Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Heart, Lung, and Blood Institute (NHLBI)
Funding Opportunity Title	Genomic Research in AAT-Deficiency and Sarcoidosis study (GRADS) Cooperative Research Project Grant: Clinical Centers (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-HL-12-013
Companion FOA	RFA-HL-12-014
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.838
FOA Purpose	The purpose of this funding opportunity announcement (FOA), issued by NHLBI, NIH, is to invite applications to participate in the NHLBI Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) program, which will assemble a multidisciplinary team of investigators to conduct state-of-art genomic, microbiomics and phenotypic studies of two serious and understudied conditions that affect the lungs: Alpha-1 Antitrypsin Deficiency (AAT) and sarcoidosis. GRADS will include up to eight Clinical Centers and one Genomics and Informatics Center (GIC). This FOA solicits applications for Clinical Centers and runs in parallel with a separate FOA that solicits applications for the GIC (see RFA-HL-12-014). The GRADS Clinical Centers will participate in a study-wide protocol by enrolling, clinically and immunologically phenotyping participants, and collecting and processing biospecimens to be shipped to the GIC for genomics and microbiomics analyses. Additionally, each Clinical Center will develop a clinic-specific research protocol aimed at identifying pathogenetic mechanisms or predictors of AAT or sarcoidosis disease development/progression. Collectively the GRADS Clinical Centers will create a program-wide cohort of approximately 400 AAT and approximately 200 sarcoidosis subjects and controls. Up to 8 Clinical Centers will be funded, each led by one or more Investigators with expertise in AAT, sarcoidosis, pulmonary medicine, immunology, genomics or cell biology. A Steering Committee of all the Clinical Center Principal Investigators will be organized by the GIC (see RFA-HL-12-014) to develop the study-wide protocol(s) and monitor study operations.

Posted Date	February 2, 2011
Letter of Intent Due Date	April 18, 2011
Application Due Date(s)	May 17, 2011
AIDS Application Due Date(s)	Not-Applicable
Scientific Merit Review	August, 2011
Advisory Council Review	January, 2012
Earliest Start Date(s)	April 1, 2012
Expiration Date	May 18, 2011
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

Nature of the research opportunity. The purpose of this funding opportunity announcement (FOA), issued by NHLBI, NIH, is to invite applications to participate in the NHLBI Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study as Clinical Centers. This initiative will 1) study patients with AAT or sarcoidosis using state of the art genomics and microbiomics analyses to identify molecular abnormalities and their relationship to patients clinical characteristics and 2) conduct hypothesis-based clinical studies at each Clinical Center to elucidate pathogenetic mechanisms or identify predictors of disease development/progression. GRADS will assemble a multidisciplinary team of investigators to conduct state-of-art genomics, microbiomics and phenotypic studies of two serious and understudied conditions that affect the lungs: alpha-1 antitrypsin deficiency (AAT) and sarcoidosis. GRADS will include multiple Clinical Centers and one GIC. This FOA solicits applications for Clinical Centers and runs in parallel with a separate FOA that solicits applications for the GIC (RFA-HL-12-014). The GRADS Clinical Centers will enroll and clinically and immuno- phenotype AAT and sarcoidosis subjects and appropriate controls. Clinical Centers will also collect and process biospecimens for biomarker, genomic, and microbiomic analyses. Up to 8 Clinical Centers will be funded, each led by Investigator(s) with expertise in AAT, sarcoidosis, pulmonary medicine, immunology, cell biology, or genomics. A Steering Committee of all the Principal Investigators involved with the project will be organized by the GIC (see RFA-HL-12-014) to develop the necessary protocols and monitor study operations. This is a one-time solicitation to support GRADS for a three-year project period.

