Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Human Genome Research Institute (NHGRI)
Funding Opportunity Title	Clinical Sequencing Exploratory Research (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	April 20, 2012 - This RFA has been reissued as RFA-HG-12-009. January 20, 2011 - See Notice NOT-HG-11-011 The purpose of this Notice is to correct the fiscal year in Part 2: Section II Award Information. January 6, 2011 - See Notice NOT-HG-11-008 Notice of Correction to Eligible Organizations. December 21, 2010 - See Notice NOT-HG-11-007 Information Teleconference and Webinar for Applications to NHGRI Sequencing and Ethical, Legal, and Social Implications (ELSI) FOAs.
Funding Opportunity Announcement (FOA) Number	RFA-HG-10-017
Companion FOA	RFA-HG-11-003, R01 RFA-HG-11-004, R21
Number of Applications	Section III. 3. Additional Information on Eligibility
Catalog of Federal Domestics Assistance (CFDA) Number(s)	93.172
FOA Purpose	The NHGRI seeks grant applications to explore, within an active clinical setting, the application of genomic sequence data to the care of patients. Our understanding of human genetic variation and its association with disease risk and with individual response to treatment continues to expand rapidly. Simultaneously, a revolution has occurred in genomic sequencing technologies, making it technically and economically feasible to consider the application and utilization of genomic sequence data in clinical care. Applications submitted in response to this FOA will address critical questions about the application of genomic sequencing to clinical care of individual patients, from generation of genomic sequence data, to interpretation and translation of the data for the physician, to communication to the patient, including an examination of the ethical and psychosocial implications of bringing broad genomic data into the clinic.

Posted Date	December 17, 2010
Open Date (Earliest Submission Date)	February 3, 2011
Letter of Intent Due Date	February 3, 2011
Application Due Date(s)	March 3, 2011
AIDS Application Due Date(s)	Not applicable
Scientific Merit Review	July, 2011
Advisory Council Review	October, 2011
Earliest Start Date(s)	December 1, 2011
Expiration Date	March 4, 2011
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 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. While some links are provided, 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 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

A new generation of DNA sequencing instruments has made it feasible to determine the complete sequence of a human genome for costs of tens of thousands of dollars rather than the millions of only a few years ago. The cost of determining the protein-coding sequences in the genome (i.e., the exome) is lower yet by a factor of five to ten. The time is rapidly approaching when health care providers will be able to obtain the complete genomic sequence of their patients, and we can already anticipate many questions about how this information will be used to inform medical and preventive care decisions. Already today, a small number of well-studied alleles may be examined and results applied to clinical decisions. Currently, individual genetic test results for a few specific conditions, such as adverse drug reactions, HLA type, and hemoglobinopathies, are available in most clinical centers, and the potential for applying data from dense SNP arrays to clinical decisions is being explored in a few. However, we do not yet understand the full potential for the application of genomic sequencing to routinely assess individual variation of medical relevance. For example, it is unclear what diseases or individual susceptibilities will be usefully addressed by a genomic sequencing approach, or what the potential range of clinical applications will be. Furthermore, incorporating comprehensive genomic sequence data in clinical care will require the development of institutional policies, standardization of procedures (including simplified analysis and interpretive tools), and development of the capacity to integrate sequence information into the clinical workflow. Much exploratory research is required to understand the current potential for the use of sequence information in personalized genomic medicine and to identify the areas of opportunity for innovation.

The research projects solicited by this FOA are expected to begin to generate a foundation on which to build the infrastructure and methods necessary to routinely interrogate a patient’s unique genetic code and to apply this fundamental knowledge to her/his medical care. This objective requires that a large fraction of each patient’s genomic sequence be obtained and analyzed. Research approaches can include high-coverage sequencing of large targeted regions of the genome, targeted whole exome sequencing, or even whole genome sequencing, pertaining to any disease where obtaining sequence information from individuals is likely to have a clinical impact. However, whole exome sequencing approaches are particularly encouraged.

