Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the NIH Office of the NIH Director, Office of Strategic Coordination (http://dpcpsi.nih.gov/osc/).  The FOA will be administered by the National Human Genome Research Institute (NHGRI/NIH), (http://www.nhgrii.nih.gov/) on behalf of the NIH.

Funding Opportunity Title

Enhancing GTEx with molecular analyses of stored biospecimens (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices

  • January 4, 2013 - See Notice NOT-RM-13-007. Pre-application Teleconference and Additional Responsiveness Information for this RFA.

Funding Opportunity Announcement (FOA) Number

RFA-RM-12-009

Companion Funding Opportunity

RFA-RM-12-019, R01 Research Project Grant

Number of Applications

See Section III. 3. Additional Information on Eligibility.

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

93.310

Funding Opportunity Purpose

To support molecular analyses of stored biospecimens from the Genotype-Tissue Expression (GTEx) project. Applicants are encouraged to address compelling scientific questions with molecular phenotypes that add value to the resource and take full advantage of the unique features of GTEx.

Key Dates
Posted Date

November 16, 2012

Open Date (Earliest Submission Date)

February 28, 2013

Letter of Intent Due Date(s)

February 1, 2013

Application Due Date(s)

March 28, 2013, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

June/July, 2013

Advisory Council Review

October, 2013

Earliest Start Date

November, 2013

Expiration Date

March 29, 2013

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This initiative is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress.

Background

The primary goal of the Genotype-Tissue Expression (GTEx) project is to establish a resource database and associated tissue bank in which to study the relationship between genetic variation and gene expression and other molecular phenotypes in multiple reference tissues and to make this resource broadly available for furthering research.  This will aid in the interpretation of genome-wide association (GWAS) and other genomic study findings, many of which do not correlate with protein-coding changes, but instead point to regulatory regions of the genome.  The resource will be a powerful tool to help unravel the complex patterns of genetic variation and gene regulation across a wide range of human tissues, a critical next step in understanding genomic associations and their translational potential.

The GTEx project involves the rapid collection of multiple tissue types from deceased donors. The collection of biospecimens from deceased individuals is not legally classified as human subjects research under 45 CFR 46. However, donor recruitment sites obtain written authorization from next-of-kin for participation in GTEx. This is typically done through an addendum or modification to an existing authorization form for research donation of tissues and organs.  It includes statements common in consent forms such as the intention to perform genetic analyses, establish cell lines, and to share data with the scientific community (see http://biospecimens.cancer.gov/resources/sops/GTEx_SOPs/I/caHUB%20GTEx%20Next%20of%20Kin%20Informed%20Consent%20Template.pdf for example language). The GTEx project obtains authorization for broad future research use and unless required by the applicant’s Institution, specific IRB review is not required for this initiative.

Currently, approximately 30 tissue types are collected from each donor, with the exact number dependent on sex and availability of each organ.  When authorized, the cerebral cortex and cerebellum are sampled immediately, and the remaining whole brain is shipped to a brain bank, where 9 additional regions are sampled.  Post-mortem donors of any racial and ethnic group and sex who are age 21-70 in whom biospecimen collection can start within 24 hours of death are eligible.  Donors are expected to have a typical prevalence of chronic diseases because there are only a few exclusionary criteria, such as human immunodeficiency virus (HIV), viral hepatitis, and metastatic cancer.  Many organs will be free of major pathology and serve as a reference set of well-characterized human tissues.

Donor enrollment, sample collection and analysis are ongoing, with approximately 200 donors enrolled in a pilot period by the fall of 2012, toward a goal of 900 post-mortem donors by the end of 2015. All donors are characterized for germline genetic variation through dense genotyping of a blood sample and all tissues of sufficient quality undergo gene expression analysis using deep mRNA sequencing. This FOA deals with potential uses of biospecimens other than dense genotyping and mRNA-seq, which are already funded.  More information about GTEx can be found at http://commonfund.nih.gov/GTEx/ and http://broadinstitute.org/gtex.

