I'm going to begin w/ an overview of some of the work that we're doing in GA4GH, since it is perhaps less well known than some of the other things I'll mention today GA4GH is an international, nonprofit alliance formed in 2013 to accelerate the potential of research and medicine to advance human health It boasts >500 member orgs from healthcare, research, patient advocacy, life science, and IT its mission is to <SLIDE>

GA4GH aims to accomplish their mission through the dev of a toolkit to promote the sharing of clinical genomic data <SLIDE>

In fall 2017, GA4GH launched GA4GH Connect, a five-year strategic plan that aims to drive uptake of standards and frameworks for genomic data sharing within the research and healthcare communities goal is to enable responsible sharing of clinical-grade genomic data by 2022 At same time, GA4GH reorg'd itself into a matrix of Work Streams and Driver Projects—real-world genomic data initiatives that help guide our development efforts and pilot our tools <SLIDE>

The priorities of each WS are ID'd and set through engagement with DPs <SLIDE>

Genomic Knowledge Standards GKS aims to develop, adopt, and adapt standards to enable the exchange of genomic knowledge Establish framework of standards that lower barriers to translating genomic knowledge into clinical practice Reusing existing knowledge is essential to future impact Knowledge repositories are a key component Collaborate with other SDOs on harmonized specifications Andy Yates and I co-chair the GKS WS, which <SLIDE> note last bullet

Genomic Knowledge Standards Variant Annotation DP priorities => WS goal Represent and link annotations, including their evidence and provenance, to variants Supports clinical (lab) interpretation Structured, curated data from publications Clinical relevance, disease association Draft spec by Q4 2018 W/in GKS we have ID'd 2 top priorities, 1st is <SLIDE> Relatively new effort, just started working Driven strongly by use cases and reqs from ClinGen, building on prior work done by that project

Genomic Knowledge Standards Variant Representation DP priorities => WS goal Create a standard model for computer readable variant representation (definitional) Simple variants (VMC) v 1.0 by Q4 2018 Peer-reviewed publication Complex variants (structural, CNV, imprecise ends) v 0.1 by Q4 2018 GKS's other main priority is <SLIDE> more mature, builds on work that started under auspices of VMC (see next)

Variant Modelling Collaboration (VMC) Participants: GA4GH, HL7, ClinGen, NCBI, SO, EBI, Ensembl Goal: to develop a technical specification for representing and communicating biological sequence variation VMC was started in 2016 by a small # of reps from key orgs <SLIDE> In the absence of a formal std for rep'g data about genetic vars, we knew that the existing fragmentation of methods would only get worse The VMC was an effort by a few individuals, with support by their parent orgs, to dev a std that would enable the more seamless exchg of var data among public repositories and facilitate the use of those data within clinical labs

Entities: Sequence, Location, Allele, Haplotype, Genotype Terminology VMC 1.0 Focus: variation that is defined by alleles — assertions of a specific sequence at precise locations on a sequence Entities: Sequence, Location, Allele, Haplotype, Genotype Terminology Information Model Minimalistic, use as part of a given use case Machine-readable schema definition VMC 1.0 has a very small scope, was designed to define core entities <SLIDE> contains 3 primary components: SLIDE terminology (took a year) IM – defs the lego building blocks that can be used as core elements w/in larger use case schema – to minimize data transformations betw systems spec is nearly 50 pages long, has buy-in from all sponsoring orgs, which have agreed to begin to adopt it at the interface (API) layer (not back end)

Sync for Genes Sync for Genes (S4G) is collaboration between ONC, NIH, and industry to help deliver on goals of the Precision Medicine Initiative (PMI) and NIH’s All of Us Research Program. Goal to standardize the sharing of genomic information between labs, providers, patients and researchers Develop and build upon Health Level Seven International (HL7)’s Fast Healthcare Interoperability Resources (FHIR) Genomic specifications Sync for Genes (S4G) is collaboration between ONC, NIH, and industry to help deliver on goals of the Precision Medicine Initiative (PMI) and NIH’s All of Us Research Program. For Phase 1, there were five pilot sites, focused on testing and validating specific technical implementations of FHIR. Counsyl & Intermountain Healthcare Illumina National Marrow Donor Program Foundation Medicine & Vanderbilt FDA precisionFDA These pilots represented laboratories, providers, government, health information technology (health IT) developers, patients, and academia, When did Phase 1 start and finish: S4G began September of 2016 Pilots began January of 2017 Concluded June 2017

Project period of performance is Spring 2018 – Winter 2018 Sync for Genes Phase 2 Takes the next step from use case and standard development (Phase 1) to actual implementation and use Phase 1 final report: https://www.healthit.gov/sites/default/files/sync_for_genes_report_november _2017.pdf Pilots selected to participate in Phase 2 will focus on: expanding the FHIR genomics profile work developed under phase 1; addressing additional core use cases from the DAM; and demonstrating the integration of genomics information into a clinical setting for supporting care and research efforts Piloting a variety of genomic data sharing scenarios, involving : Next Generation Sequence (NGS) Labs Health Provider Organizations Health Information Networks and Exchanges Note: Because this phase is focused on implementing actual use cases, standards development, and FHIR API calls, requires more time and effort than Phase 1, hence the longer time period . Project period of performance is Spring 2018 – Winter 2018 Fall 2018: Connect-a-thon Spring 2019: Final Report of findings and lessons learned

Sync for Genes Phase 2 NBS Oncology Sync for Genes Phase 2 Pilot Sites Utah Newborn Screening; Utah Health Info. Network; Intermountain Healthcare Lehigh Valley Health Network & Foundation Medicine National Marrow Donor Program & Stanford Lab Sync for Genes Phase 2 Pilot Sites NBS Oncology HLA Weill Cornell & Standard Molecular Sync for Science All of Us Genomic testing lab partnered with clinical consumer of the data