TCGC: Clinical Genome ConferenceTCGC: Clinical Genome ConferenceTCGC: Clinical Genome Conference
2013 Archived Content

June 25-26, 2013

Bio-IT World & Cambridge Healthtech Institute’s Second Annual 

 

TCGC: The Science of Investigation
and Interpretation

 

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Wednesday, June 26

EMC7:30 am Breakfast Presentation: Galaxy in a Clinical Setting: Architecture and Storage Implications

Sanjay Joshi, CTO, Life Sciences, EMC Isilon Storage Division
James Taylor, Assistant Professor, Biology, Emory University

The need for a process-level source and version control, configuration management and document life-cycle management system is reaching critical path as Research Genomics translates into Clinical Genomics. We will discuss the architectural and storage requirements for using Galaxy, the process management platform of choice for Genomics, in a Clinical environment.


Identifying Clinically Relevant Variants 

8:30 Chairperson’s Remarks

David Mittelman, Ph.D., Associate Professor, Virginia Bioinformatics Institute, Virginia Tech; Associate Professor, Department of Basic Science, Virginia Tech Carilion School of Medicine

8:35 The Need for CLARITY in Clinical Genome Sequencing

Catherine BrownsteinCatherine A. Brownstein, Ph.D., MPH, Gene Partnership, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School

The CLARITY competition was launched with the goal of surveying current practices in bioinformatic analysis, interpretation, and reporting of next-generation sequencing to diagnose rare genetic conditions. This international challenge provided contestants with DNA sequences and clinical data from three families with rare conditions for which no genetic cause had been identified. The presentation will summarize results and discuss some of the conclusions and lessons from this competition.

9:10 Identification of Disease Alleles from Whole Genome and Exome Sequencing Data Using a Unified Framework for Ranking Genetic Variation

Martin KircherMartin Kircher, Ph.D., Senior Fellow, Jay A. Shendure Laboratory, Genome Sciences, University of Washington

One remaining challenge in the analysis of genetic data is the interpretation of genetic variation and the identification of the few phenotypically causal variants or disease variants among the few million variants present in each sequenced genome. While various programs for assessing the functional impact of variants exist, they are largely limited to highly conserved positions in protein-coding sequences. We present a unified approach that integrates diverse types of available annotations and scores into a single framework that weights the functional impact of both coding and non-coding variation on a genome-wide scale.

9:45 Analytical Pipeline Workflows, Resource Interoperability and Processing of “Big” Genomics Data

Ivo D. Dinov, Ph.D., Associate Professor, University of Michigan; Director, Statistics Online Computational Resource (SOCR)

A critical component of all modern genomics studies is the ability to efficiently process high-throughput sequence data. Such genomics computing tasks require reliable cloud data management solutions, distributed computational services and effective user interfaces. The Pipeline Environment is a free workflow application enabling the navigation, exploration and discovery of available end-to-end workflow solutions, design of new computational modules, processing of graphical protocols and execution and monitoring of complex heterogeneous analyses. The Pipeline library includes Imaging and NGS Analysis Pipeline Workflows based on a wide range of tools, e.g., BLAST, EMBOSS, mrFAST, GWASS, PLINK, R, MAQ, SAMtools, Bowtie, CNVer, QC, GATK, FreeSurfer, FSL, LONI, DTK, etc.: http://Pipeline.loni.ucla.edu.

10:20 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 Optimizing Analysis Pipelines for Improved Variant Discovery from Personal Genomes

David MittelmanDavid Mittelman, Ph.D., Associate Professor, Virginia Bioinformatics Institute, Virginia Tech; Associate Professor, Department of Basic Science, Virginia Tech Carilion School of Medicine

There are many mapping strategies and variant calling methods, and while variant callers tend to identify similar base substitutions, they often differ substantially in assigning indels and copy number variants. It is therefore, critical to optimize all aspects of the analysis pipeline to maximize detection of variants, while minimizing the false discovery rate. As a case study we present our analysis pipeline for detecting human microsatellite repeat variation. Repeats are challenging to genotype, however they are an important source of clinical and subclinical variation.

11:35 PANEL DISCUSSION: GCAT: Genome Comparison & Analytic Testing - Uniting on Standards through Crowdsourcing

Panel Moderator: David Mittelman, Ph.D., Associate Professor, Virginia Bioinformatics Institute, Virginia Tech; Associate Professor, Department of Basic Science, Virginia Tech Carilion School of Medicine

The standardization and performance testing of genome analysis tools is a prerequisite to widespread adoption of high-throughput sequencing, particularly in the clinic. We present an open and collaborative platform for comparing multiple genome analysis tools across a standard set of metrics. The exact metrics and datasets are crowdsourced to encourage community involvement and input. The GCAT platform features an easy interface and automatically generates compelling visualizations of benchmark and performance testing data.