The GTEx Consortium

The GTEx Consortium includes investigators involved in biospecimen acquisition, processing, storage, and verification; laboratory, data analysis and coordination; novel statistical methods development; brain banking; and NIH program officials (POs).

Biospecimen acquisition for GTEx is accomplished through contracts issued by the National Cancer Institute’s (NCI) cancer Human Biobank (caHUB) initiative (http://caHUB.cancer.gov), part of the Biorepositories and Biospecimen Research Branch (BBRB). SAIC-Frederick, Inc. (SAIC-F), the prime contractor to the NCI, serves as the Comprehensive Data Resource.  Biospecimen collection and processing are accomplished through SAIC-F subcontracts to the Biospecimen Source Sites (BSSs) and a Comprehensive Biospecimen Resource (CBR).

caHUB has established a transformative, one-of-its-kind, high-quality program for the identification of low-post-mortem interval donors from whom we can collect many tissues of high molecular quality.  A quality management program, with more than 150 Standard Operating Procedures (SOPs), is in place, in combination with training and auditing programs and a pathology review system, all supporting a highly standardized GTEx tissue collection system.

There are 2 BSSs involved in the collection of biospecimens: the National Disease Research Interchange (NDRI - Philadelphia, PA) and Roswell Park Cancer Institute (RPCI - Buffalo, NY). The BSSs work with their Organ Procurement Organization (OPO) and American Association of Tissue Bank (AATB) partners, including Gift of Life (Philadelphia, PA), LifeNet Health (Virginia Beach, VA) and Upstate New York Transplant Service (UNYTS, Buffalo, NY) to accomplish such a challenging recruitment.

Currently, except for blood, one of the skin samples and the majority of the brain, all biospecimens are fixed and stabilized at the BSS using PAXgene Tissue reagents.

At the CBR (The Van Andel Institute, Grand Rapids, MI), an aliquot from each sampled tissue is accessioned, quality controlled, paraffin embedded, sectioned, and stained for histopathology analysis. 

Aliquots from the cortex and cerebellum are sampled and preserved in PAXgene Tissue at the BSS, while the remaining whole brain, with attached brain stem and cervical spinal cord, when possible, are shipped to an NIH-funded Brain Bank (University of Miami School of Medicine, Miami, FL). After sectioning at the Brain Bank, frozen samples from additional anatomical regions of the brain are analyzed for gene expression and the remaining brain banked for future uses.

The Laboratory, Data Analysis and Coordinating Center (LDACC), funded through a contract to The Broad Institute, Boston, MA, performs numerous activities.  An aliquot of each tissue, fixed but without paraffin embedding, is sent there for molecular analysis. The LDACC is responsible for genotyping blood samples as well as performing RNA-seq of high quality tissues. In addition, it develops, houses, and maintains databases to track, store, and provide access to the GTEx data (for open access data) as well as submits GTEx data to the database of Genotypes and Phenotypes (National Center for Biomedical Information’s (NCBI) dbGaP - for controlled access data). The LDACC is also a member, together with the statistical analysis investigators funded through RFA-RM-09-006, of the GTEx Statistical Analysis Working Group (SAWG) which is responsible for analyses of the integrated data sets. 

Together, the GTEx components mentioned above have functioned as a research consortium in a highly collaborative and synergistic effort during a 2.5-year pilot phase, and the awardees from this FOA (referred to as "enhanced GTEx" or "eGTEx" hereafter) will become part of the consortium.

Available Biospecimens

We expect to be able to make available to the scientific community the following sample types (see also a Request for Information at http://grants.nih.gov/grants/guide/notice-files/NOT-RM-12-028.html):

Available data

While not the subject of this FOA, the following data are associated with these biospecimens and might inform the research plan to be summited through this FOA. These data are expected to be made available to the scientific community in an ongoing manner:

Table 1: Summary of the tissue types collected and stored from the first 150 GTEx donors, and projections of the number of samples available by each year. Note that these are projections only and the true numbers may be higher or lower (for the most up to date table see www.broadinstitute.org/gtex).

