Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)

Funding Opportunity Title

Mendelian Disorders Genome Centers (U54)

Activity Code

U54 Specialized Center- Cooperative Agreements

Announcement Type

New

Related Notices

  • 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.
  • 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-10-016

Companion FOA

RFA-HG-10-015; RFA-HG-10-018; RFA-HG-10-019

Number of Applications

Only one application per institution is allowed Section III. 3. Additional Information on Eligibility.

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

 93.172   

FOA Purpose

This FOA seeks to establish a center or centers that will use genome-wide sequencing and other genomic approaches to discover the genetic variants underlying Mendelian disorders and other health-related Mendelian phenotypes in human.  The centers should aim to uncover the genetic basis for as many of these phenotypes as possible with the funds available during the funding period.  More generally, NHGRI intends that this effort will provide a foundation for the broader research community to elucidate the genetic basis of all Mendelian disorders, and to that end this FOA has two additional purposes that are outlined below.

First, this FOA seeks to establish and refine the most effective and efficient designs, technologies, and analysis methods for elucidating the genetic basis of Mendelian phenotypes.  This will necessitate balancing cost, efficiency, and quality.  NHGRI expects that the data obtained by the funded projects will help determine the range of tractability of Mendelian phenotypes to state-of-the-art genomic approaches.  NHGRI intends that this knowledge will be disseminated to the broader community working on these phenotypes, so that progress towards a comprehensive understanding of the genetic basis of Mendelian disorders will be accelerated.

Second, NHGRI believes that, in order to undertake a comprehensive approach to elucidating the basis of Mendelian disorders, there is a need to identify and coordinate distribution of human samples that are currently distributed among many researchers. This is true whether the sequencing will be done in a few large centers, or will be distributed among many individual laboratories, or will be a mix of these.  Thus, this FOA seeks to support the effort to create a public list of existing samples as a resource for investigators interested in studying the phenotypes that they represent.  The sample list will need to be annotated to include information that could help the community monitor the overall progress being made ­­and challenges remaining.  In principle, such a list will serve as a point of coordination for the community towards elucidating the basis of as many Mendelian disorders as possible. The information could include, for example, sample custodians and availability, whether the samples are being sequenced and by whom, and basic information about consent, OMIM identifiers, and diagnosis/key phenotypes, etc.

Together, NHGRI intends that these three broad aims will accelerate the community’s efforts towards the identification of genetic variants underlying all Mendelian disorders.

Key Dates
Posted Date
Open Date (Earliest Submission Date)

 Not Applicable

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 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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

NATURE OF RESEARCH OPPORTUNITY

Deciphering the genetic variants underlying human Mendelian disorders and other Mendelian phenotypes of relevance to health and biology is of significant biomedical relevance.  First, the knowledge of those variants, which are rare and highly penetrant by definition, will facilitate rapid and accurate diagnosis of Mendelian disorders and might lead to new therapeutic approaches.  Second, knowledge of the rare variants underlying Mendelian phenotypes can also lead to insight about the common or more complex phenotypes that involve similar genes, pathways, and phenotypes.  In the long run, a comprehensive collection of rare and highly penetrant variants would represent a highly valuable resource for understanding basic human genetics and would identify entry points into fundamental developmental and physiological pathways.

While the genetic basis of around 2800 Mendelian disorders has been determined so far, the genetic basis remains to be confirmed for a large number of additional confirmed or suspected Mendelian disorders (OMIM).  Recent advances in genome technology and computational methods have made it possible to identify the genetic basis of Mendelian disorders using genome-wide approaches in a more cost-effective way than linkage mapping and candidate gene approaches, in part because the sequence-based approach often requires a smaller number of samples.  Both whole genome sequencing, and exome-based sequencing using selective capture of genome-wide protein coding regions, have successfully been used to identify causal variants of Mendelian disorders from a few unrelated samples.  It now seems feasible to uncover the genetic basis of most, or even all, Mendelian disorders in the foreseeable future.

A program dedicated to elucidating the genetic basis of Mendelian disorders is consistent with the direction of the NHGRI Large-Scale Sequencing program.  In the past five years, medical sequencing has been the program’s primary focus, and a number of Mendelian disorders have been targeted.  The objective of supporting one or more mid-size centers implements one of the recommendations of the NHGRI’s March 2009 Workshop on the Future of DNA Sequencing (see http://www.genome.gov/Pages/Research/DER/DERReportsPublications/SeqPlanWkshopReportFinal.pdf for workshop report) and the recent NHGRI strategic planning meeting (http://www.genome.gov/27540186).  These recommendations proposed that such centers could tackle feasible and well-defined projects that address important biomedical problems in an integrated way, from sample acquisition through sequencing through analysis.

