Purpose

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 (2015 - 2024) 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. During the first four years of this Program, data were generated and made publicly available following sequencing of DNA, and some RNA, samples from pediatric cancer and structural birth defects cohorts as outlined on the Kids First Common Fund website at https://commonfund.nih.gov/kidsfirst. In addition to increased understanding of individual pediatric conditions, a goal of establishing the Data Resource is to enable discovery of shared pathways whose disruption may lead to structural birth defects and/or susceptibility to childhood cancer. Therefore, representation of a wide variety of pediatric cancers and structural birth defects within the Data Resource is essential. 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 prior FOAs ( PAR-15-259, PAR-16-150, PAR-17-063 and PAR-18-583) and is intended to identify samples for whole genome sequencing that will help elucidate genetic contributions to childhood cancers and the etiology of structural birth defects.

Data obtained from these sequencing projects will be analyzed and processed, to generate derived files and summary data, which will be compiled and made accessible alongside raw data and metadata, through the Kids First Data Resource.

Types of Research Projects

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 study designs (e.g., trio-based, family-based, or other). If other -omics data already exist on the subjects, then an integrative -omics approach may also be taken. This FOA offers a protocol of sequencing the whole genome from high quality genomic DNA by a Gabriella Miller Kids First-designated sequencing center, with the potential for genome, exome and RNA sequencing of tumor/affected tissue specimens (if available and justified). As sequencing technologies are constantly evolving, additional or alternative approaches such as long-read whole genome sequencing, may be proposed. Project design will be finalized in discussions among the X01 investigators, the sequencing centers, and NIH program staff.

For childhood cancer cohorts: This FOA invites applications that propose sequencing of DNA samples from childhood cancer cohorts (as well as DNA and RNA samples from tumors) for which a genetic basis (germline or somatic) 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 of germline DNA, as well as tumor genome, exome, and transcriptome sequencing when tumor tissue is available. Studies where the probands were born with structural birth defects and subsequently diagnosed with childhood cancer are especially encouraged. All study designs, with appropriate scientific justification, will be considered. Investigators may consider a trio or quad study design with the study population consisting of germline and tumor samples collected from participants with childhood cancer and their parents or affected first degree relatives, including those where the proband has previously been sequenced. Note that submission of nucleic acids from tumor samples is encouraged when sequencing and analysis of the tumor will provide additional insight into 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 those categories of structural birth defects that are not yet well-represented in the Kids First dataset and 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, as well as genome, exome, and transcriptome sequencing of affected tissue. 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, including those where the proband has previously been sequenced. Strong justification for the proposed sample size 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. Note that submission of DNA and RNA from affected tissue samples is encouraged when sequencing and analysis of the tissue will provide additional insight into the structural birth defect(s) under study.

Investigators with small cohort sizes are encouraged to collaborate with other investigators and pool samples together to establish adequate power to uncover variants with relevant implications to the cancer(s) or birth defects(s) under study. This approach is especially relevant for disease conditions that have not yet been sequenced by the Kids First program.

Investigators who have previously sequenced genomic DNA from probands and who have unsequenced nucleic acid samples from their parents, siblings, tumor, and/or affected tissue are also encouraged to apply to have those samples sequenced, assuming that it will result in additional insight into the genetic contribution to the cancer(s) or birth defects(s) under study.

Specific Requirements and Expectations for this Opportunity

The cohorts selected under this FOA must have already extracted genomic DNA or samples that are ready to be extracted, (DNA and RNA from tumors/affected tissue are desirable but optional). Participants must have given consent to allow broad sharing of individual-level sequence and associated clinical and phenotypic data through dbGaP or other NIH-approved repositories. Patient consent groups and/or data use limitations for proposed samples should be indicated on the submitted Institutional Certification using the current NIH template. Cohort samples that have consents that allow for broad data sharing and use, to include combining and comparing datasets across disease areas, (i.e. for General Research Use) are of higher priority. Conditions not previously incorporated into the Kids First dataset are desirable. For a list of prior projects visit: https://commonfund.nih.gov/kidsfirst/fundedresearch. No funds will be provided through this opportunity for collecting samples, performing additional phenotyping, acquiring other data types, obtaining new consent for existing samples, or performing data analysis. However, future initiatives within the Kids First program may provide support for these activities. Cohorts that have provided consent to be re-contacted for additional studies are therefore encouraged.

