It is critical that applicants follow the Research (R) Instructions in the SF424 (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.

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

This Funding Opportunity Announcement (FOA), RFA-HG-19-015, invites applications to participate as a Coordinating Center (CC) in the Electronic Medical Records and Genomics (eMERGE): Genomic Risk Assessment and Management Network, in collaboration with Clinical Sites (CS, RFA-HG-19-013) and additional CS with enhanced diversity (RFA-HG-19-014). This network will use biorepositories linked with electronic medical records (EMRs) for genomic research by developing, evaluating, and disseminating genomic risk assessment and management tools for clinical use. Specifically, this effort will use genomic variant and EMR data to: 1) calculate validated polygenic risk scores (PRS) for several complex diseases retrospectively using available datasets, validate them against EMR-derived electronic phenotypes, and disseminate the distributions and associations of these PRS; 2) develop EMR-based methods to communicate genomic risk profiles and relevant clinical recommendations based on PRS, family history, and other clinical data; 3) recruit and genotype 20,000 individuals of diverse ancestry, prospectively calculate their genomic risk for selected electronic phenotypes, and provide risk estimates and management recommendations to them and their providers; and 4) use EMR-based methods to assess uptake of risk-reduction recommendations and impact on related clinical outcomes.

The eMERGE Genomic Risk Assessment and Management Network is not intended to support a large-scale randomized controlled clinical trial of genomic risk assessment. Because it returns results to patients, and prospectively assigns an intervention evaluating the effect on patients, it meets the 2015 revised NIH definition of a clinical trial as described in NOT-OD-15-015 and below.

Definitions. For the purposes of this FOA, the following definitions are used:

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 linked to electronic personal health information in these individuals. The biospecimens may have been collected in the course of clinical care or as part of a research resource.

Clinical Information refers collectively to a patient’s non-genetic medical information such as personal medical history, clinician-collected family history, physical and laboratory measurements, lifestyle habits, and environmental exposures/social history.

Clinical outcomes refers to any biomedical or behavioral measure to determine the effectiveness of healthcare delivery, including measures such as health status, disease risk factors, lifestyle or clinical treatment changes, disease burden, cost-effectiveness, etc.

"Diversity" and diverse populations refer to the inclusion of persons who come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes.

Electronic medical records (EMRs) are defined as computerized data obtained in the course of clinical care that can be electronically accessed, manipulated, shared, and analyzed, with appropriate consent and patient protections, for research purposes and ongoing clinical care and quality improvement.

Electronic phenotypes (e-phenotypes) are defined as electronic algorithms that utilize diverse types of information from EMRs, computerized laboratory and imaging data, etc., to classify patients as having or not having a specific phenotype with a high degree of accuracy and reproducibility.

European ancestry (EA) refers to a person of European descent without significant admixture from the indigenous Americas (the latter typically including persons considered to be of American Indian, Alaska Native, Hispanic or Latino ancestry).

Genomic risk assessment is a process to quantitatively assess an individual’s probability of developing a particular disorder using mathematical or statistical models and incorporating such factors as allele frequencies of known genomic risk variants, personal health history, family medical history, physical characteristics, and laboratory measurements.

Genomic risk estimate is similar to polygenic risk score, but also incorporates additional information such as personal health history, family medical history, physical characteristics, and laboratory measurements.

Minority (also non-European ancestry, non-EA ) refers to persons who come from the following minority racial/ethnic populations: African American or Black, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander (e.g., Guam, Tonga), or Latino or Hispanic. (https://www.nimhd.nih.gov/docs/2009-2013nih_health_disparities_strategic_plan_and_budget.pdf).

Patients refers collectively to adults as well as minors and their parents or guardians; all participants recruited to this study are expected to be patients with existing and accessible EMRs.

Polygenic risk score (PRS) is a numeric estimate based on the presence of multiple genomic risk variants and their associated risk estimates (odds ratios, relative risks, etc.) to predict an individual s risk of developing a disease. PRS as used here comprises only allelic data and no other non-genetic indicators of risk.

Risk management refers to steps taken, typically due to a healthcare provider’s actions or advice, to modify a person’s risk of developing disease.

"Secondary findings refer to results unrelated to the reason for ordering the genomic test but which may be of medical value (http://www.ncbi.nlm.nih.gov/pubmed/23788249).

"Underserved" refers to populations who are "medically underserved as defined by the Health Resources and Services Administration (HRSA) (https://bhw.hrsa.gov/shortage-designation/muap).

This FOA is open to all investigators who meet the qualifications described below. To ensure that maximal scientific benefit is derived from this significant public investment, this funding opportunity has a goal to advance and accelerate research by supporting rapid sharing of the resulting data with the broad scientific community for research use, through community resource databases such as the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-Space (AnVIL), Database of Genotypes and Phenotypes (dbGaP), or ClinVar.

