Presentation by Justin Zook at GRC/GIAB ASHG 2017 workshop "Getting the most from the reference assembly and reference materials" on benchmarks for indels and structural variants.
Presentation by Justin Zook at GRC/GIAB ASHG 2017 workshop "Getting the most from the reference assembly and reference materials" on benchmarks for indels and structural variants.
Towards Precision Medicine: Tute Genomics, a cloud-based application for anal...Reid Robison
Tute Genomics is cloud-based software that can rapidly analyze entire human genomes. The cost of whole genome sequencing is dropping rapidly and we are in the middle of a genomic revolution. Tute is opening a new door for personalized medicine by helping researchers & healthcare organizations analyze human genomes.
VarSeq 2.4.0: VSClinical ACMG Workflow from the User PerspectiveGolden Helix
Earlier this year, we released VarSeq 2.3.0 which brought massive updates to our VSClinical AMP interface, such as enhanced capabilities for automation and analysis of structural variants in the cancer context. Naturally, we wanted to follow that up shortly with similar advancements to our VSClinical ACMG interface, and also make our customers doing germline variant analysis happy.
Our latest software release, VarSeq 2.4.0, was therefore focused on the advancements in VSClinical ACMG, namely support for importing and clinically evaluating structural variants, long read sequencing, advanced automation with evaluation scripts in VSClinical ACMG and end-to-end automation of ACMG workflows with VSPipeline. These new and improved features were discussed in a great webcast by our VP of Product and Engineering, Gabe Rudy, last month.
This upcoming webcast by our FAS team will be a user’s perspective on the new features in VarSeq 2.4.0 and VSClinical ACMG and how our tools can precisely and efficiently enable the full spectrum NGS analysis for Mendelian disorders.
VarSeq 2.4.0: VSClinical ACMG Workflow from the User PerspectiveGolden Helix
Earlier this year, we released VarSeq 2.3.0 which brought massive updates to our VSClinical AMP interface, such as enhanced capabilities for automation and analysis of structural variants in the cancer context. Naturally, we wanted to follow that up shortly with similar advancements to our VSClinical ACMG interface, and also make our customers doing germline variant analysis happy.
Our latest software release, VarSeq 2.4.0, was therefore focused on the advancements in VSClinical ACMG, namely support for importing and clinically evaluating structural variants, long read sequencing, advanced automation with evaluation scripts in VSClinical ACMG and end-to-end automation of ACMG workflows with VSPipeline. These new and improved features were discussed in a great webcast by our VP of Product and Engineering, Gabe Rudy, last month.
This upcoming webcast by our FAS team will be a user’s perspective on the new features in VarSeq 2.4.0 and VSClinical ACMG and how our tools can precisely and efficiently enable the full spectrum NGS analysis for Mendelian disorders.
Best Practices for Validating a Next-Gen Sequencing WorkflowGolden Helix
Validating an NGS workflow is an iterative process that begins with collaboration with personnel and planning protocols for the entire workflow from sample preparation, sequencing and variant calling, all the way to data analysis and reporting. At Golden Helix, while we do not provide pre-validated black-box workflows, we provide our customers with support to validate workflows in a transparent manner, and assist them in reaching production deadlines. This webcast will be led by members of our Field Application Scientist team, and we will explore some of the best practices for NGS workflow validation that we have observed and helped to implement based on real-world examples from our customer base. Key topics for discussion will include:
Sample preparation and collection of adequate case/control data
Designing a robust workflow with special considerations for single versus family analyses and phenotypic considerations
Generating the desired output for clinical or other reports
Real world NGS workflow validation strategies
Tune in for tips and strategies that you can deploy when designing and validating your NGS workflow.
New Drug Discovery and Development .....NEHA GUPTA
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
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Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
1. October 15, 2019
Genome in a Bottle: Developing
Benchmarks for Challenging
Variants With Linked & Long Reads
www.slideshare.net/genomeinabottle
2. NIST Human Genomics Team
• Purpose: Inspire trust in
human genome
measurements to enable
– Technology innovation
– Clinical translation
– Science-based regulatory
oversight
– Human health
• Values:
– Understand stakeholder
needs
– Collaborate with experts and
synthesize results
• Sequencing technologies
• Informatics developers
– Open science
• Open data
• Open analyses
• Open samples
3. Why start Genome in a Bottle?
• A map of every individual’s
genome will soon be possible, but
how will we know if it is correct?
