Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

In response to The Gabriella Miller Kids First Research Act (https://www.congress.gov/bill/113th-congress/house-bill/2019/text), NIH, through the Common Fund, has established the Gabriella Miller Kids First Pediatric Research Program (Kids First). The Kids First program is expected to be a ten-year effort that will build the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). The Kids First Data Resource will be populated by genomic and phenotypic data, and will be of high value to the pediatric research community by facilitating data mining across diverse conditions. It is anticipated that establishing the Data Resource will leverage discovery of shared pathways whose disruption may lead to structural birth defects and/or susceptibility to childhood cancer. The overall goal is to help researchers understand the underlying mechanisms of disease, leading to more refined diagnostic capabilities and ultimately more targeted therapies or interventions.

This funding opportunity builds upon a prior FOA (PAR-15-259, "Discovery of the Genetic Basis of Structural Birth Defects and of Childhood Cancers: Gabriella Miller Kids First Pediatric Research Program (X01)") and is intended to identify samples for genome sequencing that will help elucidate the genetic contribution to childhood cancers and the etiology of structural birth defects. Data obtained from these projects will contribute to the forthcoming Kids First Data Resource, and PDs/PIs of these projects will participate in a Kids First Data Resource Consortium that is expected to be established in FY 2016. Members of this consortium will work collaboratively to help inform the development of the integrated Data Resource.

For childhood cancer cohorts: This FOA invites applications that will propose sequencing of DNA samples from childhood cancer cohorts for which a genetic basis is suspected but not identified. Proposed study populations should address important questions about the genetics/genomics of childhood cancers that might be answered by whole genome sequencing. Cancer study populations with associated birth defects are especially encouraged. All study designs, with appropriate scientific justification, will be considered. One example is that of a trio study design with the study population consisting of samples collected from participants with childhood cancer and their parents. Note that submission of tumor DNA is encouraged when whole genome sequencing of the tumor will provide additional insight into the genetic contribution to the cancer(s) under study.

For structural birth defects cohorts: This FOA also invites applications that will propose sequencing of DNA samples from subjects with structural birth defects that are appropriate for whole genome sequencing. Proposed study populations should address important questions about the genetics/genomics of structural birth defects that might be answered by whole genome sequencing. All study designs, with appropriate scientific justification, will be considered. One example is that of a trio study design with the study population consisting of samples collected from participants with structural birth defects and their parents. Unless strongly justified, a minimum sample set of 100 trios, or a sample number that is scientifically justified, is expected in each application. Study populations with defects that affect multiple organ systems, or that are associated with susceptibility to childhood cancers, are especially encouraged. Populations with syndromic conditions that exhibit intellectual or neurobehavioral disabilities as part of the phenotype are acceptable, as long as the focus of the project is on associated structural birth defects.

The cohorts selected under this FOA must have existing genomic DNA and participants must have given consent to allow sharing of individual-level genome sequence and relevant phenotype data through dbGaP or other NIH-approved repository. Cohort samples that have consents that allow for broad data sharing (i.e. for general research purposes) are of higher priority. No funds will be provided to collect samples, perform additional phenotyping, acquire other data types, or obtain new consent for existing samples. However, future initiatives within the Kids First program may provide support for these activities; cohorts that have provided consent to be recontacted for additional studies are therefore encouraged.

Projects selected under this FOA will be expected to work in a collaborative manner with the genome sequencing component(s) selected by the NIH for this initiative. The sequencing center will produce the genome sequence and called variant data sets.

Current plans are to produce whole genome sequence data. Genome sequence data production will be carried out by a separate component of the Kids First Pediatric Research Program; genomic and phenotypic data will be made available through the Kids First Data Resource. Data from the childhood cancer cohorts will also be added to the overall genetic dataset for childhood cancers at the NCI Genomic Data Commons.