Genomic sequencing at the breadth of coverage required as a condition of this FOA will reveal thousands of rare or individually unique variants, most of which will not have been previously identified. To begin to integrate this genetic knowledge into clinical care, many steps are necessary. Annotation of variants with respect to function (e.g., those that disrupt protein structure), unambiguous association with disease susceptibility (e.g., CFH variants and macular degeneration), and clinical utility (e.g., a favorable balance of benefits to risks in terms of implications for health outcomes and personal impact to the patient) must be addressed. The subset of variants that are determined to be useful for clinical consideration must be identified and presented to the clinician in an intuitive, user-friendly summary report. Approaches to clinical translation are likely to evolve during the next decade in response to changes in healthcare, developments in sequencing and informatics, a greater understanding of disease biology, and a more mature understanding of ethical, legal, and social issues (ELSI). The collaborative and cooperative nature of this program is designed facilitate the development and standardization of best practices and common approaches to clinical translation.

Applications submitted in response to this FOA should also include an empirical (behavioral or social science) research component designed to investigate the experiences of patients and clinicians with respect to the return of individual research results. While issues related to the return of results are neither new nor unique to the context of genomics research, several unique characteristics of genomic sequencing make their resolution in this particular context especially daunting. First, these projects unlike more traditional genetics research projects that involve the interrogation of more discrete parts of the genome will involve the generation of information which will, by definition, be voluminous in quantity and comprehensive in scope. While applicants to this FOA may or may not uncover the particular variant or variants they were originally looking for (related to the disease or trait of initial interest), they will inevitably uncover a large number of incidental findings findings that are apparently unrelated to the original research questions. Such incidental findings will include variants of both known and unknown significance, information about carrier status, and information about risk for late-onset disorders. Considerable controversy exists about the precise threshold of utility that should be required before a result can or should be returned to a research subject or a patient. Deciding what to do with these findings will present researchers with significant medical and ethical challenges.

For the remainder of this FOA, the term patients , rather than participants , will be used to describe the individuals whose genomic information will be stored, analyzed, interpreted, and (potentially) communicated in this research, because such information will ultimately be used in the clinical setting. Notwithstanding this terminology, applicants should remain alert at all times to the fundamental distinction between research and clinical care and to the different ethical obligations and implications for human subjects research that apply in each context.

As the objective of this FOA is to support fundamental research on the clinical application of genome-scale sequence data, applications proposing to sequence only one or a few loci will not be responsive. Applicants must address how procedures and tools will be developed or standardized to begin to integrate sequence information into clinical care. Although research funded through this FOA may uncover novel alleles during the course of the work, proposals that focus primarily on discovery rather than clinical application will not be considered to be responsive.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NHGRI intends to commit $5.5 M/year for 3 to 6 awards anticipated in FY 2011.
Award Budget	Individual application budgets should not exceed $1,500,000 per year, direct costs and must reflect actual needs of proposed project.
Award Project Period	The total award period requested for this RFA may not exceed four years

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:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions

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

Foreign (non-U.S.) components of U.S. Organizations are allowed.

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• eRA Commons

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

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

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.

Expertise is essential in all areas addressed by the FOA: clinical medicine, genomic analysis, bioinformatics, bioethics, and social or behavioral sciences. One Principal Investigator (PI) should be designated as the clinical lead. Designation of additional PIs, with the appropriate experience and expertise to lead components 2 or 3, is encouraged, as suitable for the specific Research Plan.

The Principal Investigator(s) must devote at least 1.2 person months effort to this Cooperative Agreement

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.

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

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

The letter of intent should be sent to:

Bradley A. Ozenberger, Ph.D.
Program Director
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892
Telephone: 301-496-7531
Email: [email protected]

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

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

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

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892
Telephone: (301) 496-7531
Email: [email protected]

All page limitations described in the PHS398 Application Guide must be followed, with the following exceptions or additional requirements:

• Applications to this FOA should include separate research strategies for three projects: 1) Clinical Genomic Study (12 pages); 2) Sequencing, Analysis and Interpretation of Sequencing Data (12 pages); 3) Ethical and Psychosocial Implications Research (12 pages); plus a Project Management Plan (6 pages). Details are provided in the Research Plan section below.
  

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

Applications to this FOA will be organized in three separate, but highly integrated projects: 1) Clinical Genomics Study; 2) Sequencing, Analysis and Interpretation of Sequencing Data, and 3) Ethical and Psychosocial Implications Research, plus a Management Core describing the study management plan.