• Diagnostics and precision
medicine require high levels of
confidence
• Well-characterized, broadly
disseminated genomes are needed
to benchmark performance of
sequencing
• NIST and FDA funding for the work
O’Rawe et al, Genome Medicine, 2013
https://doi.org/10.1186/gm432
4. Human Genome Sequencing needed a new class of
Reference Materials with billions of reference values
By Russ London at English Wikipedia, CC BY-SA 3.0,
https://commons.wikimedia.org/w/index.php?curid=9923576
5. Many diverse contributors to GIAB
Government
Clinical Laboratories Academic Laboratories
Bioinformatics developers
NGS technology developers
Reference samples
* Funders
*
*
6. GIAB has characterized 7 human
genomes
• Pilot genome
– NA12878
• PGP Human
Genomes
– Ashkenazi Jewish son
– Ashkenazi Jewish trio
– Chinese son
• Parents also
characterized
National I nstituteof S tandards & Technology
Report of I nvestigation
Reference Material 8391
Human DNA for Whole-Genome Variant Assessment
(Son of Eastern European Ashkenazim Jewish Ancestry)
This Reference Material (RM) is intended for validation, optimization, and process evaluation purposes. It consists
of a male whole human genome sample of Eastern European Ashkenazim Jewish ancestry, and it can be used to assess
performance of variant calling from genome sequencing. A unit of RM 8391 consists of a vial containing human
genomic DNA extracted from a single large growth of human lymphoblastoid cell line GM24385 from the Coriell
Institute for Medical Research (Camden, NJ). The vial contains approximately 10 µg of genomic DNA, with the peak
of the nominal length distribution longer than 48.5 kb, as referenced by Lambda DNA, and the DNA is in TE buffer
(10 mM TRIS, 1 mM EDTA, pH 8.0).
This material is intended for assessing performance of human genome sequencing variant calling by obtaining
estimates of true positives, false positives, true negatives, and false negatives. Sequencing applications could include
whole genome sequencing, whole exome sequencing, and more targeted sequencing such as gene panels. This
genomic DNA is intended to be analyzed in the same way as any other sample a lab would process and analyze
extracted DNA. Because the RM is extracted DNA, it is not useful for assessing pre-analytical steps such as DNA
extraction, but it does challenge sequencing library preparation, sequencing machines, and the bioinformatics steps of
mapping, alignment, and variant calling. This RM is not intended to assess subsequent bioinformatics steps such as
functional or clinical interpretation.
Information Values: Information values are provided for single nucleotide polymorphisms (SNPs), small insertions
and deletions (indels), and homozygous reference genotypes for approximately 88 % of the genome, using methods
similar to described in reference 1. An information value is considered to be a value that will be of interest and use to
the RM user, but insufficient information is available to assess the uncertainty associated with the value. We describe
and disseminate our best, most confident, estimate of the genotypes using the data and methods currently available.
These data and genomic characterizations will be maintained over time as new data accrue and measurement and
informatics methods become available. The information values are given as a variant call file (vcf) that contains the
high-confidence SNPs and small indels, as well as a tab-delimited “bed” file that describes the regions that are called
high-confidence. Information values cannot be used to establish metrological traceability. The files referenced in this
report are available at the Genome in a Bottle ftp site hosted by the National Center for Biotechnology Information
(NCBI). The Genome in a Bottle ftp site for the high-confidence vcf and high confidence regions is:
7. Open consent enables secondary reference samples to
meet specific clinical needs
• >50 products now available
based on broadly-consented,
well-characterized GIAB PGP cell
lines
• Genomic DNA + DNA spike-ins
• Clinical variants
• Somatic variants
• Difficult variants
• Clinical matrix (FFPE)
• Circulating tumor DNA
• Stem cells (iPSCs)
• Genome editing
• …
8. Reference Genomes vs. Benchmark Genomes
• Primary uses: mapping and
annotation
• De novo assembly without
reference
• Traditionally not diploid
• Combination of individuals that
often aren’t public samples
• Primary use: benchmarking and
optimization
• Variant calls and regions on
reference genome
• Diploid-aware is essential
• Widely available individual samples
9. Design of our human genome reference values
Benchmark
Variant
Calls
10. Benchmark
Regions –
regions in which
the benchmark
contains (almost)
all the variants
Benchmark
Variant
Calls
Design of our human genome reference values
12. Variants from
any method
being evaluated
Design of our human genome reference values
Benchmark
Regions
Benchmark
Variant
Calls
13. Benchmark
Regions
Variants
outside
