarity to and synergy with other funded projects

Additional criteria for award will include:

• Public health significance of diseases and traits to be studied
• Programmatic balance among diseases
• Diversity of proposed populations in terms of age, gender and race/ethnic representation
• Availability of high-quality GWA data assaying at least 550,000 SNPs in 3,000-4,000 patients; data on larger numbers and data generated in a CLIA-certified environment would be considered advantages
• Consent for individual-level data sharing in dbGaP and return of data to EMRs for use in clinical care
• Completeness and flexibility of the site’s EMRs for incorporating genetic information into clinical practice
• Ability to implement existing eMERGE phenotypes
• Willingness of PI and major co-investigators to collaborate with the NIH and with other investigative groups participating in the program
• Quality and comparability of EMR data and systems for incorporation of genomic data into clinical care
• For existing Phase I sites, ongoing productivity and collaboration in eMERGE

The awardee must agree to the Cooperative Agreement Terms and Conditions of Award in Section VI.2.A. Award Administration Information.

3. Anticipated Announcement and Award Dates

It is anticipated that awards will be made by July 01, 2011.

Section VI. Award Administration Information

1. Award Notices

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

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

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 Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

The NIH has identified this program as a community resource project. As such, the program aims to function openly by making all data available to the scientific community in a timely manner prior to publication, with suitable restrictions for protection of human research subjects. It is expected that NIH will establish a common data release policy for GWA studies prior to the anticipated award date for the program, and all awardees will be expected to agree to the policy; see Request for Information (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

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 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:

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a study-wide Steering Committee to share design and analysis techniques and promote comparability across studies wherever possible.
• Implementing Steering Committee recommendations for improving data collection, electronic phenotyping, and standardization in their biorepository, as appropriate and feasible.
• Implementing Steering Committee recommendations for evaluating concerns among patients, clinicians, investigators, IRBs, and other relevant groups in their biorepository regarding incorporation of genomic data into clinical care.
• Sharing detailed phenotypic and environmental data derived from EMR systems and collected according to protocols validated within eMERGE or a similar definitive source with databases such as dbGaP.
• Determining needs for additional consent, IRB approval, and/or CLIA-certified genotyping prior to incorporating genomic results into genotyped patients clinical care.
• Identifying results most appropriate to report to patients and to extract using clinical decision tools, and appropriate actions to be taken in patients carrying these variants.
• Developing and implementing appropriate educational resources for patients and their clinicians.
• Evaluating impact of reporting genotyping results to patients and their clinicians on disease-centered, patient-centered, and cost-related outcomes.
• Sharing results according to the data sharing policy agreed to between the NHGRI and the applicant.
• Adhering to policies regarding data access, publication, and intellectual property established by NIH and the Steering Committee for this program.
• Adhering to NIH policies regarding genome-wide association studies and other policies that might be established during the course of this activity, as appropriate.
• Cooperating with other awardees in the development and design of research methods, protocols, tools, and strategies.
• Abiding by common definitions, protocols, procedures, etc. as chosen by majority vote of the Steering Committee.
• Accepting and complying with study policies established by NIH, and with additional non-conflicting policies approved by the Steering Committee.
• Cooperating with other awardees in the publication and dissemination of program results and the eventual release to the scientific community of methods, tools, and results, and other resources.
• Not disclosing confidential information obtained from other members of the program.
• Notifying the Project Scientist of all major interactions with another member of the Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and External Scientific Panel.
• Attending and participating in Steering Committee meetings and accepting and implementing the guidelines and procedures of the External Scientific Panel and NIH, as appropriate.

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.

The Project Scientist is a scientist of the NHGRI staff who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff 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 program and that NIH staff will be given the opportunity to offer input to this process. The Project Scientist will participate as a member of the Steering Committee and will have one vote. The Project Scientist will have the following substantial involvement:

• Participating with the other Steering Committee members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Project Scientist will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NIH, and as an information resource for the awardees about genome research activities. The Project Scientist will also coordinate the efforts of the program with other groups conducting similar studies.
• Attending all Steering Committee meetings as a voting member and assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist will be responsible for working with the Coordinating Center as needed to manage the logistic aspects of the program.
• Reporting periodically on the progress of the program to the Director, NHGRI, and to the National Advisory Council for Human Genome Research.
• Retaining the option to recommend the withholding or reduction of support from any project that fails to achieve its goals or comply with the Terms and Conditions of award.
• Serving as a liaison between the Steering Committee and the Expert Scientific Panel, attending Expert Scientific Panel meetings in a non-voting liaison member role, and arranging for timely preparation and distribution of meeting minutes.
• Serving on subcommittees of the Steering Committee and the Expert Scientific Panel, as appropriate.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.
• Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the program.

