Exploring New Features and Clinical Reports in the ACMG Guideline Workflow
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The document outlines new features and clinical reports in the ACMG guideline workflow presented by Golden Helix. It highlights improvements to the ACMG classifiers, the introduction of new report templates, and customization options for clinical reports. Additionally, it discusses NIH grant funding acknowledgments and details of service offerings related to bioinformatics solutions.
Exploring New Features and Clinical Reports in the ACMG Guideline Workflow
- 1. Exploring New Features and Clinical Reports in the ACMG Guideline Workflow 1 December 2, 2020 Presented by Julia Love: Field Application Scientist and Gabe Rudy: VP of Product Development
- 3. Exploring New Features and Clinical Reports in the ACMG Guideline Workflow 3 December 2, 2020 Presented by Julia Love: Field Application Scientist and Gabe Rudy: VP of Product Development
- 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 CNVAnalysis Pipeline: Run Workflows CNVAnalysis GWAS |Genomic Prediction Large-NPopulation Studies RNA-Seq Large-NCNV-Analysis Variant Warehouse CentralizedAnnotations Hosted Reports Sharing and Integration
- 6. Cited in 1,000s of Peer-Reviewed Publications 6
- 7. Over 400 Customers Globally 7
- 8. When you choose Golden Helix, you receive more than just the software 8 Software isVetted • 20,000+ users at 400+ organizations • Quality & feedback Simple, Subscription-Based Business Model • Yearly fee • Unlimited training & support Deeply Engrained in Scientific Community • Give back to the community • Contribute content and support Innovative Software Solutions • Cited in 1,000s of publications • Recipient of numerous NIH grant and other funding bodies
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- 10. Content Overview 10 1 ExploreVSClinical ACMG New Features 2 New Word-based Clinical Reports 3 Product Demonstration of New Features and Reporting
- 11. 11 ACMG Sample Classifier New and Improved ACMG Classifier Algorithms 1 2 • New PSV1 scoring • More modifiers for scoring criteria • Option to include custom frequency catalogs ACMG CNV Classifier • Gene scoring and classifyingCNVs • Probability segregation algorithm
- 12. 12 ACMG Sample Classifier New and Improved ACMG Classifier Algorithms 1 2 • New PSV1 scoring • More modifiers for scoring criteria • Option to include custom frequency catalogs ACMG CNV Classifier • Gene scoring and classifyingCNVs • Probability segregation algorithm
- 13. 13 ACMG Sample Classifier New and Improved ACMG Classifier Algorithms 1 2 • New PSV1 scoring • More modifiers for scoring criteria • Option to include custom frequency catalogs ACMG CNV Classifier • Gene scoring and classifyingCNVs • Probability segregation algorithm
- 14. 14 New Fields Added toVariant Catalogs New and Improved Assessment Catalogs 1 2 • Citation data • Internal notes • Store comments for individual scored criteria New CNV and Gene Dosage Sensitivity Catalogs
- 15. 15 New Project Options Interface for Creating Evaluations • Flag variants,CNVs, and coverage regions • Include custom gene lists • Set custom thresholds for ACMG criteria • Evaluate with ACGS guidelines
- 16. 16 New Project Options Interface for Creating Evaluations • Flag variants,CNVs, and coverage regions • Include custom gene lists • Set custom thresholds for ACMG criteria • Evaluate with ACGS guidelines
- 17. 17 New Project Options Interface for Creating Evaluations • Flag variants,CNVs, and coverage regions • Include custom gene lists • Set custom thresholds for ACMG criteria • Evaluate with ACGS guidelines
- 19. 19 Quick Poll What is the output of your variant interpretation workflow? Select all that apply: 1. Clinical Report 2. InternalTechnical Report 3. Structured Data (i.e. XML or JSON) 4. Patient or Consumer Report 5. Discovery and Research
- 20. PollQuestion 20 What is the output of your variant interpretation workflow? Select all that apply. 1. Clinical Report 2. InternalTechnical Report 3. Structured Data (i.e. XML or JSON) 4. Patient or Consumer Report 5. Discovery and Research
- 21. New Clinical Report Features 21 1 3 Report gene coverage 5 New ReportTemplates 4 Inline Citations and SourceVersion 2 Automating Sample Fields Import Incorporates SNVs and CNVs
- 22. 22 Gene Panel ReportTemplate • Designed for FocusedTests on a Targeted set of Genes • Provides a “Gene Grid” of every tested gene, with the count of reported variants or CNVs in each • Newly included in all templates: • Failed targets (poor coverage) • Per-gene coverage report • Versions of annotation sources
- 23. 23 Trio ReportTemplate • Supports proband and parent sample information • For reported variants, also have parental variant quality details • More expansive details sections, with medium level of detail
- 24. 24 Mendelian Disorder Report Template • Provides most level of detail of all three reports • Designed for whole exome or genome expansive reporting • Breaks out secondary findings into: • Monogenic Disease Risk • Carrier Status
- 25. 25 CustomizingWord-Based Clinical Reports • Mix and matchTemplates • Create, delete sections • Edit logo, headers, footers • Define methodology and other test specific language
- 26. 26 Product Demo
- 27. NIH Grant Funding Acknowledgments 27 • 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.
