Required Application Instructions

It is critical that applicants follow the 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

The purpose of this Funding Opportunity Announcement (FOA) is to establish 3-6 Clinical Sites with Enhanced Diversity focused on assessing the clinical utility of genome sequencing in multiple healthcare settings. These Clinical Sites with Enhanced Diversity will collectively form, along with 3-6 additional Clinical Sites and a Coordinating Center, the Clinical Sequencing Evidence-Generating Research (CSER2) Consortium. CSER2 will: 1) define, generate and analyze evidence regarding the clinical utility of genome sequencing in multiple clinical contexts; 2) research the critical interactions among patients, family members, health practitioners, and clinical laboratories that influence implementation of clinical genome sequencing; and 3) identify and address real-world barriers to integrating genomic, clinical, and healthcare utilization data within a healthcare system(s) to build a shared evidence base for clinical decision-making.

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

• "Clinical Sites" refer collectively to the sites to be funded under this FOA and the companion RFA-HG-16-010 (Clinical Sites) who will address the Objectives described further below in the "Objectives of this Research Program" and "Research Strategy" sections. Requirements specific to each Clinical Site FOA are noted within the respective FOA.
• "Clinical utility" is defined broadly as the assessment that a genomic intervention will lead to an improved health outcome, including diagnosis, treatment, management, or disease prevention that will benefit a patient or his/her family members, as described in a position statement from the American College of Medical Genetics and Genomics (ACMG; http://www.ncbi.nlm.nih.gov/pubmed/25764213). While CSER2 will focus primarily on clinical utility of sequencing to patients and family members, additional work on personal utility, related to interventions for which clinical benefit is less well defined, is also of interest.
• "Healthcare settings" refers to the healthcare context in which medical care is provided (e.g., specialized medical centers, community clinics, primary care).
• "Clinical conditions" refers to the ways in which patients are characterized according to presence or absence of disease (e.g., healthy individuals, individuals with particular diseases).
• "Diversity" is used in reference to the inclusion of patients who come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes, and will be used in part to distinguish the expectations for patient recruitment and retention by applicants to this FOA compared to those applicants to RFA-HG-16-010 (Clinical Sites).
• "Underserved" is defined according to the definition of "medically underserved (http://www.hrsa.gov/shortage/mua/)" provided by the Health Resources and Services Administration (HRSA).
• "Stakeholders" include groups traditionally outside academic research settings who will have a vested interest in the best practices and evidence generated by CSER2, such as professional societies, regulatory agencies, payers, and patient advocacy groups.
• "Genome sequencing" refers broadly to DNA-based sequencing approaches that interrogate a patient's genome sequence using next generation sequencing technologies, including but not limited to targeted gene sequencing panels of at least 100 genes, whole exome sequencing (WES) or whole genome sequencing (WGS). Large-scale targeted genotyping arrays would not be considered genome sequencing.
• "Evidence" refers to information generated in the course of CSER2, including, but not limited to: data, records, observations, outcomes, analyses, measures, publications, best practices, and recommendations.
• "Secondary" findings refer to results unrelated to the reason for ordering the genome sequencing but which may be of medical value (http://www.ncbi.nlm.nih.gov/pubmed/23788249).
• "Data integration" refers to a system or process by which data from heterogeneous sources within a healthcare system (e.g., genomic, clinical, social and behavioral, and healthcare utilization) are linked and made accessible for diagnosis and clinical decision-making.

CSER (RFA-HG-10-017, http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-10-017.html) was funded in 2011, and expanded in 2013, to explore the use of genome sequencing in clinical care and to identify associated challenges and opportunities in a variety of clinical contexts (e.g., pre-conception screening, pediatrics, cancer, and healthy adults). Additional information on CSER may be found at http://cser-consortium.org/ or http://www.genome.gov/cser/. A key feature of CSER has been integrated and coordinated efforts to address challenges and opportunities in targeted areas, implemented largely through Working Groups. To date, nine Working Groups have been established: Actionability-Return of Results, Electronic Health Records, Genetic Counseling, Informed Consent and Governance, Outcomes and Measures, Pediatrics, Practitioner Education, Sequencing Standards, and Tumor. These efforts have culminated in a number of scientific advances, including models for genomics-oriented informed consent tailored to the care setting, recommendations to improve the consistency of genomic variant interpretation, and approaches to the disclosure of primary pediatric and tumor findings and of secondary findings more broadly. Collaborating with the Electronic Medical Records and Genomics (eMERGE) network, CSER has also identified barriers and recommended approaches to incorporating genomic information in electronic health records. Valuable CSER products also include contributions to and leadership on three sets of ACMG recommendations (relating to secondary findings, variant interpretation, and clinical laboratory standards), case studies and single site publications, methodological and tool development, and collaborations with other consortia. CSER research products are available at: https://cser-consortium.org/cser-research-materials.