Pertinent background information that establishes the need for the research. AAT and sarcoidosis affect young adults in their 20-40s. Pulmonary involvement is the leading cause of morbidity and mortality for both diseases. Complex interactions between genetic and environmental exposures (involving dysregulated immune responses) probably contribute to the development of both conditions. AAT is an autosomal recessive genetic condition with an estimated prevalence of 1 case per 3000 to 5000 persons in the United States. AAT is associated with an increased but variable risk of developing chronic obstructive pulmonary disease (COPD). Overall, the sole presence of homozygous status is not sufficient to explain the clinical phenotypes found in AAT patients. Development of COPD in severe AAT is associated with a history of asthma, pneumonia, childhood respiratory illnesses, or chronic bronchitis. In addition, gender may have a role in the development of COPD in people with AAT. Sarcoidosis is a systemic disease characterized by the formation of granulomatous lesions especially in the lungs, liver, skin, and lymph nodes. Estimates of the numbers of Americans afflicted with this disease range from 13,000 to 134,000. In the U.S. between 2,600 and 27,000 new cases are diagnosed each year. Sarcoidosis has no known etiology, but a genetic predisposition to the disease is indicated by familial clustering, increased concordance in monozygotic twins, and variations in susceptibility and disease presentation among different ethnic groups. Immune dysregulation and sex hormones may play a role in disease development. For both AAT and sarcoidosis, the pathogenetic mechanisms (besides the role of the genetic mutation for AAT) are not well understood, gene modifiers remain unknown, and neither disease can be effectively managed with existing therapies, including replacement therapy in AAT. Because of these characteristics, improved understanding of the molecular abnormalities in these conditions and their relationship with the diverse clinical presentations is essential for developing better methods for detecting, diagnosing, and managing these diseases.

Scientific knowledge to be achieved through research supported by the special program. Integrated genomic and phenotypic approaches represent a feasible and promising strategy to better understand the pathogenetic mechanisms of complex diseases. This research approach is expected to generate new scientific hypotheses that will promote development of new targeted diagnostic and therapeutic applications in ATT and sarcoidosis.

Objectives of this research program. This initiative will define the molecular, cellular, and clinical characteristics of 1) representative AAT deficient adults and 2) recently diagnosed sarcoidosis patients, both with varying degrees of lung involvement. The data obtained will provide a basis for better disease definition, patient sub-type classifications, and the development of new diagnostics or therapies. Data analyses for the two different diseases will, in general, be performed independently. The two diseases are combined in this program to take advantage of efficiencies from sharing of infrastructure, resources, analytical capabilities, and clinical expertise. It is anticipated that each of up to eight Clinical Centers will recruit approximately 60-80 subjects. One or both diseases and appropriate controls will be represented in the recruited cohort. Applicants are strongly encouraged to gain access to existing cohorts of sarcoidosis and AAT patients in which careful clinical phenotyping and genetic linkage and association studies have already been performed. Utilizing such well characterized populations should facilitate the development of the GRADS program. Clinical Center applicants may propose to enroll balanced or unbalanced cohorts of each population (AAT and sarcoidosis). NHLBI will consider the availability of subjects by condition when making funding decisions to ensure a balance between the two diseases in the program.

Types of research and experimental approaches that are being sought to achieve the objectives. GRADS will support study-wide research programs in AAT and sarcoidosis as well as multiple Clinical Center-specific research studies. According to study-wide protocols, each GRADS Clinical Center will enroll, clinically phenotype (including HRCT), and immunophenotype approximately 60-80 AAT and/or sarcoidosis subjects and appropriate controls. Clinical Centers will also collect, process, and ship biospecimens to the GIC for analyses. In addition to these collaborative genomics studies, the Clinical Centers will perform center-specific, hypothesis-based research projects to elucidate pathogenetic mechanisms or identify predictors of disease development/progression in AAT or sarcoidosis.

Study-wide research programs. A Steering Committee comprised of all the Principal Investigators involved with the project will be organized by the GIC to develop study-wide protocols and monitor study operations. The final study-wide protocols (one for AAT and one for sarcoidosis) will be based on proposals submitted by the successful GIC and Clinical Center applicants. In general, GIC applicants are asked to propose in their applications those aspects of the protocol that will be performed primarily by the GIC (overall study design and management, biospecimen analyses, data processing and analysis, dissemination of results) and Clinical Center applicants are asked to propose those aspects of the protocol that will be performed primarily at the Clinical Centers (subject identification and recruitment, clinical and immune-phenotyping, and biospecimen collection and handling). The study-wide protocols will be finalized by the GRADS Steering Committee in the early stages of the program. Funds to support study-wide protocol activities at the Clinical Centers will be part of the GIC grant award and will be distributed to the Clinical Centers on a per subject basis and according to the final approved protocol budgets developed by the Steering Committee. All Clinical Centers must be willing to accept funding for the study-wide protocols according to this arrangement.

