Mendelian disorders can be caused by various classes of genetic mutations, from small variants to CNVs and even Structural Variants. With the introduction of VarSeq 2.4.0, we are excited to unveil the latest advancements in VSClinical ACMG, focusing on the integration of Structural Variants and the enhanced automation capabilities that streamline your analysis process.
Join us in this webcast as we dive into the following topics:
Integration of Structural Variants: Learn how 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.
Advanced Automation in the ACMG Interface: Discover how 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.
End-to-End Automation: 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.
Harnessing the Power of VSClinical: 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.
With the advanced capabilities of VarSeq 2.4.0 and VSClinical, you can now unlock a new level of precision and efficiency in diagnosing Mendelian disorders. This webcast will showcase the latest innovations in variant interpretation and automation, exemplifying why the VarSeq Clinical Suite is the premier NGS analysis platform for germline and cancer testing.
3. VarSeq 2.4.0: Structural Variants and
Advanced Automation in VSClinical ACMG
May 17, 2023
Presented by Gabe Rudy, VP of Product & Engineering
4. NIH Grant Funding Acknowledgments
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
Golden Helix 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
8. The Golden Helix Difference
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
VP of Product & Engineering
VarSeq 2.4.0: Structural Variants and Advanced Automation in VSClinical ACMG
10. Content Overview
10
Demonstration
1) Review cancer 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 algorithm and 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
14. Evolving use of Structural 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 one type 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
Illumina TSO500 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 Analysis Workflow
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 Events in 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 of Structural 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: Automate Inputs 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
23. Wrapping up
24
A snapshot of 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 Funding Acknowledgments
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.
26. 25 Licenses for 25 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 Genetics Conference, 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
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.
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.
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.
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?
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.
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
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
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.
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.
Overview of somatic workflow in VarSeq/VSClinical
Previously used CMA, fusion detection PCR kits
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
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
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)
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
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.
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.
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.
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.
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.
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.