In prioritizing opportunities for clinical genome sequencing research, NHGRI sought wide input in a series of workshops: Future Opportunities for Genome Sequencing and Beyond (http://www.genome.gov/27558042), Genomic Medicine VIII Workshop (http://www.genome.gov/27561558), Roundtable on Inclusion and Engagement of

Underrepresented Populations in Genomics (https://www.genome.gov/Pages/About/NACHGR/February2016AgendaDocuments/2015_09_16_Roundtable_Report_final.pdf) and Integrating Genomic Sequencing into Clinical Care: CSER and Beyond (http://www.genome.gov/27562330). The scope and objectives of CSER2 outlined below reflect the highest priority recommendations focusing on the clinical encounter: defining, generating and analyzing evidence for clinical utility of genome sequencing; addressing research at the intersections of patients, family members, practitioners, and laboratories to improve implementation of genomic sequencing during the clinical encounter; and identifying and addressing real-world barriers to integrating genomic, clinical, and healthcare utilization data within a healthcare system and exchanging data across healthcare systems.

To address these recommendations, the multidisciplinary approach to characterizing the clinical encounter and broad spectrum of clinical conditions that characterized CSER will continue. However, several new aspects are proposed for CSER2:

• CSER2 will have a more specific Consortium-wide focus on assessing the clinical utility of genome sequencing that includes the identification, generation, and analysis of consensus measures.
• CSER2 will focus more deeply on research opportunities at the intersections of three key domains: 1) patient and family, 2) health practitioner, and 3) clinical laboratory.
• Ethical, legal and social implications (ELSI) research will continue to be required, but may be integrated throughout each site and need not be segmented into a separate sub-project.
• CSER2 Clinical Sites will compare two or more genomic testing modalities (genomic sequencing, standard of care, etc.) to facilitate rigorous evidence generation and evaluation, such as through randomized trials or comparative effectiveness research. Clinical Sites will be expected to include at least one modality that is a DNA-based genome sequencing approach, as defined above. In contrast to CSER, this may include multi-gene sequencing panels, as well as WES and WGS.
• CSER2 will have an expanded focus on patient diversity by requiring a minimum of 60% diverse patients who satisfy the above definition of "diversity" for this FOA. At least 25% of patients who satisfy this definition of "diversity" will be required for the companion FOA soliciting applications from Clinical Sites (RFA HG-16-010).
• CSER2 will have increased emphasis on broadening the range of healthcare settings beyond academic medical centers, to advance the effective use of clinical genomics outside of tertiary academic hospitals.
• CSER2 will increase its collaborative efforts with stakeholders in the clinical implementation of genomic sequencing.

The objectives of this research program, to be addressed by each CSER2 Clinical Site and for which the CSER2 Coordinating Center will facilitate and coordinate, are to:

1. Define, generate and analyze evidence regarding the clinical utility of genome sequencing in multiple clinical contexts.

CSER2 Clinical Sites will each propose site-specific measures of clinical utility relevant to the clinical condition(s) and patients at each site and to the healthcare setting in which care is being provided. They will work together and with the Coordinating Center to identify consensus measures for clinical utility, which, as described in the "Definitions" section above, may include evaluations of patient diagnosis, family implications, and personal utility. Proposed measures of clinical utility may be novel or existing. It is expected that some measures may be site specific. However, consensus will be needed across sites to identify and implement common measures. Each CSER2 Clinical Site is anticipated to include and analyze at least 1,100 patients over the entire term of the award, with the potential for larger sample sizes per site as funding and scientific priorities permit. By using standardized measures, the >10,000 patients anticipated to be studied across CSER2 will provide a large sample of ancestrally, clinically and socioeconomically diverse patients, from a spectrum of clinical conditions and healthcare settings, that can be used for Consortium-wide analyses, including comparisons and sub-group analyses. An important component of CSER2 evidence generation will include comparing the clinical utility of genome sequencing to alternative modalities, with preference for established modalities such as standard of care or targeted gene sequencing panels. Sites are encouraged to evaluate the utility of clinical genomic applications across diverse populations and healthcare settings, to assess whether differences in utility exist and if so, how to address them.

2. Research the critical interactions among patients, family members, health practitioners, and clinical laboratories that influence implementation of clinical genome sequencing.

CSER2 Clinical Sites will each propose research focused at the point of the clinical encounter, where patients and family members, health practitioners and clinical laboratories intersect. Many such topics were initially explored in CSER; CSER2 will expand upon these topics as well as investigate more deeply the outcomes and implications of returning genomic results. Topics include, but are not limited to:

• Patient-centered recruitment and retention, including approaches tailored to diverse or underserved patients, or for use in varied healthcare settings
• Genomic variant interpretation and disclosure of genomic results, including approaches tailored to ancestrally diverse populations
• Collection of structured phenotype information to facilitate data sharing between health practitioners and clinical laboratories and across sites
• Patient/family-centered measures of utility
• Reanalysis of existing genomic data, e.g., in the context of new outcomes, new variant interpretation
• Characterizing the implications of a genomic finding on subsequent clinical outcomes or healthcare utilization

3. Identify and address real-world barriers to integrating genomic, clinical, and healthcare utilization data within an existing healthcare system to build a shared evidence base for clinical decision-making.

In the course of addressing the two aims above, CSER2 will contribute to understanding how genomic information may be clinically useful to patients, family members, practitioners and laboratories. Such evidence will be disseminated in a number of ways, e.g., directly to the individuals involved, through publication of best practices and recommendations, and through data sharing via resources such as dbGaP and ClinVar. To realize the potential of such evidence to accelerate translation of genomic findings, CSER2 Clinical Sites will also identify and address barriers to integrating genomic, clinical, social and behavioral, and healthcare utilization data that tend to be siloed within a prototypical healthcare system(s).