Project 1. Clinical Genomic Study. The Research Strategy should emphasize one or more areas of medical investigation (i.e., disease or therapeutic approach) or a specific approach to the use of genotype-phenotype data within a clinical context (e.g., risk prediction modeling or cancer mutation profiling). Efforts to discover new disease alleles may be included in a Research Plan but are not necessary or encouraged. Applicants should justify the features of the disease or approach that make incorporation of clinical genomic sequence data particularly compelling. Power calculations may be used to justify study design; however, given the exploratory nature of this FOA, other metrics may be acceptable. Phenotypic data elements should be described fully, including methods for ascertainment, standardization and validation as relevant. Additionally, applicants should provide a detailed description of any ongoing study/cohort recruitment, including plans to reconsent patients for the return of results, or of readiness to enroll new appropriately consented patients in the study. The informed consent must describe the potential benefits and risks of genomic sequencing and how individual research findings are expected to be offered back to patients and incorporated into the patient’s clinical care. Given the significant ethical complexities involved in acquiring large amounts of genomic sequence data relating to identified patients, in deciding which individual findings to offer to return to patients, and in deciding when and how to communicate such findings, it is likely that all patients recruited for these studies even those who have previously provided consent to participate in genomic research--will need to provide informed consent appropriate for participation in the study.

The Research Strategy for Project 1 should address:

A) Medical Objectives and Rationale

• supporting evidence and preliminary findings that the disease emphasis has a genetic component,
• justification for the approach why the disease or clinical approach is important, and why the proposed approach is especially suitable for exploring the utility of genome sequencing in a clinical setting?
• description of the proposed study sample, including details on study design, sample size, selection, and plans for obtaining appropriate informed consent (note that the funds available for sequencing and analysis, as described in the following sections of this FOA, may limit the number of patients actually sequenced, and hence the statistical power),
• description of phenotypic data elements to be included in this study.
• B) Translation and Dissemination of Sequence Information in the Clinical Setting
• description of how the proposed research will advance the translation of sequence information to clinical care,
• description of measurable outcomes relevant to the integration of sequence information in clinical care, including physician-centered (e.g., comprehension; changes in clinical care, outcome, or efficiency; quality of doctor-patient interaction) and, as appropriate, patient-centered (e.g., adherence, screening or treatment of family members, quality of life, satisfaction with care),
• discussion of how potentially actionable research findings will be identified and replicated in a laboratory certified under the Clinical Laboratory Improvements Amendments (CLIA) (unless the original sequencing results were obtained in a CLIA-certified laboratory),
• description of the human subjects research protections that will be employed, including how patient privacy will be protected, how the informed consent process will be designed, how the benefits and risks associated with the generation of comprehensive genomic sequence data and any plans to return individual research findings will be communicated to patients, and any other pertinent issues relating to human subjects protections,
• description of the general process by which individual research findings will be offered to patients, including who will be responsible for offering these findings and how the processes for returning individual findings will be monitored to ensure patient protection. Applicants should describe possible approaches or best practices for returning findings relevant to clinical care, and recognize the need for such processes to evolve over the project period in response to recommendations made by the Institutional Review Board, the Clinical Sequencing Exploratory Research Steering Committee, or implementation of NIH policies.

Project 2. Sequencing, Analysis, and Interpretation of Sequencing Data. Most clinicians will have neither the expertise nor the time during the normal clinical workflow to analyze extensive genomic sequencing datasets and extract from these voluminous data the subset of information that is of medical relevance and clinically actionable. This FOA therefore anticipates not only the need to generate individual sequence data in the course of clinical care, but the need to categorize sequence variants efficiently and identify those that are potentially clinically actionable, and to provide this information to the practicing clinician in a user-friendly format with rapid turnaround time. Investigations of more facile methods for sequencing data interpretation and timeliness of delivery of findings, from sequence generation to clinical summary, are important objectives of this FOA. Applications should thus include as part of the Research Plan the development of methods to analyze genomic sequence data for clinically actionable variants, parse the data into manageable components (to be defined by the applicant), and translate findings into a format to ease interpretation by the clinician. Subsequently, the transmission of this information to the patient requires a high level of comprehension by the physician or other healthcare provider (such as a genetic counselor or nurse). This component also contains the genomic sequencing data generation description.