Cohorts proposed for sequencing must include a minimal amount of associated clinical and phenotypic data sufficient to enable association with genomic variants and analysis. Applications with rich clinical and phenotypic data that can be shared to facilitate cross-disease research among the pediatric research community will be prioritized.

Projects selected under this FOA will be expected to work in a collaborative manner with the designated Kids First Sequencing Center which will be selected through RFA-RM-18-030. The sequencing centers will produce sequence read and called variant data sets. Some applicants may wish to further collaborate with the sequencing center for custom analysis and validation of variants for a subset of cases. Such scientific collaboration will be arranged between the applicant and sequencing center staff with oversight from the NIH, however such services may reduce the total number of samples that can be sequenced.

Data from the studies selected under this FOA will be submitted to the Kids First Data Resource Center led by investigators at the Children's Hospital of Philadelphia, in partnership with the Ontario Institute for Cancer Research, the University of Chicago, Children's National Health System, the Oregon Health and Science University and Seven Bridges. All Kids First data will be processed and harmonized, and made accessible through the newly established cloud-based infrastructure of the Kids First Data Resource Portal, where investigators are encouraged to interact with the data. Investigators selected for this opportunity are encouraged to submit subsequent analytical results to the Data Resource upon publication. Decisions about secondary results and other external datasets that are accepted into the Data Resource will be made by Kids First program staff.

PDs/PIs of selected cohort projects will participate in a collaborative effort to inform the development of the integrated Data Resource to maximize its impact on the research community.

Investigators selected for this opportunity will be notified by NIH Kids First program staff with the estimated number of samples approved for sequencing. Approval to access the sequencing capacity is conditional on the submission of a completed Institutional Certification covering all samples to be submitted for sequencing. If the document does not meet the Kids First program's expectation for broad data sharing (i.e. General Research Use), another cohort with broader sharing may be selected instead. After approval, investigators will work with the NIH and the designated sequencing center to determine the timing and final number of samples to be sequenced, as well as which sequencing technologies will be used. Details of sample and shipping requirements (amount, concentration, quality) will be provided to investigators.

Background

Genetic alterations underlie etiologic contributors to pediatric disease, including childhood cancers as well as multiple birth defects and related syndromes. 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 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 during the first four years of life 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 is the leading cause of childhood disease-related mortality beyond year four of life. In toto, it is the leading disease-related cause of childhood death beyond age one during childhood. 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. Kids First and NCI sponsored workshops of leading childhood cancer genomics researchers in February 2015, May 2016, and March 2018. These recent workshops emphasized the importance of further large-scale germline sequencing of well-annotated pediatric cancer patient and parent trios, as well as paired diagnostic and/or relapse tumor specimens when available and the value of collecting and sharing rich clinical and phenotypic data.

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 or 2nd degree relatives. However, with the advent of genome-wide 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 have identified that as many as 5-10% of children with osteosarcoma may harbor a germline TP53 mutation. Ongoing studies have evaluated 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.

Pre-Application Webinar

1. Eligible Applicants

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

• 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)

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.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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)

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution

2. Content and Form of Application Submission

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:

Valerie Cotton [C]

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Telephone: 301- 594-1519

Email: valerie.cotton@nih.gov

, with the following exceptions or additional requirements:

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

Total Federal Funds Requested: Enter $0.

Total Federal & Non-Federal Funds: $0.
Estimated Program Income: Enter 0.

Other Attachments: The application must include the following attachments.