Each Clinical Site will pilot the meaningful integration of multiple data sources within a healthcare system to facilitate clinical decision-making. This could be envisioned as linking genomic findings to outcomes, encapsulating this knowledge at the systems-level (e.g., via clinical decision support or other informatic approaches), and making the resulting information "actionable" within the healthcare system. As part of an iterative process, genomic findings from a patient or family member might subsequently benefit diagnosis, treatment, or outcomes in other patients with similar genomic variants and findings. Not all findings from CSER2 may be suitable for such data integration and the optimal approach may not be known at the time of application, positioning this aim as a real-world, "effectiveness" pilot at each site, compared to a study done under ideal "efficacy" circumstances. Applicants should design and implement a pilot integration study, describe how the results of the pilot study would be evaluated to determine whether the pilot might be useful and scalable, and define the necessary steps to further optimize the initial approach.

CSER's work establishing clinical sequencing pipelines at each site, in diverse clinical contexts, helped establish recommendations and best practices to allow for collaborative studies of clinical genome sequencing. Similarly, CSER2 will endeavor to facilitate a data integration process at each site and encourage interoperability of processes, standards, best practices, and data across sites and with external healthcare systems as feasible. As common opportunities or best practices that apply across diseases and healthcare settings are identified, these opportunities will in turn contribute to broader efforts to build a shared evidence base for clinical decision-making, such as through the ClinGen Program (https://www.clinicalgenome.org/), which aims to build an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research, or the NIH Precision Medicine Initiative Cohort Program (https://www.nih.gov/precision-medicine-initiative-cohort-program), which leverages advances in genomics, emerging methods for managing and analyzing large data sets while protecting privacy, and health information technology to accelerate biomedical discoveries.

ELSI

ELSI research will remain a major aspect of CSER2, and each Clinical Site should propose ELSI research that extends beyond the forays into return of results and psychosocial outcomes that were the main focus of CSER to the broader set of ELSI issues raised by the assessment of clinical utility in the diverse populations and healthcare settings being studied in CSER2. ELSI expertise and research should be integrated across all three CSER2 aims and need not be (although it may be) segmented into a separate sub-project. As appropriate to the setting, the ELSI research should include a focus on issues arising uniquely in diverse populations or in healthcare settings outside of academic medical centers, or that address health disparities. The ELSI research proposed may include both empirical and normative methodologies, as well as legal research.

Patient diversity and breadth of clinical conditions and healthcare settings

Applicants to this FOA are expected to recruit a minimum of 60% of patients who come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes. In contrast, applicants to the companion RFA HG-16-010 are expected to recruit a minimum of 25% of such patients. The inclusion of diverse patients, a broad range of healthcare settings and a spectrum of clinical conditions will be crucial to accomplishing CSER2's goals. Central to this focus is research that will assess and improve the current processes of recruitment, testing, and follow-up of patients from diverse racial and ethnic groups, as well as those from the range of as-yet understudied clinical healthcare settings where genomic medicine might be put into practice. This research includes the examination of novel ELSI issues that may arise as genomic medicine is implemented more broadly across the United States (U.S.), including research designed to explore how best to maximize the likelihood that clinical genomics will help to ameliorate, rather than exacerbate, health disparities in the U.S.

As appropriate, the scientific relevance of patient diversity or breadth of clinical conditions and healthcare settings should be addressed in each of the aims above. Examples of scientific questions of interest include, but are not limited to:

• What practical strategies can be adopted to address the challenges that arise in connection with clinical sequencing of patients, particularly those unique to minority and underserved populations? Examples of challenges include those related to the informed consent process, interpretation and communication of genetic information, and responses to and use of this information.
• Do any of these challenges alter the approaches of laboratories or physicians, or the patient experience? Do any of them require new or specialized tools?
• What are the perceptions of the benefits and risks of clinical sequencing, and of the associated clinical and personal utility of genomic data, among patients from minority and underserved populations?
• What are the most effective community engagement strategies to inform the culturally sensitive translation of clinical sequencing technology in underserved and minority populations?

Stakeholder Engagement

The meaningful involvement of stakeholders such as professional societies, payers, regulatory agencies and patient groups will be important to CSER2. CSER2 sites are expected to solicit and be responsive to stakeholder input regarding clinical utility measures or other relevant evidence to be generated and refined in CSER2. In turn, this process is anticipated to enhance the applicability of CSER2 evidence for decision-making by stakeholders, such as the establishment or refinement of best practices or implementation or reimbursement policies, or contribution to other evidentiary frameworks. Finally, through regular interactions and collaborations with stakeholders, CSER2 will be well positioned to respond to emerging needs for evidence and accelerate adoption of genome sequencing approaches demonstrated to have clinical utility. The CSER2 Consortium will develop and implement a consortium-wide Stakeholder Engagement Plan to identify and collaborate with relevant stakeholders throughout the research process, in their roles as co-investigators, liaisons, or other capacities. Individual sites are encouraged to suggest stakeholders relevant to their proposed work, and to incorporate experience in stakeholder engagement to take advantage of and contribute to centralized efforts.

All applicants are strongly encouraged to contact NIH Staff (see Agency Contacts) to discuss the alignment of their proposed work with the goals of this FOA.

