Next generation sequencing (NGS) has revolutionized genomics and is now being widely adopted for clinical sequencing. Whole exome or whole genome sequencing (WES/WGS) is the ultimate genetic test and many success stories provide a taste of its power. Targeted NGS-based gene panels are typically an order of magnitude smaller than WES/WGS-based testing but follow the same principles. However, while the cost of generating high-quality whole genome sequence data is rapidly dropping, analysis of the enormous number of variants detected is still very complex, and a task of annotating NGS data for clinical grade reporting and interpretations remain a challenge. Cambridge Healthtech Institute’s Second Annual NGS Diagnostics: Data Considerations, Annotation and Interpretation conference is designed to discuss best practices in NGS data analysis, and NGS results annotation, interpretation, disclosure and applications.
WEDNESDAY, AUGUST 24
10:30 am Registration
12:50 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:25 Ice Cream and Cookie Break in the Exhibit Hall with Poster Viewing
1:50 Chairperson’s Opening Remarks
Wayne W. Grody, M.D., Ph.D., Professor, Medical Genetics and Molecular Pathology, Pathology & Lab Medicine, Pediatrics, and Human Genetics; Director, Molecular Diagnostic Laboratories and Clinical Genomics Center, University of Calfornia Los Angeles School of Medicine
2:00 Keynote Presentation: Why Precision Medicine Requires Imprecise Measures
Isaac Kohane, M.D., Ph.D., Professor and Chair, Department of Biomedical Informatics, Harvard Medical School; Professor of Pediatrics, Boston Children's Hospital
Much has been written about the importance of new molecular markers for precision diagnostics and therapeutics. I will illustrate with several examples how the focus on the molecular is causing diagnostic and prognostic imprecision. I will highlight integrative approaches that address this problem.
3:00 Annotation and Interpretation of Clinical Exome Sequencing
Wayne W. Grody, M.D., Ph.D., Professor, Medical Genetics and Molecular Pathology, Pathology & Lab Medicine, Pediatrics, and Human Genetics; Director, Molecular Diagnostic Laboratories and Clinical Genomics Center, University of Calfornia Los Angeles School of Medicine
Our center has been performing clinical-grade whole-exome sequencing (WES) for the diagnosis of rare Mendelian disorders since January 2012. In addition to our in-house bioinformatics pipeline and externally available databases and algorithms, all mutations and variants are interpreted by a unique “Clinical Genomics Board” comprised of lab directors, technologists, bioinformaticists, genetic counselors, medical geneticists, and the ordering clinicians. We find that this approach provides the most “value-added” clinical insight for proper annotation and reporting of variants. As a result, definitive pathogenic variants were identified and reported in 27% of all cases, and likely pathogenic variants were detected in an additional 28%, producing an aggregate diagnostic yield of up to 55%. While similar diagnostic yields are reported by other centers offering WES, there appear to be wide differences in the number of less certain, uncertain, and off-target variants being reported. The genomic testing community needs to consider whether a greater or lesser scope of reported variants helps the ordering physician or merely makes their job more difficult and causes greater anxiety for the patient.
3:30 FDA Perspective on NGS Data Analysis
Xueying Sharon Liang, M.D., Ph.D., Regulatory Scientist, Division of Molecular Genetics and Pathology, OIR/CDRH/FDA
Next generation sequencing (NGS) is increasingly employed for use in the clinical setting. Analyzing big data generated by NGS is challenging, such as data format standardization, bioinformatics pipeline validation standards, methodologies, and reference material availability. As part of the Precision Medicine Initiative (PMI), FDA is actively engaging stakeholders to develop sufficiently flexible standards to assess performance of NGS-based tests, including analytical standards and framework on bioinformatics pipeline validation and clinical validity of NGS tests.
4:00 Refreshment Break in the Exhibit Hall with Poster Viewing
4:45 Interpretation of Wes Variants: Uncertain Until Proven Guilty
Karen Weck, M.D., Professor, Pathology & Laboratory Medicine and Genetics, University of North Carolina, Chapel Hill
The use of whole exome sequencing (WES) for diagnosis of genetic diseases is quickly becoming standard diagnostic procedure in many cases. However, a major hurdle is the interpretation of the large number of sequence variants identified. In the NCGENES study, we have employed various strategies to streamline variant analysis and interpretation, including establishment of diagnostic gene lists tailored to the patient’s clinical phenotype. Nonetheless, a significant proportion of results are of uncertain clinical significance for the individual diagnosis. I will discuss different categories of uncertain results generated by WES and the imperative of distinguishing uncertain results from definitive diagnostic results in reporting of WES analysis.