Specific content of Clinical Centers applications. Clinical Center applicants are asked to propose those portions of a study-wide protocol that deal with background information about the diseases, subject selection and enrollment, characterization and phenotyping, and biospecimen collection and handling. Clinical Center applicants may describe phenotypical (clinical and immunological) characterization protocols for AAT or sarcoidosis or both diseases, depending on their expertise and access to patients. Clinical Center applications must also include a distinct proposal for a Clinical Center-specific research study that seeks to identify mechanisms of pathogenesis or predictors of AAT or sarcoidosis disease development/progression. Applicants should use the following content guidelines in preparing their applications:

• Introduction/background: description of the importance of the study-wide protocol and of the clinic-specific study in the context of the current understanding of the disease (AAT, sarcoidosis, or both).
• Inclusion/exclusion criteria for enrollment in the study-wide protocols and the Clinical Center-specific study (these may or may not differ between the studies). Plans for identifying and enrolling the proposed number of subjects. Characteristics of the anticipated subject population(s).
• Proposed methods for clinical phenotyping, including immunophenotyping and microbiome methods as appropriate. Rationale for choosing these phenotypes for the interrogation of the molecular biospecimen data in the integrative analyses to be performed by the GIC.
• Description of biospecimen collection and sample in vitro manipulation/processing for the study-wide protocols and for the clinical-specific study (if applicable). Samples to be analyzed by the GIC will be prepared by the Clinical Centers. Applicants should propose and justify the collection of specific biospecimens (e.g. blood and bronchoalveolar lavage (BAL) for AAT subjects, and blood, skin or lung tissue and bronchoalveolar lavage (BAL) for sarcoidosis subjects). Microbiome and transcriptome analysis of mRNAs and miRNAs are anticipated, and these will be performed by the GIC (see RFA-HL-12-014). Preparation of samples for GIC measurements of mRNA and miRNA transcripts for phenotyping may include biospecimen immune-stimulation to allow assessment of evoked phenotypes.
• Description of and justification for the Clinical Center specific study: hypothesis, research objectives (i.e. to elucidate pathogenetic mechanisms or identify predictors of disease development/progression in AAT or sarcoidosis), methods, and statistical analysis. Applicants are encouraged to identify possible synergy and leveraging between the Clinical Center-specific and study-wide studies.

Study-wide research program objectives may include but are not limited to the research questions listed below:

• What is the transcriptional profile, as assessed by mRNA and miRNA expression analysis, in lung, blood cells, and plasma of AAT subjects at steady state? Can these data be correlated with the clinical characteristics of the subjects in reference to appropriate control subjects?
• What is the transcriptional profile, as assessed by mRNA and miRNA expression analysis, in lung, other affected pathological tissues, blood cells and plasma in sarcoidosis patients? Can these be correlated with the clinical characteristics of the subjects in reference to appropriate control subjects?
• What are the dynamic molecular patterns of biomarkers and mRNA and miRNA expression in peripheral blood mononuclear cells and plasma before and after stimulation with specific TLR agonists in AAT patients, sarcoidosis patients, and appropriate control subjects? Can these be correlated with the clinical characteristics of the subjects?
• Are there differencies in RNA and miRNA expression in sarcoidosis patients at different stages; aggressive or mild disease; diffuse or localized disease?
• What viral and/or bacterial phyla are present in lung or extra pulmonary tissues in AAT and sarcoidosis patients? Does the microbiome correlate with clinical characteristics of the subjects?

Clinical Center-specific research study. In addition to the study-wide protocols, Clinical Centers will each propose and conduct a research study aimed at identifying mechanisms of pathogenesis or predictors of disease development/progression. These Clinical Center-specific studies may address AAT or sarcoidosis or both diseases, depending on the availability of expertise and research subjects at the Clinical Center. Clinical Center applicants are strongly encouraged to utilize in their Clinical Center-specific studies subjects, data, and biospecimens available through the study-wide protocols whenever possible to minimize the costs and burden to subjects.

Clinical Center specific research program objectives may include but are not limited to the research questions listed below.