- 29. End ofYear Bundles 29 o 3: SVS Imputation Module w/CADD & OMIM (2-users) – $7,995 o 3:VSClinical, CNV, SentieonTier 1 (2-users) - $19,995 o 3:VSClinical, AMP, CNV, SentieonTier 1 (2-users) - $29,995 o 3: SmallWarehouse License:VS-CNV,VSClinical+ AMP, SentieonTier 1,VSReports,VSPipeline - (2-users) - $48K o 3: LargeWarehouse License:VS-CNV,VSClinical + AMP, SentieonTier 1,VSReports,VSPipeline (<10 users) - $120K **Please note that due to COVID-19 limiting budgets we are extending our End-of-Year Bundle deals to go until Feburary 2021. Don't wait, reserve your bundle today!** o Also offering temporary remote licenses for Golden Helix customers who are unable to access their machines. Please contact our team to learn more.
- 30. 30 Inc 5000 Recognition Golden Helix was named to the 2020 Inc 5000 List of Fastest-Growing Private Companies • Second year in a row receiving this award • Thank you to our customers and partners for our sustained success
- 31. COVID-19 Publications &Articles 31 Investigating the Global Spread of SARS-CoV-2 Leveraging Next- Gen Sequencing and Principal ComponentAnalysis European Journal of Clinical and Biomedical Sciences Christiane Scherer, James Grover, Darby Kammeraad, Gabe Rudy, Andreas Scherer Diagnosing andTracking COVID-19 Infections Leveraging Next- Gen Sequencing The Journal of Precision Medicine Feature | July 8, 2020 Golden Helix: Enabling Precision Medicine with Cutting-Edge NGS Technologies Clinical OMICs Feature | July 15, 2020 Leveraging Next-Generation SequencingTechnology in the Fight Against COVID-19 Clinical Lab Manager Feature | May 4, 2020 SARS-CoV-2Global Spreading Investigation using Principal ComponentAnalysis of SequenceVariants Journal of Genetics and Genome Research Christiane Scherer, James Grover, Darby Kammeraad, Gabe Rudy, Andreas Scherer
- 32. 32 ClinGen Requirements Genomic Analysis Software Platforms
Editor's Notes
- #2: Im really excited to share with you all today some updates and new features that are being incorporated in this upcoming release of VarSeq. Recently ,We have been talking about the addition of the new ACMG guidelines specifically for CNV analysis, but there is so much more that has been added to VarSeq and the ACMG workflow. Actually, many of these new features have been developed and incorperated from feedback from VarSeq users which makes this all the more exciting to talk about.
- #4: Im really excited to share with you all today some updates and new features that are being incorporated in this upcoming release of VarSeq. Recently ,We have been talking about the addition of the new ACMG guidelines specifically for CNV analysis, but there is so much more that has been added to VarSeq and the ACMG workflow. Actually, many of these new features have been developed and incorperated from feedback from VarSeq users which makes this all the more exciting to talk about.
- #5: Before we start diving into the subject, I wanted mention our appreciation for our recently received 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. Additionally we are also grateful for receiving 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. Again, 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.
- #6: Golden Helix was founded back in 1998, and we are one of the few bioinformatic companies that can say we have 20 years of experience building NGS solutions in the research and clinical space. These solutions have a very broad range of capabilities, and we won’t be covering all of these today, but they do cover a lot of use cases in both the clinical and research realms. What we will be focused on today is our VarSeq product suite, which focuses primarily on the clinical application of the software. VarSeq supports clinincal analysis workflows in which you can filter and annotate variants and then evaluate those variants according the ACMG and AMP guidelines. However, If you are interested in any of these other capabilities please visit our website. We have recorded numerous webinars and other material for you to browse at your own pace.
- #7: We have been cited in over thousands of peer reviewed publications, and we are always happy to celebrate the success of our customers in performing their research with our tools. And actually, if you check out our blog, you will often see us highlighting those publications!
- #8: We serve over 400 customers globally, and these customers span many different industries, from academic institutions, to research hospitals, to commercial testing labs and government institutions.
