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VarSeq 2.4.0: Structural Variants and Advanced Automation in VSClinical ACMG
The document presents an overview of the VarSeq 2.4.0 software, focusing on its capabilities for structural variants and automation in genomic analysis, showcased in a presentation by Gabe Rudy. It highlights the support and research funding from NIH and the core features of the Golden Helix platform designed for flexible and automated clinical genomic reporting. Additionally, the document details the agenda, demonstrating the software's applications in cancer and germline testing, emphasizing the importance of automation and customization in genomic workflows.
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VarSeq 2.4.0: Structural Variants and Advanced Automation in VSClinical ACMG
- 1. VarSeq 2.4.0: StructuralVariants and Advanced Automation in VSClinical ACMG May 17, 2023 Presented by Gabe Rudy, VP of Product & Engineering
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- 3. VarSeq 2.4.0: StructuralVariants and Advanced Automation in VSClinical ACMG May 17, 2023 Presented by Gabe Rudy, VP of Product & Engineering
- 4. NIH Grant FundingAcknowledgments 4 • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: o Award Number R43GM128485-01 o Award Number R43GM128485-02 o Award Number 2R44 GM125432-01 o Award Number 2R44 GM125432-02 o Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 • PI is Dr. Andreas Scherer, CEO of Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- 5. Who Are We? 5 GoldenHelix is a global bioinformatics company founded in 1998 Filtering and Annotation ACMG & AMP Guidelines Clinical Reports CNV Analysis CNV Analysis GWAS | Genomic Prediction Large-N Population Studies RNA-Seq Large-N CNV-Analysis Variant Warehouse Centralized Annotations Hosted Reports Sharing and Integration Pipeline: Run Workflows
- 6. Cited in 1,000sof Peer-Reviewed Publications 6
- 7. Over 400 CustomersGlobally 7
- 8. The Golden HelixDifference 8 FLEXIBLE DEPLOYMENT On premise or in a private cloud BUSINESS MODEL Annual fee for software, training and support CLIENT CENTRIC Unlimited support from the very beginning SINGLE SOLUTION Comprehensive cancer and germline diagnostics SCALABILITY Gene panels to whole exomes or genomes THROUGHPUT Automated pipeline capabilities QUALITY Clinical reports correct the first time
- 9. Today’s Agenda 9 Gabe Rudy VPof Product & Engineering VarSeq 2.4.0: Structural Variants and Advanced Automation in VSClinical ACMG
- 10. Content Overview 10 Demonstration 1) Reviewcancer fusions with TSO-500 2) Example structural variants in WGS VSClinical Interpretation Support AMP and ACMG support all these variant types in annotation, interpretation and reporting NGS Mutation Types Overview of types of mutations that impact diagnosis and prognosis that can be detected with NGS tests
- 11. Keys to Profitability:Capability, flexibility, automation 11 The core tenets of long-term success Ability to create new tests quickly according to market demand Bottom line-oriented business partners enabling your lab Scalable solutions and a high degree of automation
- 12. 12 • Local-first algorithmand data strategy • Building from-scratch algorithms and integrated data storage strategies • FASTQ to clinical reporting in one solution, with training and support • Industry standard guidelines: o ACMG: Germline interpretation for diagnosis and hereditary disease risk o AMP: Somatic interpretation for targeted molecular therapy and cancer prognostics • Automation and customization of lab- specific needs • Long term data storage and knowledgebase management with VSWarehouse Bottom Line-Oriented Partners Enabling your Lab Golden Helix Clinical Suite
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- 14. Evolving use ofStructural Variants in NGS tests 14 Use in both Oncology and Germline testing • CNVs and SVs are involved in genetic disorders • Clear use case in cancer, and extended to ACMG germline scoring • Driving forces to adoption in NGS tests • Affordability and accuracy of long-read technology (PacBio, Nanopore) • Kits that simplify and integrate RNA detection with DNA • Adoption of whole genome sequencing with callable structural variants • Comprehensive tests can increase diagnosis yield, fewer tests PacBio read length histogram https://www.pacb.com/technology/hifi-sequencing/how-it-works/