The Research Strategy for Project 2 should address:

A) Genomic Sequencing Plan

• description of specimen processing and tracking,
• justification for and description of the genomic sequencing strategy; it is anticipated that the focus of most proposals will be on the use of whole exome sequencing, but sequencing of targeted regions (500 genes or 1,000,000 basepairs is a minimum requirement) or whole genomes will be acceptable if adequately justified; cohort size is described in section 1.A,
• description of genomic sequence generation, the facilities and instrumentation to be utilized for sequence generation or, if sequencing is to be subcontracted, the sequence provider,
• detailed description of genomic sequencing experience and demonstration of quality data production at the scale required to achieve project goals; it is suggested that a report on the prior quarter s sequencing production and quality measures employed be included,
• detailed description of bioinformatics infrastructure/capabilities to securely transmit and store genomic data files for the research project
• description of the pipeline from acquisition of specimens through sequencing data generation, including time components.

B) Genomic Sequence Analysis

• description of computational and analysis resources,
• description of anticipated analysis strategy, including file hierarchy and structure, and primary sequence data quality assessments,
• description of variation calling strategy, including algorithm development, if any,
• preliminary results.

C) Clinical Interpretation and Transmission

• description of methods for variant stratification,
• description of integration of phenotypic and clinical data (e.g., medications, family history, lifestyle factors),
• an analysis plan, integrated with project components 1 and 3, for identifying potentially clinically actionable variants, including a description of how sequence variants will be confirmed in a CLIA-certified laboratory,
• description of anticipated challenges in the analysis plan, and strategies to overcome these challenges,
• description of how information about genetic variants will be presented to the clinician so that they will be available for use, where appropriate, during the normal clinical encounter, including anticipated turnaround time from DNA collection to transmission of results to the clinician, including any point-of-care tools that are proposed for development,
• detailed description of the plan for developing a process to determine which specific categories of individual sequence results will or will not be offered to patients, how the results will be returned to the patient and incorporated into the medical record, and how any necessary follow-up (e.g., genetic counseling, referrals for additional testing) will be handled.

D) Costs

• an itemized breakdown of costs per patient for genomic sequencing and primary analysis.

Project 3. Ethical and Psychosocial Implications Research. Most ethicists agree that individual sequence variation results should be offered only in circumstances where they have actual utility. However, considerable controversy exists about the precise threshold of utility that that is required before a result can or should be returned. Some take the position that proven clinical utility is necessary (i.e., that some recognized preventive or therapeutic intervention must exist), while others believe that personal utility (e.g., the possibility that the information could be used for reproductive decision-making or general life planning) or even the mere recognition that the information may be useful in and of itself (e.g., by enhancing one’s sense of personal identity) may be sufficient.

Given the lack of consensus in this area, a pressing need exists to develop rational and workable criteria to help guide decision-making about what types of information can, should, or should not be offered to patients. Such criteria must, however, be informed by solid empirical data. This FOA thus seeks proposals for studies that will investigate how patients understand, react to, and use individual genomic results when they are offered and returned. Studies that examine the actual psychosocial and behavioral impact of receiving (or not receiving) such results are especially invited. The generation of such data about patient responses will be important in the development of guidelines and policy.

This FOA also invites studies that investigate the experiences of clinicians regarding the return of results. For example, to what extent are clinicians decisions motivated by a normative sense of duty, versus concerns about the potential for legal liability (e.g., for failing to disclose a clinically actionable result for a serious disorder for which a preventive or therapeutic intervention exists, or for disclosing information that turns out to be unwanted, causing the patient undue psychological distress)? What are the advantages and disadvantages of various institutional processes or shared decision-making processes for deciding which results can, should, or should not be returned? What are the implications of attempts to mine the data for potentially relevant information, versus limiting the focus to potentially relevant information merely stumbled upon ? What practical, logistical, and budgetary considerations enter into the calculus? What are the implications of CLIA? What practical difficulties do clinicians encounter when attempting to discern patients wishes and expectations regarding the return of results during the informed consent process? What practical and regulatory challenges do they encounter when considering whether or how to incorporate such information into participants' medical records? Are there intellectual property impediments to returning certain types of results?