NHGRI initiated the eMERGE Network in fiscal year (FY) 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 EMRs. From FY2011-2014 eMERGE expanded to include pediatrics and pharmacogenomics and 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 FY2015-2019 eMERGE is continuing this research, leveraging data from large biorepositories as well as sequencing data derived from two eMERGE Network genome sequencing and genotyping facilities to build upon the genome sequencing, phenotyping, and implementation methods and knowledge generated previously and to assess penetrance of variants in 109 clinically actionable genes. In prioritizing opportunities for the future of eMERGE, NHGRI sought wide input in a series of workshops including: eMERGE & Beyond: The Future of Electronic Medical Records and Genomics (https://www.genome.gov/27569445) and Genomic Medicine XI: Research Directions in Genomic Medicine Implementation (https://www.genome.gov/27571869). From these workshops, it has become clear that a major barrier to large-scale adoption of genomics-based risk assessment and management is the integration of genomic information and tools into EMRs with associated electronic clinical decision support (eCDS).

If genomic risk assessment is to be utilized effectively by clinicians, the information will need to be seamlessly integrated into EMRs and delivered with recommended clinical actions in a user-friendly manner, but such EMR tools have yet to be developed and validated. If EMR-derived phenotypes are to be used as outcomes for assessing the impact of genomic risk reporting, their predictability by these methods should be defined. To date, development and validation of PRS has been conducted almost exclusively in European ancestry (EA) populations; their predictive value should be assessed in non-EA populations. PRS based on e-phenotypes are needed in non-EA populations as well and will help to leverage clinical informatic tools developed in EA populations, thereby reducing barriers for genomic medicine implementation in patients of diverse ancestries. Patient and provider uptake of risk reduction recommendations across a range of conditions should be assessed. The added value of genotypic information over standard clinical data in a variety of complex diseases and demographic subgroups should also be assessed.

The objectives of the eMERGE Genomic Risk Assessment and Management Network are to support Clinical Sites involving diverse populations and a CC to conduct and validate existing genomic risk assessment methods in a largely retrospective analysis of existing data; develop a single, network-wide, combined genomic risk assessment and management protocol that estimates risk for common, complex diseases of public health importance and provides guideline-based management recommendations through the EMR for patients at highest risk; and then apply the risk assessment and management protocol to a cohort of 20,000 individuals to assess prospectively the ability and impact of integrating this information into clinical care.

During the five-year project period, the eMERGE Genomic Risk Assessment and Management Network will support 6-10 Clinical Sites (CS) and a Coordinating Center (CC). Much of the first year will focus on utilizing existing genotype and e-phenotype data to validate a genomics-based risk assessment approach for roughly 20 common, complex diseases using publicly available data on 83,000 eMERGE participants and other available data from studies such as All of Us or the Million Veteran Program. This initial effort will focus on widely validated (and preferably peer-reviewed) PRS and will assess the predictive value of these scores for e-phenotypes in both EA and non-EA populations. It will also include developing and validating genomic risk estimates utilizing risk information in addition to allele frequencies and associated risks and incorporating them into disease-specific risk assessment and management protocols. These protocols will utilize EMR-based methods to communicate genomic risk assessments (quantitative genomic risk estimates plus appropriate explanatory information) and clinical recommendations for patients at highest risk based on professional guidelines. A subset of roughly 15 common, complex disease protocols with the most predictive genomic risk estimates and most effective and feasible risk reduction recommendations will be selected for network-wide implementation.

Following this developmental work, CS applying to RFAs HG-19-013 and HG-19-014 will collectively recruit and consent 20,000 patients who have not previously received genomic risk information. Applicants to this RFA (HG-19-015) will coordinate with the CSs to recruit 20,000 patients. The cohort will undergo genomic risk assessment using a clinically certified (preferably commercially available) SNP array assaying variants predictive of modifiable disease risk. Other clinically available, large-scale measures of genomic variation or function such as exome sequencing or expression arrays may be considered as the field evolves, if feasible within programmatic and funding constraints. The genomic risk assessment will also include online tools for patient-entered family history information and other clinical data to be extracted from the EMR. Individualized genomic risk assessments for each of the roughly 15 conditions will be estimated and provided to all patients and their clinicians, with those at highest risk (likely the top 2%, or possibly those at 3-fold or greater risk compared to the remaining population) receiving specific, guideline-based risk-reduction recommendations. Individualized risk estimates will be reported to providers and patients along with guideline-based risk management information through eCDS incorporated in the EMR. Actions taken on these recommendations, such as increased disease screening and surveillance or changes in therapy, will be assessed through the EMR, and changes in modifiable risk factors will be identified and quantified. CC will be expected to coordinate the capture of all network-wide data needed to assess the impact of risk assessment and management recommendations on patients outcomes.

