PAR-27-071-Full-Announcement.html

Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

Office of Strategic Coordination (Common Fund)

This Notice of Funding Opportunity (NOFO) is a Common Fund initiative (Common Fund) through the NIH Office of the Director, Office of Strategic Coordination (https://dpcpsi.nih.gov/). All NIH Institutes and Centers participate in Common Fund initiatives. The NOFO will be administered by a cross-NIH team led by the National Cancer Institute (NCI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Funding Opportunity Title

Discovery of the Genetic Basis of Childhood Cancers and of Congenital Anomalies: Gabriella Miller Kids First Pediatric Research Program (X01 Clinical Trial Not Allowed)

Activity Code

X01 Resource Access Award

Announcement Type

Reissue of

PAR-24-082

Related Notices

Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON)

PAR-27-071

Companion Funding Opportunity

None

Number of Applications

See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.310

Funding Opportunity Purpose

As part of the Gabriella Miller Kids First Pediatric Research Program (Kids First Program), the NIH invites applications to submit samples from pediatric cohorts for whole genome sequencing at a Kids First Program supported genomic data generating centers. Applicants are encouraged to propose sequencing of existing pediatric cancer or congenital anomaly cohorts to elucidate the genetic contribution (somatic and/or germline) to childhood cancers, to investigate the genetic etiology of congenital anomalies, to study the molecular basis of the associations between congenital anomalies and increased cancer risk, or to expand the range of pediatric disorders included within the Kids First Data Resource. The program will accept applications that propose whole genome, exome, and transcriptome sequencing, as well as clinical-grade sequencing, long-read sequencing, proteomics, and epigenomic assays of tumor or affected tissue, when justified. Applicants are encouraged to propose cohorts to increase representation of existing Kids First Program projects. These data, and associated clinical and phenotypic data, will become part of the Kids First Data Resource Center for sharing with the research community.

Funding Opportunity Goal(s)

This listing covers the Common Fund, administered by the Office of Strategic Coordination (OSC) in the NIH Office of the Director which offers assistance awards or supplements to assistance awards.

Key Dates

Posted Date

June 18, 2026

Open Date (Earliest Submission Date)

December 11, 2026

Application Due Date(s)

Applications are due January 11th, 2027 (01/11/2027).

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not applicable.

Scientific Merit Review

A Scientific Merit Review will be performed by members of the Gabriella Miller Kids First Working Group in March 2027.

Advisory Council Review

Not applicable.

Earliest Start Date

April 2027.

Expiration Date

January 12, 2027

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

The Gabriella Miller Kids First Pediatric Research Program (Kids First) was established by The Gabriella Miller Kids First Research Act, or Kids First (https://www.congress.gov/bill/113th-congress/house-bill/2019/text), for an initial 10 years, 2015-2024. The program was reauthorized as Kids First 2.0 by the 118th Congress for an additional five years, and the program was transferred from The Common Fund to the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI). DPCPSI and Common Fund have agreed that Common Fund would continue to administer Kids First on behalf of DPCPSI.

The overall goal of the Gabriella Miller Kids First Program is to help researchers uncover new insights into the biology of childhood cancer and congenital anomalies, including the discovery of shared genetic pathways between these disorders, to understand the underlying mechanisms of disease. This understanding would lead to novel and more refined prevention tools, diagnostics, and ultimately more targeted therapies and interventions for patients and families.

This funding opportunity builds upon prior NOFOs (PAR-15-259, PAR-16-150, PAR-17-063, PAR-18-583, PAR-19-104, PAR-19-390, PAR-21-040, PAR-22-054, PAR-23-035, and PAR-24-082) and is intended to identify samples for germline whole genome sequencing (standard short-read whole genome sequencing or long-read sequencing, or clinical-grade sequencing, when justified), as well as genomic, exome, transcriptomic (RNA), and epigenomic (e.g., genome-wide methylation, chromatin accessibility) data generation for tumors and/or affected tissue that will help elucidate genetic contributions to childhood cancers and the etiology of congenital anomalies.

Data obtained from these 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 Center's portal.