This FOA is intended to support efforts that aim to contribute to the discovery of the genetic basis of all Mendelian disorders and other health-related Mendelian phenotypes in human in two main ways.  The first is to use genome-wide sequencing and other genomic approaches to discover the genetic variants underlying as many as possible disorders and health-related phenotypes, spanning the various Mendelian inheritance patterns, with the funds available during the funding period.  The second is to build a better foundation for elucidating the genetic basis of all Mendelian disorders by 1) establishing and disseminating information about effective approaches to the identification of the causative genetic variants of Mendelian disorders, and gaining insight about the overall tractability of Mendelian disorders to state-of-the-art genomic approaches, and 2) compiling a comprehensive list of existing human samples of Mendelian disorders and other health-related Mendelian phenotypes as a public resource to help coordinate genetic variant discovery activities that will be carried out by many groups.

RESEARCH OBJECTIVES (30-page limit)

This FOA solicits proposals for Mendelian Disorders Genome Centers that can undertake related activities in two main areas.  The first will be the discovery of the genetic variants underlying Mendelian disorders and other health-related Mendelian phenotypes in human, by developing and operating a production pipeline for sample acquisition, sequencing and other genomic approaches, and data analysis.  The applicant should undertake to elucidate as many of these phenotypes as possible with the funds available during the funding period.  Tied into this activity will be the development and dissemination of efficient approaches to the identification of the genetic variants underlying Mendelian phenotypes, and gaining insight about the overall tractability of Mendelian phenotypes to state-of-the-art genomic approaches.  The second will be the creation of a comprehensive public list of Mendelian disorders and other health-related Mendelian phenotypes in human that will provide information about available samples and sequencing status, along with other relevant information, thereby facilitating community coordination towards elucidating the basis for most or all of these phenotypes. 

Overall, the applicant should propose a research plan that includes a succinct description of relevant past experience, a description of current genomic capacity, and how a state-of-the-art genome center will be established and operated to fulfill the research objectives of the proposed center.  Of particular interest is experience in acquisition of human samples, production of next-generation sequence data and subsequent identification of genetic variants of interest, public release of genomic data, development of community resource data or tools, dissemination of scientific findings, and management of scientific collaborations.  Specific background and guidance on critical elements of the application are provided below.

Sample Acquisition and Allocation

Sample availability has been a bottleneck for many genomic research efforts, and, NHGRI expects the availability of a sufficient number of samples to be the most significant barrier to achieving comprehensive elucidation of the genetic basis of human Mendelian disorders.  A Mendelian Disorders Genome Center is expected to obtain sufficient human samples from sample custodians within the medical research community to fully utilize the sequence production capacity that it will build.  Samples should be properly consented for data release into a public “controlled access” repository (dbGaP).  Because NHGRI anticipates that it will take several months for the Mendelian Disorders Genome Center and other potential mechanisms (see below) to develop a sample pipeline, the applicant is expected to identify and obtain in advance an adequate number of samples for at least the first six months of operation in order to avoid any delay in sequence data production. 

In order to obtain information about the range of tractability of Mendelian phenotypes to state-of-the-art genomic approaches, it will be important for the center to find and sequence samples representing a wide range of clinical and other biologically informative phenotypes and different Mendelian inheritance patterns.

The applicant must describe how existing samples will be identified, and obtained, and propose well-supported milestones and timelines for the types and number of samples to be obtained.  Finally, the timelines should take into consideration the likely increase in the number of sequencing projects that the Mendelian Disorders Genome Center will be able to complete as a result of innovation in project design or implementation of new technologies or methods.

In addition to the samples that will be acquired with NHGRI funding, NHGRI anticipates that other NIH institutes will identify and provide samples.  In the event that such samples are accompanied by additional funds, those samples will be given high priority in pipeline assignment.  Should there be limiting pipeline capacity for such samples immediately, their priority will be determined by NHGRI in consultation with the other funding institutes.  “Excess” samples that cannot be initiated in a reasonable time may also be assigned to other NHGRI-funded large-scale sequencing centers so that the projects can be completed expeditiously. 

