Next-Generation Sequencing Analysis in VSClinical
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VarSeq is a tertiary analysis platform that allows users to filter and annotate NGS sequencing data to identify clinically relevant variants. Following this workflow, VSClinical can then be used to automate both germline and somatic variant analysis in accordance with the ACMG and AMP guidelines by using a variety of functional prediction models and clinical and reviewer-based annotations. Once variant or biomarker interpretations are completed, they can be rendered in a customizable clinical report and stored in an internal assessment catalog as an internal variant database repository. Together, implementation of VSClinical will promote increased lab throughput as well as accuracy and compliance with the ACMG and AMP guidelines, which in turn can save time and money. To show the capabilities of our software, this webcast will provide a demonstration of how to use VarSeq and VSClinical for the evaluation of both germline and somatic variants in accordance with the ACMG and AMP Guidelines. In this webcast, we will cover: - Filter logics for germline and somatic variants and selecting them into the VSClinical interface - Capabilities of functional prediction and splice site algorithms for edge case variants - The functionality of changing the clinically relevant transcript on variant interpretation - Rendering a clinical report with germline and somatic variants with the inclusion of clinical trials
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Next-Generation Sequencing Analysis in VSClinical
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- 2. 2 Questions & Answers All questions will be anonymous
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- 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 is Vetted • 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
- 10. Simple Flexible Scalable Variantannotation filtering, andinterpretation PowerfulGUIwith richvisualizations Repeatable workflows
- 11. 11 Golden Helix TemplatesExample Projects
- 12. Getting Started with VarSeq 12 Trio Analysis • De novo candidates • Dominant Heterozygous • Compound Heterozygous • Recessive Homozygous • X-Linked • Known Rare Pathogenic Included Default Workflows Example Projects • Example TruSight Cardio Gene Panel • Example YRI Exome Trio Analysis • Example Tumor-Normal Pair Analysis Hereditary Gene Panels Somatic Mutation Workflows • Cancer Gene Panels • Tumor/Normal Pair Analysis
- 13. VarSeq Annotations 13 Lorem ipsum dolor sit Curated Public Databases: • 1kG Phase3 Variant Frequencies • ClinVar • CIViC • dbNSFP Functional Predictions • dbSNP • ExAC • RefSeq Genes, NCBI • ClinGen Dosage Sensitivity Mapping Notifications for Track Updates Premium Annotations: • CADD • COSMIC • Conservation Scores • SIFT/PolyPhen2 • Splice Site Algorithms • OMIM phenotypes and Genes
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- 15. VSClinical 15 Lorem ipsum dolor sit • Increased lab throughput • Consistent results • Shorten learning curve • Staying abreast of new developments ACMG & AMP Guidelines in One Suite Germlin e Somatic
- 16. VSClinical 16 Four-Phased Workflow Filter and select variants for evaluation • Follows existing VarSeq filter workflow Assess all evidence for variant • Presented in VSClinical interpretation hub Develop final classification • Directly follows ACMG Guidelines • 33 criteria for evaluating evidence • 5 possible classifications built from criteria • Include caveats and discussion for evaluating criteria in different contexts • Develop and catalog variant interpretation Include interpretation in final clinical report Uncertain Significance Benign Pathogenic 1 2 3 4
- 17. VSClinical 17 Lorem ipsum dolor sit ACMG Rules for Classification Pathogenic Likely Pathogenic Uncertain Significance Likely Benign Benign Rules Presented in VSClinical Richards et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 2015, Genet Med 17: 405-424.