Types of Research Projects The Kids First Program seeks applications for sample sets that can be ready for whole genome sequencing (whether short-, long-, or clinical-grade sequencing) and other omic assays, as soon as possible after the application due date of this NOFO. 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). An integrative -omics approach (e.g., transcriptomic) may also be taken. This NOFO offers a protocol of sequencing the whole genome from high quality genomic DNA by one of Kids First Program's genomic data generating centers, as well as protocols for exome, transcriptomic, and epigenomic sequencing and analyses of tumor/affected tissue specimens (if available and justified). As sequencing technologies are constantly evolving, additional or alternative approaches may be proposed. For example, applicants may propose long-read sequencing approaches based on evidence of structural variations from previous short-read sequencing and analysis. Clinical-grade sequencing may be proposed but must be justified. Proteomics may be proposed, with justification, and may be accommodated if available. Project design will be finalized in discussions among the X01 investigators, the genomic data generating centers, Kids First Data Resource Center, and NIH program staff.

For childhood cancer cohorts: This NOFO invites applications that propose sequencing of DNA samples from childhood cancer cohorts (as well as RNA samples from tumors) for which a genetic basis (germline or somatic) is suspected but not identified, or for which understanding of recurring somatic mutations may address important questions of biology and therapy, or that analysis may uncover relationships with conditions already represented in the Kids First Data Resource. Proposed study populations should address important questions about the genetic basis, predispositions, or genomic aberrations of childhood cancers that might be answered by the approach proposed (e.g., whole genome sequencing of germline DNA, as well as tumor genome, exome, transcriptome, and epigenomic sequencing when tumor tissue is available). Clinical-grade sequencing may be proposed but must be justified. Proteomics and/or metabolomics of tumor samples may be proposed, with justification; and may be accommodated if available. Studies where the probands were born with congenital anomalies and subsequently diagnosed with childhood cancer are also 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 materials from tumor samples is encouraged when sequencing and analysis of the tumor will provide additional insight into the cancer(s) under study.

For congenital anomalies cohorts: This NOFO also invites applications that will propose sequencing of DNA samples from subjects with those categories of congenital anomalies that are appropriate for whole genome sequencing; that are not yet well represented in the Kids First dataset, or that analysis may uncover relationships with conditions already represented in the Kids First dataset. Proposed study populations should address important questions about the genetics/genomics of congenital anomalies that might be answered by whole genome sequencing, as well as genome, exome, transcriptome, and epigenomic sequencing of affected tissue. Clinical-grade sequencing may be proposed but must be justified. Proteomics of relevant tissue samples may be proposed, with justification; and may be accommodated if available. 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 congenital anomalies 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 congenital anomalies. Note that submission of material 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.

For all cohorts: 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 under study, or to improve representation of racial and ethnic diversity in the datasets. 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 un-sequenced nucleic acid samples from their parents, siblings, tumor, and/or affected tissue are also encouraged to apply to have those samples sequenced, if it will result in additional insights into the genetic contribution to the cancer(s) or birth defects under study.

Specific Requirements and Expectations for this Opportunity The cohorts selected under this NOFO 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 and use of individual-level sequence and associated clinical and phenotypic data through dbGaP or other NIH-approved repositories. Unless otherwise prohibited, clinical and phenotypic data will be openly shared through the Kids First Data Resource Center's portal. Consent groups and/or data use limitations (DULs) for proposed samples should be indicated on the submitted Institutional Certification using the current NIH template. Cohort samples that have consents allowing 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. A list of prior Kids First Program X01 projects is available for reference.

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, other NIH initiatives 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 minimum amount of associated clinical and phenotypic data sufficient to enable association analysis with genomic variants. Applications with rich clinical and phenotypic data that can be shared to facilitate cross-disease research among the pediatric research community will be prioritized. Examples of other data types include other omics data, imaging data, and information from health records.

Projects selected under this NOFO will be expected to work in a collaborative manner with a designated Kids First Program genomic data generating center. These centers will produce sequence read and called variant data sets, as well as genome-wide methylation profiling and chromatin accessibility assay data (e.g., ATAC sequencing), where applicable. Some applicants may wish to further collaborate with the data generating center for custom analysis and validation of variants for a subset of cases. Such scientific collaboration will be arranged between the applicant and data generating 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 NOFO will be submitted to the Kids First Data Resource Center. All Kids First data will be processed, harmonized, and made accessible through the cloud-based infrastructure of the Kids First Data Resource Center, where investigators are encouraged to interact with the data.