NCI Priorities

NCI welcomes applications that align with its priorities. CSER2’s diversity requirements are consistent with NCI’s interest in addressing cancer health disparities. Related to NCI’s interest in precision oncology, topics of interest include, but are not limited to: evaluation of how genomic information from the germline and somatic sequence can improve treatments and outcomes for individual cancer patients; inter-laboratory concordance; interactions with regulators; strategies for capturing correlations between sequences and clinical outcomes; comparison of the clinical utility of sequencing vs. other genomic technologies currently used in practice, such as cancer gene panels. Consistent with CSER2’s healthcare systems goals, NCI is also interested in applications which include, but are not limited to: implementation research looking at strategies to improve uptake of evidence-based genetic and genomic interventions; healthcare delivery research on screening and outcomes relevant to diverse stakeholders (including payers); health communication research; and ELSI research on incorporating populations experiencing health disparities.

NIMHD Priorities

NIMHD welcomes applications that address the mission of the Institute, research that advances the understanding of minority health and health disparities. Minority health populations are based on the Office of Management & Budget race and ethnic standards (e.g., African American, Hispanic, American Indian or Alaskan Native, Asian or Pacific Islander). A health disparity is defined as a health difference that adversely affects disadvantaged populations, based on one or more health outcomes. NIMHD is particularly interested in applications that include, but are not limited to patient-provider communication, health literacy, shared decision making, and the role of culture, socioeconomic status and access to care on incorporating minority populations experiencing health disparities.

AIDS applications

Projects examining ways in which clinical genome sequencing can be applied to improve the understanding of HIV/AIDS prevention, diagnosis, treatment, and related complications will also be considered in accordance with the high priority topics listed in the NIH AIDS Research Priorities document (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-137.html). AIDS applications not proposing to use clinical genome sequencing to address one or more of these high-priority topics will be considered non-responsive and will not be reviewed.

Applicants are encouraged to include HIV/AIDS patients in their plans for clinical sequencing research; however, only applications proposing to have the entire focus on HIV/AIDS research questions are eligible for the AIDS submission deadline. Applications proposing research on multiple disease outcomes, only a portion of which are HIV/AIDS focused, are due on the regular submission deadline and will be returned if received thereafter. Applicants are strongly encouraged to contact NIH staff (see Agency Contacts) before submitting an AIDS application in response to this FOA.

Awards made under this FOA 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. A Consortium will be organized with all of the principal investigators and key personnel funded under this FOA and the companion CSER2 FOAs.

The Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) from each Clinical Site, Clinical Site with Enhanced Diversity, and Coordinating Center, along with the NIH Project Scientist(s), will be responsible for the scientific direction of the Consortium and will meet in person as a Steering Committee three times per year and by conference call on an ongoing (likely monthly) basis. Soon after funding, the CSER2 Steering Committee will meet to set CSER2-wide goals for the project period. The Steering Committee will propose and collect Consortium-wide measures of clinical utility; identify and address common recruitment, sequencing, analytic, translational and ELSI issues; review preliminary results; explore opportunities for synergy among studies; develop best practices, and design and implement a Stakeholder Engagement Plan. The Steering Committee is expected to establish subcommittees and Working Groups to facilitate collaborative work and standardize approaches. CSER2 Working Groups may build on existing CSER Working Groups or be newly formed to meet CSER2 goals. 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 Consortium. Key collaborators and pre- and postdoctoral trainees, in addition to the PD(s)/PI(s), will be eligible to attend Steering Committee meetings.

A separate FOA will be issued to support investigator-initiated research in clinical sequencing that enhances our understanding of how genome sequencing can best be used in clinical care (PAR-16-209). These grantees are expected to conduct research independent of CSER2. They will be introduced to the Consortium shortly after award and invited, but not required, to attend CSER2 Steering Committee meetings. As was done in CSER with the inclusion of investigators on several grants studying the ELSI issues related to the return of results, investigators on other relevant NHGRI-funded investigator-initiated ELSI grants may also be integrated into CSER2 to augment the ELSI expertise available at the Clinical Sites.

Consistent with achieving the goals of the program, NIH expects that the project datasets (for phenotypic, environmental, covariate, process, and other relevant data) and associated sequencing data from CSER2 will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information. This includes outcomes and measures standardized across CSER2 sites, particularly those generated by CSER2 Working Groups or as part of the CSER2 Stakeholder Engagement Plan. Awardees are expected to comply with the NIH Genomic Data Sharing Policy (https://gds.nih.gov/). Resources such as study protocols, informed consent form templates, results report templates, and bioinformatic tools are expected to be made available through an open access section of a database such as dbGaP, other public web sites, and publication in the scientific literature. Although NHGRI expects project datasets from genomic studies selected as part of this FOA to be available through NIH databases such as dbGaP and ClinVar, the NHGRI does not intend these databases to become the exclusive source of this program’s data.

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.

Stakeholder Engagement Plan. As described above, the CSER2 Steering Committee will design and implement a Stakeholder Engagement Plan - a Consortium-wide strategy to seek input from stakeholders such as professional societies, payers, regulatory agencies, and patient groups on evidence used to assess clinical utility. Acknowledging that engagement can take many forms, particularly in the context of diverse patients and different clinical conditions and healthcare settings, applicants are encouraged to propose both site-specific and CSER2-wide approaches for stakeholder engagement.

External Scientific Panel.

