The Search for Cancers Causes and Cures

Wade L. Schulz, MD, PhD

Yale University, Department of Laboratory Medicine

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Cancer Statistics An Improving Outlook?

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Incidence Mortality

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Precision Medicine

Tailoring medical therapy to a particular patients characteristics

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Presentation to Precision Care

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Images adapted from Servier Medical Art, CC-BY

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When Cells Go Bad

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Genetics in 60 Seconds

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Genetics in 60 Seconds

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Searching for Mutations

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Gels and Capillaries

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Next Generation Sequencing

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Massively Parallel

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NGS The Technology

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Moore's Law Cost per Genome

Cost of Sequencing

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Bases to Bytes

23 chromosomes 21,000 genes 3,300,000,000 base pairs

3.3e9 bases X 2 bits 825 MB/sequence

With metadata: 150 GB/sequence

3,000,000 variants/genome

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How big is the genome?

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What are the Problems?

Constantly evolving data schema

Ability to integrate diverse data silos

Rapidly increasing needs for data storage

Need for easy, flexible analysis

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Why Elasticsearch?

- Rapid on-premise and cloud installations

- Dynamic schema that supported clinical results and annotation data

- Availability of libraries for multiple languages (NEST, elasticsearch-py)

- Tool availability (Kibana, Shield)

Its great!

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Sequencing and Interpretation Pipeline

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Gene Sequencing

Sequence Alignment

Quality Assurance

Variant Annotation

Clinical Interpretation

Clinical Trial Eligibility

ResearchManagement

{galileo} {kepler}

{galileo} {galileo/kepler}{galileo/kepler}

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Whats in a Variant?

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60G6V:01053:03044 16 chr1 161383 0 16M * 0 0 TTTGCCAGAAAGCAAG

)///7;;6*669:1:5 ZP:B:f,0.00279573,0.0054005,2.19516e-07

ZM:B:s,244,0,242,0,0,242,2,270,494,300,0,248,36,0,0,0,272,0,204,272,398,248,246,268,270,0,0,0,302,0,0,0,550,

38,44,194,14,32,204,2,666,212,222,494,2,2,238,630,92,220,4,102,438,2,60,384,2,76,2,2,294,394,34 ZF:i:28

RG:Z:60G6V. PG:Z:tmap MD:Z:16 NM:i:0AS:i:16 XA:Z:map4-1 XS:i:16

60G6V:00605:00113 0 chr1 415215 2 8M5I31M3S * 0 0

CCAGCCTGGGTGCGTGACAGAGCAAGACTCCGTCTAAAAAGAAAGGT

B

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Whats in a Variant?

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{ "chromosome": "chr7", "position": 148506396, "type": "snv", "refAllele": "A", "altAllele": "C", "totalReads": 1998, "forwardReads": 1038, "forwardRefReads": 524, "forwardAltReads": 514, "reverseReads": 960, "reverseRefReads": 500, "reverseAltReads": 460, "refReads": 1024, "altReads": 974, "vaf": 48.749, "variantRegion": "intronic", "variantEffect": "", "snvEffect": "A>C", "gene": "EZH2

}

- Variant location in genome

- Nucleotide change

- Sequencing statistics

- Variant prevalence in specimen

- Variant coding/protein effects

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{Elastic} Searching for Meaning

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AzureElasticsearch

Local SQL and Elasticsearch

OMIM

COSMIC

dbSNP

ClinVar

Public Databases

Sequencers Variant AnalysisEffect Prediction

Public Variant Data

Private Variant Data

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{Elastic} Searching for Meaning

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OMIM

COSMIC

dbSNP

ClinVar

Public Databases

Sequencers Variant AnalysisEffect Prediction

Public Variant Data

Private Variant Data

MVC Application(NEST)

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Kibana Drilldown

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Rapid population stats

Physicians/researchers can quickly analyze data

Integration with health record

Demographics

Laboratory testing

Comorbidities

Treatment information

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Kibana Drilldown

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Service Integration

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Predictive Algorithms

Quality Assurance-3

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Variant Database

Clinical Interpretation

System

Web Service

Interfaces

Custom Validation

Scripts

Third-Party

Data Analysis

Software

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Data Sharing

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Variant Database

Clinical Interpretation

System

Web Service

Interfaces

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Conclusions

- Genetic sequencing and

clinical consultation complete

within one week of biopsy

- Integrated multiple analysis

pipelines for clinical

interpretation and research

applications

- Frequently identify patients

eligible for clinical trials

Clinical implications

- Two Elasticsearch clusters

- Over 60 million variant

annotations

- Nearly 10 million documents

related to cancer-associated

mutations

- Kibana and custom web

applications using NEST for

data visualization

System statistics

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Thank you!

Wade L. Schulz, MD, PhD

wade.schulz@yale.edu

http://www.wadeschulz.com

Many images adapted from Servier Medical Art, CC-BY

Henry Rinder MD, Richard Torres MD, Christopher Tormey MD, Brian Smith MD, John Howe PhD,

Karl Hager PhD, Rodion Rathbone MD, Nathaniel Price, Alexa Siddon MD

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This work is licensed under the Creative Commons

Attribution-NoDerivatives 4.0 International License.

To view a copy of this license, visit:

http://creativecommons.org/licenses/by-nd/4.0/

or send a letter to:

Creative Commons

PO Box 1866

Mountain View, CA 94042

USA

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