clinical research platform to enable precision medicine ... · in collaboration with emc’s...
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1 © Copyright 2016 Dell . All rights reserved. 1 © Copyright 2016 Dell. All rights reserved.
Clinical Research Platform to Enable Precision Medicine and Govern Sensitive Data
Dr. Long Phe Le, Assistant Professor @MGH Dmitry Etin, eHealth Architect @ECD
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• Partners HealthCare System is an integrated health care network founded in 1994 by Brigham and Women’s Hospital and Massachusetts General Hospital, both teaching affiliates of Harvard Medical School.
• In addition to its two academic medical centers, the Partners HealthCare System includes community and specialty hospitals, a managed care organization, community health centers, a physician network, home health and long-term care services, and other health-related entities.
BWH MGH
PARTNERS HEALTHCARE SYSTEM
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Dell EMC/PHC Project GOALS In Collaboration with EMC’s Federation of Companies Partners will
develop a “Big Science” Research Computing Platform (RCaaS) – Flexible and elastic high performance computing (HPC) in hybrid clouds – Dynamic linking with data repositories across Academic Medical Centers – Utilizing of data from Epic, imaging, genomic, Lab and instrument feeds – A state-of-the-art Apps and Analytics Core for collaborative scientific
discovery
An investment to develop an innovative IT platform for realizing the “Learning HealthCare System”
– Meets the research and clinical innovation needs while bringing new commercialization / IP opportunities to EMC and PHC
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BioBank
Research Imaging
Genomic
EMR / HIE
Medical Imaging
Labs
Instruments
Research
Clinical
ETL
Service B
us S
SH
/Kerberos
Cloud Foundry
Cloud-Native Apps, Microservices, DevOps
Security and Data G
overnance
Security and Data Governance
Security and Data G
overnance
Scientific Computing Platform
• Medical image processing • Genome sequencing • Monte Carlo simulation • MPP workloads • Very large memory jobs
File Shares
CCR/CCD
Authentication and Authorization
Partners Authentication System
Active Directory
Kerberos LDAP
Data Ingestion Services
Spark Kafka
Scoop
Flume
Storm
Storage Services
Isilon Cloud Array Elastic Cloud Storage (ECS)
HDFS
SMB
NFS
S3
Platform Management
FBDL Ambari
vCenter
ESRS
YARN
Data and Analytics Services
Spark Hive
MapReduce
HAWQ
Greenplum
Raw Data
Research Sandboxes
dbSNP
Curated Data
CT.gov PHR / IoT
Genomic Data Trusts
Compute
VxBlock
VxRack
GPU
VxRail
ARCHITECTURE FRAMEWORK
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Clinical Cancer Genomics in Practice
Long Phi Le, MD, PhD
Director of Technology Development Department of Pathology
Center for Integrated Diagnostics Massachusetts General Hospital
Boston, MA [email protected]
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Clinical cancer genotyping Our current approach Clinical genomics workflow Clinical NGS informatics
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The New Paradigm in Cancer Treatment
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EGFR: Erlotinib/ Gefitinib 20% Lung adenocarcinomas
ALK: Crizotinib 3-5% Lung adenocarcinoma
BRAF V600E: PLX4032 60% Melanoma
BRAF 1799 T>A
V600E
KRAS: Cetuximab resistance 36-50% Colon adenocarcinoma
Molecular Markers and Targeted Therapy
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Complex Variants
copy number indels
SNVs
epigenetics non-coding RNAs
proteomics
gene expression
rearrangements
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Not So Common Recurrent Variants
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Real Life in a Molecular Diagnostic Lab
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More With Less
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Increasing Throughput; Decreasing Cost
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Next-Generation Sequencing: 1 tube to many reads
Next-Generation Sequencing
First Generation Sequencing
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Illumina Sequencing by Synthesis
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Cost of Next Generation Sequencing
Adapted from Nature 1 April 2010
Library Preparation Cost
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MGH CID Tumor Profiling
copy number indels
SNVs
epigenetics non-coding RNAs
proteomics
gene expression
rearrangements
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NGS Assays Comparison
Assay Sample Input Cost Turnaround Time Informatics Interpretation Discovery Potential
Hotspot + TSP + $ 1-2 weeks + + +
Rearrangement + $ 1-2 weeks + + +
100-200 Gene Panel ++ $$ 2-4 weeks +++ +++ ++
1000+ Gene Panel ++ $$$ 2-4 weeks ++++ ++++ ++++