1) Institutional Certification:

Provide the Institutional Certification(s) using the current NIH template (https://osp.od.nih.gov/scientific-sharing/institutional-certifications/), which demonstrates that it is permissible to share individual-level data to be generated for all samples proposed, consistent with achieving the goals of the program. Institutional Certifications specify the data use limitations and data use limitation modifiers, as determined by the institution's IRB after reviewing the informed consent agreed to by the participants. If the Institutional Certification is not available, provide a Provisional Certification and describe the anticipated data use limitations and associated modifiers separately. If submitting a Provisional Certification with the application, please note that a completed Institutional Certification will be required before a final selection can be made.

2) Sample Information:

• Describe the characteristics and number of specimens proposed for sequencing in table format.
• Describe the number of specimens currently ready to ship to a sequencing center, and those that could be shipped at a later date in the same fiscal year (please provide a timeline if all proposed samples are not currently ready for shipment).
• Provide a detailed inventory of the sources of the DNA (and RNA if available for tumors and/or affected somatic tissue): number of samples from blood, number of samples from saliva or buccal swabs, and number of samples from frozen tissue versus embedded tissue (including fixation method). Please note that costs associated with assaying/processing saliva samples contaminated with bacteria could reduce the total number of samples that can be sequenced; therefore, blood- or tissue-derived nucleic acids are preferable. Additionally, DNA from patient-derived cell lines will not be accepted due to the possible introduction of mutations that could confound the identification of disease-causing rare variants.
• Describe the status of the DNA and any RNA samples, including the extraction methods used for each source and the approximate nucleic acid concentrations. Address their quantity and quality in terms of suitability for whole genome sequencing, as well as exome and transcriptome sequencing for tumors/affected tissue (if appropriate). Describe the quality metric and method of quantification used.
• For tumor specimens, describe the pathology review to which the specimens were subjected and the percentage of tumor cells within the specimen used for DNA and/or RNA isolation.

3) Clinical, Phenotypic, and Demographic Data:

Describe what clinical, phenotypic, and demographic information was collected from all study participants and what is available for submission to the Kids First Data Resource to be shared with the wider research community. At a minimum, the following data elements are expected:

• sex,
• race,
• ethnicity,
• age at enrollment and/or age at diagnosis,
• diagnoses (e.g., type of birth defect, primary tumor type),
• phenotypes for affected cases (list all variables collected),
• phenotypes for unaffected families members (list all variables collected),
• vital status,
• age at last known vital status,
• clinical information (list all available clinical data elements),
• and family medical history (e.g., family history of cancer or birth defects).

Describe whether electronic health records may be available for additional data extraction.

If appropriate, describe any available environmental or exposure data.

4) Family Structure (if applicable)

If proposing a non-trio design, provide any additional information that will help explain the family structures for your proposed cohort (e.g., pedigrees). Convey the total number of affected and unaffected family members? proposed for sequencing.

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

Research Strategy: Cohorts for childhood 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:

1) Describe the proposed cohort of children with cancer for which a genetic predisposition to cancer is suspected, but not yet identified, or for which understanding of recurring somatic mutations may address important questions of biology and therapy.

2) Clearly explain why genome sequencing (as well as genome, exome, and transcriptome sequencing for any tumors) is likely to reveal previously unknown variants underlying cancer predisposition or previously unrecognized associations between known variants and specific childhood cancers. Describe previous germline and somatic genomic sequencing that has been done on the samples proposed. Have known cancer predisposition genes been excluded? This is especially relevant where the proband has previously been sequenced, and sequencing the parents is proposed.

3) Present evidence that the number and type of DNA and RNA samples proposed are likely to be sufficient to detect genetic variants affecting cancer risk for the population under study.

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

5) Provide any additional background that supports the value of the samples proposed for genomic sequencing.

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 or that define it as a cancer population likely to have recurring genomic alterations. 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. Submission of nucleic acids from tumor samples is encouraged. Applicants proposing submission of tumor samples should describe whether both DNA and RNA are available for sequencing.