• What molecular and clinical characteristics predict the progression of lung disease in AAT subjects?
• Do COPD exacerbations with or without antibiotic treatment induce changes in the microbiome of induced sputum in subjects with AAT?
• What clinical and biochemical measures are associated with the presence of fibrosing lung disease in sarcoidosis patients?
• Are there rare, nonsynonymous genetic variants in exomes encoding immunity-related proteins in genomic or granuloma DNA from subjects with sarcoidosis?
• Is there a diagnostic marker or panel of markers that can be used to predict early development of lung disease in AAT subjects?
• Can the pathogenesis of sarcoidosis or AAT be understood using models derived from human induced pluripotent stem (iPS) cells?

Organization of NHLBI’s GRADS. GRADS will be supported and governed by Cooperative Agreements of up to eight Clinical Centers and one GIC with NHLBI.

• Both GIC and Clinical Center investigators will contribute to the development and implementation of the study-wide protocols; the conduct of the research; the analysis, interpretation, and publication of the results; and the dissemination of study findings. Each Clinical Center will be required to participate in a cooperative and interactive manner with all other Clinical Centers and the GIC in all aspects of the research.
• The GRADS Clinical Centers will provide expertise regarding the two diseases and methods of clinical phenotyping. The Clinical Centers will each enroll, clinically phenotype (including HRCT), and immunophenotype approximately 60-80 AAT and/or sarcoidosis subjects and appropriate controls, using common protocols in a study-wide effort. Clinical Centers will also collect, process, and ship biospecimens to the GIC for analyses. In addition, Clinical Centers will receive funding to support core activities and carry out a center-specific protocol aimed at elucidating pathogenetic mechanisms or identifying predictors of AAT or sarcoidosis disease development/progression.
• The Principal Investigator(s) and other investigators of the Clinical Centers will provide expertise in AAT, sarcoidosis, immunology, microbiology, and cellular and molecular pathobiology. At a minimum, each clinical center must contribute expertise in clinical aspects of at least one of the diseases and in at least one scientific discipline relevant to pathogenesis and subject phenotyping. The multiple principal investigators (PI) option (see http://grants.nih.gov/grants/multi_pi/index.htm) may be used.
• Clinical Centers may include satellite recruitment and protocol implementation sites (that is, additional recruitment sites at a different location than the Clinical Centers).
• The GIC will lead the development of study-wide protocols, oversee conduct of the overall study, serve as a repository for study data and biospecimens, perform or subcontract the analysis of biospecimens, coordinate the activities of the Steering Committee and OSMB, provide quality assurance, and carry out the primary analyses of study data. The GIC will provide expertise in study design; transcriptome, viro-, and phylo-chip analyses; systems biology; and statistical analysis of data sets with high dimensionality. The GIC will prepare a study dataset in an accessible format for sharing and distribution. The GIC will be responsible for distributing protocol funds to the Clinical Centers for the implementation of study-wide protocols on a capitation basis.
• The NHLBI will be responsible for directing and providing overall support for GRADS. The NHLBI Program Office and Office of Grants Management will be responsible for the overall management of GRADS. In addition to regular grant stewardship, the NHLBI Project Officer(s) will be involved substantially with the awardees as a NHLBI partner, consistent with the Cooperative Agreement mechanism. The NHLBI will appoint the Observational Study Monitoring Board (OSMB) and the Steering Committee Chair.
• A Steering Committee (SC) composed of the Principal Investigators of the Clinical Centers, the PI of the GIC, the NHLBI Program Officer(s), and the Study Chair will be the main governing body of GRADS. The NHLBI will appoint the Study Chair, who may be independent of the Clinical Centers and the GIC, to preside over SC meetings and serve as a SC representative. All major scientific decisions, including use of study data and biospecimens, will be determined by majority vote of the SC. Each Clinical Center, the GIC, and the NHLBI will have one vote; the Study Chair will have one vote in case of a tie vote among the other SC members. It is anticipated that the SC will meet one time every month by telephone conference call and three times by in-person meetings in the first year, with an initial in-person meeting two months after award. In subsequent years, the SC will meet one time every month by telephone conference call and two times by in-person meetings. The SC will have primary responsibility for prioritizing proposed topics for investigations, developing the protocols for the studies of each disease, conducting and monitoring the studies, reporting study results in a timely manner, and working with the NHLBI to disseminate the findings. The SC has final responsibility for proposing protocols, protocol budgets, and protocol revisions. Subcommittees of the SC may be established to perform specific functions such as Publications and Presentations, Quality Control/Assurance, and Ancillary Studies. The SC will monitor disclosures of financial interests and potential conflicts of interest among investigators and clinic coordinators according to NHLBI conflict of interest policy (see http://www.nhlbi.nih.gov/funding/policies/coi-res.htm), but such monitoring will not preclude the investigators responsibility to make financial disclosures to their respective institutions.
• An independent Observational Study Monitoring Board (OSMB), established by the NHLBI in accordance with NIH policies and with input from the SC, will monitor patient safety and review study progress and performance. The OSMB will consist of a chair, clinicians with expertise in AAT and sarcoidosis, and scientists with expertise in clinical research, -omics, bioethics, and biostatistics. An NHLBI scientist, other than the NHLBI’s GRADS Project Officer(s), will serve as the Executive Secretary to the OSMB. The OSMB will meet semi-annually by telephone conference call or in-person meetings in the Bethesda area, MD. The OSMB will review serious adverse event reports on an ongoing basis, according to NHLBI policies. Following each meeting, the OSMB will submit recommendations to NHLBI regarding the continuation of the study. The NHLBI will prepare a summary of the OSMB recommendations that Principal Investigators can provide to their Institutional Review Boards.