 

N

Estimated N by 12/31/2013

Estimated N by 12/31/2014

Estimated N by 12/31/2015

Tissue Type

(End of Collection)

Tissues currently being collected

Adipose, Subcutaneous

144

476

764

864

Adipose, Visceral (Omentum)

17

349

637

737

Adrenal Gland

107

354

568

642

Artery, Aorta (Ascending or Thoracic)

133

440

706

798

Artery, Coronary

97

321

515

582

Artery, Tibial

142

470

754

852

Breast, Mammary Tissue (male & female)

87

288

462

522

Colon, Transverse

144

476

764

864

Colon, Sigmoid

15

347

635

735

Esophagus, Gastroesophageal Junction

16

348

636

736

Esophagus, Mucosa

139

460

738

834

Esophagus, Muscularis

140

463

743

840

Heart, Atrial Appendage

12

278

509

590

Heart, Left Ventricle

116

384

616

696

Kidney, Cortex

73

241

387

438

Liver

81

268

430

486

Lung

129

427

685

774

Muscle, Skeletal

146

483

775

876

Nerve, Tibial

139

460

738

834

Ovary

45

149

239

270

Pancreas^

130

430

690

780

Prostate

83

274

440

498

Salivary Gland, minor

15

171

306

353

Skin, Sun exposed (Lower Leg)

147

486

780

882

Skin, Not sun exposed (Suprapubic)

17

356

650

752

Spleen^

137

453

727

822

Stomach^

144

476

764

864

Terminal Ileum (Peyer’s patch)

15

347

635

735

Testis

92

304

488

552

Thyroid

126

417

669

756

Uterus

41

136

218

246

Vagina

48

159

255

288

Whole Blood*

149

493

791

894

Brain tissues currently being collected (donor cannot be on ventilator 24 hours before death)

Brain, Cerebellum

36

140

230

261

Brain, Cortex

35

139

229

260

Brain, Amygdala#

34

138

228

259

Brain, Anterior cingulate cortex (BA24)#

35

139

229

260

Brain, Caudate (basal ganglia)#

35

139

229

260

Brain, Cerebellar Hemisphere#

35

139

229

260

Brain, Frontal Cortex (BA9)#

35

139

229

260

Brain, Hippocampus#

34

138

228

259

Brain, Hypothalamus#

34

138

228

259

Brain, Nucleus accumbens (basal ganglia)#

35

139

229

260

Brain, Putamen (basal ganglia)#

33

137

227

258

Brain, Spinal cord (cervical c-1)#

24

93

153

174

Brain, Substantia nigra#

33

137

227

258

Pituitary Gland

33

109

175

198

Tissues collected only during the pilot phase

Bladder, Urinary^

121

   

121

Cervix, Ectocervix

32

   

32

Cervix, Endocervix

34

   

34

Fallopian Tube

32

   

32

Kidney, Medulla

41

   

41


PAXgene preserved tissue unless indicated with #.

# Fresh Frozen Tissue;

^ 15-30% of samples show severe autolysis;

* Blood for RNA collected in PAXgene Blood RNA tubes, Blood for DNA collected in acid citrate dextrose (ACD) tubes;

Research Objectives

GTEx is designed to help unravel the complex interplay between genetic variation and gene regulation across a wide range of human tissues.  The first step of assaying genetic variation and mRNA gene expression in over 30 different tissue types is underway.  This will yield extensive tissue-specific and cross-tissue expression quantitative trait loci (eQTL) by correlating genotype with gene expression levels.  But fully understanding how a genetic variant regulates gene expression, such as through changes in DNA methylation or the binding affinity of a transcription factor, and determining the downstream effects of differential gene expression, will require additional studies.  The NIH is interested in making maximal use of the GTEx resource to address these and other questions in an efficient manner.