- 18. VarSeq Clinical Reports 18 One Click Option • Auto-populated data o Public and Premium databases in VarSeq o Variant interpretations in assessment catalogs Value • Consistent report standards (according to ACMG) • Faster reporting • Multiple templates o Trio o Gene Panel o Tumor/Normal Customization • Simple configurable options in software • In depth customization options via scripting
- 19. VSClinical Clinical Reports 19 VSClinical conducts the clinical variant analysis based on ACMG and AMP guidelines • Automated population of the clinical report based workflow outcome • Standardizing of variant level interpretation based on customizable assessment catalogues • In the case of somatic variants, GHI provides predefined clinical assessments via our CancerKB catalog Rendering of clinical reports within seconds Supported output formats • Word • PDF
- 20. Global Developmental Delay 20 Lorem ipsum dolor sit • Significant delay in two or more developmental domains o Gross and fine motor skills o Speech and language o Personal and social development • Measured over the past 12 years, prevalence estimated 17.1% • Males have 2x the prevalence compared to females • 66% of cases not diagnosed by history/examination o Chromosomal microarray and karyotyping o Targeted Gene Panels o Metabolic investigations o Targeted MRI
- 21. Etiologies of GDD 21 Lorem ipsum dolor sit • Down syndrome • Fragile X syndrome • Rett Syndrome (MECP2 gene mutation) • DiGeorge syndrome • Prader-Willi
- 22. VSClinical Project Demonstration 22 • Hereditary Risk Gene Panel Analysis o One sample: Sample 1 o Edge-case variants manually added: Clinical Example o Imported external CNV results • Comprehensive coverage of 175 genes with known associations to Global Developmental Delay • Targeted phenotypes: GDD • Pathogenic classification: ClinVar & ACMG Guidelines with VSClinical
- 24. NIH Grant Funding Acknowledgments 24 • 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.
- 25. 25 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
- 26. 26 Questions & Answers All questions will be anonymous
Editor's Notes
- First and foremost, we recently received grant funding from NIH which we are incredibly grateful for. 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 provides huge momentum in developing the quality software we provide. Now let’s learn more Golden Helix as a company.
- GoldenHelix 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 of pharmacogenomics work performed at GalxoSmithKline who still is a primary investor in our company. We currently have two flagship products Varseq and SNP and Variation Suite (SVS) for short. VarSeq, is our clinical application platform that is used for filtering and annotating variants of interest. Varseq comes shipped with clinically relevant workflows so you can quickly get started evaluating variants according to the ACMG and AMP guidelines. You also have the capability to perform CNV analysis on targeted panels, whole exome and whole genome data Utilizing VarSeq project templates, full scale automation can be achieved with VSPipeline Automation can include the rendering of clinical reports from VSClinical for your various workflows. To maximize your workflow efficiency VarSeq can be paired with VSWarehouse’s powerful storage capabilities. Overtime you will collect a large amount of genetic data VSWarehouse is your solution for handling the massive amounts of genomic data. All of the data in VS Warehouse is queryable, and can be shared amongst collaborators. Additionally it is where you store your project data, standardized reports, and variant catalogs containing interpretations and classifications. 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 GWAS, Genomic Prediction, RNA-Seq analysis and the ability to process CNVs
- 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. top-tier institutions, Stanford and yale government organizations, NCI clinics, Sick kids genetic testing labs, prevention genetics and lineage With now well over 20,000 installs of our products and with 1,000’s of unique users. So why is this relevant to you?
- This means that over the course of 20 years our products have received a lot user feedback, which we immediately incorporate into developing and releasing newer versions of our products. We receive active research grants (Include NIH graphic?) to support the advancement of our software capability which is always directed from our user feedback and awareness of the industry needs. We also stay relevant in the community by regularly attending conferences and providing useful product information via eBooks, tutorials, and blog posts. Your access to the software is a simple subscription based model where we don’t charge per sample nor per version. You also maintain full access to our support and training staff to get you up to speed quickly with your analysis
- 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 both MLPA and Chromosomal microarray results. 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.
- VarSeq is a power, flexible, and scalable variant annotation filtering and interpretation engine. This commercial grade software designed for your local hardware so it is a desktop application that is installed locally on your computer and is very simple to use (as well see). In VarSeq, you’re not limited to looking at a simple list of variants in a spreadsheet, you can also explore the data visually with our plotting capability in GenomeBrowse. One of the most notable features of VarSeq is that you can build and run repeatable workflows. So once you have developed a workflow and decided the type of filtering you would like to do, what annotation sources you would like, you can save that workflow as a template and use it later with new data which can really streamline your analysis time.