- #9: That being said, as a company, our software is being vetted by our large and established customer base. We have had many years to perfect the development process, and are always incorporating feedback from our customers and their diverse set of needs and use cases. We are extremely integrated with the scientific community, providing content in the form of ebooks and webinars like this one. As a business, we want to be aligned with the success of our customers. One way we do that is that we provide our software on a simple per-use subscription model that comes with unlimited training and support. We are invested in supporting your research or setting up your test so that you can run as many samples through our software as possible. Since we are an established and trusted business in this space, you might already know someone who uses Golden Helix, but if not, we are happy to find you a reference in your area. So before I jump into today's topic, I want to provide a conceptual overview of how VarSeq and more specifically VarSeq clinical fits into your NGS analysis workflows.
- #10: Conceptually, Varseq's application comes into play for all tertiary analysis of variants and copy number variants. VarSeq comes fully equipped with algorithms, annotations and metrics that help you understand the impact of clinically relevant variants. VSClinical can essentially be thought of the second stage of the analysis. So after you have identified clinically relevant variants , these variants can be evaluated with either the ACMG of AMP guidelines to determine pathogenicity or oncogenicty respectively. VSClinical automates the application of the ACMG/AMP guidelines, simplifying what is normally a tedious and complex process. Lastly, once an evaluation is complete, the interpretation can then be stored in your internal assessment catalogs and rendered into a clinical report. Together, VSClinical is an ideal paradigm to streamline analysis for clinical variants and CNVs. That said, there are many new features and updates to the ACMG GUideline workflow that we want to cover, so let's get started!
- #11: Many of the new features for the ACMG Guidelines workflow that we are going to go over today come into play when you are setting up your project and evaluation. Then these new features are nicely incorporated into a clinical report. I will start by going through a few slides that will discuss the VSClinical ACMG features that are now available. Some of these are new algorithms, new ways to catalog and save classifications, and improving the customization options for clinical evaluations. Then our VP of product development , Gabe Rudy will deep dive into the new reporting capabilities for the AMG Workflow. The reports are now word-based and there are a couple of different templates to choose from to report your findings. With that the word-based report offers more opportunities to easily customize your clinical reports. Lastly, the product demonstration will allow you to see these new features in action! First I will walk you through setting up a new evaluation and customizing your workflow. I will also show how to carry the variant and CNV interpretations over into the new reports. Finally, Gabe will demonstrate how users can easily customize their clinical reports.
- #12: As some of you may know, VSClinical uses the ACMG classifer algorithm which computes classifications for each variant based on the ACMG guidelines. These classifications are based on evidence such as population frequencies, conservation scores, splice site algorithms, and functional predictions. Since the publication of the original article describing the ACMG Guidelines in 2015, there have been a few updates and additional scoring options added to the guidelines.
- #13: In particular, ClinGen, more specifically the Sequence Variant Interpretation (SVI) working group refined the scoring for PVS1 variants. The guidelines now elaborate on specific considerations for the different types of loss of function variants, and provide decision-making pathways assimilating information about the variant type, its location, or any additional evidence for the likelihood of a true null effect. The result of taking these nuances into account is that instead of a single very strong criteria, the scoring allows null variants to range from supporting to very strong. VSClinical has been updated to automate the decision and suggest the appropriate strength for any given potential lof variant. On a related note, we have expanded the ability to change the evidence strength to many additional scoring criteria, allowing your lab to customize the scoring process to meet its own needs.
- #14: The final addition to the ACMG Sample Classifier algorithm is that you can include custom population frequency tracks like Kavair TopMed, gnomAD genomes, and a few others which can be used to evaluate variants within VSClinical. Of course if you have established your own population cohort, you can utilize that as well. If you do want to include your own cohort for analysis, we recommend that you have at least 2000 samples. Even more exciting the addition of the new CNV Classifier for evaluating CNVs according to the ACMG Guidelines. We have had previous discussions on the new ACMG CNV Classifier, but now can run this scoring for CNVs just like the autoscoring that runs with variants. Going hand-in-hand with the ACMG CNV Classifer is a second algorithm, the probability segregation algorithm which computes the expected copy number for each called CNV. It also identifies other samples that are likely to share the CNV and in the case for trios, it computes the probability that the CNV is present in the mother/father. These algorithms can be incorporated into your workflow to narrow down your search for variants to be evaluated with the ACMG scoring criteria. Integrated into the Classifier algorithms and the ACMG workflow overall are the assessment catalogs.