The Research Strategy for Project 3 should include:

A. A clear statement of the specific empirical research questions related to the return of results to patients that will be studied,

B. A detailed description of the methodologies that will be used to study those questions,

C. A concise description of how this component of the research will be integrated into the development and implementation of the overall study design, including the informed consent process.

Applicants may choose to include in their applications a component aimed at the analysis of normative

or legal issues related to the return of results, but are not required to do so. Applicants proposing studies with a primary normative or legal focus should consider applying instead under RFA-HG-11-004 (R21). Applicants proposing studies with a primarily research (non-clinical) focus should consider applying under RFA-HG-11-003 (R01).

4. Management Core. Research projects proposed in response to this FOA will require close and consistent interaction among the Research Projects to ensure successful integration of all elements. This section will contain:

A. A detailed description of the integration of and interdependent associations between Projectss 1, 2, and 3,

B. A description of management structure, leadership roles, and mechanisms of communication; note that the senior investigator for each project is required to devote at least 1.2 person months of effort to this project,

C. A description of institutional human subjects protections oversight, and

D. Specific Aims for the overall project and each research component.

Program Formation and Governance / Cooperative Agreement

Awards funded 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. Furthermore, a consortium will be organized with all of the principal investigators and key personnel funded under this FOA; the consortium may include other investigators who are working on the same or similar research issues, as well as investigators to be funded under two related FOAs relating to the ethical, legal, and psychosocial implications of returning results, referenced above, that are being issued concurrently.

The Principal Investigator(s) from each investigative group and the NIH Project Scientist(s) will meet as a Steering Committee at least annually, and by conference call on an ongoing basis, to identify and address common sequencing, analytic and translational issues, review preliminary results, explore opportunities for synergy among studies, develop best practices, and explore the crucial psychosocial and ethical issues and findings. Subcommittees and working groups may be established to facilitate collaborative work and standardize approaches. 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 co-investigators, and pre- and postdoctoral trainees, in addition to the PIs, will be eligible to attend Steering Committee meetings. The costs of 5-6 persons to attend these meetings, as well as the costs associated with monthly conference calls, should be included in the proposed research budget.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS) as provided in the PHS398 Application Guide.

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide,

In addition to the instructions above regarding the Research Plan sections, the application should include the following:

Data Sharing Plans.

The NHGRI large-scale sequencing program has long championed the concept of rapid pre-publication data release. However, privacy issues associated with clinical research, such as in the program described in this FOA, can provide a rationale for exception to those long-held precepts. Some genomic sequencing and variation data sets generated as a result of this research may become a part of an individual patient’s medical record. However, sequence and phenotype data resulting from this research may have value beyond that intended by the submitting investigators. Therefore, submission of data sets to the database of Genotype and Phenotype (dbGaP), while not required before publication, is encouraged, and should be released at the time of publication, within the rules and regulations of the controlling IRB and local jurisdiction and with informed consent to permit broad data release via an NIH database. Applications to this FOA must include a discussion of whether or not release to dbGaP will be authorized in the informed consent for the study. Any restrictions on data use (such as limitations to a specific disease or condition) should be described. Although this information must be included in the application, the plans for data sharing will not be a review criterion.

The general NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity and requesting $500,000 or more per year direct costs are expected to include a description of how research data will be shared.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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 received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will be returned to the applicant without review.

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

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

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Do the applicants generally highlight new opportunities or address gaps in the communities overall knowledge related to how to use large-scale sequencing to address important biological and biomedical questions? Does the project make a direct and important contribution to the implementation of sequence information in a clinical setting and to understanding the ethical and psychosocial implications of returning sequence results? Does the project address and overcome barriers or challenges to implementation that extend beyond the applicant’s institution to the wider field?

Investigator(s)

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

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Does the applicant propose development of any point-of-care tools or clinical decision-making resources that will facilitate routine incorporation of sequence information into clinical care? Is the proposed approach or methodology dynamic and responsive to evolving changes in clinical care? Does the applicant propose the development of innovative approaches to the return of results to patients?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Does the management plan ensure the integration of researchers from all three Research Projects into the development and implementation of the overall research plan?

Does the application provide a clear plan for timely, accurate and efficient dissemination of sequence information to the practicing clinician in a user-friendly way?