benchmark
regions are
not assessed
Majority of
variants unique
to method should
be false positives
(FPs)
Majority of
variants
unique to
benchmark
should be
false
negatives
(FNs)
Matching
variants
assumed to be
true positives
Variants from
any method
being evaluated
Benchmark
Variant
Calls
Design of our human genome reference values
16. GIAB has extensive public,
unembargoed data
Short reads
• BGISEQ
• Complete
Genomics
• Illumina
• Ion Torrent
• SOLiD
Linked reads
• 10x Genomics
• BGISEQ stLFR
• Illumina 6kb
mate-pair
• HiC
• Strand-seq
Long reads
• PacBio
• PacBio CCS
• Promethion
• Ultralong Oxford
Nanopore
Optical/electronic
mapping
• BioNano
• Nabsys
ftp://ftp-trace.ncbi.nlm.nih.gov/giab/ftp/data/
17. GIAB has extensive public,
unembargoed data
Short reads
• BGISEQ
• Complete
Genomics
• Illumina
• Ion Torrent
• SOLiD
Linked reads
• 10x Genomics
• BGISEQ stLFR
• Illumina 6kb
mate-pair
• HiC
• Strand-seq
Long reads
• PacBio
• PacBio CCS
• Promethion
• Ultralong Oxford
Nanopore
Optical/electronic
mapping
• BioNano
• Nabsys
ftp://ftp-trace.ncbi.nlm.nih.gov/giab/ftp/data/
Now >100x
public 10-15kb
CCS data for
HG002
18. Extensive “ultralong” ONT Data
3 Promethion
flow cells
110 MinION
flow cells
3 Promethion
flow cells
110 MinION
flow cells
4x >250kb
7x
>100kb
David Catoe
Nate Olson
Noah Spies
Marc Salit
Matt Loose
Nick Loman
Josh Quick
19. Extensive “ultralong” ONT Data
3 Promethion
flow cells
110 MinION
flow cells
3 Promethion
flow cells
110 MinION
flow cells
4x >250kb
7x
>100kb
David Catoe
Nate Olson
Noah Spies
Marc Salit
Matt Loose
Nick Loman
Josh Quick
20. Now using linked and long reads for
difficult variants and regions
GIAB Public Data
• Linked Reads
– 10x Genomics
– Complete Genomics/BGI stLFR
– Hi-C
– Strand-seq (underway)
• Long Reads
– PacBio Continuous Long Reads
– PacBio Circular Consensus Seq
– Oxford Nanopore “ultralong”
– Promethion
GIAB Use Cases
• Develop structural variant
benchmark
• Diploid assembly of difficult
regions like MHC
• Expand small variant benchmark
21. 50 to 1000 bp
Alu
Alu
1kbp to 10kbp
LINE
LINE
Discovery: 498876 (296761 unique) calls >=50bp and 1157458 (521360 unique) calls >=20bp
discovered in 30+ sequence-resolved callsets from 4 technologies for AJ Trio
Compare SVs: 128715 sequence-resolved SV calls >=50bp after clustering
sequence changes within 20% edit distance in trio
Discovery Support: 30062 SVs with 2+ techs or 5+ callers predicting
sequences <20% different or BioNano/Nabsys support in trio
Evaluate/genotype: 19748 SVs with consensus variant
genotype from svviz in son
Filter complex: 12745 SVs not within
1kb of another SV
Regions: 9641 SVs inside
2.66 Gbp benchmark
regions supported by
diploid assembly
v0.6
tinyurl.com/GIABSV06
22. Reference genomes and benchmark genomes
are converging
Reference genomes
that are polished
diploid assemblies of
open cell lines
Benchmark genomes
and tools to stratify
by genome context
and variant type
New diploid
assembly-derived
benchmarks
New tools to assess
diploid assembly
quality
23. The road
ahead... 2019
Integration pipeline development
for small and structural variants
Manuscripts for small and
structural variants
2020
Difficult large variants
Somatic sample development
Germline samples from new
ancestries
Diploid assembly
2021+
Somatic integration pipeline
Somatic structural variation
Large segmental duplications
Centromere/telomere
Diploid assembly benchmarking
...
24. Acknowledgment of many GIAB contributors
Government
Clinical Laboratories Academic Laboratories
Bioinformatics developers
NGS technology developers
Reference samples
* Funders
*
*
25. For More Information
www.genomeinabottle.org - sign up for general GIAB and Analysis Team google groups
GIAB slides, including 2019 Workshop slides: www.slideshare.net/genomeinabottle
Public, Unembargoed Data:
– http://www.nature.com/articles/sdata201625
– ftp://ftp-trace.ncbi.nlm.nih.gov/giab/
– github.com/genome-in-a-bottle
Global Alliance Benchmarking Team
– https://github.com/ga4gh/benchmarking-tools
– Web-based implementation at precision.fda.gov
– Best Practices at https://rdcu.be/bqpDT
Public workshops
– Next workshop planned for April 1-2, 2020 at Stanford University, CA, USA
Justin Zook: jzook@nist.gov
NIST postdoc
opportunities
available!
Diploid assembly,
cancer genomes,
other ‘omics, …
Editor's Notes
This is a good slide for 644:
give a clinical anecdote
Also numbers - attendance, publications, data, RM unit sales
Reference sample distributors
How much money from IAA?
- sustained funding
Quantify collaborators' input
GIAB steering committee
Examples of others contributing data, analyses
How to describe emails
This is a good slide for 644:
give a clinical anecdote
Also numbers - attendance, publications, data, RM unit sales
Reference sample distributors
How much money from IAA?
- sustained funding
Quantify collaborators' input
GIAB steering committee
Examples of others contributing data, analyses
How to describe emails