This FOA seeks applications to enhance GTEx by performing molecular analyses of stored biospecimens.  GTEx is first and foremost a community resource with rapid data release, and applicants are encouraged to generate results that, when integrated with existing data, add scientific value to the resource as a whole. While data production is important, applications should also address a scientific question, even if it cannot be definitively answered, given the size and duration of awards under this FOA. An incomplete set of topics that capitalize on some of the unique aspects of GTEx, such as a large number of subjects, many disease-free tissues collected from each individual, most of which are not cell lines, and are already characterized for genetic variation and gene expression, include:

Numerous molecular phenotypes (defined broadly as involving nucleic acids, protein, protein/DNA interactions, metabolites, cellular characteristics, etc.) may be appropriate to address these and other questions. This FOA does not focus on any particular assay or areas of biology, but rather is open to the most compelling ideas.  Assays should be well established and the required throughput for the proposed work must already be in place to generate high-quality data, be cost-effective, and be efficient in the use of biospecimens. Assays that are "-omic" level are strongly encouraged; those that involve analysis of a very small portion of the genome, proteome, etc. are not considered responsive.

Applications that are adequately powered to definitively answer a scientific question are encouraged. Such applications might take 3 years to complete, with a large proportion of the assays and associated cost occurring in year 2.

However, since sample collection and analysis are ongoing and will continue for several years, those that provide compelling preliminary data for a scientific question could also be considered responsive.  Such demonstration projects might provide convincing preliminary data for an R01 research application, significantly increase the scientific value of the resource to the broader scientific community, or suggest that a question could be definitively addressed in the full, final GTEx resource should additional funds become available, and may require only 2 years. Therefore the size and duration of each proposal will vary, resulting in a mix of 2- and 3-year awards.

While there is not a minimum number of samples or assays, applicants are encouraged to submit applications that go deeply in at least one dimension, taking advantage of some of the unique aspects of GTEx: for example, a large number of individuals, a wide range of different tissues, or comprehensive analysis of one or more complementary molecular phenotypes. Applications that study a single or only a few tissue types in a small number of individuals with less than a comprehensive assay will not be considered responsive. The GTEx biospecimen resource should not be viewed as a biobank of convenience.  Applications should clearly state why GTEx biospecimens are the most appropriate to study for a given question; those that could be readily performed using other biospecimen collections are discouraged.  Clearly describe how the proposed eGTEx analyses will add significantly to other GTEx data, or how existing GTEx data (e.g., gene expression measurements), will be leveraged to interpret the proposed analyses.

For the purpose of this FOA, only samples from deceased donors will be available.

Program Governance and Structure

The awards funded under this FOA will be a cooperative agreement (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award).  Close interaction between the eGTEx awardee and the NIH will be required.  Decisions affecting exclusively or primarily eGTEx awardees of this FOA will be arrived at by consensus, when possible, with each Program Director/Principal Investigator and the NIH Project Scientist having one vote.  eGTEx awardees will also become members of and work within the GTEx Consortium. The GTEx Consortium will be responsible for the scientific direction of the overall program, and will develop, for example, appropriate consensus approaches for molecular phenotype data integration, data quality standards, and integrative analysis plans.

The ultimate governance of the GTEx project rests with the NIH Common Fund Working Group and its Co-chairs, with input from the GTEx External Scientific Panel (ESP). The GTEx Consortium has established and/or will establish subcommittees and working groups to facilitate development, implementation, and monitoring of specific functions as needed.

Section II. Award Information
Funding Instrument

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

This funding opportunity will use the U01 award mechanism.

Application Types Allowed

New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The NIH expects to provide approximately $10,000,000 (total costs) over the next three fiscal years, with $3,800,000 in FY2014. Two to ten awards are anticipated from this solicitation.

Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Award Budget

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary.