Other clinical risk factors (such as hypertension, obesity, and health behaviors) as well as medication use and e-phenotypes for pre-existing disease, will be extracted from EMRs. Outcomes of interest will include proportions of patients receiving risk reduction recommendations in whom at least one risk-reduction strategy (such as a screening test or a drug prescription change) was applied, estimating that roughly 50% uptake will be needed for the genomic risk assessment and communication effort to be deemed clinically useful. Uptake rates lower than that during the study’s course could prompt stakeholder consultation and revisions of the tools as needed. Outcomes to be assessed could also include change in a quantifiable disease measure (such as bone mineral density or cholesterol level) as a pilot measure of the impact of risk reduction recommendations. CC will be expected to collect all outcome data from the CSs to enable network-wide analyses.

The design and components of the genomic risk assessment, including the guideline-based risk reduction recommendations to be delivered, will be proposed by each applicant; a single network-wide combined protocol for risk assessment, risk modification, and outcome ascertainment for roughly 15 common, complex diseases will be finalized by consensus among the awardees and NHGRI.

In this five-year period, the eMERGE Genomic Risk Assessment and Management Network will also support biorepositories to expand and validate the eMERGE library of e-phenotypes such as those available in eMERGE Phenotype KnowledgeBase (PheKB), by focusing on phenotypes related to the common, complex diseases selected for genomic risk assessment and management. Continued enhancements to phenotyping tools will be needed to increase phenotyping efficiency and transportability. In its most recent phase, eMERGE e-phenotyping efforts included a conversion to the Observational Medical Outcome Partnership (OMOP) common data model, as well as the incorporation of Natural Language Processing (NLP). For this next phase (FY2020-2024), eMERGE Clinical Sites will advance e-phenotyping by using the OMOP common data model and integrating NLP into e-phenotype development. The network will also conduct association analyses using genotyping data and existing genome-wide genotyping and sequencing data for available e-phenotypes.

It is anticipated that for the FY2020-2024 phase of eMERGE, datasets from all phases of the eMERGE Genomic Risk Assessment and Management Network will be made available through AnVIL, a scalable and interoperable platform. AnVIL was established by NHGRI to reduce barriers for collaboration by leveraging a cloud-based infrastructure for democratizing genomic data access and sharing, and for securely computing across large genomic related datasets.

The eMERGE Genomic Risk Assessment and Management Network will incorporate genotyping information into EMRs using the Fast Health Interoperability Resource (FHIR) standard for transmitting clinical reports where feasible and will utilize the collaborative infrastructure developed in prior phases of eMERGE. Sharing of expertise and experience within and outside eMERGE is a key goal, with the intent of incorporating robust genomic technologies and approaches into medical care as appropriate.

NHGRI intends to support a single, network-wide, combined risk assessment and management protocol that can be implemented across a large and diverse patient population, address issues of public health significance, and have a high potential to inform future clinical practice. Each applicant should offer an approach to accomplishing the aims of this research project and describe their reasons for choosing their approach. A single network protocol will be established during the first year after the award.

Examples of topics that could be addressed in evaluating genomic risk assessments include:

• Impact of genomic risk assessment on patient management, healthcare utilization, clinician workload, and patients health behaviors and attitudes
• Assess patient understanding and/or acceptance of genomic risk assessments
• Added value of genomic variant information and/or family history information to other clinically derived risk information
• Effectiveness of genomic risk assessment in identifying and managing individuals at high risk of Mendelian conditions
• Effectiveness and ease of use of genomic CDS tools in returning genomic risk assessment results and making them available for clinical use
• Uptake of risk reduction strategies among patients and providers
• Value of NLP and the OMOP common data model in expanding and enhancing electronic phenotyping
• Value of AnVIL and similar data resources in reducing barriers to, and increasing efficiencies of, genomic medicine research and implementation

Applicants are not limited to addressing this list of topics and are encouraged to contact NHGRI to discuss their proposed topic(s) to ensure pertinence to the objectives of this FOA.

The CC will play a major research role in the coordination of the development, finalization, implementation, and distribution of the risk assessment and management protocols; preparation and distribution of network-wide datasets for distributed analysis; joint analyses of network-wide data including validation of existing risk algorithms; and analysis of clinical and cost-effectiveness outcomes and subgroup effects, and coordination of protocol finalization and implementation. The CC will also collect data on patient recruitment and enrollment and will report progress to the Steering Committee (SC), External Scientific Panel (ESP), and NHGRI. These data will be used to inform SC evaluation and recommendation of protocol modifications as needed. The CC will also be responsible for contracting and coordinating all genomic and other centralized testing of biospecimens. The CC will ensure that robust and efficient informatics tools are established at the CSs and CC to collect, store, transmit, and analyze the data as required by the common risk assessment and management protocol. The CC will coordinate transfer of deidentified CS data to an NHGRI-approved data repository for network-wide analysis, and will be responsible for sharing the network dataset with the broader research community through submission to controlled access databases such as AnVIL, dbGaP, or ClinVar.

