Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Funding Opportunity Title

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

Activity Code

U01 Cooperative Agreement

Announcement Type

New

Related Notices
  • August 23, 2011 - Frequently Asked Questions (FAQs) for RFA-HG-11-022. See NOT-HG-11-027.
Funding Opportunity Announcement (FOA) Number

RFA-HG-11-022

Companion FOA

RFA-HG-10-009: The Electronic Medical Records and Genomics (eMERGE) Network, Phase II – Study Investigators (U01)
RFA-HG-10-010: The Electronic Medical Records and Genomics (eMERGE) Network, Phase II – Coordinating Center (U01)

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.172; 93.865

FOA Purpose

The purpose of this funding opportunity announcement (FOA) is to provide support for existing pediatric biorepositories with electronic medical records 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.     

Dates
Posted Date

July 6, 2011

Open Date (Earliest Submission Date)
Letter of Intent Due Date

August 13, 2011

Application Due Date(s)

September 13, 2011, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

November/December 2011

Advisory Council Review

January 2012

Earliest Start Date(s)

May 2012

Expiration Date

September 14, 2011

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Nature of the Research Opportunity

The purpose of this funding opportunity announcement (FOA) is to provide support for existing pediatric biorepositories with electronic medical records and genome-wide genotyping data 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 is being expanded to incorporate this knowledge into clinical research and ongoing clinical care in eMERGE Phase II.  Up to 8 adult biorepositories and a Coordinating Center are expected to be funded in FY11-FY14 under RFA HG-10-009 (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-10-009.html) and RFA HG-10-010 (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-10-010.html. Pediatric Study Investigators (PSI) to be funded through this solicitation are expected to join eMERGE Phase II in Spring 2012. 

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 on 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 assent/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.  “Pediatric” and “children” mean study subjects ages 21 or under at the time of EMR-defined phenotyping and collection of DNA for GWA genotyping, regardless of their ages when the actual GWA genotyping and EMR-defined phenotyping was done.

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 children and other under-represented populations such as racial/ethnic minorities; 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 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 in children.  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 pediatric 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 concerns of patients and their parents/guardians 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, their parents/guardians, 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 pediatric 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:

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.  Expansion of agreed-upon variants and informatics procedures relevant to children will occur late in year 1 when the PSI have joined the Network.  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 child 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 children 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. 

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 children with sufficient assent, where appropriate, and parental/guardian consent for sharing individual-level data through dbGaP and incorporating them into clinical care. 

Each application should clearly define the source population, assent and consent process, and numbers and demographics of children 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, 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 assent, consent, and approvals; plans for reconsent at the age of majority; ability to conduct appropriate consultations with patients, their parents or guardians, 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 assent, consent, and approvals as needed consistent with 45CFR46 Subpart D on children's research, available at http://ohsr.od.nih.gov/guidelines/45cfr46.html#subpartd.  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 children, their parents/guardians, and clinicians. 

Adequacy of current informed assent and parental/guardian 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 parents/guardians, 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 should clearly describe the diversity of their pediatric study populations, particularly in regard to minority populations with important health disparities; availability of high-quality GWA genotyping data in 3,000-4,000 children from platforms testing at least 600,000 SNPs; and public health importance of the traits to be studied.  Applicants should include the full age range of children, as described in NIH Guidelines (http://grants.nih.gov/grants/guide/notice-files/not98-024.html)and in the International Conference on Harmonization (ICH) E11 guidelines (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4/E11_Guideline.pdf), in roughly similar proportions to those in the US population, unless a strong justification is given for proposed substantial deviations.  Applicants should also 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 Program Director/Principal Investigators (PD/PI)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 (as appropriate), their parents or guardians, 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 Pediatric Study Investigators will join the eMERGE Steering Committee to set goals and proposed milestones.  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 PD/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. 

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.  Consistent with achieving the goals of this program, NHGRI expects that Project Datasets (including phenotypic, environmental, covariate  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), consistent with achieving the goals of the program.  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.  

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New

The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NHGRI and NICHD intend to commit $1.6 million in FY 2012.

Award Budget

The expected direct costs for each individual research group award are not to exceed $500,000 per year for each of the three years.

Award Project Period

May 1, 2012 through April 30, 2015; a 36-month project period.

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

Eligible Organizations

Higher Education Institutions

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

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

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

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator)

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

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

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

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: lir2@mail.nih.gov

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

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

PHS 398 Research Plan Component

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

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies; GWAS) as provided in the SF424 (R&R) Application Guide.

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

3. Submission Dates and Times

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

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.   

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD/PIs must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.  

In order to expedite review, applicants are requested to notify the NHGRI Review Office by email at  pozzattr@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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

The applicant must address human subjects issues, including potential barriers to sharing phenotypic/exposure and genetic data from individual patients with the broad scientific community.  Approaches for obtaining pediatric patients' assent, as appropriate, and fully informed consent at the age of majority, must be clearly described.

Applicants are expected to demonstrate that the proposed uses under this FOA are acceptable to pediatric biorepository patients, their parents/guardians, 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.  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.

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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 review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? 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 pediatric biorepository patients, their parents/guardians, investigators, IRBs, and other relevant groups?  What are the potential value and utility 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 appropriate for pediatric patients and 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, parents/guardians, and clinicians, in consultation with appropriate decision-makers, to participate in this FOA ?     

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Protections for Human Subjects

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

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHGRI , in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:

Additional criteria for award will include:

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.      

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) 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.

The PD(s)/PI(s) will have the primary responsibility for:

NIH staff 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

Areas of Joint Responsibility include:

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.

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:

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 seven 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.

Dispute Resolution:

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 regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

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

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement. 

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.      

Application Submission Contacts

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

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

Scientific/Research Contact(s)

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: lir2@mail.nih.gov

Lynne Haverkos, MD, MPH
Child Development and Behavior Branch
Center for Research for Mothers and Children
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
6100 Executive Boulevard, Room 4B05G
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: 301-435-6881
Fax: 301-480-0230
Email: Lynne.Haverkos@nih.gov

Peer Review Contact(s)

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: pozzattr@mail.nih.gov

Financial/Grants Management Contact(s)

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: ChickC@mail.nih.gov

Bryan S. Clark, M.B.A.
Chief Grant Managements Officer
Eunice Kennedy Shriver National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: (301) 435-6975
FAX: (301) 402-0915
Email: clarkb1@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


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