Genetic alterations are underlying etiologic contributors to pediatric disease, including childhood cancers as well as multiple birth defects and related syndromes. The disruption of development may affect the structure of one or more organ systems, and may predispose to disabilities and to childhood cancers. Investigations of the genetic architecture of various diseases, by exome sequencing and other genome-wide interrogations, suggest that large sample sizes will be required to achieve a comprehensive understanding of the genetic etiology of these disorders. Those studies highlight the genetic heterogeneity of various developmental disorders and also the genetic overlap between various diseases. An integrated data resource will help aggregate data sets to increase power; catalog myriad data sets to enable rational organization of data resources; and facilitate cross linking of diverse data sets to enable novel research collaborations and knowledge connections.

Approximately one in 33 infants born in the United States has a birth defect, and these are the leading cause of death for infants during the first year of life. Next to accidents, birth defects are the leading cause of death in children of all ages and account for half of all pediatric hospitalizations. Technical advances (such as the decreased cost of genomic sequencing) have made powerful tools available to help researchers uncover the genetic variants, genes, and pathways that underlie birth defects. Together with our ability to describe clinical characteristics in detail, there are emerging opportunities for research on genetic and environmental influences on development and for illuminating common pathways that may link different birth defects.

Cancer remains the leading cause of childhood disease-related mortality beyond the first year of life. Major advances have been made in understanding the genetics and genomics of childhood cancers, particularly in the past decade through the work of large projects such as the NCI Childhood Cancer TARGET Initiative, the St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, and projects of other research teams throughout the world. NCI sponsored a workshop of leading childhood cancer genomics researchers in February, 2015, and one key message from the workshop was that the discovery phase of pediatric oncology genetics and genomics is not complete.

The causes of some pediatric cancers are not well understood. Many of the rare familial cancer syndromes include pediatric cancers in which tumor formation is directly related to a structural defect or mutation in the germline. Historically, germline alterations were identified in only a small fraction of children with cancer, even in those with a family history of cancer in 1st/2nd degree relatives. However, with the advent of genome-scale sequencing, potentially causative germline alterations have been observed in approximately 10 percent of children with cancer. Germline sequencing data from many more children with cancer are needed to fully elucidate the germline contribution to specific childhood cancers.

NCI has a long-standing commitment to the support of family-based studies, particularly in pediatric cancer, which includes careful clinical evaluation, collection of blood and tumor, and consent to both conduct genetic analyses and share data with researchers according to NIH policies. The investment in families with pediatric cancer has led to the identification and characterization of many rare pediatric cancer syndromes, including the Li-Fraumeni Syndrome (LFS) in which a TP53 mutation has been identified in 70% of cases. Recent surveys of sporadic pediatric cancers, such as osteosarcoma, have identified that as many as 5-10% of children with osteosarcoma may harbor a TP53 mutation. Ongoing studies have collected pediatric cancer patients with family history who do not fit known hereditary cancer syndromes. New advances in whole genome sequencing provide an opportunity to search for novel mutational events in families, either inherited or de novo.

The Kids First Program seeks applications for sample sets that can be ready for whole genome sequencing as soon as possible after the application due date of this FOA. In general, applications may aim to discover influential genetic variants underlying their targeted disorder using various experimental approaches (e.g., trio-based, family-based, case-control, or other). If other -omics data already exists on the subjects, then an integrative -omics approach may also be taken. This FOA offers a standard protocol of sequencing the whole genome from high quality genomic DNA by a Gabriella Miller Kids First-designated sequencing center. The sequencing center(s) will produce whole genome sequence and called variant data sets. Some applicants may wish to collaborate with the sequencing center for custom analysis and validation of variants for a subset of cases. Such scientific collaboration will be arranged by the applicant and investigator from the sequencing center.

After approval to access the genome sequencing capacity, investigators will work with the NIH and the designated sequencing center to determine the timing and number of DNA samples to be sequenced. Details of sample requirements (amount, concentration, quality) will be provided to investigators. It is expected that the sequencing center(s) will provide reasonable funds to cover costs of shipping of samples, if needed.

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
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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

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

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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

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

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

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

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

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

The letter of intent should be sent to:

Jonathan Kaltman, MD
Telephone: 301-435-0510
Fax: 301-480-2858
Email: kaltmanj@nhlbi.nih.gov

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

• For this specific FOA, the Research Strategy section is limited to 6 pages.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

Total Federal Funds Requested: Enter $0.