Award Project Period

Scope of the proposed project should determine the project period. NIH expects to make 2- and 3-year awards. The maximum period is 3 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

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Directors/Principal Investigators (PD(s)/PI(s)) 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 6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator)

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

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

Letter of Intent

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

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

The letter of intent should be sent by email to:

Simona Volpi, Ph.D.
Program Director, GTEx
Division Of Genomic Medicine
National Human Genome Research Institute
5635 Fishers Lane, Suite 4076
Rockville, MD 20852-9305
T (301) 443-6453
F (301) 480-2770
nhgrigtex@mail.nih.gov

Required and Optional Components

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

Page Limitations

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

R&R Budget Component
PHS 398 Research Plan Component

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

Research Strategy

Applicants should include discussion of the following topics/questions within the Research Strategy:

Assays must demonstrate experimental reproducibility and be well-characterized (quantitatively measured, benchmarked).

The focus of this FOA is on experimental approaches to generating data; those that propose exclusively or primarily computational approaches will not be considered responsive.

In addition, applicants should discuss the following items within the Research Strategy:

Data Standards. Applicants should describe plans for adopting and following existing data and other standards whenever possible (and their subsequent refinements).  For example, data standards for some of the assays that might be proposed under this FOA include: http://www.encodeproject.org/ENCODE/dataStandards.html for the ENCODE project; http://www.roadmapepigenomics.org/protocols for the Roadmap Epigenomics protocols and standards; http://ihec-epigenomes.net/research/operating-procedures/ for the International Human Epigenome Consortium standards and protocols.  Standard ontologies should be used for experimental metadata and other data whenever possible (see http://www.bioontology.org).

Preliminary data.  Given the relatively short grant period, little or no time for optimization will be available and the assay must be shown to work using the sample types available from GTEx (e.g. PAXgene fixed tissues, flash frozen brain samples, etc.).

Many GTEx tissue aliquots are fixed in the PAXgene Tissue fixative, a solution containing alcohols (ethanol and methanol), acetic acid, and a soluble organic compound; this fixative primarily works by protein precipitation. Pathological interpretations of the fixed tissues have shown that they are well preserved but their performance in many molecular assays is unknown. The GTEx Consortium has shown that these samples yield robust gene expression by RNA sequencing, but no other assessments of sample suitability have been performed.  Therefore, the suitability of GTEx samples for the proposed assays should be included in the application. We encourage applicants to test their assays by collecting enough human or mammalian tissues processed with PAXgene Tissue or other relevant GTEX collection methods (e.g., flash frozen) to show technical suitability.  For details on the GTEx Tissue Procurement Procedure using the PAXgene Tissue solutions, see http://biospecimens.cancer.gov/resources/sops/GTEx_SOPs/II/A/GTEx%20Tissue%20Procurement%20SOP%20(PR-0004%20v1.2.1).pdf.

Primary data analysis. Applications should describe in detail an efficient, accurate informatics pipeline for processing the primary data produced by the molecular assay. This should include things like quality control and baseline analysis required to result in data usable by the wider scientific community (e.g., rpkm counts for gene expression). This informatics pipeline must be well documented and have procedures in place to capture associated metadata. A laboratory information management system (LIMS), if available, should be described. Applicants should address how they intend to track biospecimens and collaborate with the LDACC and CBR to facilitate integration with existing GTEx data.

Data submission. A separate informatics pipeline should be described for the submission of the primary and processed data in standardized formats to the GTEx LDACC and to other appropriate public repositories such as dbGaP.  In addition, any metadata such as information about experimental procedures and analysis methods used to generate the data should be described and included in the submission.  Finally, upon publication of results and analyses, a workflow with links to all software, data and metadata that will enable other investigators to reproduce any published analyses should be described.  All groups participating in the GTEx Consortium will work together to establish the exact types and formats of data and metadata that will be transferred to the LDACC and other data repositories.  