An External Scientific Panel (ESP) will evaluate the progress of the CSER2 program, providing recommendations to the network about the progress and scientific direction of all components of the program. The CSER Steering Committee will meet with members of the ESP twice a year, once in-person and once through teleconference. The Steering Committee will receive, consider, and respond in writing to a report of the ESP’s comments. 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 in response to 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)
• 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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) (formerly CCR) 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.
• 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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).

Awards will not be made to the same PDs/PIs in any of the CSER2 FOAs (RFA HG-16-010, RFA-HG-16-011, or RFA-HG-16-012) and PAR-16-209 . Investigators are allowed to apply for both the CSER2 FOAs and PAR-16-209, but should be cautioned that they will not be eligible to be funded for both.

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

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

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

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:

Lucia A. Hindorff, Ph.D., M.P.H.
Telephone: 240-271-1509
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• For this specific FOA, the Research Strategy section is limited to 30 pages.

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. The PD/PI is expected to devote at least 1.8 person months (15% of full-time professional effort) to this Program. For applications proposing multiple PD(s)/PI(s), at least one PD/PI must devote a minimum of 1.2 months (10% of full-time professional effort) to this Program. Individuals with expertise in clinical implementation, sequencing, integration of genomic variants into EMR, informed consent, genetic counseling, assessment of clinical and psychosocial outcomes, ELSI, and healthcare utilization should be included.

Past experience with genome sequencing in a clinical setting should be highlighted, including experience with developing and implementing reporting formats, identifying primary or secondary findings, and disclosing genomic results in clinical care. Applicants should detail prior experience with assessing clinical utility, setting up systems for data integration, and conducting ELSI and health disparities research. Prior experience(s) working in multi-site research networks or consortia to meet individual study and collaborative goals should also be highlighted.

All instructions in the SF424 (R&R) Application Guide must be followed. Costs associated with any sequencing technology, e.g., targeted gene sequencing panels, whole exome or whole genome sequencing, must be clearly itemized. Applicants should provide a fully loaded cost with an itemized cost plan for a per person, per genome analysis that includes, but is not limited to:

• Sample receipt and tracking
• DNA isolation and library preparation
• Sequencing Cost
• Variant calling
• Quality control/quality testing
• CLIA confirmation and reporting for primary and secondary findings
• Associated materials, incidentals, equipment
• Informatics, data storage
• Labor, fringe
• Indirect costs

The costs of 5-6 persons to attend Steering Committee meetings three times per year, as well as the costs associated with monthly conference calls, should be included in the proposed research budget.

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:

Specific Aims: List each aim for the study site and how it supports the Objectives of this Research Program as described in Section I. Funding Opportunity Description.

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

Applicants should justify the proposed clinical condition(s) that they plan to study and describe the relevance to each CSER2 aim. Applicants are neither required nor discouraged from including multiple clinical conditions in their application.

Applicants should detail plans for the following: obtaining informed consent and recruitment of at least 1,100 patients with the potential for larger sample sizes per site as funding and scientific priorities permit. Applicants should also describe plans for: genome sequencing; disclosure of results to patients, their family members and practitioners, as appropriate; and collection and analysis of demographic, clinical, psychosocial, and healthcare utilization outcomes. This should include description of any longitudinal follow-up of patients, including plans for recontact and metrics and milestones for patient retention over the course of the project.

Clinical utility aim. Applicants to this FOA should describe why it is important to assess the clinical utility of genome sequencing in the context of the proposed clinical condition(s), patients, and healthcare setting(s). Recognizing that the definition of clinical utility described in the "Definitions" section above includes patient diagnosis, family implications, and personal utility, applicants should discuss how this broad definition will form the basis for targeted research to address this objective. Applicants should propose consensus approaches to identifying standardized measures of clinical utility for use across multiple CSER2 sites, and describe how such consensus approaches could refine and improve upon site-specific measures that may initially be proposed. Ideas for Consortium-wide analyses, including potential sub-group analyses, should also be proposed. Applicants should specify necessary site-specific or disease-specific clinical utility measures along with any aspects of the proposed approach that generalize beyond the specific condition(s). The reliance of the proposed consensus measures and approaches on sharing data from individual patients or participants among sites should be described. An important aspect of CSER2 evidence generation will include comparing the clinical utility of genome sequencing to alternative genomic testing modalities. The specific genomic sequencing modalities should be described, including information on what portions of the genome will be interrogated and what types of genetic variation will be assessed and disclosed. One or more of the modalities should meet the definition of "genomic sequencing" included in the background section.

Research at the intersection of patients, family members, practitioners and laboratories. Applicants should describe research questions at the specific "intersection(s)" (such as patients with practitioners, practitioners with laboratories, etc.) that are the focus of the proposed research and how the proposed research might generalize to other CSER2 sites and settings. Applicants should propose and justify other research opportunities that may fall outside these examples but are broadly relevant to the application or potentially to other CSER2 sites. Potential for enlarging the intersections to include relevance to other domains and to stakeholders over the project period should be described. Relevance to the diversity goals of CSER2 as well as the contribution of the proposed research to reduction of health disparities should also be described.