Total Federal & Non-Federal Funds: $0.

Estimated Program Income: Enter $0

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

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

Other Attachments: Provide Institutional Certification (http://gds.nih.gov/Institutional_Certifications.html), which demonstrates that it is permissible to share the data, consistent with achieving the goals of the program. Institutional Certification should specify whether individual level variant data can be shared and whether there are any data use limitations. If Institutional Certification is not available, provide a sample consent form.

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

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

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

Specific Aims: The Specific Aims should refer directly to the goals of this Funding Opportunity Announcement.

Research Strategy: Cohorts with cancers and structural birth defects have distinct requirements as indicated below.

Research teams who have previously been approved to have cohorts sequenced through Kids First may submit a new application, provided that the required elements, described below, are addressed in the application. In addition, these applicants must provide scientific justification for why further samples should be sequenced (e.g., analysis of a different subpopulation), and demonstration of what progress, if any, has been made on analyzing the data from the previously submitted cohort.

For cohorts with childhood cancers:

Applicants should describe their proposed cohort of children with cancer for which a genetic predisposition to cancer is suspected, but not yet identified. The applicant should clearly explain why genome sequencing is likely to reveal previously unknown variants underlying cancer predisposition or previously unknown associations between variants and specific childhood cancers. The applicant should present evidence that the number and type of DNA samples proposed are likely to be sufficient to detect genetic variants affecting cancer risk for the population under study.

Applicants with cancer cohorts are strongly encouraged to address all of the following points in their application:

1) Study Population: Describe the cohort and the characteristics that define it as a distinctive population that is likely to have a genetic basis for cancer predisposition. Describe current understanding of the genetic contribution to the cancer(s) affecting the proposed cohort. Describe the rationale for the proposed cohort as one that will provide key contributions to answering important questions about the genetics/genomics of childhood cancers through the application of whole genome sequencing to the cohort. Describe how the study design will be likely to lead to discovery of variants contributing to the cancer of interest. Note that submission of tumor DNA is encouraged when whole genome sequencing of the tumor will provide additional insight into the genetic contribution to the cancer(s) under study.

2) Phenotype Data: Describe what phenotype information is available on all study participants. At a minimum, the following data elements are expected: demographics (age, sex, race, ethnicity), clinical information (e.g., detailed cancer history), other phenotypic information (e.g., other phenotypic measurements that may be related to the primary outcome), and family medical history (e.g., family history of cancer).

3) Consent: Confirm the consent used to obtain the samples allows sharing of individual level genome sequence and relevant phenotype data through a controlled access, NIH-approved repository such as dbGaP http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/about.cgi. Include information such as ability to recontact participants for additional phenotyping or collection of additional samples. Describe whether the consent requires any data use limitations.

4) Sample Information: Describe the characteristics and number of specimens ready for submission to a sequencing center. Provide a detailed inventory of the sources of the DNA (e.g., number of samples from blood, number of samples of embedded tumor tissue, number of samples from saliva). Describe the status of the DNA samples, including the extraction methods used for each DNA source and the approximate DNA concentrations. Address their quality in terms of suitability for whole genome sequencing. Address their readiness for shipping, and estimate the time required to ship DNA samples to a sequencing center after approval. For tumor specimens, the pathology review to which the specimens were subjected and the percentage of tumor cells within the specimen used for DNA isolation should be described. Estimate the shipping costs per sample. Describe genotyping that has been done on the DNA samples proposed. Have known cancer predisposition genes been excluded?

5) Data Analysis: Provide a plan for data analyses. Include methods for variant filtering and follow up. If there is a plan to analyze the data obtained with earlier data, describe the strategy for that process. Describe why the number of samples proposed for whole genome sequencing is adequate to draw reliable conclusions about the contribution of genetic alterations to the cohort. Use power analyses to describe the range of effect sizes detectable by the study.

5) Data Management: Describe the institutional computing resources available for this study, the type of data base that will be used, and how the data will be managed. Highlight the team's experience with management of large data sets (especially those similar to the proposed project). Also describe strategies to maintain data security.