The applicant should propose how prioritization and allocation of available samples will be done to fully occupy the sequencing pipeline.  Sample prioritization and allocation should consider scientific and practical factors such as: significance of disease, inheritance pattern, range and complexity of phenotype, impact on understanding common disease, tractability, sample quality, strength of community, etc., so that at the end of the funding period the program as a whole will provide an understanding of the overall challenge entailed in aiming to understand the genetic basis for all Mendelian disorders and the value of doing so.  Coordination with the other Mendelian Disorders Genome Center, in the event that two are funded, must be addressed.

Genome Sequencing and Identification of Genetic Variants

85% or so of the known Mendelian variants reside in the protein-coding regions of the human genome, implying that many additional Mendelian variants will be found in coding regions.  Moreover, it is easier to interpret and test the functions of coding variants, offering higher likelihood of identifying actionable drugs for disease treatment.  Thus it is logical to begin with exons for the discovery of the causative genetic variants of Mendelian phenotypes.  This approach also has cost advantage over the whole genome approach.  Because the coding sequences of all of the proteins only make up 1% of the human genome, whole exome sequencing currently costs only around 5% of the cost of whole genome sequencing using the same sequencing platform.  At the same cost, whole exome sequencing can be done for 20 times as many samples, which will either increase the statistical power for analysis of rare variants, or allow more phenotypes to be analyzed.  We expect that the cost advantage of exome sequencing will more or less be maintained for the foreseeable future, even as costs for both sequencing strategies decrease during the next several years.  While NHGRI considers whole exome sequencing to be the current state-of-the-art for discovery of the genetic basis of Mendelian phenotypes, applications submitted in response to this FOA are not limited to this approach.  Other strategies will be considered and such applications should provide justification, for example in terms of reasonable and credible advantages in cost and/or quality, for the strategy proposed.  Moreover, alternative approaches may be appropriate for instances in which the whole exome approach fails.  The most competitive applications will be those that can demonstrate the highest potential to meet the research objectives with the available funds.  

The research plan should be described in relation to the main features of the current state-of-the-art summarized below.  If the proposed research plan will use a different genome-wide approach, then equivalent features should be addressed. 

The main features of a state-of-the-art approach to discover genetic variants underlying Mendelian disorders include: 

As guidance, the applicant should provide details on the following in discussing these points:

Project design.  Applicants should discuss sequencing and analysis designs for variant discovery and validation, with consideration of phenotype traits, inheritance patterns, penetrance, sample size, etc.  Potential difficulties in associating a variant to a phenotype trait should be discussed, along with alternative approaches.

Whole exome capture and sequencing.  The applicant should describe the advantages of the chosen target capture methods in terms of 1) sample input requirement, 2) completeness (% of the whole exome that is captured), uniformity, and specificity of the captured targets, 3) scalability of the capture process, and 4) cost. All sequencing and other genome technologies and approaches for the discovery and validation of genetic variant should be clearly described.  The applicant must provide a description of his or her track record in using the proposed technologies and approaches, and the current status of implementation.

Quality assurance.  The applicant should describe how sample quality, captured targets, sequence reads, and variant calling are currently, and will be, measured or assessed.  Quality metrics should assure high variant calling sensitivity and specificity.  The qualities to be measured or assessed should include, for example, quantity, integrity, and genotyping of samples; evenness, specificity, yield, and reproducibility of whole exome capture; minimal level of sequencing coverage; and percentage of mappable reads. 

Production flexibility.  At this point, it is difficult to predict whether samples will be available at a constant rate during the funding period.  Samples that might be provided by other NIH institutes, for example, might temporarily increase sample availability.  On the other hand, delayed delivery or sample quality issue, for example, might temporarily decrease sample availability.  Thus the applicant should provide information about how the proposed center will be able to cope with what may be temporary increases or decreases in sample availability.

Cost. Sequencing production costs should be reported for the past three months or most recent quarter if this information is available, and projected for the first planned year of effort.  The applicant must also describe a cost reduction plan for the entire funding period (see the paragraph below).  Production costs should be expressed as cost per exome at a quality to be stated by the applicant, and range of costs per disorder.  Production costs must include all production-related costs (management, administrative support, personnel, supplies, reagents, equipment (3-year amortization schedule), informatics support, and allocated indirect costs, from sample handling and preparation through identification of genetic variants underlying the disorder/phenotype under study.  Costs associated with sample acquisition, further characterization of the identified variants, data deposition, and technology development should not be included as production costs.  Applicants proposing whole exome sequencing may choose, but are not required, to use the suggested production reporting table posted at http://www.genome.gov/27541956, to summarize the description of current capability and research plan for the first year about throughput and costs.  The purpose of this suggested table is to facilitate a uniform summary of the information from applicants to ensure fair review of the applications.  Note that this table is included in the 30-page limit.