5:15 Precision Medicine – Challenges Associated with Annotation and Interpretation of Somatic Mutation Data
Roger D. Klein, M.D., J.D., Medical Director, Molecular Oncology, Cleveland Clinic Foundation
The past several years have seen a significant increase in the demand for somatic mutation testing in human cancers in order to specifically tailor therapeutic management strategies to specific patients. Many laboratories have begun testing for various numbers of mutations in large numbers of genes using massively parallel sequencing to provide genomic profiles that would direct therapeutic selection. This lecture will discuss the challenges associated with data analysis from the perspective of annotation, and interpretation for routine clinical practice.
5:45 PANEL DISCUSSION: Incidentalome in Genomic Medicine: An Obstacle or a Driver?
Moderator:
Wayne W. Grody, M.D., Ph.D., Professor, Medical Genetics and Molecular Pathology, Pathology & Lab Medicine, Pediatrics, and Human Genetics; Director, Molecular Diagnostic Laboratories and Clinical Genomics Center, University of Calfornia Los Angeles School of Medicine
Panelists: Isaac Kohane, M.D., Ph.D., Lawrence J. Henderson Professor of Pediatrics; Chair, Boston Children’s Hospital Informatics Program; Co-Director, Center for Biomedical Informatics, Lawrence J. Henderson Professor, Pediatrics and Health Sciences and Technology, Harvard Medical School
Xueying Sharon Liang, M.D., Ph.D., Regulatory Scientist, Division of Molecular Genetics and Pathology, OIR/CDRH/FDA
Karen Weck, M.D., Professor, Pathology & Laboratory Medicine and Genetics, University of North Carolina, Chapel Hill
Roger D. Klein, M.D., J.D., Medical Director, Molecular Oncology, Cleveland Clinic Foundation
Next-generation sequencing has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings.
Application of NGS at the clinical level represents a true paradigm shift that will require new standards for actionable interpretation, access to patented sequences of the genome, and revelation of "off-target" results. This panel will discuss best practices and approaches for dealing with so called incidentalome, both in cancer genomic profiling and inherited disease testing.
6:15 Close of Day
6:00 Dinner Short Course Registration
THURSDAY, AUGUST 25
7:30 Interactive Breakout Discussion Groups with Continental Breakfast
This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants.
Public and Private Database for Somatic and Germline Mutations
Moderator: Susan Mockus, Ph.D., Manager, Clinical Analytics & Curation, The Jackson Laboratory for Genomic Medicine
- Is there a single nomenclature source for genes and variants that should be adopted across all databases?
- How should databases provide transparency to data collection sources and evaluation processes?
- What levels of evidence should be required for somatic predictive biomarkers?
Challenges in Whole Exome Sequencing
Moderator: Karen Weck, M.D., Professor, Pathology & Laboratory Medicine and Genetics, University of North Carolina, Chapel Hill
- Whole exome versus whole genome sequencing
- Strategies to streamline variant analysis and interpretation
- Distinguishing uncertain results from definitive diagnostic results in WES analysis
8:25 Chairperson’s Remarks
Susan Mockus, Ph.D., Manager, Clinical Analytics & Curation, The Jackson Laboratory for Genomic Medicine
8:30 The Precision Pathology Biobanking Center at MSK: The Pathology Hub for Clinical Trials
Michael H. A. Roehrl, M.D., Ph.D., Memorial Sloan Kettering Cancer Center
The talk will describe the brand new Precision Pathology Center at MSK, its five strategic pillars, and its cutting-edge vision to build a proactive platform for pathology to become a hub for next gen precision trials. In particular, we will discuss ongoing developments in big data analytics and data federation that includes NGS data, other omic data, and real-time federation to a broad set of research samples for correlative discovery research and companion diagnostics development within trials.
9:00 Pushing the Limits- Challenges of Somatic Variant Detection
Robert Daber, Ph.D., Vice President, Genomics Operations and Development, Laboratory Medicine, Bio Reference Laboratories
NGS continues to emerge as a powerful diagnostic methodology for the characterization of mutation status in a variety of tumors. Here we describe our experience detecting various complicated somatic mutation types in across a variety of tumor types, including both low allele frequency mutations as well as complicated insertion and deletion events. We will also discuss our strategies for decreasing the lower limit of detection by customizing the limits of detection for each genomic loci independently.