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 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 The intersection between human development and cancer is not a new concept. Multiple findings have substantiated the shared biology between congenital anomalies and childhood cancer. For example, BRAF, MAPK, and ALK mutations are found in both birth defects and cancers. These proteins are validated clinical oncology drug targets; thus suggesting potential new treatments for pediatric conditions. A 2019 publication showed increased cancer risks for kids born with birth defects in a large-scale study including 10 million live births.

Genetic alterations underlie etiologic contributors to pediatric disease, including childhood cancers as well as multiple congenital anomalies 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.

The Kids First Program has developed a data resource in the cloud to accelerate pediatric cancer and congenital anomalies research leading to better prevention, diagnosis, and treatments for patients and families. The program's goal is to grow a resource with Findable, Accessible, Interoperable, and Reusable (FAIR) data, promote data sharing, develop tools for data analysis and data visualization, and foster collaborative research. The Kids First Data Resource Center provides integrated data sets to increase study power; catalogs myriad data sets to enable rational organization of data resources; and facilitates cross-linking of diverse data sets to enable novel research collaborations and knowledge connections.

The contribution of genetic factors to human health due to the relative frequencies of both deleterious and beneficial alleles among human populations is an important area of interest.

Approximately 3% of all babies 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, summing to 20% of all infant deaths. Next to accidents, congenital anomalies 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 congenital anomalies. 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 death from disease among children. Kids First Program's workshops and symposia have 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 have emphasized 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 and congenital anomalies are needed to fully elucidate the etiology of these conditions and accelerate the development of novel prevention, diagnostics, and treatments for patients.

Pre-Application Webinar The Gabriella Miller Kids First Pediatric Research Program (Kids First) staff intends to hold a Pre-Application Webinar for all interested prospective applicants. Webinar date and other details will be posted on the Kids First website: https://commonfund.nih.gov/kidsfirst.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

Funding Instrument

Other: A financial assistance mechanism that is not a grant or cooperative agreement. Examples include access to research resources or pre-applications.

Application Types Allowed

New

The OER Glossary and the How to Apply - Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials. Note: Applications may propose activities involving human subjects that are not deemed clinical trials.

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

Not applicable; there are no funds associated with a resource access award.

Award Budget

Not applicable; there are no funds associated with a resource access award.

Award Project Period

The scope of the proposed project should determine the project period. The maximum project period is 1 year. Investigators are expected to ship samples to designated Kids First Program's data generating center within 6 months of the award notification. This period may be extended only in exceptional cases upon justification and approval.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Local Governments

Federal Governments

Eligible Agencies of the Federal Government

U.S. Territory or Possession

Other

Independent School Districts

Public Housing Authorities/Indian Housing Authorities

Native American Tribal Organizations (other than Federally recognized tribal governments)

Faith-based or Community-based Organizations

Regional Organizations

Foreign Organizations/Foreign Collaborations

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

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

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

Applicant Organizations Applicant organizations must complete and maintain the following registrations as described in the How to Apply - 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information System for Award Management (SAM) – 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. Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.

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.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for 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 How to Apply - Application Guide.

2. Cost Sharing This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility Number of Applications

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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

Section IV. Application and Submission Information

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 NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed

, with the following exceptions or additional requirements: For this specific NOFO, the Research Strategy section is limited to 6 pages.

Instructions for Application Submission

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover All instructions in the How to Apply - Application Guide must be followed.

Total Federal Funds Requested: Enter $0.

Total Federal & Non-Federal Funds: $0.

Estimated Program Income: Enter 0.

SF424(R&R) Project/Performance Site Locations

SF424(R&R) Other Project Information

Other Attachments: The application must include the following attachments.

1) Institutional Certification for Genomic Data Sharing:

Provide the Institutional Certification(s) using the current NIH template (https://grants.nih.gov/policy-and-compliance/policy-topics/sharing-policies/gds/completing-institutional-certification-form), which demonstrates that it is permissible to share individual-level genomic 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 (or equivalent body) 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. For guidance on obtaining an Institutional Certification, see: https://commonfund.nih.gov/kidsfirst/FAQ.

2) Sample Information:

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:

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

For an example template of clinical and phenotypic data elements, visit https://commonfund.nih.gov/kidsfirst/FAQ.

If appropriate, describe any available environmental or exposure data.

If a proposed cohort is selected, a data dictionary or additional data elements may be requested.

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.

For optional tables to facilitate organizing and providing sample information, clinical and phenotypic data information, and family structure visit, https://commonfund.nih.gov/kidsfirst/FAQ.

