Webinar Instructions• Welcome to the X01 Pre-Application Webinar hosted by the

Gabriella Miller Kids First Pediatric Research Program

• Every participant is muted upon entry. Please remain muted until the question/discussion period. You can unmute yourself by selecting *6 on your telephone or clicking on the mic symbol under “Audio Connection”.

• You can ask technical questions using the chat service to the host throughout the webinar. Please save questions related to the program or the FOA for the question period. Additional program-related questions can be emailed to: KidsFirst@od.nih.gov.

This Webinar will be recorded and posted to the Kids First website.

We will start at 3:00 pm (EST) 1

Pre-Application Webinar for Discovery of the Genetic Basis of Childhood Cancers and of

Structural Birth Defects: Gabriella Miller Kids First Pediatric Research Program (X01)

January 23rd, 20173:00 pm EST

Introductions:Kids First Leadership Group

Program Officers/StaffLorette Javois (NICHD)Jonathan Kaltman (NHLBI)Adam Felsenfeld (NHGRI)Malcolm Smith (NCI)Jaime Guidry Auvil (NCI)James Coulombe (NICHD) – Sequencing Center Project ScientistMaarten Leerkes (NHLBI) – Data Resource Project Scientist

Common Fund, ODMarie Nierras – ProgramTBD – Policy, Planning, Evaluation, and CommunicationsMichael Steenstra – Operations, and Budget

Admin Point-of-ContactValerie Cotton (NICHD) valerie.cotton@nih.gov

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Background• Initiated in response to the 2014 Gabriella Miller Kids First

Research Act– Signed into law on April 3, 2014– Ended taxpayer contribution to presidential nominating conventions– Transferred remaining $126 million into the Pediatric Research

Initiative Fund– Authorized appropriation of $12.6 million per year for 10 years to the

NIH Common Fund for pediatric research; first appropriation was for FY2015

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Kids First Working Group

• Kids First is a trans-NIH effort supported by the NIH Common Fund

• Institutes that chair the Kids First Working Group: NICHD, NHLBI, NCI, NHGRI

• Other Institutes that are part of the Working Group: NIDCR, NIDA, NIAAA, NIDDK, NIEHS, NEI, NIAMS, NIAID, ORIP, and the CDC

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Kids First Overall Goal

Develop a data resource, called the “Gabriella Miller Kids First Pediatric Data Resource”, where the pediatric research

community can access well-curated clinical and genetic sequence data that will allow them to

identify genetic pathways that underlie childhood cancer and structural birth defects.

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Kids First Major Initiatives

1. Cohort identification and DNA sequencing

2. Gabriella Miller Kids First Pediatric Data Resource

3. Data Analyses

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Kids First Major Initiatives

1. Cohort identification and DNA sequencing• Identify children with childhood cancer and/or structural birth

defects and their families for whole genome sequencing

2. Gabriella Miller Kids First Pediatric Data Resource

3. Data Analysis

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X01: Third CycleDiscovery of the Genetic Basis of Childhood Cancers and of Structural Birth Defects: Gabriella Miller Kids First Pediatric Research Program (X01)

1. FY 2015: PAR-15-259• 2 childhood cancer cohorts• 5 structural birth defects cohorts

2. FY 2016: PAR-16-150 • 3 childhood cancer cohorts• 5 structural birth defects cohorts

3. FY 2017: PAR-17-063

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X01 mechanism• Not an “award”• Recipients are selected for the opportunity to have their

cohort sequenced• No funds, but can apply for R03 to support analysis of

X01 project: PAR-16-348: Small Research Grants for Analyses of Data for the Gabriella Miller Kids First Data Resource (R03)

• Not listed in the NIH RePORTER– Abstracts and X01 information listed on Kids First website:

https://commonfund.nih.gov/kidsfirst/fundedresearch

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PAR-17-063 Goals & Expectations

Visit X01 FAQs: https://commonfund.nih.gov/kidsfirst/faq

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Sequencing Centers

HudsonAlpha Institute for Biotechnology• Shawn Levy, Ph.D, Director of the

Genomic Services LabSt. Jude Children’s Research Hospital• Jinghui Zhang, Ph.D.• John Easton, Ph.D.

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Broad Institute of MIT & Harvard• Stacey Gabriel, Ph.D., Senior Director,

Genomics Platform• Michael Talkowski, Ph.D.• Daniel MacArthur, Ph.D.• Gad Getz, Ph.D.

Sequencing Centers

HudsonAlpha Institute for Biotechnology• Shawn Levy, Ph.D, Director of the

Genomic Services LabSt. Jude Children’s Research Hospital• Jinghui Zhang, Ph.D.• John Easton, Ph.D.

Childhood Cancer Cohorts

Broad Institute of MIT & Harvard• Stacey Gabriel, Ph.D., Senior Director,

Genomics Platform• Michael Talkowski, Ph.D.• Daniel MacArthur, Ph.D.• Gad Getz, Ph.D.