6) Contribution to Data Resource: Describe how the genome sequence, phenotypes, and size of the proposed study population will contribute to the pediatric data resource. For example, how do the cancers of this study intersect with other cancer or birth defect phenotypes and what types of genetic and/or phenotypic overlap have been identified between the proposed cancer and other cancers or birth defects? Describe willingness to participate in a consortium to establish the Kids First Data Resource and to the overall genetic dataset for childhood cancers at the NCI Genomic Data Commons.

For cohorts with structural birth defects:

A minimum sample set of 100 trios, or a sample number that is scientifically justified, is expected in each application.

Significance:

1) Describe the phenotype and how it is defined. Explain the biological, biomedical, and/or public health significance of the phenotype under study. Include details about the phenotype data available, e.g., whether the phenotype affects multiple organ systems, or whether there are significant co-morbidities.

2) Document the evidence for a genetic component of this phenotype and the likely strength of that component, including the heritability and complexity.

3) Describe earlier genetic studies on this disorder, and what has been found so far. Describe other identified risk factors.

4) Describe known environmental risk factors for this trait, and the evidence for their involvement. Also discuss any evidence for gene-environment interactions.

5) If this request is a direct follow up of an earlier study, describe those results.

6) Provide any additional background that supports the value of the samples proposed for genomic sequencing. This may also include information on the ability of the investigator to obtain further samples for follow-up studies or to acquire additional data such as exposure data.

Innovation and Approach:

1) Study Population: Clearly describe the study population. Include detailed information about how subjects were identified and sampled and the method(s) of phenotypic characterization. If the subjects provided for this study are a subset of a family population, explain which individuals were included and how they were selected. Highlight special features of the study population that would enhance success. Describe the ancestry, if known, of the individuals whose samples will be submitted for genome sequencing. How do considerations of ancestry factor in to the design of the study? Describe how the study design will be likely to lead to discovery of variants contributing to your phenotype of interest.

2) Phenotype Data: Describe what phenotype information is available on all study participants. At a minimum, the following data elements are expected: demographics (age, sex, race, ethnicity), clinical information (e.g., type of birth defect), other phenotypic information (e.g., other phenotypic measurements that may be related to the primary outcome), and family medical history (e.g., family history of birth defects).

3) Consent: Confirm the consent used to obtain the samples allows sharing of individual level genome sequence and relevant phenotype data through a controlled access, NIH-approved repository such as dbGaP http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/about.cgi. Include information such as ability to recontact participants for additional phenotyping or collection of additional samples. Describe whether the consent requires any data use limitations.

3) Sample Information and Service(s) Requested: Provide a description of the samples such as collection site; number of samples included in the study; a detailed inventory of the sources of the DNA (e.g., number of samples from blood, number of samples from saliva); and previous genotyping or sequencing. If data from other subjects will be included in the analysis, describe those samples. Provide supporting text that justifies the choice of samples. Describe the extraction methods used for each DNA source and the approximate DNA concentrations. Describe the status of the DNA samples, in particular their readiness for shipping and appropriateness for whole genome sequencing. Estimate the time required to ship DNA samples to a sequencing center after approval. Estimate the shipping costs per sample. Describe previous genotyping or sequencing done on these subjects. Have known genes that cause the same or similar phenotype been excluded?

4) Data Analyses: Provide a thorough plan for data analyses. Include analytical approaches to be used and their justification; plans for quality control analyses; methods to control for possible confounding effects such as genotype and/or phenotype uncertainty; how false positive rates will be controlled in light of multiple testing etc. Discuss how the causal variant would be identified and validated. If there is a plan to analyze the data obtained with earlier data, describe your strategy for that process. Also, explain plans for filtering the SNPs detected. Use power analyses to describe the range of effect sizes detectable by the study. Describe the role of each team member in the analysis process.

5) Data Management: Describe the institutional computing resources available for this study, the type of database that will be used, and how the data will be managed. Highlight the team's experience with management of large data sets (especially those similar to the proposed project). Also describe strategies to maintain data security.