Funding Instrument	Cooperative Agreement (U01): 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	The total amount of funding that NHLBI intends to commit for GRADS (for up to 8 Clinical Centers in response to this FOA and 1 Genomics and Informatics Center (GIC) in response to RFA-HL-12-014) is $12,000,000 total costs for a project period of 3 years. Designated funding levels are subject to change at any time prior to award, due to unforeseen budgetary, administrative, or scientific developments.
Award Budget	The NHLBI anticipates awarding $3,600,000 total costs over 3 years for up to 8 Clinical Centers for core funds to provide infrastructure for implementing study-wide protocols and to carry out a clinic-specific research study aimed at identifying predictors of AAT or sarcoidosis disease development/progression. Requested Direct Costs for Clinical Centers core expenses and site-specific studies may not exceed $100,000 per year for three years. In addition to the direct costs awarded to each clinical center, the NHLBI anticipates providing approximately $115,000 per year per Clinical Center over 3 years to the GIC to support study-wide protocol activities at the Clinical Centers on a capitation basis. The protocol activities funds will be awarded to the GIC and will be distributed by the GIC to the Clinical Centers in accordance with final protocol budgets (see RFA-HL-12-014). These funds will cover subject screening and enrollment; clinical and radiographic characterization; immunophenotyping; and biospecimen collection, handling, and shipment to the GIC..
Award Project Period	The total project period for an application submitted in response to this funding opportunity may not exceed three years.

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

Higher Education Institutions:

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American tribal organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7214, MSC 7924
Bethesda, MD 20892-7924 (Express zip: 20817)
Telephone: (301) 435-0270
Email: [email protected]

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

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

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

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7214, MSC 7924
Bethesda, MD 20892-7924 (Express zip: 20817)
Telephone: (301) 435-0270
Email: [email protected]

All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed.

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

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..

• All applications, regardless of the amount of direct costs requested for any one year, should address data sharing.

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.

Foreign (non-US) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the PHS398 Application Guide.

Part I. Overview Information contains information about Key Dates. 

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

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

This initiative is not subject to intergovernmental review.

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

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

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Refer to NOT-OD-10-097 for budgeting of genomic arrays.

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 not be reviewed.

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

Qualifications and Experience. Applicants should describe the investigators qualifications and experience in the appropriate narrative sections of the application and in biosketches. Applications for the Clinical Centers must have personnel with the necessary experience and expertise to conduct clinical studies in patients with AAT and/or sarcoidosis. Applicants should have an established research program in the field and demonstrated leadership in the design and conduct of clinical studies. When using the multiple PD/PI option, a Leadership Plan must be included in the research plan section of the application (see below).