Integrated Data Analysis. The data generated from this initiative will be integrated with other GTEx data and made widely available to the scientific community for analyses.  Integrative analysis of the data being generated by the different technologies being employed within GTEx will be coordinated by the SAWG of the GTEx Consortium.  However, applicants are encouraged to describe and budget for statistical analysis of the data they generate, either alone or in combination with other GTEx data.  Given the relatively short period of performance, however, the focus of this initiative should be on basic statistical analysis and biological interpretation.  More complex, in-depth analyses of the data are outside of the scope of this FOA and might be supported by other funding mechanisms (e.g. RFA-RM-12-019).

Letters of Support

A letter from the PO verifying sample availability and the impact on the remaining biorepository will be provided to the applicant. This confirmation of sample availability should be uploaded in the letters of support.

Resource Sharing Plan

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

Data Release Principles and Standards. Data from this FOA are expected to be shared in an easily accessible format so as to increase the value of the significant public investment.  Consistent with achieving the goals of this program, the NIH expects that information such as data syntheses, study protocols, bioinformatics tools, and any other meta data collected will be widely shared with the scientific community for research and made publicly available through the GTEx data portal and other data repositories.

Applicants should indicate their willingness to cooperate with the GTEx Consortium and other stakeholders in the development and design of research and standardization methods, procedures, policies and strategies to be applied for this resource. Applicants should also describe prior experience in working as part of a research consortium, developing consensus approaches for data sharing and other research-related topics, or other collaborative activities to meet individual study and collaborative goals.

Data sharing plan. All controlled access data generated from GTEx samples are expected to be deposited into dbGaP (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) or other NIH Trusted Partners databases. All data without privacy concerns are expected to be returned to the GTEx portal (www.broadinstitute.org/gtex) and other appropriate repositories with open access.

Rapid deposition of data into repositories is expected. Depending on the type of data, the duration of data production, as well as the quantity of the samples assayed in a given period, the frequency of data deposition might vary. All data are expected to be deposited once data generation is completed. Before this and other data deposits, a period of quality control of up to 3 months might be needed. Interim or periodic deposition might be expected if the data are produced over an extended period of time (e.g. >12 months) and are of sufficient size. For example, in a study generating results on a large number of samples over an 18 month period, data deposition may be expected at regular intervals.

NIH does not anticipate a publication embargo. However, a holding period of up to 6 months after each deposit might be considered before the data are made publicly available. This policy might be revised should an NIH-wide data sharing policy be issued (see http://grants.nih.gov/grants/guide/notice-files/NOT-HG-10-006.html).  

Applicants should provide a specific proposal for release of data, and are encouraged to address the issue of frequency of the release, based on practical considerations or previous experience and the recommendations above. The reasonableness of the proposed data sharing plan will be assessed by the reviewers.

As is the case for SNP genotyping and RNA-seq data already produced by GTEx, similar data generated in this FOA that contains extensive genetic variation information (e.g., genome-wide methyl-seq) are expected to be deposited into the controlled access part of dbGaP or other NIH Trusted Partners databases.  Applicants should address whether they anticipate any of their data requiring controlled access.

Appendix

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

Foreign Institutions

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

3. Submission Dates and Times

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

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

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

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

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

A “Material Transfer Agreement” (MTA) is required and will need to be in place before samples are shipped, ideally before the award is made. An MTA is not required at the time of submission. If a fully executed MTA is still pending, a restricted award might be necessary. The final MTA is still being developed. 

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

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

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

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by the Office of Strategic Coordination (Common Fund) and NHGRI, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Pre-Application Information Call

An Information Session for this FOA is planned for January 2013. The Information Session will be conducted as a teleconference.  No provisions will be made for in-person attendance.  During the Information Session, GTEx leadership will present an overview of this FOA and answer questions from prospective applicants.  The Information Session is open to all prospective applicants, but participation is not a prerequisite to applying.

Details of the Information Session will be provided in an NIH Guide Notice.