Does the research plan adequately address how any research findings to be returned to patients will be obtained or validated in a CLIA-certified laboratory?

Does the research plan include an adequate description of the proposed informed consent process and of how the IRB will be involved in any plans to return individual research findings?

Is the Psychosocial and Ethical Implications Research Project fully integrated with the other components of the researach plan?

Has the application described possible best practices or approaches for integrating genomic sequence data into clinical care, or an intent to develop such activities?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

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

Protections for Human Subjects

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

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

Informed consent: Given the significant ethical complexities involved in generating large amounts of genomic sequence data relating to identified patients, in deciding which individual findings to offer to communicate to patients, and in deciding when and how to communicate such findings, it is expected that all patients recruited for these studies even those who have previously provided consent to participate in genomic research--will need to provide a new informed consent for participation. Plans for consent or reconsent will be reviewed.

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

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.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

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

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

Applications will compete for available funds with all other recommended applications submitted in response to this FOA . Following initial peer review, recommended applications will receive a second level of review by the 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.
• Programmatic balance among diseases to be studied and approaches to be implemented.
• Public health importance of conditions to be studied.
• Diversity of study sample in terms of under-studied minorities and those suffering health disparities.
• Applicability of the proposed approach to other clinical 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.

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 business official.

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

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

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.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a study-wide Steering Committee to share design and analysis techniques and promote comparability across studies wherever possible.
• Implementing Steering Committee recommendations for improving data collection, 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 in their project regarding incorporation of sequence data into clinical care.
• Obtaining the necessary consent or reconsent, 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-certified laboratory.
• 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 genomic sequencing results to patients on disease-centered, patient-centered, and cost-related outcomes.
• Sharing results according to the data sharing policy agreed to between the NHGRI and the applicant.
• Abiding by common definitions as chosen by majority vote of the Steering Committee.
• Accepting and complying with study policies established by NIH, and with additional non-conflicting policies approved by the Steering Committee.
• Cooperating with other awardees in the publication and dissemination of program results and the eventual release to the scientific community of methods, tools, and results, and other resources.
• Not disclosing confidential information obtained from other members of the program.
• Notifying the Project Scientist of all major interactions with another member of the Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and External Scientific Panel.
• Attending and participating in Steering Committee meetings and accepting and implementing guidelines and procedures, as appropriate.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Scientist is a scientist of the NHGRI staff who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the program and that NIH staff will be given the opportunity to offer input to this process. The Project Scientist will participate as a member of the Steering Committee and will have one vote.

The Project Scientists 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 Director, NHGRI, and to the National Advisory Council for Human Genome Research.
• Retaining the option to recommend the withholding or reduction of support from any project that fails to achieve its goals or comply with the Terms and Conditions of award.
• Serving on subcommittees of the Steering Committee, as appropriate.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.

The assigned program director may also serve as an NIH Project Scientist.

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

• 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.

Areas of Joint Responsibility include:

• Participate in the Steering Committee. A Steering Committee will serve as the main governing board of the Clinical Sequencing Exploratory Research Program. The Steering Committee membership will include one NHGRI Project Scientist and the P.I.(s) of each awarded cooperative agreement. The Steering Committee Chair will not be an NHGRI staff member. Additional members may be added by action of the Steering Committee. Because of the range of scientific activities in this program, other NHGRI staff will participate in the consortium and attend Steering Committee meetings. NHGRI staff will have one collective vote on the Steering Committee.

The Steering Committee:

• Will discuss progress in meeting the goals of the Program;
• Will develop recommendations for uniform procedures and policies necessary to meet the goals of the Program;
• Serves as a venue for consideration of ethical and psychosocial implications of returning genomic data results to patients.
• Each full member (limited to one person per awarded center, in the case of multiple PI’s per center) will have one vote as will the NHGRI Program Officials. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.
• Develop and disseminate guidelines and best practices for incorporation of sequencing data into clinical care.
• 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.

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.

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.

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

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]

Bradley A. Ozenberger Ph.D.
National Human Genome Research Institute
Telephone: 301-496-7531
Email: [email protected]

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
5635 Fisher Lane, Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 435-1580
Email: [email protected]

Cheryl Chick
Grants Management Branch()
Telephone: 301- 496-7531
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 Parts 74 and 92.