Exome ++ $$$$$ 3-4 weeks +++++ ++++++ ++++++
Whole Genome ++ $$$$$$$ 4-8 weeks ++++++++ +++++++++++ ++++++++
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Solid Tumor DNA Panel
Clinical targeted sequencing of FFPE DNA • 1100+ amplicon targets (91 genes) • 100-200 median coverage • ~1-2 Gb data per sample • 5-10% analytical sensitivity • 2-3 week turnaround time Desired
• Sensitivity for hotspots • SNV, indel, copy number
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Solid Fusion Assay
Clinical targeted sequencing of FFPE DNA+RNA • 54 genes • ~0.5-1 Gb data per sample • 2-3 week turnaround time Desired
• Intragenic and intergenic fusion transcripts • Gene expression (future)
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Dr. Ignatius Ou, UC Irvine
Rapid Response to Crizotinib
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Identification of PF2341066
PF2341066 Inhibits ALK activity
PF2341066 demonstrates cytocidal activity in cells exhibiting ALK fusion (Pfizer in house)
PF2341066 activity in cells exhibiting ALK fusion in broad screen (MGH-McDermott)
Discovery of EML4-ALK fusions in NSCLC (CREST) Japan Science & Technology Agency)
2007
PF2341066 FIP May
2005 2006 2008 2009
Objective responses demonstrated in ALK fusion positive NSCLC and IMT
Phase III study of PF02341066 in ALK positive NSCLC starts
Slide Courtesy of Ross Camidge
Timeline for PF2341066 and ALK in NSCLC
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ROS1-translocated NSCLC Crizotinib Response
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SQSTM1-NTRK1 Fusion
Farago et al. JTO in press
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Clinical Response to Entrectinib
Farago et al. JTO in press
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Clinical Response to Entrectinib
Farago et al. JTO in press
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Clinical Genomics Workflow
Order Sample Submission
Pre-Analytical Wet Lab Sequencing
Primary Analysis
Variant Store
Variant Filtering
Variant Vetting
Variant Curation
Reporting Decision Support Action Outcome New
Knowledge
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MGH Molecular LIMS circa 2012
Report
Results
Worksheets
Path Review
Requisition
Consent
Path Report
* 1 Patient with 1 surgical specimen may have 6+ different tests
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Clinical Genomics Workflow: The Laboratory
Order Sample Submission
Pre-Analytical Wet Lab Sequencing
Molecular LIMS
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Molecular Lab Asset Graph
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Clinical Genomics Workflow
Order Sample Submission
Pre-Analytical Wet Lab Sequencing
Primary Analysis
Variant Store
Variant Filtering
Variant Vetting
Variant Curation
Reporting Decision Support Action Outcome New
Knowledge
Molecular LIMS
Pipeline VarVault VarVetter WikiVar
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Clinical Genomics Workflow: Primary Analysis
Primary Analysis
Variant Store
Variant Filtering
Variant Vetting
Variant Curation
Alignment Variant Calling Reads Variant Annotation
BRAF p.V600E (c.1799T>A)
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Bioinformatics
Collaborator
Cloud
Cluster
• Takes days to prepare • Error-prone • Different versions • Unknown behaviors
CIDer2.0: MGH CID Bioinformatics Pipeline
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From Seeds to Trees
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Clinical Genomics Workflow: Primary Analysis
Primary Analysis
Variant Store
Variant Filtering
Variant Vetting
Variant Curation
#CHROM POS ID REF ALT QUAL FILTER INFO 1 866319 rs9988021 G A SNPEFF_EFFECT=INTRON;SNPEFF_EXON_ID=3;SNPEFF_FUNCTIONAL_CLASS=NONE;SNPEFF_GENE_BIOTYPE=protein_coding;SNPEFF_GENE_NAME=SAMD11;SNPEFF_IMPACT=MODIFIER;SNPEFF_TRANSCRIPT_ID=ENST00000342066;alt_fpir=12;alt_rpir=137;contaminant_fraction=0.02;contaminant_lod=-0.008774;covered=UNCOVERED;dbsnp_site=DBSNP;failure_reasons=fstar_tumor_lod,possible_contamination;improper_pairs=0;init_n_lod=-0.693147;init_t_lod=4.782546;judgement=REJECT;map_Q0_reads=0;n_alt_count=0;n_alt_sum=0;n_lod_fstar=0;n_q20_count=0;n_ref_count=0;n_ref_sum=0;normal_best_gt=TT;normal_f=0;normal_name=none;normal_power=0;normal_power_nsp=0;normal_power_wsp=0;observed_in_normals_count=0;power=0;power_to_detect_negative_strand_artifact=0;power_to_detect_positive_strand_artifact=0.999333;score=0;strand_bias_counts=(0,0,0,1);t_alt_count=1;t_alt_sum=39;t_del_count=0;t_ins_count=0;t_lod_fstar=4.377067;t_lod_fstar_forward=0;t_lod_fstar_reverse=4.377067;t_q20_count=1;t_ref_count=0;t_ref_sum=0;total_pairs=1;tumor_alt_fpir_mad=0;tumor_alt_fpir_median=12;tumor_alt_rpir_mad=0;tumor_alt_rpir_median=137;tumor_f=1;tumor_name=P701_A01;tumor_power=0;dbSNPBuildID=1191 866371 . G T . .