Structural Birth Defects Cohorts

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Sequencing TechnologyPerform sequencing & variant calling (generate BAM/FASTQ & VCF files)

Birth Defects Cohorts– Standard WGS at 30X coverage

Childhood Cancer Cohorts– Germline: Standard WGS at 30X coverage– Tumor (when available): 30X WGS + WES + RNASeq

Possible: linked long read /phased genomes small pilot study currently underway

“Project design will be finalized in discussions among the X01 investigators, the sequencing centers, and NIH program staff"

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dbGaP Registration & Data Submission

Birth Defects– Register with dbGaP– Phenotype data dbGaP Submission Portal– Sequence data NCBI Sequence Read Archive (SRA)

Childhood Cancers– Register with dbGaP– Biospecimen, Phenotype & Sequence data NCI

Genomic Data Commons (GDC; https://gdc.cancer.gov/)

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Sequencing

• Goal: Use Whole Genome Sequencing (as well as whole exome, and transcriptome sequencing for tumors) to discover genetic variants contributing to pediatric conditions through germline (and tumor) sequencing

• Expectation: DNA (and RNA for tumor) extractions must be of sufficient quality and concentration for WGS (and WES and RNASeq for tumor)

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Phenotype Harmonization

• Goal: Facilitate cross-cohort analyses based on common data elements

• Expectations:– Basic data elements are expected, and deep

phenotyping is preferred– For cancer cohorts, NCI’s GDC requires the

submission of specific biospecimen and clinical/phenotype data

• for details, visit: https://docs.gdc.cancer.gov/Data_Dictionary/viewer/

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Program Balance

• Goal: Broaden the diversity of both pediatric cancer and structural birth defects datasets that are represented in the data resource

• Expectation: Priority may be given to cohorts with conditions not previously sequenced under Kids First (if many applications score well during peer review)

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Data Sharing• Goal: Make data generated by Kids First as

accessible to the research community as possible• Expectations:

– Cohort participants must have given consent to allow sharing of individual-level sequence and relevant phenotype data through an NIH-approved repository (e.g. dbGaP, SRA, GDC)

– Samples that are consented for broadest level of data sharing are of higher priority (e.g. general research use > disease-specific)

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Sample Size & Family Structure

• Goal: Sample sizes and family structures are sufficient to lead to genetic discovery

• Expectations: – Large sample size preferred – Minimum of 100 trios; fewer must be scientifically

justified• Consider collaborating with other investigators to pool

samples together – Non-trios: sufficient number of probands and

affected/unaffected family members

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Analysis Plans

• Goal: Have investigators demonstrate that the proposed project has an adequate research design for genetic discovery, and that the X01 applicants are prepared to perform these analyses

• Expectations:– While Kids First recognizes that analytical power will

increase when the data from each individual study is incorporated with other data that will be part of the Data Resource, it is important to demonstrate that the data will be useable on its own

– Consider partnering with other research teams with relevant expertise to develop the analysis plan

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Other Attachments

1) Institutional Certification (provisional certification or sample consent form)

2) Sample Information 3) Phenotype Data 4) Family Structure (Optional)

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fillable form(optional)

Provide an institutional certification, provisional certification, or sample consent form that…

– covers all sites that contribute samples to your project – specifies whether data is consented for deposition in

dbGaP or other NIH-approved repositories– indicates the data use limitations (DULs) and data use

limitation modifiers (see example DULs below)

Use current template: https://gds.nih.gov/Institutional_Certifications.html

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Other Attachments: Institutional Certifications

Other Attachments: Fillable TableSample Information

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Phenotype Information & Demographics

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Other Attachments: Fillable Table

Other Attachments: Pedigree or Table

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Describe Family structures (proband-parent dyads, proband-parent-sibling quads, multiplex families, consanguineous families)• How many samples per family? How many are affected/unaffected?

Other Application Considerations

You are eligible to apply if:• You have already sequenced a case/proband

and have unsequenced nucleic acids from their parents/siblings/tumor

• You are part of or collaborating with the NIH Intramural Research Program

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For FY 2017,• Kids First highly encourages all investigators

with a cohort that meets the minimum requirements to consider applying

For FY 2018 (future solicitations),• Kids First encourages research teams to start

collecting samples that meet our requirements now

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FY17 X01 Timeline

29Fall 2016

December 1st – Published X01 FOA

Spring 2017

Jan 23rd – Webinar for X01 applicants

Feb 7 – X01 Letters of Intent Due

Mar 7 – X01 applications due

April – HG-SEP Review X01 applications

Summer 2017

June-July – Finalize X01 cohort decision & notify recipients

Aug – X01 cohorts enter pipeline

Fall 2017

Questions?

Email Additional Questions and Comments to the Kids First Mailbox: kidsfirst@od.nih.gov

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Thank You!