7) Contribution to Data Resource: Describe how the genome sequence, phenotypes, and size of the proposed study population will contribute to the Kids First Data Resource. For example, how do the phenotypes of this study intersect with other birth defect phenotypes or cancers and what types of genetic and/or phenotypic overlap have been identified between the proposed birth defect and other birth defects or cancers? Describe willingness to participate in a consortium to establish the Data Resource.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• The overall goal of the Kids First Program is to produce an integrated data resource to help researchers to effectively mine data across diverse conditions, understand the underlying mechanisms of disease, uncover shared pathways, and lead to more refined diagnostic capabilities and more targeted therapies or interventions.
• All applications should address a Data Sharing Plan under the guidance of the NIH Genomic Data Sharing policy http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html. Applicants are expected to agree that all genome sequence and related phenotype data will be deposited in a repository designated by the Kids First Common Fund staff in a manner consistent with NIH policy http://grants.nih.gov/grants/policy/data_sharing/ and achieving the goals of the program.

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

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

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

NIH intramural scientists may 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.

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

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

For this particular announcement, note the following:

The X01 Resource Access Program invites eligible institutions to seek access to NIH research resources, which are specified in each X01 FOA. This includes programs where institutions will request access to submit to the resource (e.g., whole genome sequencing) as well as programs where access to a specific NIH research resource is needed to conduct certain research. Important factors in the peer review of X01 applications are the need for, and potential benefit of, gaining access to the resource, specifications for any assays proposed, timelines for completion and plans for follow-on studies.

Genomic and phenotypic data will be made available through the Kids First Data Resource. Consent to recontact participants for additional phenotyping or collection of additional samples is strongly encouraged.

Information from successful projects will be used to help design future activities of the Kids First Pediatric Research Program. Future activities may include mechanisms to support collection of additional information from existing cohorts.

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

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

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

Is the trait under study significant to human health and/or the understanding of biology? Is there strong evidence for a genetic component? Are the proposed studies likely to provide important new information about genetic variants that contribute to structural birth defects, to address important questions about the genetics/genomics of childhood cancers, and/or to reveal shared genetic pathways? Is there an ability to recontact participants for additional phenotyping or collection of additional samples? Is there additional information (e.g., environmental exposure data) that is likely to add value for further studies?

If the applicants have previously been approved to have cohorts sequenced by Kids First, is there compelling justification for why further samples should be sequenced? Have the applicants demonstrated what progress, if any, has been made on analyzing the data from the previously submitted cohort?

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?

Do the investigators have previous experience in analyzing current genome sequence data?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Are the sequencing services requested appropriate for the question addressed? Are the specific phenotypic measures appropriately chosen and carefully determined? Is the study design appropriate for the trait/cancer under study? Does the cohort consist of highly informative cases? Will the analysis plan(s) enable the investigators to draw reliable conclusions about the contribution of genetic alterations to the cohort? Are validation plans in place?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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

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

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

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

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

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 score.

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

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS). Has the investigator confirmed that consent used to obtain the samples allows for sharing of individual-level genome sequence and relevant phenotype data through dbGAP? Does the consent require any data use limitations? Has the investigator indicated a willingness to participate in a Kids First Data Resource Consortium?

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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

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

As part of the scientific peer review, all applications:

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

Applications will be assigned on the basis of established PHS referral guidelines 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 Common Fund and NIH staff involved in the Kids First Program. The following will be considered in making selection decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of capacity for genomic sequencing.
• Compliance with resource sharing policies as appropriate.
• Program balance, including making available sequence data for a diverse set of disorders. In particular, we will seek to ensure that both pediatric cancer studies and structural birth defects studies are well represented

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Jonathan Kaltman, M.D
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0528
Email: kaltmanj@nhlbi.nih.gov

Lorette Javois, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Telephone: 301-435-6890
Email: javoisl@mail.nih.gov

Adam Felsenfeld, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-496-7531
Email: adam_felsenfeld@nih.gov

Malcolm A. Smith, M.D., Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6087
Email: Malcolm.Smith@nih.gov

Barbara Thomas, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-8837
Email: Barbara.Thomas@nih.gov

Not Applicable

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.