- #15: An essential component to the ACMG workflow is saving variant classifications, interpretations for your reference, but also for application in future samples. For instance if you have previously evaluated a variant and then you see that variant again in another sample, you will not have to classify that variant all over again. To be able to save even more information about the variants that are being evaluated, additional fields have been incorporated into the new ACMG assessment catalogs to capture every user provided detail about the variant. With the addition of the CNV interpretation with the ACMG Guidelines, there is the need to save both CNV and gene interpretations as well. This is important in particular for CNV workflows as the information on certain genes or CNVs can be limited. The assessment catalogs allow your lab to essentially build an internal database for interpretations and classifications for the CNVs and genes that you evaluate within VSClinical. Setting up the assessment catalogs for saving variant and gene interpretations is the first step in the VSClinical workflow, the next step is to set up the project specific details defining how you will evaluate variants and regulate the information that will be included in your clinical report.
- #16: Many new project options have been added to offer more customization for your workflow. I also want to mention these options are also available in the AMP workflow as well for those of you working in the cancer sapce. But let’s discuss some of these features and customization options now. Some of you may be familiar with the ability to flag, track, and organize variants for analysis within the current release of VarSeq. These flags can now can also be applied to CNVs and coverage regions. The flags are essential to not only track variants and CNVs within your VarSeq project, but they are also useful to pre-select Variants, CNVs, and coverage regions to be included in your clinical reports. There are many applications for these flags as they are fully customizable but one example may be that want to flag a specific region that had low quality exon coverage and include this information in the clinical report.
- #17: The next feature I want to mention is that you can now include Custom gene lists/gene panels. Even more, you can include that gene list in your report and you can even calculate coverage statistics based on that gene list and visualize the coverage for those genes specifcally.
- #18: SO next on the list, You can still define custom threshold for the ACMG criteria like the allele frequency for a variant to be considered common in the control population for example. However, you can now choose the HGVS representation notation for display and reporting. This is important as I know particularly in Europe there is a specific way that variants must be reported so the ability to control this display is essential. On a related note, we also have included the option to score variants according to the ACGS Guidelines which are based more on European best practices. The difference in the ACGS guidelines is that they have potentially a improved way to sum up the scoring criteria when distinguishing between likely pathogenic and pathogenic classification for variants. Before we change gears to discuss new reporting capability, there is one more new feature that I want to mention and that is the ability to define and lock the annotations that are used in evaluations
- #19: Currently, VS has been able to guarantee consistency in using the same annotation sources by having those versions incorporated into the project template. However, VSClinical has always used the latest version of the annotation source that is downloaded. Now, by default vsclinical will remember all the sources used to create a an evaluation even if a newer version of that source is available. To ensure those same versions are used you can lock these so they will be used for future evaluations within this project and if you find you want to continue to use the same sources in other projects, these locked sources can also be integrated into a project template as well . Like the other features we have talked about, these annotation source versions can now be appended into the clinical report. Speaking of reports, I am happy to introduce our VP of product development, Gabe Rudy, who will discuss the new reporting capabilities and how you can customize your clinical reports.
- #20: Title: Any Questions Category: Backgrounds Tags: section, title, background, image, picture, book, glasses
- #21: Gabe asks. Lots of reasons for reports..
- #22: ****Screen shot of PDF preview within VS****
- #23: Gene Grid. Covergae for gene list.
- #24: Trio bring info from parents automatically, more details
- #25: Mendel break out incidental findings and more details on CNVs exomes and genomes. Which ones are a heditary disease risk over time vs just carrier status
- #26: Screen shot- zoom into results-top section. Pass to Julia for starting demo
- #27: Bone Disease– gene panel---- CRExome6 sample Orient VS interface Sample, cnv, variant table- mentioned CSV file for reporting brought in at import. Start from scratch to set up assessment catalogs- mention can crate new, convert old, or use old assessment catalogs, and mention frequency track set up Show the acmg and cnv classifiers in table- mention prob segregation algo. Open VSClincal for first time- first prompt is the source versions dialog, project option prompts (create record sets, acgs…) Start new evaluation- see the same variants added… 4total variants (previously evaluated- highlighting the assessment catalogs saving variants/cnvs)------- PVS1 verbal discussion for CBS about Mediated decay 1 variant and CNV for primary findings one variant for secondary findings 1 CNV VUS And now you can create record sets for variants and CNVs in just one click in project options quickly organizing your variants. Briefly go over scoring - gene coverage tab-mention gene list coverage mention record sets- different sections we are saving these variants for the report Go over each report section (sample info, coverage, variant sections, etc) edit these sections too. Gabe- create report template- gene panel change logo… Move content (delete/create section) Take section from another template Simple change- |dateEU Complex change- Function within a function- failed target coverage below certain threshold a certain sentence pops up- join to list- comma separate. Just list of gene less than 20x coverage Retest these genes. Mention that can change language
- #28: Again, I want to mention how grateful we are we for grants such as these which provides huge momentum in developing our software. At this point Ill turn things back over to Delaina and she will talk about some Golden Helix updates and then we will go into the Q and Answer period.
- #30: 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.
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