The CC will also perform traditional network coordination and support activities and will promote standardization of terminologies and methodologies to be used. Maintaining patient involvement throughout the study is key to the success of this project. The CC will be responsible for working with the CSs to establish and implement a plan for continued patient involvement network-wide. It is encouraged that the investigators participating in the CC come from diverse backgrounds, such as racial and ethnic minority populations, to ensure a diversity of experience and perspectives.

The CC awardee will work collaboratively with the eMERGE CS and NHGRI to conduct a comprehensive genomic risk assessment and management study. This FOA supports the coordination and facilitation of the activities of this program. In addition, the CC will have primary responsibility for overseeing the drafting, submission, and approval of a single, shared IRB as described in NIH’s Single IRB Policy for Multi-site Research. The CC will also be responsible for registering the network in, and submitting results information submitted to, ClinicalTrials.gov as described in NOT-OD-16-149, NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information. .

Due to regulatory requirements for using research results in clinical care, genetic testing will be expected to be performed Laboratory Improvement Amendments (CLIA). It is expected that the CC will establish a contract with a CLIA certified genomic testing laboratory that is willing and able to transmit the genomic data and metadata to the CS and CC data repositories. The applicant should document the ability of the Fgenetic testing provider to handle the logistical aspects of clinical testing such as shipping, receipt, tracking, and reporting, as well as participating as needed in development of protocols for sample collection, transmittal, and reporting for the Network. In addition, a Food and Drug Administration (FDA) Investigational Device Exemption (IDE) may be needed for new sequencing methods used in clinical care, separate from the requirement for the test to have been conducted within a CLIA-certified environment. The Coordinating Center should be prepared to support the Clinical Groups in discussing the need for an IDE with the study’s IRB and documenting the outcome of those discussions, and in engaging in pre-submission discussions with the FDA. These typically involve submission of actual study protocols, including the entire sequencing pipeline from sample preparation to data analysis.

CSs are responsible for conducting the research (patient recruitment and implementation of all study procedures) and disseminating research findings in collaboration with the CC and NHGRI. In conjunction with the CC and NHGRI, CSs will be responsible for finalizing, prioritizing, and implementing the combined, network-wide genomic risk assessment and management protocol, developing common definitions and standardization across disease-specific protocols, assessing uptake of risk reduction recommendations and other process and health outcomes, and analyzing and interpreting research results. Each CS will participate in a cooperative and interactive manner with all other CSs and the CC in all aspects of the network, including developing network procedures and working groups; finalizing protocols and costs; developing a collaborative IRB process for submission to a single, shared IRB as described in NIH’s Single IRB Policy for Multi-site Research; writing template informed consents; delivering risk reduction recommendations; and assessing clinical uptake and outcomes. As noted above, retention of patients will be a new and key aspect of this project. The CSs will work collaboratively with each other and the CC to establish a plan for patient engagement and retention across the network. The CSs will also need to work collaboratively with each other and the CC for timely and efficient transmission, in as automated a fashion as possible, of data needed for the CC to monitor recruitment, retention, progress, and study outcomes across the entire network. It is encouraged that the investigators participating in the CSs come from diverse backgrounds, such as racial and ethnic minority populations, to ensure a diversity of experience and perspectives. Applicants should refer to RFA-HG-19-014 for more details on the enhanced diversity eMERGE CSs.

NHGRI is responsible for organizing and providing overall support and management for eMERGE through the NHGRI Program Office and Grants Management Branch. In addition to regular grant stewardship, the NHGRI Project Scientist(s) will be involved substantially with the awardees, consistent with the Cooperative Agreement mechanism. The NHGRI Project Scientist will be a voting member of the SC.

A SC comprised of Program Director(s)/Principal Investigator(s) [PD(s)/PI(s)] of the CSs and the CC, and the NHGRI Project Scientist(s), will constitute the main governing body of eMERGE. All major scientific decisions will be determined by majority vote of the SC. It is anticipated that the SC will meet at least twice per month by conference call and four times per year in-person meetings in the first year as needed for protocol development, and then monthly by conference call and three times per year in-person meetings in years 2-5. The SC will have primary responsibility for the general organization of eMERGE, finalizing disease-specific and combined risk assessment and management protocols, facilitating the conduct and monitoring of the combined protocol, reporting results in a timely manner, and working with NHGRI to disseminate the findings. The SC will be responsible for creating a plan for clinical and genomic data sharing consistent with NHGRI policies during the first year of the program. Working groups of the SC will be established to address specific activities, such as recruitment and retention, publications and presentations, genomic testing, risk assessment and management, clinical decision support, and quality control and assurance. Awardees will be expected to accept and implement policies approved by the SC.

Awards made under this FOA and the companion FOAs will be cooperative agreements (see Section VI.2., 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.