Technology and methods improvement.  Past experience and planned implementation of improved methods and technologies for sample handling, laboratory automation, sequencing, base calling, read mapping, assembly, variant calling and statistical analysis should all be considered and described.

The research plan should also discuss the following points:

Production milestones and timelines.  The research plan must include quantifiable milestones (deliverables and timelines), and contingency plans for dealing with potential bottlenecks, for the entire funding period for 1) number and types of disorders/phenotypes to be resolved, 2) implementation of new or improved technologies and software tools, and 3) cost reduction.  

Scientific collaborations.  NHGRI expects that the Mendelian Disorders Genome Centers will collaborate with sample providers and the broader biomedical community for each variant discovery project to be successful.  Such collaboration will also lay the foundation for further characterization of the identified genetic variants beyond what will be funded by this FOA.  NHGRI appreciates that this FOA may not provide adequate funds for complete characterization (e.g., validation in many samples, etc.) of every Mendelian disorder once the genetic variants have been identified.  With this in mind, the applicant should describe a plan to manage a productive collaboration with what are likely to be many sample providers.

Dissemination of genomics “know-how”.  It will be extremely valuable for the community to adopt the technical “know-how” that the Genome Centers will establish for study design, production pipeline management, quality control, sequencing strategy, data analysis and variant identification, tractability of Mendelian disorders to state-of-the-art genomic approaches, and standard practice in data release.  Thus the Genome Centers are expected to promulgate this knowledge.  More generally, the Genome Centers are expected to take a leadership role in working towards a comprehensive genomic approach to elucidating the genetic basis of Mendelian disorders.  The applicant should propose a plan for the dissemination of genomics “know-how”.

Public Sample List

In addition to obtaining samples to provide for the sequencing goal, another major objective of the Mendelian Disorders Genome Centers is to compile a list of as many as possible of the existing human samples of Mendelian disorders and other health-related Mendelian phenotypes, as a public resource.  Such list is intended to catalyze the identification of genetic variants underlying all Mendelian disorders, by serving as a point of coordination for genetic variant discovery efforts that will be carried out by many groups, for example as a tool to prevent duplication of effort or to focus attention on less tractable, but important, problems.  In order to maximize utility of the sample list, the applicant should propose what information the sample list will be annotated with.  For example, the OMIM record number; diagnosis and/or key phenotypes; contact information for the sample custodian; sample availability for genetic variant discovery studies; sample form (tissue, DNA), quality and quantity; and sequencing and data analysis status and contact information for the sequencing and data analysis groups; can be considered as useful information.  To meet minimal requirements for public data release (see below), the status of consent for data release and a URL to released data (in dbGaP, for example) should also be indicated.  The applicant should propose the specific elements in the sample list for annotation, with justification in terms of how the information could facilitate coordination.  The applicant should discuss how he/she will communicate with prospective sample custodians to ensure that information about the identified samples will be appropriately provided in the public list.  In addition to annotating the sample list, the applicant should describe what functions (downloadability, for example) will be built into the sample list and how the list will be maintained.  The applicant must propose a plan to publicize the sample list in order to invigorate the research community and to facilitate sample identification and acquisition.  Finally, the applicant should describe how, in the event that two Mendelian Disorders Genome Centers are funded, the proposed Center will coordinate with the other Center to produce and post a single list.

Center Management

The P.I. funded under this FOA is expected to devote at least 1.8 person months, based on a 12-month calendar (equivalent to 15% of his/her time and effort) to the project.  In response to this FOA, the applicant should describe an organization and management plan for the proposed center.  The plan should describe the organization and reporting structure within the proposed center, including key personnel and section leaders, and decision-making processes.  Recruitment and training of personnel should be discussed.  Overall, the plan should discuss how the proposed organization and management structure will likely lead to success in attaining center goals.  At a higher level, the applicant can also describe any plans for inter-center coordination in the event that two Mendelian Disorders Genome Centers are funded. 

In sum, in response to this FOA, the application should include the following:

Data Release

In general, the NHGRI expects that the sequence and genetic variant data generated by the Genome Centers will be released into a public “controlled access” repository (see http://www.ncbi.nlm.nih.gov/gap).  This award does not explicitly anticipate including funds for obtaining new consents.  NHGRI understands that some critical samples may have been consented using language that is less than clear regarding the ability to deposit data, which may in some cases limit data release.  NHGRI staff will work with the grantees on this issue as it arises.  Data release plans should be discussed in detail in a separate section of the grant application (see Section IV.2 of this FOA).