SF424(R&R) Senior/Key Person Profile

PHS 398 Cover Page Supplement

PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

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

Research Strategy: Cohorts for childhood cancers and congenital anomalies have distinct requirements as indicated below. Applicants should note requirements that apply to all cohorts.

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 sequencing should be supported (e.g., analysis of a different subpopulation, analysis of racial or ethnic groups, the addition of long read sequencing to confirm suspected structural variants, the addition of epigenomic profiling), 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, transcriptome, and/or epigenomic sequencing for 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) Proteomics and/or metabolomics of tumor samples may be proposed, with justification, and may be accommodated if available. Provide the rationale for doing proteomics and/or metabolomics characterization, as well as a prioritized list of available samples.

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

7) Provide information on the value of adding data from this cohort to the Kids First Data Resource. This includes highlighting potential relationships with cohorts already represented in the Kids First Data Resource.

Applicants with cancer cohorts are strongly encouraged to address all 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 is a population for which understanding of recurring somatic mutations may address important questions of biology and therapy. Describe current understanding of the genetic contribution (germline and somatic) 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 the discovery of variants contributing to the development and/or progression of the cancer of interest, or to an enhanced understanding of the contribution of known variants to the development and/or progression of 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 NOFO (note that no funds are provided under this NOFO to support analysis or other activities). Including methods for variant filtering and follow up. If there is a plan to analyze the data obtained from 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 condition. Use power analyses to describe the range of effect sizes detectable by the study. If RNA sequencing or other –omics are proposed for tumors, describe how the results will be analyzed to better understand key biological and clinical characteristics of the cancer under 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, upon acceptance of publication of associated findings. Describe willingness to participate in the Childhood Cancer Data Initiative (CCDI), as applicable.

4) Consent and Data Sharing: Confirming the consent used to obtain the samples allows sharing of individual level sequence data through a controlled access, NIH-approved repository such as dbGaP (dbgap.ncbi.nlm.nih.gov/home/) 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. It includes information such as the ability to re-contact participants for additional phenotyping or collection of additional samples. If submitting a provisional certificate because the full Institutional Certification is not available, describe the anticipated data use limitations based on the consent.

5) Data Management: Investigators are encouraged to use the cloud-based infrastructure of the Kids First Data Resource Center wherever possible; however, if the investigative team intends to download the data to an institutional computing environment, describe how the data and security will be managed.

For cohorts with congenital anomalies:

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. If proposing the sequencing or epigenomic profiling of affected tissue, clearly describe the evidence for somatic mutations, mosaicism, or epigenomic factors.

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.

7) Proteomics of relevant tissue samples may be proposed, with justification, and may be accommodated if available. Provide the rationale for doing proteomics characterization, as well as a prioritized list of available samples.

8) Provide information on the value of adding data from this cohort to the Kids First Data Resource. This includes highlighting potential relationships with cohorts already represented in the Kids First dataset.

Applicants with congenital anomalies 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 into 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 NOFO (note that no funds are provided under this NOFO 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 condition. Use power analyses to describe the range of effect sizes detectable by the study. If RNA sequencing is proposed for affected tissue, describe how the results will be analyzed to better understand key biological and clinical characteristics of the structural birth defect under 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 congenital anomalies 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, upon acceptance of 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 (dbgap.ncbi.nlm.nih.gov/home/) 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: Investigators are encouraged to use the cloud-based infrastructure of the Kids First Data Resource, wherever possible; however, if the investigative team intends to download the data to an institutional computing environment, describe how the data and security will be managed.

For all applications:

The overall goal of the Kids First Program is to create a data resource that makes individual and integrated datasets broadly accessible 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 include an Institutional Certification which indicates the data use limitations and/or modifiers stating how individual level sequence data can be shared with and used by secondary users, consistent with the terms of the NIH Genomic Data Sharing policy https://grants.nih.gov/policy-and-compliance/policy-topics/sharing-policies/gds.Applicants are expected to agree that all sequence data generated by Kids First and associated clinical and phenotype data will be deposited in repositories designated by the Kids First Common Fund staff, in a manner consistent with NIH policy https://grants.nih.gov/policy-and-compliance/policy-topics/sharing-policies and achieving the goals of the program.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

A Data Management and Sharing Plan is not applicable for this NOFO.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

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…