- 15. More than onetype of genetic mutation can drive disorders • Mutations that activate genes: o Missense o In-frame insertions/deletions o Fusions o Copy number amplifications • Functions that inhibit or disable genes: o Gene deletions o Loss of function nonsense, frameshift indels o Disabling fusions, structural variants o Genomic Signatures that describe overall state of the mutated genome Comprehensive Genomic Profiling Tests 15 Copy Number Rearrangements Base Substitutions Deletions Insertions Genomic Signatures
- 16. TruSight Oncology 500 16 IlluminaTSO500 Comprehensive Cancer Panel Kit • 523 genes • DNA + RNA • DNA: small variants, CNVs, TMB, MSI (HRD) • RNA: fusions, exon skipping • Solid tumor vs liquid biopsy (does not require biospy of tumor) • Bioinformatic pipeline that computes calls, produces files
- 17. Multi-Variant Type AnalysisWorkflow 18 1. Import Wizard • “Records” are split based on their type • Variants, CNVs, Break-end Pairs 2. Variant Type Specific Tables • Annotate and filter variant types individually • Gene impact analysis • Type-specific annotations • Auto-classifiers (ACMG, CNV, AMP) 3. VSClinical Analysis • Brings in variants from VarSeq tables • Only analyze filtered or “marked” variants, CNVs, fusions • Import sample QC details, phenotype, clinical features 4. Integrated Reporting • Report sections: Primary, Secondary, VUS • All variant types can be reported in any section
- 18. Interpreting Break-end Eventsin VarSeq 19 Break-end Location • Rearrangements within and in between chromosomes • Coding genes, non-coding genes, introns Orientation and SV Type • Translocations • Deletions • Duplications • Inversions Effect on Gene • In-frame Fusion • Frameshift fusion • Transcript ablation, frameshift, start loss • Transcript fusion • Non-functional rearrangement • Intronic, intergenic, upstream, downstream, start gain Gene 2 Gene 1 Exon 3 Exon 34 Gene 1 e3 :: Gene 2 e34
- 19. VSClinical Interpretation ofStructural Variants 20 • Adding SVs to an Evaluation o Filtered result of break-end table o Selected SVs for analysis based on Record Sets o Automation with Evaluation Scripts • Add all variants, CNVs, SVs • Sync with Report Status using Record Sets o Manually • Structural Variant Analysis o Interpretation and classification o SV Catalog to save assessments • Reporting o Report SNVs, CNVs and SVs together in one report o Report as primary and secondary findings or uncertain significance o Customized report templates
- 20. VarSeq Suite: AutomateInputs and Outputs 21 • VarSeq built for flexibility and automation • A modular set of capabilities at the disposal • Support all records in VCF 4.3 • Custom pipelines support built-in: • VCFs with all types of variants • Custom callers output such as ArcherDx • Sample or patient info • Automation of VSClinical input and outputs • Reduction or elimination of custom work
- 21. 22 Automation in Review Powerful,modular NGS testing Secondary Analysis Tertiary Analysis Interpretation • Strong Starting points with Sentieon • Ability to import results of any secondary pipeline • Reliance on validated, reproducible VarSeq templates • Thorough automation options with VSPipeline • Automatically pull from vast, expert- review repositories like CancerKB • Interface with VSWarehouse to track assessments across your institution
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- 23. Wrapping up 24 A snapshotof the vast capabilities of automation • Structural variants support allows for comprehensive NGS tests for both cancer and germline use cases • VarSeq Suite can accommodate automation from the straightforward to the complex • Overall reduction in work and human error, while retaining expert input • We invite you to give our software a try!