Panelists:

Gholson Lyon, M.D., Ph.D., Assistant Professor, Human Genetics, Cold Spring Harbor Laboratory

Martin Kircher, Ph.D., Senior Fellow, Jay A. Shendure Laboratory, Genome Sciences, University of Washington

Gabe Rudy, Vice President, Product Development, Golden Helix and Author, “A Hitchhiker’s Guide to Next Generation Sequencing

Marc Salit, Group Leader, Biochemical Science and Multiplexed Biomolecular Science, National Institute of Standards and Technology

Jason Wang, Co-Founder and CTO, Arpeggi, Inc.

12:10 pm Close of Session

12:15 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own


Identifying Clinically Relevant Variants cont. 

1:30 Chairperson’s Remarks

Elaine Lyon, Ph.D., Associate Professor of Pathology, University of Utah School of Medicine; Medical Director of Molecular Genetics/Genomics, ARUP Laboratories

1:35 Temporal Genetic and Clonal Events in the Progression of Human Disease

Hanlee JiHanlee Ji, M.D., Assistant Professor, Division of Oncology, Department of Medicine, Stanford University School of Medicine; Senior Associate Director, Stanford Genome Technology Center

With the improvements in genome sequencing technology, one’s ability to determine genetic variation temporally is providing a wealth of information about disease progression.  Namely, we are increasingly able to track the presence, expansion and disappearance of pathogenic variants in cancer, infectious diseases and other human diseases over the course of time.  This longitudinal and thus temporal component to the genetics of human disease is providing incredible insight into the biology of diseases as well as opportunities to refine diagnostic assessment based on genetics.  Several examples are discussed as to the clinical relevance of temporal genetics.

2:10 The Clinical Exome and Symptom-Guided Analysis

Elaine LyonElaine Lyon, Ph.D., Associate Professor of Pathology, University of Utah School of Medicine; Medical Director of Molecular Genetics/Genomics, ARUP Laboratories

As next-generation sequencing technologies improve in accuracy and cost effectiveness, they are being integrated into clinical diagnostics. However, interpretation of the exome or genome remains a challenge. This presentation will review analysis steps to identify clinically significant variants. Strategies to prioritize relevant variants based on a patient’s symptoms will be discussed.

2:45 Streamlining Genetic Diagnostics for Patients with Consanguinity

Anna LehmanAnna Lehman, M.D., FRCPC, Assistant Professor, Medical Genetics, Adult Metabolic Diseases, University of British Columbia

Patients with consanguineous ancestry presenting with congenital diseases have a high likelihood of having an autosomal recessive genetic cause. If a single gene candidate is not clinically recognizable, then SNP microarray is usually the best next step. Perusal of OMIM diseases within large regions of homozygosity may indicate the likely causative gene. If that step fails, then exome sequencing, ideally in a different affected relative if available, will provide a short list of homozygous rare damaging variants within the regions of homozygosity. In the presenter’s experience using this parsimonious protocol with consecutive, unselected patients, the diagnostic yield exceeds 50%.

3:20 Toward More Accurate Variant Calling for “Personal Genomes”

Gholson LyonGholson Lyon, M.D., Ph.D., Assistant Professor, Human Genetics, Cold Spring Harbor Laboratory

We are working to optimize variant calling in personal genomes, including SNVs and indels, and we are leveraging the power of families to increase accuracy. There is still substantial room for improvement in attaining a clinical-grade comprehensive set of variants with high sensitivity and specificity in any one personal genome. Further ancestry tracking and family history data, when combined with whole genome sequencing, can facilitate genetic prediction for rare, highly penetrant diseases in families.

3:55 Refreshment Break in the Exhibit Hall with Poster Viewing


4:30 PLENARY KEYNOTE PRESENTATION 

Whole Genome Phasing and Analysis of a Personal Methylome

Michael SnyderMichael Snyder, Ph.D., Professor and Chair, Genetics; Director, Stanford Center for Genomics and Personalized Medicine, Stanford University

Differences in DNA methylation patterns between paternal and maternal chromosomes have been shown to influence the allelic expression of a number of important genes. In spite of their important role, a global analysis of all allelic differential methylated regions (DMRs) has not yet been performed in humans. This is largely due to the fact that few haplotypes have been accurately mapped at the genome level. Here, we describe a novel method to accurately determine the phased genome of a single individual without a priori parental information, and then perform allelic MethylC-Seq analysis to generate the first genome-wide allele-specific DNA methylation map in humans. We identify 539 DMRs, and find that 90% of them lie in proximal or distal cis-regulatory regions. Many DMR-marked enhancers are associated with allele-specific transcription factor binding, open chromatin sites, and expression of neighboring genes. Moreover, DMRs are enriched for variants associated with human diseases. Our study introduces a novel approach for defining phased haplotypes and allele-specific DNA methylation, and demonstrates its importance for the functional analysis of personal genomes.


5:15 Close of TCGC: The Science of Investigation and Interpretation 

5:30 Registration for Dinner Short Course and TCGC: The Business of Integration and Implementation 

6:00 - 9:00 Dinner Short Courses 



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