Feasibility of genomic, clinical and healthcare utilization data integration. Applicants should describe how the integration of genomic, clinical, social and behavioral, and healthcare utilization data will facilitate clinical decision making. Restrictions or limitations at their institution or healthcare system that impact the accessibility and sharing of the data types that will be collected in their proposed research should be identified and addressed. This should include the nature of the data to be integrated in CSER2, and proposed approaches to address both methodological and ELSI or governance-related challenges. Approaches and strategies for integrating data in a way that can be accessed when needed at the point of care or extended to additional genomic findings or individuals are encouraged. The means by which genomic findings are codified and made available for clinical decision-making, including any initiating actions, data formats, and clinical decision support tools, should be described. Institutional commitment to facilitating the data exchange aim should be described and documented in the application.

Data standards. As relevant to each of the three CSER2 aims above, applicants should describe relevant standards for data and metadata to facilitate data analysis, integration and exchange within and among sites. The lack of mature standards should not constrain creative or innovative approaches to accomplishing CSER2 aims; however, where such standards do exist, applicants should indicate their commitment to interoperability and sharing in the following areas as appropriate and consistent with achieving the goals of the program:

• Phenotype information
• Genome sequencing data
• Genomic variant interpretation
• Psychosocial outcomes
• Healthcare utilization data
• Outcomes measures for clinical utility
• 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.

Use of existing data or data to be generated by external efforts. Reliance of CSER2 efforts on such data should be clearly documented, including:

• Population characteristics and quality and completeness metrics for phenotype or sequence data
• Integration of data with CSER2 aims
• Timeframe and scope of data availability, including IRB approval or any necessary data sharing agreements
• Ability to commit data to cross-Consortium efforts
• The possibility of recontacting patients from whom existing data were generated and/or obtaining additional data from them if needed

Patient diversity and breadth of clinical conditions and healthcare settings. Applicants should explain how their site proposes to recruit and retain diverse patients, enhance understanding of genomic medicine in healthcare settings beyond specialized academic medical centers, or reduce health disparities that are relevant to the U.S. population. Investigator expertise related to technology implementation and clinical genetics in diverse communities and broader healthcare settings should be noted. Past experience with patient recruitment and retention, including in diverse and underserved settings, should be summarized. Proposed milestones for recruitment and retention to meet the 60% requirement for patients from diverse populations should be described. If patients from medically underserved areas are proposed, applicants should document that the regions from which they are recruited are designated as medically underserved areas by the Health Resources and Services Administration (HRSA), as described in "Definitions." Inclusion of HRSA’s Index of Medical Underservice (IMU) scores for proposed areas would be particularly helpful. CSER2 applicants should give appropriate leadership roles to collaborating investigators from or with experience working with diverse and underserved settings or from settings outside of academic medical centers.

Genome Sequencing.

• Applicants must report per-patient retrospective and projected genome sequencing costs for all sequencing modalities proposed during this project period. Reporting costs will allow evaluation of whether the proposed activity is capable of producing data as efficiently as possible, and the potential for achieving reduced costs over time. Retrospective costs should be reported for the most recent quarter or three-month (minimum) period. Projected costs should be presented for the entirety of the project period and should include an explanation of how any reductions would be achieved, including potential adoption of new sequencing platforms.
• Given the importance of minimizing costs and maximizing efficiency, shortly after review NHGRI will compare prevailing costs and timeframes for sequencing proposed at each Clinical Site to those at large-scale, high throughput clinical sequencing centers. Should NHGRI decide to redirect selected Clinical Sites to a lower-cost clinical sequencing center, Clinical Site awards could be reduced accordingly or applicants could propose to redirect funds to subcontracts with lower-cost clinical sequencing centers. Applicants should describe the feasibility of sending samples to a clinical sequencing center and prior experience in collaborating with such facilities.
• Applicants should concisely indicate their metrics of sequence quality.
• Prior experience working with the laboratory who will conduct the proposed variant interpretation and results reporting should be described.
• Due to regulatory requirements for using research results in clinical care, some sequencing data will be expected to be in compliance with the Clinical Laboratory Improvement Amendments (CLIA). 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. Investigators must be prepared to discuss the possible need for an IDE with their IRBs and document the outcome of those discussions, and to subsequently engage in pre-submission discussions with the FDA if the IRB determines they are needed. These typically involve submission of actual study protocols, including the entire sequencing pipeline from sample preparation to return of results. Applicants may wish to consult the following Points to Consider in Assessing When an Investigational Device Exemption (IDE) Might be Needed: http://www.genome.gov/27561291.

Cross-Consortium efforts. Applicants should describe their ideas for working with other sites to accomplish CSER2 goals, including their preferred approaches for identifying measures of clinical utility, and describe suggestions to facilitate and implement consensus approaches. Applicants should also describe their:

• Willingness to adhere to Consortium-wide policies and procedures to be determined by the CSER2 Steering Committee. Applicants should also describe plans for, and willingness to abide by, Memoranda of Understanding or other sharing agreements potentially needed for data and sample sharing within the Consortium.
• Plans for how their research team will interact with other CSER2 sites in the development and design of research and consultation methods, procedures, policies and strategies to be applied in this program.
• Anticipated challenges at their institution(s) and proposed ways to overcome them.

Stakeholder engagement

• Applicants should propose possible CSER2-wide approaches to stakeholder engagement and describe the value of developing an engagement plan throughout the research process, including but not limited to: study development and refinement, analysis of data/evidence, and dissemination and implementation of findings. Ideas for implementation and dissemination strategies to ensure effectiveness from the stakeholder perspective would also be valuable.
• Applicants should also describe their individual, site-specific plans for stakeholder engagement, and how those efforts will augment and complement Consortium-wide approaches.
• Past experience(s) working with stakeholders to meet collaborative goals should be summarized.