2) Data Analysis: Provide a plan for analyzing the data to be generated under this FOA (note that no funds are provided under this FOA to support analysis or other activities). 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 as well as the associated clinical and phenotypic data are 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.

3) Contribution to Data Resource and value to the pediatric research community: Describe how the overall study design, sample size, available clinical and phenotypic, and the sequence data to be generated will contribute to the Kids First Data Resource and empower research and collaborations among the pediatric research community. 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 collaborative effort to inform the development of the Kids First Data Resource. Describe a willingness to contribute secondary results to the Data Resource, after publication of associated findings.

4) Consent and Data Sharing: Confirm the consent used to obtain the samples allows sharing of individual level sequence data through a controlled access, NIH-approved repository such as dbGaP (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/about.cgi) and allows for sharing of the associated clinical and phenotypic data. Describe whether the consents allow for broad use of the data including combining and comparing datasets of various disease phenotypes. Include information such as ability to re-contact participants for additional phenotyping or collection of additional samples. If submitting a provisional certification because the full Institutional Certification is not available, describe the anticipated data use limitations based on the consent.

5) Data Management: Describe the institutional computing resources or the cloud-based infrastructure that will support this study, the type of database that will be used, and how the data will be managed locally or on the cloud. Highlight the team's experience with management of large datasets (especially those similar to the proposed project). Also, describe strategies to maintain data security.

For cohorts with structural birth defects:

Applicants should:

1) Describe the phenotype and explain its biological, biomedical, and/or public health significance. Include details about whether multiple organ systems are affected 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, complexity, and a description of any earlier genetic studies on this disorder. Describe previous genotyping that has been done on the samples proposed.

3) Present evidence that the study design (e.g. family structure) and sample size proposed are likely to be sufficient to detect genetic variants underlying the condition under study.

4) Describe other identified risk factors, including any known environmental risk factors 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 include information on the ability of the investigator to obtain additional samples for follow-up studies or to acquire additional data such as exposure data.

Applicants with structural birth defects cohorts are strongly encouraged to address the following points in their application:

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 and how this information will 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) Data Analysis: Provide a plan for analyzing the data to be generated under this FOA (note that no funds are provided under this FOA to support analysis or other activities). 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 as well as the associated clinical and phenotypic data are 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.

3) Contribution to Data Resource and value to the pediatric research community: Describe how the overall study design, sample size, available clinical and phenotypic, and the sequence data to be generated will contribute to the Kids First Data Resource and empower research and collaborations among the pediatric research community. For example, how do the phenotypes of this study intersect with other birth defect or cancer phenotypes 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 collaborative effort to establish the Kids First Data Resource. Describe a willingness to contribute secondary results to the Data Resource, after publication of associated findings.

4) Consent and Data Sharing: Confirm the consent used to obtain the samples allows sharing of individual level sequence data through a controlled access, NIH-approved repository such as dbGaP (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/about.cgi) and allows for sharing of the associated clinical and phenotypic data. Describe whether the consents allow for broad use of the data including combining and comparing datasets of various disease phenotypes. Include information such as ability to recontact participants for additional phenotyping or collection of additional samples. If submitting a provisional certification because the full Institutional Certification is not available, describe the anticipated data use limitations based on the consent.

?5) Data Management: Describe the institutional computing resources or the cloud-based infrastructure that will support this study, the type of database that will be used, and how the data will be managed locally or on the cloud. Highlight the team's experience with management of large datasets (especially those similar to the proposed project). Also describe strategies to maintain data security.

The following modifications also apply:

• The overall goal of the Kids First Program is to create a data resource that makes individual and integrated datasets broadly available to the research community to help researchers to effectively mine data across diverse pediatric conditions, understand the underlying mechanisms of disease, uncover shared pathways, and develop more refined diagnostic capabilities and more targeted therapies or interventions for childhood diseases.
• All applications should address a Data Sharing Plan and include an Institutional Certification which indicates the data use limitations and/or modifiers stating how individual level data can be shared with and used by secondary users, 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 sequence data generated by Kids First and related phenotype data will be deposited in repositories 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.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

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.