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, 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 $10M in total costs; two awards are anticipated in FY2011.  Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

Award Budget

Individual application budgets should not exceed $10M total costs per year; direct costs must reflect actual needs of proposed project.

Award Project Period

The total project period for an application submitted in response to this funding opportunity 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.

Section III. Eligibility Information

1. Eligible Applicants
 
Eligible Organizations

Higher Education Institutions:

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

Nonprofits Other Than Institutions of Higher Education

For profit Organizations

Governments

Other

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

Required Registrations

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.

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

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

Eligible Individuals (Project Director/Principal Investigator)

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.

 The lead Principal Investigator must devote at least 1.8 person months, based on a 12-month calendar (equivalent to 15% of his/her time and effort) to this Cooperative Agreement.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed.

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

Section IV. Application and Submission Information

1. Address to Request Application Package

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

2. Content and Form of Application Submission

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.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Lu Wang, Ph.D.
Program Director
Large Scale Sequencing
National Human Genome Research Institute
National Institutes of Health
5635 Fishers Lane, Suite 4105 MSC 9305
Bethesda, MD 20892 (mail)
Telephone: 301 594-7303
Email: wanglu@mail.nih.gov

Application Submission

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: pozzatr@mail.nih.gov

Page Limitations

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

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.  

Budget Request

The budget requested must be described clearly and be well justified.  Applicants should submit the Detailed Budget for the Initial Budget Period (page 4 of PHS-398) and the Budget for Entire Proposed Period of Support (page 5 of PHS-398).

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.  

The application should include the following resource sharing plans.

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

Data Release Plan

The application in response to this FOA should include a plan for sharing research data.  NHGRI strongly endorses rapid release of genomic data and materials.  Applications submitted in response to this FOA should include a plan for data release.  The NHGRI policy on release of sequence data is available at http://www.genome.gov/10506376.  Since the purpose of this FOA is to support the genome research activities that will result in large amounts of DNA sequence and other types of genomic data, the utility of the data is largely dependent on how quickly they can be deposited into public databases for use by the scientific community.  NHGRI considers the data produced under this FOA to be community resource as discussed in “Sharing Data From Large-Scale Biological Research Projects - 2003: A System of Tripartite Responsibility” available at http://www.genome.gov/10506376.  The general NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.  Given any potential issues about patient confidentiality, it may be appropriate for some sequencing information to be released with certain safeguards of confidentiality.  NHGRI has developed policies for such data release (http://www.genome.gov/20019650).  Applicants should discuss data release in the context of these policies.  The data release plan should discuss the release of sequence reads, alignment, variant data, clinical and phenotype data, whole exome (or genome) assemblies and annotation, and other types of genomic data.  NHGRI data deposition policies evolve with time.  Currently, NHGRI is developing policies regarding the specific data to be released from “short-read” sequencing technologies, especially for "medical sequencing projects" and policies regarding public notification about individual sequencing projects and terms of use of data from those projects.  Applicants should check http://www.genome.gov/10506376 for updates that may occur during the time this FOA is being competed.  Quality of the data release plan will be a criterion in the review of the application.  Appropriate data release plans will be made a condition of the awards made as a result of this FOA. All successful applicants will be expected to abide by policies during the award period.

Plan for Sharing Research Resources

NIH policy requires that grant awardees make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131).  Applicants should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resource sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm).  See Section VI.3. Reporting.

Description of available samples:  The applicant is expected to bring on board at least enough samples for the initial six months of the funding period and acquire more samples for the entire funding period.  If additional space is needed for detailed description of the available samples and what will be acquired, then the applicant can provide that information as an Appendix.

Plan for Intellectual Property Management

It is intended by the NIH that the tools of scientific discovery necessary to rapidly and effectively develop new medical applications be widely available for research use.  Possible resultant inventions in sample preparation, exome capture, sequencing, and data processing and analysis will benefit research in general.  Moreover, a great number of genetic variants underlying Mendelian diseases will be identified, which will be invaluable for a wide range of clinical applications and the understanding of the biology of the human genome.  Applicants should propose a comprehensive intellectual property (IP) and data management plan that is consistent with the NIH Research Tools Policy (http://ott.od.nih.gov/policy/research_tool.html) and other related NIH sharing policies (http://sharing.nih.gov).  Examples which applicants may wish to consider include the recommendations cited in NIH’s Best Practices for the Licensing of Genomic Inventions (http://www.ott.nih.gov/policy/genomic_invention.html). 