Project Management plan. Applicants should note the absence of a requirement for a formal Project 1/2/3 substructure that was required for CSER (RFA-HG-12-009 and RFA-HG-10-017). Instead, applicants are encouraged to propose any substructure judged necessary to accomplish CSER2 aims within and across CSER2 sites. All applicants should describe how the PD(s)/PI(s) will manage the proposed project, who will serve as the project’s Program Manager to oversee the day-to-day activities and how the management structure will support achievement of the proposed goals, including how decisions will be made regarding reallocation of resources that may be necessary. A description of management structure, leadership roles, and mechanisms of communication should be provided.

Applicants from existing CSER sites should also:

• Document the site’s ongoing productivity
• Describe additional activities and accomplishments made possible by supplemental funding as part of CSER
• Describe leadership contributions to CSER 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 Data Sharing Plan.
• Applicants should clearly describe data or resource sharing with external NIH resources such as dbGaP and ClinVar.
• Applicants should also describe plans for sharing of software and analysis tools.Data and resource sharing plans proposed through this FOA should clearly describe the proposed timing and scope of data to be shared. Willingness to share interim data or existing data generated outside CSER2 for stakeholder engagement and Working Group efforts should also be described.

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

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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

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 there a strong scientific premise for the project? 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? How will the proposed research contribute to assessment of the clinical utility of genome sequencing and help evaluate additional impact of clinical sequencing? Does the proposed project have the potential to improve healthcare and outcomes? Are the clinical and healthcare utilization outcomes meaningful to the patient, family and practitioner population under study? Are the proposed approaches likely to yield important contributions applicable to diverse patients and a range of clinical conditions and healthcare settings? What is the public health relevance of the disease or outcome in the populations that are the particular focus of the proposed research? Will the proposed research contribute to understanding or directly alleviate health disparities, or generate data that will have the potential to do so?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Have the PD(s)/PI(s) participated in any collaborative, multi-center networks or contributed substantially to efforts involving stakeholders? Do the investigators demonstrate relevant experience with patient recruitment and retention in diverse, minority and underserved populations and settings? Do the PD(s)/PI(s) have experience with collecting, analyzing, and publishing phenotypic and genomic data, and with returning genomic results to patients? Is there adequate ELSI expertise on the project team? Is the management plan well-described and commensurate with the level of complexity required for this FOA?

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? Is the proposed approach or methodology dynamic and responsive to evolving changes in clinical care? Does the applicant demonstrate the ability to be facile and responsive to external input in this rapidly moving field?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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? Is the informed consent process adequate or if patients need to be re-consented, are the plans for re-consenting appropriate? Are the genomic, clinical, and healthcare utilization data to be used in the study of sufficient quality and completeness to provide maximal scientific value, or do they have the potential to be such within the project period? Does the application include adequate plans to recruit and retain the proposed numbers of diverse patients? Is there potential for larger sample sizes as funding and scientific priorities permit? Are the proposed plans for sequencing technically sound and cost-effective, and is there potential to improve clinical sequencing through reduction of costs, turn-around-time or other barriers? Is the proposed ELSI research sound, well integrated and relevant to the overall aims off the CSER2 consortium? 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 children, justified in terms of the scientific goals and research strategy proposed?

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? Is institutional commitment to facilitating the data integration aim evident? Are appropriate resources available to institutions and investigators who are working directly with the diverse patients and populations?

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.

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

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

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 children 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. For existing CSER sites, how productive have their sites been and have they demonstrated leadership in Consortium-wide efforts?

Not Applicable

Additional Review ConsiderationsAs 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.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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). Does the application provide a clear plan for timely, accurate and efficient dissemination of these data that could also be refined according to Steering Committee or stakeholder discussions?

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, 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 to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA and to RFA-HG-16-010.. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Human Genome Research. 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.
• Complementarity to and synergy with other funded projects
• Programmatic balance among diseases to be studied, healthcare settings, and approaches to be implemented
• Ability to work effectively in large collaborative efforts or research consortia
• Public health importance of conditions to be studied
• Diversity of study patients, particularly with respect to inclusion of minority or underserved populations in the U.S., and relevance of proposed research questions related to diversity and health disparities
• Ability to recruit and study large sample sizes efficiently and cost-effectively
• Applicability of the proposed approach to other healthcare settings

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.

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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