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Clinical Genomics Workflow: Secondary Analysis
Primary Analysis
Variant Store
Variant Filtering
Variant Vetting
Variant Curation
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Clinical Genomics Workflow: Tertiary Analysis
Primary Analysis
Variant Store
Variant Filtering
Variant Vetting
Variant Curation
Variant
Chromosome Position
REF
ALT
Gene Coding Change Protein Change
Relevance Association
Evidence
Therapy
Reference
Tissue
Disease
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Emerging
Other relevant variants Prognostic
Diagnostic
Therapeutic/Predictive Unknown
Actionable
Reportable
Consensus
FDA
Guidelines
Late trials
Early trials
Case Reports
Preclinical
Strong evidence
Variants in known oncogenes
Variants in known tumor suppressor
genes
Other relevant genomic alterations
Pathways
Dienstmann R. et al, Molecular Oncology 2014
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• Next-generation sequencing offers the throughput and scalability to achieve
broad-based clinical cancer genotyping
• Challenges in broad deployment:
• Lack of training/expertise
• Complex variant assessment/interpretation with dynamic evidence
• Lack of end-to-end informatics solution
Summary
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Acknowledgments
John Iafrate Marianne Boswell Gaddy Getz Joe Lennerz Zongli Zheng Hayley Robinson Julie Batten Yi Cao Amelia Raymond Caitlin Finn Valentina Nardi Dora Dias-Santagata Miguel Rivera Darrell Borger Kerry Lynch
Maciej Pacula Saeed Al Turki Elliott Moy Sekhar Duraisamy Allison Macleay Mick Zomnir Edana Merchan Lev Lipkin Martin Aryee Spring Liu
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Universal case: Treating Cancer Patient with Precision Medicine
Cancer Patient
Genomics Diagnostics
Pathology
EMR
Public KB
NGS
Curated DB
Therapy
Orde
r
Targeted Therapy
Protocol 1
Protocol 2
Protocol 3Clinical Diagnostics
Compliant Data Lake
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Searchable domain-specific data layer
Data Catalog
Governance / Access policies
Compliant Data Store (Externally certified
data)
Secondary data
EMC Business Data Lake Foundation
Clinical
DICOM
OMICs
Sensors
Domain-specific tools, apps and services
Database indices
NLP indices BI indices
Associations
Meta4
Text analytics
Termino logy
Bio informatics pipelines
Anoni mization
Community sharing
Data lake refactoring Research Sandboxes
Collaboration toolset
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Compliancy For the Healthcare Data Lakes
Health and Genomic Data
Clinical Trial and Research results
Integrated Clinical Genomics Data Model
Unstructured Data
Ingest ETL
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Take aways
Patient centric
Driven by clinicians
Regulation isn’t a
showstopper Data
accessibility
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ECD SERVICES
Genius Labs Garden Level
Foyer
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Solution for growth
Persistent Data Vault
Inferred Data Vault
Data Lake Foundation
2 3
Platform Services
Platform Tools
1
Searchable Data Layer
Data Lake UI BI Analytical
Workbench
Governance / Access Policies Store
4Data Catalog
56 7