Documenting Sample Availability

Applicants are encouraged to use the sample search capability of the GTEx data portal (www.broadinstitute.org/gtex) to query whether the required samples are available.  However, sample collection will be ongoing during this FOA, and complex searches may not be possible. Therefore, before submitting an application, applicants are strongly encouraged to contact the PO well in advance at nhgrigtex@mail.nih.gov to obtain instructions on documenting sample availability. The turnaround time for the request will be at least 3 weeks once the PO receives complete information of sample requirements. As described above, the letter should be included in the application.

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, supplies, travel, and other items typically listed under Other Expenses.  Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits. 

If selected, appropriate funding will be provided by the NIH Intramural Program.  NIH intramural scientists will participate in this program as PD/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights. 

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Post Submission Materials

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

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

Scored Review Criteria

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

Significance

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

Will the proposed use of the samples generate data complementary to existing GTEx data? Is the study maximizing the strengths of GTEx? Would the new molecular phenotypic data answer a critical question, which cannot be addressed otherwise, for a specific field? Can the hypothesis proposed only be addressed by use of the samples from GTEx?

Investigator(s)    

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

Does the PD/PI have prior experience working as part of a research consortium, developing consensus approaches to address particular research-related topics, or other collaborative activities to meet individual study and collaborative goals?

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? 

Are the requested samples uniquely suited and scientifically appropriate for the requested study?  Are sufficient preliminary data presented to demonstrate accuracy and robustness of the proposed assay(s), as well as compatibility with GTEx tissue processing? Are the size (e.g. number of tissues and donors) and the laboratory approach appropriate for the budget and duration of the project? Will a parsimonious use of samples be conducted?


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 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 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.

2. Review and Selection Process

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

As part of the scientific peer review, all applications:

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for 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’s business official.

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

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

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

NIH staff has 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 NIH 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 GTEx Consortium.  The Project Scientist will have the following substantial involvement:

Other NIH Working Group staff may assist the awardee as designated by the PO.  Additionally, an agency PO 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.

Collaborative Responsibilities

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop appropriate strategies and tools to design, perform, and analyze additional molecular assays on the stored GTEx biospecimens. The PD/PI from each awarded cooperative agreement will be part of the GTEx Consortium which meets two times per year (the GTEx in-person meeting). In addition they will meet with the project scientist monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results.  Key co-investigators and pre- and postdoctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, in addition to the PD(s)/PI(s), are eligible to attend these meetings.

It is envisioned that a working group will be in place to facilitate interactions of PD/PI from each eGTEx awardee with the SAWG to plan and implement cross-study activities.  Awardees agree to work collaboratively to:

External Scientific Panel

An ESP will continue to evaluate the progress of the GTEx program. The ESP will provide recommendations to the NIH Working Group co-chairs about the progress and scientific direction of all components of the program.

The ESP is currently composed of six senior scientists with relevant expertise.  The ESP will continue to meet at least twice a year; some meetings may be conducted by telephone conference. Occasionally, the ESP may be asked to advise GTEx Investigators and the GTEx leadership on timely issues during the interim period between meetings.  At least once a year, there will be a joint meeting with the consortium to allow the members of both the ESP and the consortium to interact directly.  Twice a year the ESP will make recommendations regarding progress of the program to the NIH WG co-chairs about changes, if any, which may be necessary in the program.

Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the eGTEx awardees chosen without NIH staff voting, one NIH designee, and a third designee chosen by the other two with expertise in the relevant area; 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 annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

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

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

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

Scientific/Research Contact(s)

Simona Volpi, Ph.D.
Program Director, GTEx
National Human Genome Research Institute (NHGRI)
TEL: 301-443-6453
Email: nhgrigtex@mail.nih.gov

Peer Review Contact(s)

David Filpula
Scientific Review Officer
Center for Scientific Review (CSR)
TEL: 301-435-2902
Email: filpuladr@csr.nih.gov

Financial/Grants Management Contact(s)

Cheryl Chick
Chief Grants Management Officer
National Human Genome Institute (NHGRI)
TEL: 301-435-7858
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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