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

In order to expedite review, applicants are requested to contact the NHGRI Scientific Review Officer by email at pozzattr@exchange.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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

If selected, appropriate funding will be provided by the Common Fund through the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/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 and intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

1. Criteria

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

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., high throughput screening assays) 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.

The Kids First Data Resource Center will process and analyze sequence data generated under this FOA and make genomic and phenotypic data accessible to the research community to facilitate comparative analyses. Consent to re-contact participants for additional phenotyping or collection of additional samples is strongly encouraged. Cohort samples that have consents that allow for broad data sharing (i.e. General Research Use) will be viewed with the highest priority.

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

In addition,

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, or to address important questions about the genetics/genomics of childhood cancers, and/or to reveal shared genetic pathways? Is the cohort likely to strengthen the impact of the Kids First Data Resource and empower research and collaborations among the pediatric research community?

Is there an ability to re-contact participants for additional phenotyping or collection of additional samples?

Will deep clinical and phenotypic data be submitted to the Data Resource to foster cross-disease comparisons among the pediatric research community? Is there additional information (e.g., environmental exposure data) that is likely to add value for further studies?

Investigator(s)

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

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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?

Additionally,

Does the proposed cohort consist of highly informative cases? Are the specific phenotypic measures appropriately chosen and carefully determined? Is the depth of available clinical and phenotypic data sufficient to support the analysis plan and overall genetic discovery? Is the study design appropriate for the cancer or birth defect under study?

Are sequencing services requested appropriate for the questions posed? In the context of other data available through the Kids First Data Resource, is the cohort likely to reveal previously unknown variants associated with pediatric cancer and/or structural birth defects?

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?

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 individuals of all ages (including children and older adults), 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?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the 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 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.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) 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.

Vertebrate Animals

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.

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

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) Genomic Data Sharing Plan (GDS) . Has the investigator confirmed that consent used to obtain the samples allows for sharing of individual-level sequence and relevant phenotype data through an NIH-approved repository such as dbGaP? Does the consent require any data use limitations and/or modifications outside of "General Research Use" that could impede the goals of the program (i.e. combining and comparing datasets representing a variety of diseases)? Has the investigator indicated a willingness to participate in a collaborative effort to inform the development of Kids First Data Resource?

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

• 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.

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 cohort selection:

• 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.
• Value of incorporating the dataset into the Data Resource to empower research among the pediatric research community.
• Program balance: Kid First seeks to ensure that a broad diversity of both childhood cancer studies and structural birth defects studies are well represented. We prioritize cohorts with conditions not previously sequenced under Kids First.
• Informative study design and sufficient clinical and phenotypic data.
• Availability of samples in timely manner.
• Sample quality in terms of suitability for whole genome sequencing (as well as exome and transcriptome if applicable).
• Compliance with resource sharing policies as appropriate and ability to broadly share and use data from the cohort in line with the goals of the program (i.e. combining and cross-analyzing genomic datasets). Kids First program staff reserves the right to not include cohorts that cannot be broadly shared or cross-analyzed with other Kids First cohorts.

3. Anticipated Announcement and Award Dates

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

1. Award Notices

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

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

Any application awarded in response to this FOA will be subject to 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.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the andNIH 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.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.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

3. Reporting

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

James Coulombe, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Telephone: 301-451-1390
Email: CoulombeJ@mail.nih.gov

Jonathan Kaltman, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0510
Email: kaltmanj@mail.nih.gov

Lu Wang, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4846
Email: wanglu@mail.nih.gov

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

Jaime M. Guidry Auvil, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-781-3307
Email: jaime.guidryauvil@nih.gov