Selection of genomic risk assessment and management protocols (one for each disease) for support in eMERGE will be based on the accuracy with which each protocol predicts a common, complex disease; the public health importance of that disease; the nature, complexity, and potential impact of the associated risk management protocol, and the availability of funding. Genomic risk assessments to be conducted in eMERGE will be selected from among those proposed by successful applicants in response to this FOA as well as any newly-emerging, well-validated risk assessments available at the time of award, as agreed upon by the SC. The estimate of 15 disease-specific protocols to be implemented allows for a broad range of conditions to be studied (such as cardiovascular, cancer, diabetes, musculoskeletal, neuropsychiatric, opioid dependence, and pediatric phenotypes) and will identify roughly 25% of the cohort as being at highest (top 2%) risk and eligible to receive risk reduction recommendations for at least one condition. While genomic risk estimates will be provided to all patients for all conditions, risk reduction recommendations will only be provided to those at the highest risk as consistent with guideline-directed care. Limited support may be available for recommended additional testing and other risk management interventions not covered by insurance in these highest risk patients, as funds permit. If disease-specific protocol development leads to more than the top 2% per disease (or 25% overall) needing guideline-directed care, other resources will need to be identified to support providing this care or other conditions may need to be selected for implementation.

Soon after funding, the eMERGE SC will meet to set network-wide goals for the five-year project period. The SC is expected to establish working groups to facilitate collaborative work and standardize approaches. PDs/PIs or working groups may propose new research collaborations with non-network investigators and organizations, as long as the activities are conducted in accordance with the policies and practices of the eMERGE Genomic Risk Assessment and Management Network. Key collaborators and pre- and postdoctoral trainees, especially those who are members of underrepresented minority groups or those from different but related disciplines, will be eligible to attend SC meetings in addition to the PD(s)/PI(s).

eMERGE Genomic Risk Assessment and Management Network will have an External Scientific Panel (ESP). The ESP will advise NHGRI and the network on performance and overall progress of eMERGE. The ESP will consist of experts in genomic risk assessment and management, genomic medicine, bioethics, biostatistics, informatics and clinical coordination. An NHGRI scientist will serve as the Executive Secretary to the ESP. The ESP will be appointed by NHGRI and will meet semi-annually (one conference call and one in-person meeting per year). Following each meeting, the ESP will submit recommendations to NHGRI, from which NHGRI will prepare a report for PD(s)/PI(s). The eMERGE SC members will receive and consider the ESP’s comments and will provide a written response to the recommendations through NHGRI.

NHGRI recognizes that data sharing is essential to advance genomic research and will expect awardees to address and adhere to NIH data sharing policies.

NHGRI intends that Project Datasets (including clinical, phenotypic, and other relevant data) and associated genomic data from this study will be widely shared with the scientific community for research uses through NIH-supported databases, such as AnVIL, dbGaP, and ClinVar. In addition, it is expected that individual-level genomic datasets generated for the eMERGE program will be designated in institutional certification documents as General Research Use (GRU) as described at https://osp.od.nih.gov/scientific-sharing/researchers-institutional-certifications/ when submitting datasets to NIH-supported databases.

Although NHGRI expects all project datasets from genomic studies selected as part of this FOA to be available through databases such as AnVIL, dbGaP, and ClinVar, the NHGRI does not intend for any single database to become the exclusive source of this program s data. Information such as study protocols, software code and algorithms, descriptions, and publications are expected to be made available through databases such as AnVIL, dbGaP, and ClinVar; other public web sites; and/or publication in the scientific literature.

Data on newly-defined or revised genome sequencing variants, phenotypes, or exposures should be deposited in AnVIL, dbGaP, and/or ClinVar on a timely and regular basis.

Data security encompasses confidentiality, data integrity, and availability. Confidentiality includes managing data access to maintain data security and making data accessible to authorized users only for authorized purposes. Data security protection and proper stewardship of human genomic, phenotypic, clinical, and other sensitive information stored and distributed is of the utmost importance. The Notice for Use of Cloud Computing Services for Storage and Analysis of Controlled-Access Data Subject to the NIH Genomic Data Sharing (GDS) Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-086.html) allows investigators to perform genomic analyses on a cloud platform. The NIH security best practices and provisions (https://www.ncbi.nlm.nih.gov/projects/gap/pdf/dbgap_2b_security_procedures.pdf) should be implemented to protect the privacy and confidentiality of research participants and prevent unauthorized access to data. Investigators are expected to develop policies and procedures for notifying NHGRI, and managing, and mediating any loss of data or compromise of data confidentiality.

To assist in improving data sustainability and utility, applicants are encouraged to align the development of their data sets using the Findable, Accessible, Interoperable, Reproducible (FAIR) Guiding Principles (https://www.nature.com/articles/sdata201618).