Collaboration. Applicants should state their general support of collaborative research and their willingness to participate in a collaborative and interactive manner with other Clinical Centers, the GIC, and the NHLBI in all aspects of the GRADS program. Applicants are encouraged to describe any special expertise or unique strengths they can offer to the collaborative effort (e.g., innovative study design, genetics/genomics/proteomics, bioinformatics, team leadership and training, patient recruitment strategies, dissemination activities, access to already characterized cohorts of patients).

Applicants must agree, if awarded, to accept the Cooperative Agreement Terms and Conditions of Award in Section VI. 2.

Study Population. Applicants should demonstrate access to a sufficient number of patients to accomplish their portion of the proposed protocols. For application purposes, it is assumed that each Clinical Center should have access to a minimum of 60-80 subjects. While representation of both AAT and sarcoidosis is desirable, applicants may propose to enroll balanced or unbalanced representation of each population (AAT and sarcoidosis). NHLBI will consider the availability of subjects by condition when making funding decisions to ensure a balance between the two diseases in the overall program. Patient access may be accomplished by establishing links with other groups (e.g., other health care providers in the community, such as pulmonary practices, primary care practitioners, and health maintenance organizations) in addition to the applicant’s institution. If links with other groups are anticipated, the application should include a plan with appropriate letters of support that describes (1) how the applicant Clinical Center will link to and operate with the other groups, and (2) how the Clinical Center will monitor the quality of the other groups performance (recruitment and, if applicable, patient visits and data collection). The application should include a brief description of anticipated problems with recruitment and plans for addressing these problems, including letters of support if additional groups will be used. Note that proposed solutions to recruitment problems may not include requesting additional funds.

NHLBI BioLINCC repository: mandated clinical data sets preparation and optional biospecimen collection storage. GRADS will be expected to deposit datasets in the BioLINCC repository (see https://biolincc.nhlbi.nih.gov/new_data_set_policy/) and will be encouraged to offer residual biospecimens to the NHLBI Biorepository, consistent with achieving the goals of the program.

Links with NIH resource centers. Applications from institutions that have a General Clinical Research Center (GCRC) or Clinical and Translational Science Award (CTSA) funded by the NIH National Center for Research Resources should identify the resources that could be available to support the proposed GRADS Clinical Center, commenting particularly on those aspects that will enhance their programmatic and scientific efficiency. A description of the GCRC or CTSA and how the applicant proposes interacting with it should be included, as well as letter of agreement from either the GCRC/CTSA Program Director (PD) or Principal Investigator (PI).

Dissemination Plan. The GIC will be responsible for coordinating the dissemination of GRADS research findings and relevant protocol materials. Applicants to this FOA for GRADS Clinical Centers should indicate here their willingness to collaborate with the GIC and other SC members in dissemination efforts.

Budget Plans. Clinical Center applicants must submit a detailed budget for core costs related to the study-wide protocol (including investigator salaries) and for research costs required to conduct the Clinical Center-specific research study. This budget should include travel costs to attend Steering Committee meetings in the Bethesda area, MD, and other travel related to GRADS operations. The core costs and clinic-specific research budget must not exceed $100,000 Direct Costs in each year.

In addition, a cost estimate for subject phenotyping and biospecimen collection and shipping for the study-wide protocols (AAT and/or sarcoidosis) should be presented, using a budget table or spreadsheet rather than the PHS 398 budget page forms. The budget should indicate the Direct Costs of implementing the proposed phenotyping and biospecimen collection at all Clinical Centers, not just at the applicant’s Clinical Center. Facilities and Administrative ( Indirect ) Costs should not be provided. The budget should not include GIC costs (e.g., for sample analyses and data interpretation, forms development, training, and data collection, quality control and analysis). The protocol cost estimate should include all per-patient costs associated with the conduct of the proposed study at the Clinical Centers (recruitment, enrollment, participant reimbursements, clinical characterization, sample preparations, study personnel, PI oversight, and supplies). Phenotyping /biospecimen costs should not be included in the PHS 398 budget page forms or totals. For application purposes, it may be assumed that the final study cohort will be composed of approximately 400 AAT patients and controls and approximately 200 sarcoidosis patients and controls in total. Protocol funds ($2,750,000 total costs) provided to execute the clinical and immunophenotyping characterization of participants as part of the study-wide protocol, will be awarded to the GIC and will be distributed by the GIC to the Clinical Centers in accordance with budgets approved by the Steering Committee and NHLBI.