9:30 Sapientia - Faster, More Accurate Diagnosis Using a Data Sharing Platform
Mike Furness, Head, Sales & Marketing, Congenica
Using NGS technology, genetic testing is moving from small gene panels to whole genome testing, such as the UK 100,000 Genomes Project. Our platform SapientiaTM is already in the majority of NHS clinical genetics labs, and we are providing clinical reports on rare disease patients for the 100,000 Genomes Project. Other commercial and academic sites around the world are also adopting Sapientia. Examples of the benefits of genomic versus panel approaches will be shown.
10:00 Coffee Break in the Exhibit Hall
10:50 Challenges and Solutions with Interpretation of Large Genomic Panels
Susan Mockus, Ph.D., Manager, Clinical Analytics & Curation, The Jackson Laboratory for Genomic Medicine
Somatic tumor profiling in the clinic has been widely dependent on single-gene assays and small hotspot panels, however with the decreased cost and more mature NGS technology, larger gene panels are more routinely utilized. Interpretation challenges associated with large gene panels include co-mutations and connectivity to targeted therapies and available clinical trials. Systematic data capture solutions for interpretation will be discussed in context.
11:20 Advantages and Challenges of Detecting Molecular Biomarkers in Oncology: Data Analysis Perspective
Francine B. Blumental de Abreu, Ph.D., Genomic Analyst, Laboratory for Clinical Genomics and Advanced Technology (CGAT), Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center
In recent years, NGS has become an integral tool in routine clinical molecular diagnostics. For this reason, the number and diversity of sequencing and data analysis solutions have increased at an exponential rate. However, despite the breath of solutions available, there still remain a number of challenges associated with the bioinformatics of NGS data, though sample quality and preparation remain critical components in generating high quality NGS data.
11:50 AI & Cognitive Computing: Implications for Digital Pathology
Navid Farahani, M.D., Pathology, Informatics, University of Pittsburgh Medical Center
Artificial Intelligence (AI) and so-called cognitive computing technologies, which are derived from the various branches and sub-branches of AI, are becoming increasingly pervasive across multiple sectors, including the healthcare industry. This presentation aims to familiarize one with various types of AI approaches, cognitive technologies, and review the relevance of both of the aforementioned in the realm of digital pathology
12:20 pm Q&A with the Speakers
12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:20 Session Break
2:00 Chairperson’s Remarks
Matthew Lebo, Ph.D., FACMG, Director, Bioinformatics, Partners Personalized Medicine; Instructor, Pathology, Brigham and Women’s
2:05 Viscap: Inference and Visualization of Germ-Line Copy-Number Variants from Targeted Clinical Sequencing Data
Matthew Lebo, Ph.D., FACMG, Director, Bioinformatics, Partners Personalized Medicine; Instructor, Pathology, Brigham and Women’s
Effective implementation of precision medicine will be enhanced by a thorough understanding of each patient’s genetic composition to better treat his or her presenting symptoms or mitigate the onset of disease. This ideally includes the sequence information of a complete genome for each individual.
2:35 Navigating the Landscape of Commercially Available Knowledge Bases: How to Find the Right Fit for Your Clinical Application and Laboratory Environment
Jamie Platt, Ph.D., Managing Director, BRIDGenomics, LLC.
The upsurge of clinical NGS applications has created an increasing demand for bioinformatics solutions and knowledge bases. Clinical research labs are no longer constrained solely to in-house manual curation of the literature in order to support their clinical NGS offerings. A number of knowledge bases and annotation solutions are now commercially available. However, it is still difficult to understand the nuances of each of these solutions and find the best fit for the application and the specific laboratory environment. An overview of the commercial landscape of knowledge bases and annotation solutions will be provided with respect to each lab’s unique needs.
3:05 Complex Cases: The Rarest of the Rare
Daniel Helbling, Senior Clinical Genomics Analyst, Human Molecular Genetics Center, Medical College of Wisconsin
The world of NGS diagnostics for rare disease tends to favor results that deviate from the norm. However, beyond the expected unusual lies another layer of complex cases. I will present these cases and their molecular diagnosis.
3:35 Q&A with Speakers
4:05 Close of Conference