The eMERGE Genomic Risk Assessment and Management Network meets the 2015 revised NIH definition of a clinical trial as described in NOT-OD-15-015, Notice of Revised NIH Definition of Clinical Trial. It is expected that the network will be registered in, and results information submitted to, ClinicalTrials.gov by the CC for the network as a whole as described in NOT-OD-16-149, NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information.

After the initial review, NHGRI program staff will conduct an additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement.

See Section VIII. Other Information for award authorities and regulations.

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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 allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• o NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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 SF424 (R&R) Application Guide.

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) 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.

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:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Robb Rowley, MD
Telephone: 301-827-9126
Fax: 301-480-5159
Email: [email protected]

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

The CC budget should include the costs required for active network participation and coordination, including regular teleconferences and meetings of the SC and its working groups. For budgeting purposes, applicants should budget for attendance of 4-5 investigators from the CC at four SC meetings (2 days, 1-2 nights) in the first year and three times per year in years 2-5. The CC budget should include costs for twice monthly Steering Committee conference calls in the first year, and monthly conference calls in years 2-5.

The CC budget should include costs such as preparation of manuals of operation and patient and clinician education material. The CC budget should also include the cost to manage and update the network-wide website. The website should be capable of tracking network-wide activities and products for broader distribution. Costs of network-wide, CLIA-validated genotyping, sequencing, or other genomic technologies will also be borne by the CC. The CC should estimate that 20% of the 20,000 patients will have genetic testing in FY2020, 35% in FY2021, 35% in FY2022, and 10% in FY2023. For application purposes, the genetic testing cost should not exceed $350 total costs per patient, including all applicable fees and facility and administrative costs. Investigators can refer to NIH policy, Budgeting for Genomic Arrays for NIH Grants, Cooperative Agreements and Contracts NOT-OD-10-097, for additional guidance.

Both CC and CSs are expected to conduct both site-specific and large-scale collaborative analyses on AnVIL platform. CC will need to budget for compute and egress charges on AnVIL based on the cloud platform market pricing. NHGRI will continually assess the utilization of AnVIL and determine whether limited support for site-specific analyses on platforms external to AnVIL is needed. In addition, the CC should provide a contingency budget for data storage external to AnVIL.

CC budget should include an estimate to create a central repository or create a federated data structure that allows for network-wide analysis. The central repository budget should include the cost to host on AnVIL vs. establishing a new cloud-based data structure. The budget should include the necessary informatics personnel to be able to manage this network for the duration of this study. The CC should also include cost required to periodically analyze the dataset to see if certain thresholds are met that would require modification of the genomics risk assessment or management protocol.

CC budget should include the cost to coordinate all activities of the network including overseeing that all stakeholders, such as patients, clinicians, and investigators, are informed of the ongoing efforts of their involvement in the network.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

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

Research Strategy: Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project as well as the aspects listed below.

Network coordination

The CC provides critical strategic coordination of all activities of the eMERGE Genomic Risk Assessment and Management Network. Applicants should provide evidence of their successful participation in and oversight of multiple clinical research sites to achieve common aims. This includes but is not limited to integrating genomic and other complex information into EMRs, capturing research and clinical data from disparate data systems, and coordinating research analyses across multiple groups. Applicants should describe plans for coordinating, facilitating, and supporting the activities of eMERGE in collaboration with the CS and NHGRI, including archiving and tracking all materials relevant to the development and implementation of the network. They should describe their plans for serving as the communication and coordination center within the consortium, including organizing and supporting consortium working group calls and in-person consortium meetings, and their experience managing cross-study functions. Since variation in the performance of each CS is likely, applicants should describe their approach to monitoring site performance, anticipating and resolving emerging issues, and assisting any poorly-performing sites. In addition, they should propose plans for transitioning CC activities and existing data if an award is made to a new eMERGE CC in FY2020 and describe how the existing and new CC personnel would work together to implement these plans.

Retrospective validation and adaptation of PRS to EMR-defined phenotypes

Applicants should describe how they would coordinate the network effort to identify and select common, complex diseases of public health importance relevant to eMERGE aims for validation of available PRS. They should also describe their approach for coordinating the selection of the most robust, generalizable, and scientifically valid PRS (when more than one PRS is available for a given disease, such as breast cancer), optimizing that PRS where feasible for patients of diverse ancestries or other defining characteristics, and validating its predictions against e-phenotypes.

Applicants should describe their approach for overseeing the utilization of existing publicly available, densely imputed SNP datasets, plus any proprietary datasets from which they can broadly share results, to calculate PRS for these common, complex diseases and validate them against e-phenotypes.

Applicants should describe their expertise in overseeing the development and validation of genomic risk assessment and management protocols and how to seamlessly integrate the resources into the EMR for clinical care. They should describe how they will develop consensus among the network members to identify appropriate guidelines on which to base risk reduction recommendations.