- When you’re getting started with VarSeq there are several default workflow templates built into the system. These templates are simple designs for trio analysis, hereditary and cancer gene panels, as well as a tumor/normal workflow. These are meant to be a simple example for you to get started and gain familiarity with the software. Feel free to modify these templates however you would like or even build a new project from scratch. Additionally, we include some example projects with variants in them, so you can see some direct examples of a complete workflow.
- When you’re getting started with VarSeq there are several default workflow templates built into the system. These templates are simple designs for trio analysis, hereditary and cancer gene panels, as well as a tumor/normal workflow. These are meant to be a simple example for you to get started and gain familiarity with the software. Feel free to modify these templates however you would like or even build a new project from scratch. Additionally, we include some example projects with variants in them, so you can see some direct examples of a complete workflow.
- VarSeq being a filtration and annotation engine, we seek to provide the best quality and comprehensive list of databases for your analysis. Our public annotation server host all of our quality curated public databases which come default with the VS software. Additionally, depending on the license package you purchase, users can gain access to our premium annotations which come with the Clinical + Reports or the full VSClinical stack. This of course also includes and extensive list of cancer annotations such as COSMIC for AMP guidelines as well. These annotations are versioned for their updated release and users will be notified when the updates are available without automatically integrating into your established workflow. If you have recommendations for additional public databases, please let us know as we are receptive to user feature requests. However, you can always integrate a custom database by use of our convert wizard to get your database into VarSeq.
- Within VarSeq is VSClinical which serves as our ACMG and AMP guideline interpretation hub. It is worth discussing the value points in having a true automated guideline interface. First off, you want to maintain consistency in results. This is relevant even for a single user suffering from potential workflow fatigue or comparing multiple user’s interpretations. More discretely, is the added value of getting new users familiar with the guidelines more quickly. The interpretation hub serves as a great educational interface to account for all relevant guideline criteria. Lastly, but critical is our support for integrating these guidelines into the software so that users spend more time processing variant and less time tweaking their bioinformatic pipeline. Consistent results Shorten learning curve Staying abreast of new developments
- The major hurdle VSClinical overcomes is the inherent limitation with manually accounting for all evolving knowledge for any given variant. This is especially true regarding cancer databases which evolve and grow exponentially, and it is unrealistic for a single person to promptly keep track of all the information. The need for automation is critical and VSClinical is the solution. Not only is consistency upheld through handling all available evidence across multiple databases, but it also removes any issue with underlying workflow fatigue. Moreover, the improved efficiency with VSClinical allows less users to process more data more quickly while still maintaining interpretation consistency. A more subtle value but just as critical is the educational interface VSClinical provides in familiarizing new users to the AMP and ACMG guidelines. And lastly, users benefit from the fact that we integrate advances in these guidelines directly into the software so users spend more time performing variant analysis and less time having to modify or update their bioinformatic pipeline. Because VSClinical serves as the ACMG and AMP guideline interpretation hub it is important to discuss the cancer-based annotations that much of the interpretation is based on.
- Before interpreting variants in VSClinical, users will prefilter variants through VarSeq’s basic filter chain. This could include eliminating low quality, common, or known benign variants for example. Next, the user can hone-in on a potentially clinically relevant variant that is selected for interpretation deep dive in VSClinical. Through VSClinical all relevant criteria or evidence for the variant will be presented to the user to achieve the most up to date and comprehensive understanding of the variant’s impact. The last step will be to report on the variant’s final interpretation and classification which will be stored for future reference in the assessment catalogs.