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 an NIH Project Scientist.

• If re-consent is necessary, plans for re-consent, including consent forms, must be reviewed by the NHGRI Program Official prior to implementation.
• The Program Official may withhold or reduce support from any awardee that fails to achieve its goals or comply with the Terms and Conditions of Award.

Other NHGRI staff may assist the awardees as designated by the Program Official.

2.A.3. Collaborative Responsibilities

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop appropriate strategies and tools to incorporate genomic results into clinical care. The awardees and the Project Scientist will meet as the program Steering Committee three times per year and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. Key co-investigators and pre- and postdoctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, in addition to the PIs, are eligible to attend these meetings.

The Steering Committee will serve as the main scientific body of the program. The Steering Committee will be responsible for coordinating the activities being conducted by the program. The Steering Committee membership will include one NHGRI Project Scientist and the P.I. from each awarded cooperative agreement. The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired. It is anticipated that additional coordination mechanisms may be set up with other U.S. and international groups that may collaborate with the program.

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.

To address particular issues, the Steering Committee may establish working groups as needed, which will include representatives from the program and the NIH and possibly other experts. Awardees agree to work collaboratively to:

• Share experience and expertise across participating biorepositories and develop guidelines on consultation and consent for such research, and on collecting, formatting, depositing, and documenting phenotype and exposure data for databases such as dbGaP, for dissemination to other biorepositories.
• Review documentation of existing consent processes, community consultation, and IRB approvals in participating biorepositories to identify best practices for genomic studies, data sharing, results reporting, and incorporation into clinical care.
• Develop approaches for evaluating concerns among biorepository patients, clinicians, investigators, IRBs, and other relevant groups regarding addition of genomic technologies to the biorepository and widespread data sharing.
• Establish best practices for IRB interactions, patient consent and results reporting, and for collecting, formatting, documenting, and sharing data.
• Define optimal approaches for incorporating genomic research into clinical care so as to speed the translation of genomic findings into improved genetic risk assessment, prevention, diagnosis, treatment, cost-efficiency, and, ultimately, improved health and reduced disease.

External Scientific Panel

An External Scientific Panel (ESP) will continue to evaluate the progress of the program. The ESP established in Phase I will continue to provide recommendations to the National Advisory Council for Human Genome Research about the progress and scientific direction of all components of the program.

The ESP is currently composed of five senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed. The ESP will meet at least twice a year, one in-person meetings and one telephone conference. At least once a year, there will be a joint meeting with the Steering Committee to allow the members of the both the ESP and the Steering Committee to interact directly. Twice a year the ESP will make recommendations regarding progress of the program to the National Advisory Council for Human Genome Research about changes, if any, which may be necessary in the program.

2.A.4. Dispute Resolution 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 Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

Awardees will be required to submit electronically quarterly reports that describe the status and progress for all aspects of the study. The quarterly report will be used as a management tool for the NIH and the program’s Steering Committee. Reporting on cost will also be required.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

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

1. Scientific/Research Contacts:

Rongling Li, MD, PhD
Office of Population Genomics
National Human Genome Research Institute
5635 Fishers Lane
Suite 3058, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail
Rockville, MD 20852 (FedEx/UPS/courier service; non-USPS service)
Telephone: 301-594-6524
FAX: 301-480-8811
Email: [email protected]

2. Peer Review Contacts:

Rudy Pozzatti, PhD
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-496-7531
FAX: 301-435-1580
Email: [email protected]

3. Financial or Grants Management Contacts:

Ms. Cheryl Chick
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9306
Bethesda, MD 20892-9306 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-435-7858
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 (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

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.

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

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

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

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-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

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

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

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

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

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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

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.