Prospective risk assessment and management using EMR tools

To ensure adequate study power as described in the Background, applicants should describe plans and document their ability to obtain informed consent and recruit 2,500 patients, at least 35% of patients who come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes, who have not previously received genetic risk information. Applicants should also describe plans for overseeing the CS recruitment of clinicians and educating them as needed in the genomic risk assessment and management protocols. Each CS will have common and unique requirements to report genomic risk estimates and risk reduction recommendations to patients, their family members, and practitioners, as appropriate; facilitating additional testing or implementation of risk recommendations, as needed; and for collection and analysis of demographic, clinical, genomic, psychosocial, and healthcare utilization outcomes. The CC should describe mechanisms for rapid, timely, and secure deposition of study data from the CS.

Applicants should describe their ability to assist CS with obtaining institutional approvals they will need for the integration of genomic testing and patient-derived family history into their patients EMRs. They should also describe the informatics expertise they will engage to capture genomic and related risk information and ensure its timely integration into the central repository; share it with network investigators; maintain version control of these tools; manage and ensure the quality of the deposition in data resources such as AnVIL, dbGaP, and ClinVar. Applicants should describe the policies, technology, and procedures for sharing deidentified information within the eMERGE Genomic Risk Assessment and Management Network and with designated data repositories to accomplish the research aims.

The eMERGE Genomic Risk Assessment and Management Network is intended to include children under age 18 where feasible. All sites should describe their ability, perhaps through partnerships, to implement protocols relevant to children as well as adults.

Applicants should describe plans for identifying and solving operational problems involving recruitment, data and sample collection, quality assurance, and genomic risk assessment and management. Ideas for network-wide analyses, including potential subgroup analyses, should also be proposed.

The CC will coordinate the genotyping of all participants using a CLIA- and FDA-approved SNP genotyping assay or other CLIA- and FDA-approved genomic variant assay. The CC should identify a genetic testing provider and include all associated costs in the budget. The CC should describe the metrics they used to select the organization proposed to run the selected assay(s) on CS provided biospecimens. The CC should describe the metrics they will use to evaluate performance throughout the entire research project.

Data management and standards

Applicants should describe how they will work with the CS to collect, store, transmit, harmonize, and analyze study data as agreed upon by the SC. They should describe plans for hosting, managing, and distributing the large amount of clinical, genetic, and family history data to be collected; harmonizing data across CS; and leading cross-study analyses. Applicants should describe plans for the receipt, protection, and management of data obtained from the CS, genetic testing laboratories, and other investigators. These plans may include regular data queries, monitoring and cleaning to ensure data completeness, and data analysis. They should describe data security measures and protection of patients' privacy and confidentiality consistent with requirements of the Health Insurance Portability and Accountability Act (HIPAA) and other applicable regulations. This should include precautions taken to ensure removal of personally identifying information (PII), prevention of inadvertent release of data, or identification of participating individuals or groups. They should describe plans for back-up data systems robust enough to prevent loss of data following diverse natural and human causes along with the ability to meet HIPAA requirements.

Applicants should describe relevant standards for data and metadata to facilitate data analysis, integration, and exchange within and among eMERGE sites, as well as deposition and broad use by the scientific community. The lack of mature standards should not constrain creative or innovative approaches to accomplishing the aims of this program; however, where such standards do exist, applicants should indicate their commitment to using them to promote interoperability and sharing in the following areas as appropriate and consistent with achieving the goals of the program:

• Health records data
• Genome sequencing data
• Genomic variant interpretation
• Healthcare utilization data
• Outcomes measures
• Fast Health Interoperability Resources standard for transmitting genetic testing results and other clinical data
• Infrastructure (e.g., tools and databases) and data models related to the data integration aim, such as the Observational Medical Outcomes Partnership/Observational Health Data Sciences and Informatics (OMOP/OHDSI) or PCORI Common Data Models.
• Familiarity with the utilization of Natural Language Processing (NLP) in developing e-phenotypes
• Leveraging cloud-based resources to reduce barriers for implementing genomics into clinical care

Other issues

Applicants should describe investigators expertise in genomic risk assessment, reporting, and management; data quality assessment and data management; analysis of genotype, phenotype, clinical, and outcomes data in diverse populations; and informatics, clinical care, and statistical genetics. They should describe the synergy, experience, and expertise of the CC team, avoiding duplication of information provided in individual biosketches. Applicants should describe their experience and success in working as part of a research consortium or similar collaborative activities and indicate their willingness to cooperate with CS investigators supported under RFA-HG-19-013 and RFA-HG-19-014 and with NHGRI in the development and design of research and consultation methods, protocols, procedures, policies, and strategies to be applied in this program.