- Here are the 5 potential classifications and the associated rule logic for all relevant criteria. The images above are the rules for combining criteria, sourced from the ACMG standard guidelines article. Focusing on the pathogenic classification, you can see a number of different paths the criteria can follow. For example, pathogenicity can be achieved with a single “very strong” and at least one strong criteria, or maybe having at least 2 strong criteria met. You’ll see in a RAF1 example variant in todays demo, we will be determining pathogenicity based on rule 3 (one strong, three moderate, and two supporting criteria). So, though automated, the user will always be presented with the true to form ACMG classification rules. In the demo we will also use this variant to demonstrate how to produce a clinical report
- Final result following variant classification is the need to generate a clinical report. VarSeq provides a simple interface for rendering a custom clinical report. Most fields in the project can auto-populate within the clinical report, across multiple annotations and final interpretations for your clinically relevant variants. The value in defining your own report template is to maintain consistency in reporting. Which also results in faster turn around from variant analysis to reporting. We ship example report templates that also follow the ACMG/AMP guidelines, like Trio Gene panel or Tumor/normal. Users can access these templates and develop their own specific customizations. These customizations can be simple configurable settings or more detailed javascript/hmtl changes. There is also the option for a service contract if you would like us to help you with these changes as well.
- One of the main value points of VsClinical’s ACMG/AMP reports is in the auto-population of data from your workflow into your clinical reports. In doing so, the results are faster reporting and allowing users to have control over the standardization of the reporting which reduces errors throughout the reporting process. With Varseq users can create custom clinical reports based on findings. For our reporting functionality, this is another option where we use the word “template” quite a bit. We provide a ACMG guideline based clinical report just like the one seen here, but with some easy configurable options users can customize their report to include all necessary lab information. More detailed customizations are also optional with some javascript and html experience that allows for the inclusion of any additional annotation or samples fields in your VarSeq project.
- Significant delay in two or more developmental domains: gross and fine motor, speech and language, cognition, personal and social development, or activities of daily living Developmental disabilities are a diverse group of severe chronic conditions that are due to mental and/or physical impairments. People with developmental disabilities have problems with major life activities such as language, mobility, learning, self-help, and independent living. Developmental disabilities begin anytime during development up to 22 years of age and usually last throughout a person’s lifetime. Stats for uncommon diagnosis leading to genetic testing
- Down syndrome (trisomy 21) Fragile X syndrome (FMR1 gene, CGG triplet repeat expansion, X-linked inheritance) Most common cause of male GDD after Down syndrome Rett Syndrome (MECP2 gene mutation) Most common cause of female GDD after Down syndrome DiGeorge syndrome (22q11 deletion) Prader-Willi
- In this example today we will be looking at 2 samples that were sequenced using the Hereditary risk gene panel. This kit provides comprehensive coverage of 175 genes associated with a inherited cardiac conditions, hereditary cancers, and other inherited diseases. In addition to the two samples in this panel, I have included some edge case variants in a clinical example which will best serve the purpose of demonstrating the scope of interpretation VSClinical provides. Our focus will be to demonstrate the implementation of the auto classifier results into our workflow, then explore VSClinical in depth with our Clinical example. Want to discuss filtering logic, calling CNVs (karyotype is included in report).
- GoldenHelix 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 of pharmacogenomics work performed at GalxoSmithKline who was and still is a primary investor in our company. We currently have two flagship products Varseq and SNP and Variation Suite (SVS) for short. SVS is our research application platform that enables researchers to perform complex analysis and visualizations on genomic and phenotypic data. SVS has a broad range of tools to easily perform GWAS, Genomic Prediction, Differential expression analysis on RNA-Seq Data and has the ability to process CNV analysis, which we will demonstrate today. VarSeq, on the other hand, is our clinical application platform that is used for filtering and annotating variants of interest. We can also evaluate variants according to the ACMG guidelines with VSCLincal and have the option to automatically create clinical reports from the results of various workflows. Using the same software, we can also perform CNV analysis on targeted gene panels and whole genome sequencing, which we will demonstrate today and We also have an add-in function called VSPipeline – which can take the workflow that you created and automates the process with very little human interaction. Now all of the information produced from VarSeq can be stored in our Warehouse solution, which is designed to be installed on a server location and serve as a repository for your variants evaluations, annotations, and hosted reports. Lastly, VSWarehouse can also be implemented for sharing and integration between license holders.
- First and foremost, we recently received grant funding from NIH which we are incredibly grateful for. 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 provides huge momentum in developing the quality software we provide. Now let’s learn more Golden Helix as a company.
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