It is expected that GRADS research resources such as Manual of Operations, study manuals, case-report forms, phenotype ascertainment instruments will be made available to the public after publication of study findings (e.g., through the National Technical Information Service, see http://www.ntis.gov/index.aspx). The GIC applications are expected to include a plan for sharing these resources in response to RFA-HL-12-014. Clinical Center applicants should indicate their willingness to cooperate with this resource sharing plan.

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

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

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

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

Significance

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

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? Is there evidence of experience with clinical research in AAT and/or sarcoidosis ?

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?

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.

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.

Capability of recruiting adequate numbers of research subjects with AAT and/or sarcoidosis.

Willingness to participate collaboratively in all aspects of the GRADS program.

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

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

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 NHLBI Advisory Council . The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities. Willingness, and evidence of potential, to participate collaboratively in all aspects of the GRADS program.

Willingness to participate in dissemination of the findings of the program with the GIC. Agreement to accept the Cooperative Agreement Terms and Conditions of Award delineated in this FOA .

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

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

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

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

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

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

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS 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:
The Principal Investigator(s) will have the primary responsibility for all aspects of the GRADS studies, including proposing protocols, participating in their overall development, preparing protocol budgets in collaboration with the GIC, modifying proposals if indicated, recruiting study participants, conducting the research, assuring quality of study participant care and protocol adherence, assuring the accurate and timely transmission of data collected, analyzing and interpreting data, preparing publications, and working with the GIC and NHLBI to disseminate research findings. Support or other involvement of industry or any other third party in the GRADS studies may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI. Awardees must follow NHLBI policy concerning third party agreements. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
GRADS will have two NIH Project Scientist(s) (PS) who will also serve as Program Officials; they will share participation in Steering Committee activities.

The NHLBI PS may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees (e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment). The NHLBI PS, on behalf of the NHLBI, will have the same access, privileges, and responsibilities regarding the collaborative data as the other members of the Steering Committee.

The NHLBI reserves the right to phase out or curtail a GRADS study (or an individual award) in the event of (1) failure to develop or implement mutually agreeable collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of a protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; (4) attaining of a major study endpoint before schedule with persuasive statistical significance, or (5) human subject ethical issues that may dictate a premature termination.

Annual continuation and level of funding for each Clinical Center will be based on NHLBI review of actual recruitment and overall performance, determined as part of the NHLBI review of the annual non-competing continuation grant progress reports submitted by awardees.

Additionally an agency Program Official or IC Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned program director may also serve as the NIH Project Scientist.

Areas of Joint Responsibility include:
Awardees agree to the governance of the study through a Steering Committee (SC). All Principal Investigators and a Chairperson, to be appointed by the NHLBI, will comprise the SC. All major scientific decisions will be determined by majority vote of the SC. Each Clinical Center, the GIC, and the NHLBI PS will have one vote; the Chair will have one vote in case of a tie. If a Clinical Center has two principal investigators, each Clinical Center still has one vote. It is anticipated that the SC will meet one time every month by telephone conference call and three times by in-person meetings in the first year, with an initial in- person meeting at two months after award. In the subsequent years the SC will meet one time every month by telephone conference call and two times by in-person meetings. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

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 regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

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.

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

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

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

Antonello Punturieri, M.D., Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Room 10146
6701 Rockledge Drive
Bethesda, MD 20892-7952 (Express mail zip: 20817)
Telephone: 301-435-0230
Email:[email protected]

Sandra Colombini-Hatch, M.D., Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Room 10162
6701 Rockledge Drive
Bethesda, MD 20892-7952 (Express mail zip: 20817)
Telephone: 301-435-0223
Email:[email protected]

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7214, MSC7924
Bethesda, MD 20892-7924 (Express mail zip: 20817)
Telephone: 301-435-0270
Email: [email protected]

John Diggs
Office of Grants Management
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7128, MSC 7926
Bethesda, MD 20816-7926(Express mail zip: 20817)
Telephone: 301-435-0166
Email: [email protected]

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

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