Applicants from existing or prior eMERGE sites should also include any information not documented in the biographical sketches that demonstrates the site's ongoing productivity and leadership contributions to eMERGE collaborative efforts. Applicants not previously involved in eMERGE should provide evidence of their productivity and leadership in other collaborative efforts.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Resource Sharing Plan.
• A plan for sharing project datasets (phenotypic, environmental, covariate, process data, outcome measures, etc.) and associated genomic data should be provided. Awardees are expected to comply with the NIH Genomic Data Sharing Policy (https://gds.nih.gov/). The plan should also describe how informed consent will be designed and obtained to allow broad data sharing of project datasets for General Research Use as defined by NIH at https://osp.od.nih.gov/wp-content/uploads/standard_data_use_limitations.pdf . Broad data sharing for general research use is strongly encouraged for the eMERGE datasets. A plan to share computerized resources such as study protocols, informed consent form templates, results report templates, and bioinformatic tools should also be provided

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 3 - Protection and Monitoring Plans

3.2 This is a multi-site study that will use the same protocol to conduct non-exempt

human subjects research at more than one domestic site?

Applicants should describe their experience and willingness to use a single IRB (sIRB); it is expected that the CC’s institution will serve as the sIRB.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date 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.

This initiative is not subject to intergovernmental review.

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.

Applications must be submitted electronically following the instructions described in the SF424 (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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(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. See Section III of this FOA for information on registration requirements.

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 System for Award Management. 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 and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Reviewers will provide an overall impact 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).

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.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy, or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors, or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management, and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Additionally, for this FOA: Do the investigators have appropriate experience working in multi-site research networks or consortia, integrating disparate data systems to capture data across a federated environment, and overseeing clinical genomic testing to ensure the results are high quality and are produced in a timely way?

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?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Additionally, for this FOA: Have the investigators presented adequate plans for how their research team will interact with and facilitate the work of the Genomic Risk Assessment and Management Network? Have they provided appropriate plans for selecting, overseeing and assessing quality of clinical genomic testing? Does the applicant have the ability to select and oversee a CLIA certified lab that is capable of managing all aspects of clinical genetic testing?

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?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Does the applicant have the institutional support to select and oversee a CLIA certified lab that is capable of managing the logistical and time-constraint challenges of clinical genetic testing? The CC should be able to manage a genetic testing provider that should be able to track chain of custody of samples before they arrive at the lab, support staff to help clinicians with collection and shipping, and supplies for collection of samples. of samples.

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 score, but will not give separate scores for these items.

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate? Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

For research that involves human subjects but does not involve one of the 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 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 Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

For Renewals, the committee will consider the progress made in the last funding period.

Not Applicable

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 score.

Not Applicable

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).

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) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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

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

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines 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:

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

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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.

• 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 selection of PRS to be validated and disease-specific risk assessment and management protocols to be implemented.
• Identifying concerns unique to underserved and underrepresented populations such as children and minority patients.
• Collaborating with all eMERGE sites in making eMERGE findings and procedures as widely available and applicable as possible.
• 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, genomic data sharing 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.
• 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.
• Submit datasets generated from the eMERGE CS to public data repositories such as AnVIL, dbGaP, and ClinVar

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 DHHS, PHS, and NIH policies.

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:

• 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.
• Serving as a liaison between the Steering Committee and the External Scientific Panel, attending External Scientific Panel meetings in a non-voting liaison member role, and arranging for timely preparation and distribution of meeting minutes.
• Serving as a liaison between the Steering Committee and other federal agencies such as the Food and Drug Administration (FDA) or the Centers for Medicaid and Medicare Services (CMS).
• Serving on working groups of the Steering Committee and the External 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.
• 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
• 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 NHGRI Project Scientist.

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 for genomic medicine discovery and implementation research. The awardees and the Project Scientist will meet as the program Steering Committee four times per year and twice monthly on conference calls in the first year, and three times per year and monthly on conference calls in years 2-5, to share information on data resources, methodologies, analytical tools, as well as data analyses and preliminary results. In addition to the PIs, 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, 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. Cooperative agreements with multi-PI arrangements will have a single vote to be decided as desired within the multi-PI award. 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, 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 CS and develop guidelines on consent, education, regulation, and consultation for such research, and on collecting, formatting, depositing, and documenting phenotype, genotype, clinical, and related data for dissemination to other participating CS and deposition into databases.
• Establish best practices for IRB interactions, patient consent or assent (as appropriate), and results reporting, and for collecting, formatting, documenting, and sharing data as appropriate.
• Develop e-phenotypes and analyze genotype-phenotype associations using network data.
• Develop methods and tools for estimating genomic risk and communicating risk recommendations using EMRs.
• 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.
• Analyze resulting data to understand uptake and impact of genomic risk assessment and management protocols on patient care.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, 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.

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Robb Rowley, M.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-827-9126
Email: [email protected]

Rudy Pozzatti, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-8739
Email: [email protected]

Lisa Oken
National Human Genome Research Institute (NHGRI)
Telephone: 301-594-5250
Email: [email protected]

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.

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 Part 75.