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

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

• 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.
• Sharing Consortium-wide clinical utility measures and other standardized metrics with the Consortium, as agreed upon by the Steering Committee.
• Implementing Steering Committee recommendations for improving data collection, phenotyping, and standardization in their project, as appropriate and feasible.
• Implementing Steering Committee recommendations for evaluating concerns among patients, clinicians, investigators, IRBs, and other relevant groups and stakeholders in their project regarding incorporation of sequence data into clinical care.
• Obtaining the necessary consent or reconsent and IRB approval for the potential return of results, according to the proposed research protocol.
• Ensuring that any results to be returned to patients are generated or validated in a CLIA-compliant environment.
• Identifying the results that are most appropriate to extract using clinical decision tools and to report to patients, as well as appropriate actions to be taken by patients carrying these variants.
• Developing and implementing appropriate educational resources for patients and clinicians.
• Evaluating the impact of reporting genome sequencing results to patients on disease-centered, patient-centered, and cost-related outcomes.
• Identifying concerns unique to minority and underserved populations, and to diverse healthcare settings.
• Providing protocols, reports and data in a timely fashion as agreed upon by the Steering Committee.
• Cooperating with other awardees in the timely publication and dissemination of program results and the eventual release to the scientific community of methods, tools, and results, and other resources.
• Abiding by common definitions, protocols, procedures, etc. as chosen by majority vote of the Steering Committee.
• Sharing results according to the genomic data sharing policy, and any other data sharing policy agreed to between the NIH and the applicant.
• Adhering to policies regarding data access, publication, and intellectual property established by NIH and the Steering Committee for this program.
• Not disclosing confidential information obtained from other members of the program.
• Notifying the Project Scientist(s) of all major interactions with another member of the Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and External Scientific Panel.
• Attending and participating in Steering Committee meetings and accepting and implementing guidelines and procedures, as appropriate.
• Abiding by relevant policies, including, but not limited to:
  • NIH Genomic Data Sharing policy (https://gds.nih.gov/)
  • 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)
  • Notice on Clarifying NIH Priorities for Health Economics Research (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-025.html)
  • FDA policy on Investigational Device Exemptions (IDE): http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/default.htm
• 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, NCI or NIMHD 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(s) will participate as a member of the Steering Committee and will have one vote. The Project Scientist(s) will have the following substantial involvement:

• Participating with the other Steering Committee members in the group process of setting research priorities, 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 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.
• Reporting periodically on the progress of the program to the Directors of NHGRI, NCI and NIMHD, as appropriate, and to their respective National Advisory Councils, as appropriate.
• Retaining the option to recommend the withholding or reduction of support from any project that fails to achieve its goals or comply with the Terms and Conditions of award.
• Serving on subcommittees of the Steering Committee, as appropriate.
• Serving as a liaison between the Steering Committee and the External Scientific Panel, attending ESP 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).
• 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.
• Other NHGRI, NCI or NIMHD 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 NIH 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 to incorporate genomic results into clinical care. The awardees and the Project Scientist will meet as the program Steering Committee three times per year and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. Key co-investigators and pre- and postdoctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, in addition to the PIs, are eligible to attend these meetings.

The Steering Committee will serve as the main scientific body of the program. The Steering Committee will be responsible for coordinating the activities being conducted by the program. The Steering Committee membership will include one NHGRI Project Scientist, one Project Scientist from component IC's funding an award, and the PD/PI from each awarded cooperative agreement from this and accompanying CSER2 FOAs. The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired. It is anticipated that additional coordination mechanisms may be set up with other U.S. and international groups that may collaborate with the program.

Each CSER2 Clinical Site and Coordinating Center will have one vote and the NIH Program Scientist(s) together will have one vote. Cooperative agreements with multi-PI arrangements will have a single vote to be decided as desired within the multi-PI award. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

To address particular issues, the Steering Committee may establish Working Groups as needed, which will include representatives from the program and the NIH and possibly other experts.

The Steering Committee will:

• Discuss progress in meeting the goals of the Program
• Develop recommendations for uniform procedures and policies necessary to meet the goals of the Program
• Develop and implement a CSER2-wide Stakeholder Engagement Plan
• Serve as a venue for consideration of ethical and psychosocial implications of returning genomic data results to patients
• Develop and disseminate guidelines and best practices for assessing clinical utility and for incorporation of sequencing data into clinical care
• Develop a set of standardized clinical utility measures and other metrics to be shared across the program
• Identify and pursue opportunities for cross-site analyses
• Define state-of-the-art approaches for incorporating sequence data into clinical care that are responsive to evolving changes in clinical care, to facilitate translation of genomic findings into improved genetic risk assessment, prevention, diagnosis, treatment, cost-efficiency, and, ultimately, improved health
• Meet in person three times a year, and monthly via conference calls
• Interact with other relevant NHGRI and NIH activities, as needed, to promote synergy and consistency among similar projects

External Scientific Panel

An External Scientific Panel (ESP) will evaluate the progress of the CSER2 program, providing recommendations to the network about the progress and scientific direction of all components of the program.

The ESP is currently composed of nine senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed. The CSER2 ESP will meet at least twice a year, once per year in person and once by telephone conference. At least once per year, there will be a joint meeting with the Steering Committee to allow the members of the ESP and the Steering Committee to interact directly. Twice a year the ESP will make recommendations regarding progress of the program to the network about changes, if any, which may be necessary.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

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.

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

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Telephone: 301-710-0267

Lucia A. Hindorff, Ph.D., M.P.H.
National Human Genome Research Institute (NHGRI)
Telephone: 240-271-1509
Email: [email protected]

Charlisse Caga-Anan, J.D.

National Cancer Institute (NCI)
Telephone: 240-276-6738
Email: [email protected]

Regina James, M.D.

National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-496-3462
Email: [email protected]

Ken Nakamura, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-8823
Email: [email protected]

Deanna Ingersoll
National Human Genome Research Institute (NHGRI)
Telephone: 240-669-2989
Email: [email protected]

Carol Perry
National Cancer Institute (NCI)
Telephone: 240-276-6282
Email: [email protected]

Priscilla Grant, J.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8412
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.