Restrictive licensing and sharing practices could substantially diminish the biomedical value and public benefit provided by this community resource project. Management practices that would prevent or block access to, or use of, discoveries on Mendelian disorders will be considered to be hindering the goals of this FOA.  Applicants are encouraged to clearly demonstrate in their IP management plan how their strategies will achieve the desired public benefit and programmatic goals through effective sharing of data and tools.  IP Management Plans that are submitted, once approved, will also become Terms and Conditions of award.

3. Submission Dates and Times

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

6. Other Submission Requirements and Information

Applications must be 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 NHGR.I   Applications that are incomplete and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115 with the following modification: NHGRI review staff will only accept updated lists of available samples for sequencing..

Section V. Application Review Information

1. Criteria

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

Overall Impact

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

Scored Review Criteria

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? 

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? 

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?

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?   

Additional Review Criteria

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not applicable

Renewals

Not applicable

Revisions

Not applicable

Additional Review Considerations

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

Applications from Foreign Organizations

Not applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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:

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center and 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:

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

defining the details for the funded center within the guidelines of this FOA and for performing the scientific activities.  The P.I. will agree to accept close coordination, cooperation, and participation of NHGRI staff in the aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities".

The P.I. of a Mendelian Disorders Genome Center will be responsible for the following:

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

The NHGRI Project Scientists will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination.  However, the role of NHGRI 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 Steering Committee.  NHGRI Project Scientists will participate as members of the Steering Committee and will have one collective vote.

The Project Scientists will:

Areas of Joint Responsibility include:

Participate in the Steering Committee.  A Steering Committee will serve as the main governing board of the Mendelian Disorders Genome Centers.  The Steering Committee membership will include the P.I. of each awarded cooperative agreement, the NHGRI Project Scientists and staff representatives of other NIH funding institutes.  The Steering Committee Chair will not be an NIH staff member.  Additional members may be added by action of the Steering Committee.  Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions.

The Steering Committee will:

Another area of joint responsibility is that NHGRI and the grantees will work with and provide information to a Scientific Advisory Panel.

The Scientific Advisory Panel will be responsible for approving the annual goals of members of the Genome Sequencing Research Network, including the Mendelian Disorders Genome Centers.  The Scientific Advisory Panel will also be responsible for reviewing and evaluating the progress of the members of the Genome Sequencing Research Network towards meeting those goals. The Scientific Advisory Panel will provide recommendations to the Director, NHGRI, about continued support of the components of the Genome Sequencing Research Network. The Advisory Panel is composed of four to six senior scientists with relevant expertise who are not P.I.s of a cooperative agreement involved in the Genome Sequencing Research Network. The membership of Scientific Advisory Panel may be enlarged permanently, or on an ad hoc basis, as needed.   Subdivisions in the Scientific Advisory Panel may be created to better manage the growing number of components of the Research Network.

The Scientific Advisory Panel will meet at least once a year. During this meeting, there will be a joint meeting with the Steering Committee to allow the Scientific Advisory Panel members to interact directly with the awardees.  Annually, the Scientific Advisory Panel will make recommendations regarding progress of the Genome Sequencing Research Network and present advice about changes, if any, which may be necessary in the Genome Sequencing Research Network program to the Director, NHGRI.

Dispute Resolution:

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

3. Reporting

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

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

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

Section VII. Agency Contacts

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

Lu Wang, Ph.D.
Program Director
Large Scale Sequencing
National Human Genome Research Institute
National Institutes of Health
5635 Fishers Lane, Suite 4105 MSC 9305
Bethesda, MD 20892 (mail)
Telephone: 301 594-7303
Email: wanglu@mail.nih.gov 

Application Submission Contacts

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

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

Scientific/Research Contact(s)

Lu Wang, Ph.D.
Program Director
Large Scale Sequencing
National Human Genome Research Institute (NHGRI)
National Institutes of Health
5635 Fishers Lane, Suite 4105 MSC 9305
Bethesda, MD 20892 (mail)
Telephone: 301 594-7303
Email: wanglu@mail.nih.gov

Peer Review Contact(s)

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute (NHGRI)
5635 Fisher Lane
Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 435-1580
Email: pozzattr@mail.nih.gov

Financial/Grants Management Contact(s)

Cheryl Chick
Grants Management Branch
National Human Genome Research Institute (NHGRI)
Telephone: 301-496-7531
Email: chickc@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

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


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