- 24. NIH Grant FundingAcknowledgments 25 • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: o Award Number R43GM128485-01 o Award Number R43GM128485-02 o Award Number 2R44 GM125432-01 o Award Number 2R44 GM125432-02 o Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 • PI is Dr. Andreas Scherer, CEO of Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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- 26. 25 Licenses for25 Months 27 Celebrating 25 Years in Business • Limited quantity • Licenses are 25-month license periods • Available to new customers only • Orders must be received by June 15, 2023 • Visit goldenhelix.com/forms/25-for-25 or scan the QR code below
- 27. Conferences 28 European Human GeneticsConference, Booth #566 • June 10 – 13, 2023 • Glasgow, UK • Monday, June 12, 12:00 - Corporate Satellite Talk (ALSH 1, Level 0) Achieving Economic Success as an NGS Lab: Strategy and Implementation AMP Europe, Milan, Italy, Booth #14 • June 18 – 20, 2023 • Milan, Italy • Monday, June 19, 1:00 – Industry Symposium Achieving Economic Success as an NGS Lab: Strategy and Implementation
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Editor's Notes
- #5 Before we start diving into the subject, I wanted mention our appreciation for our grant funding from NIH. The research reported in this publication was supported by the National institute of general medical sciences of the national institutes of health under the listed awards. We are also grateful to have received local grant funding from the state of Montana. Our PI is Dr. Andreas Scherer who is also the CEO at Golden Helix and the content described today is the responsibility of the authors and does not officially represent the views of the NIH. So with that covered, lets take just a few minutes to talk a little bit about our company Golden Helix.
- #6 Golden Helix is a global bioinformatics software and analytics company that enables research and clinical practices to analyze large genomic datasets. We were originally founded in 1998 based off pharmacogenomics work performed at GlaxoSmithKline, who is still a primary investor in our company. VarSeq, our flagship product, serves as a clinical tertiary analysis tool. At its core, it serves as a variant annotation and filtration engine. Additionally, however, users have access to automated AMP or ACMG variant guidelines. VarSeq also have the capability to detect copy number variations scaling from single exome to large aneuploidy events. Lastly, the finalization of variant interpretation and classification is further optimized with the VarSeq clinical reporting capability. Users can integrate all of these features into a standardized workflow. Paired with VarSeq are VSWarehouse and VSPipeline. VSWarehouse serves as a repository for the large amount of useful genomic data wrangled by our customers. Warehouse not only solves the issue of data storage for ever-increasing genomic content, but also is fully queryable and auditable and allows for the definability of user access for project managers or collaborators. In tandem with this, VSPipeline, which will be a large part of today's discussion, allows for the automated execution of routine workflows, further optimizing users' abilities to handle large amounts of data and throughput. Lastly, our research platform, SVS, enables researchers to perform complex analysis and visualizations on genomic and phenotypic data. SVS has a range of tools to perform GWAW, genomic prediction, and RNA-Seq analysis, among other common research applications.
- #7 Our software has been very well received by the industry. We have been cited in thousands of peer-reviewed publications, and that’s a testament to our customer base.
- #8 We work with over 400 organizations all over the globe. This includes top-tier institutions, like Stanford and yale, government organizations like the NCI and NIH, clinics such as Sick Kids, and many other genetic testing labs. We now have well over 20,000 installs of our products and with 1,000’s of unique users. So how is this relevant to you?
- #9 At Golden Helix, we focus on the seven pillars of customer success. Golden Helix offers a single software solution that encompasses germline, somatic, and CNV analysis. Our software is also highly scalable, supporting gene panel to whole genome sequencing workflows. With our complete automation capabilities, we now offer a FASTQ or VCF to report pipeline. Our software can be locally deployed, or installed in cloud, and our business model of annual subscription per user means you are able to increase your workload without increasing analysis fees. And it goes without saying, that our FAS team is here to support you on your analysis journey.
- #10 Today, you'll be hearing from myself, Solomon Reinman, a Technical Field Application Scientist, and Gabe Rudy, our VP of Product & Engineering. We've both put a lot of blood, sweat, and tears into the realm of automation, and dare I say we even enjoy most of it. I'm now going to hand things over to Gabe to talk a little bit about VarSeq before we dissect the complexity of the automation problem and the full scale of improvement organizations can see with effective automation. Gabe, take it away. Casey: Intro Solomon: 1-9 Gabe: 10-13 Solomon 14/15 Gabe: 16-19 Solomon: Demo part 1 Gabe: Demo part2 Solomon Wrap-up, hand to Casey for Marketing & QA
- #11 Review the steps and various technology components of an NGS test This will make it clear that there is a need to integrate quite a few pieces of technology Review how automation can tackle this problem, both the complexity of the integration but also improving quality of your test output Demonstrations in two parts: How far automation can take you: fastq to report, and how human interpretation and review is still incorporated into the process with the rich VSClinical interface
- #12 ESHG talk pitch Labs are successful when then have a test in production that is economical to run. But this is a changing landscpape Need to respond to the marketplace, improving tests and adding new tests So for both new labs and existing labs, the time it takes to take a test through the design and validation process and move to production can be the key to profitability Choosing your vendors wisely can make all the difference. Do they have the capability, flexibility and ability to automate these process. Once in production, do they scale with you. Both performance and per-unit costs.
- #13 The Golden Helix stack provides the capability to start with an initial FASTQ file all the way down to a clinical report. This is achievable through our partnership with Sentieon providing the alignment and variant calling steps to produce the VCF and BAM files. This output serves as the basis for CNV detection and import data for your tertiary analysis in VarSeq. If you are performing NGS based CNV analysis, Golden Helix is the market leader; supported by studies like Robarts Research Institute showing 100% concordance with MLPA. Additionally, the imported variants in your VarSeq project can be run through VSClinical’s automated ACMG and AMP guidelines. After completing secondary and tertiary processing, all analysis can be rendered into a clinical report which can be stored in VSWarehouse providing researchers and clinicians with access to this information and to view previous findings.
- #14 Overview of somatic workflow in VarSeq/VSClinical
- #15 Previously used CMA, fusion detection PCR kits
- #16 FoundationOne CDx broke ground as the first FDA-approved CGP for all solid tumors. MSK-IMPACT was FDA approved for their large panel test that included MSI
- #17 Wea added support for this in VarSeq 2.3.0, we can no bring in all these mutation types into the cancer interpretation workflow for AMP
- #18 Title: Funnel Category: Processes Tags: process, funnel, icon, product, path, flow
- #19 Diagram of going from vcf => three table => one evaluation (fan out and fan in) Variants (SNVs, InDels 100bp CNVs (Deletion, Duplications, LOH) Break-end Pairs (resulting in fusions, inversions etc)
- #20 Can result in both CNV and break-end We do a lot of work on import and with our gene annotation algorithm Additional inserted sequences can be called insertion inversions
- #21 VarSeq 2.4.0 enables you to import and incorporate Structural Variants into your VSClinical ACMG evaluations and reports, providing a comprehensive understanding of the genetic landscape. Gain insights into how VarSeq 2.4.0 empowers you to tackle complex genomic data, enabling faster and more accurate identification of Mendelian disorders and facilitating personalized patient care.
- #22 evaluation scripts can be employed to automate the VSClinical ACMG interface, allowing you to perform custom actions or eliminate manual steps, thus increasing efficiency and reducing the risk of errors.
- #23 Explore how VSPipeline can fully automate your analysis process, from raw VCF to report, ensuring a streamlined and consistent workflow that saves time and resources.
- #25 Thanks for the great demo Gabe, and thanks to all of our viewers for being here today. We hope you've been impressed with the breadth of complexity that is handled by the VarSeq suite and our demonstration of how far we can take automation. We'd love to work with you to explore how you can reduce the overall amount of work, mitigate human error, and maintain control through automation of your NGS testing capabilities. We invite you to demo and evaluate our software if you are interested. The evaluation process with Golden Helix is a comprehensive look at both our software and the support we provide our users in getting started and keeping at it. If you'd like to see how your workflow can be integrated and automated with VarSeq, please reach out to us so we can get you to your production goals.
- #26 Before wrapping up, we'd like to again state our appreciation for the grants included here. And with that, I'll hand things back to Casey to talk about some exciting marketing updates and take us through a Q&A session.
- #28 Title: Project resources Category: Data, Images Tags: table, project, resources, data, cost, picture, image, vial, bottle
- #29 Again, I want to mention how grateful we are we are thankful of grants such as this which support the advancement and development of our software to create the high quality software you'll see today. So with that covered, lets take a few minutes to talk a little bit about our company Golden Helix.