clinical research platform to enable precision medicine ... · in collaboration with emc’s...

Clinical Research Platform to Enable Precision Medicine and Govern Sensitive Data

Dr. Long Phe Le, Assistant Professor @MGH Dmitry Etin, eHealth Architect @ECD

• 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

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

BioBank

Research Imaging

Genomic

EMR / HIE

Medical Imaging

Instruments

Research

Clinical

Service B

/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

Storage Services

Isilon Cloud Array Elastic Cloud Storage (ECS)

Platform Management

FBDL Ambari

vCenter

Data and Analytics Services

Spark Hive

MapReduce

Greenplum

Raw Data

Research Sandboxes

Curated Data

CT.gov PHR / IoT

Genomic Data Trusts

Compute

VxBlock

VxRack

VxRail

ARCHITECTURE FRAMEWORK

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 lple@partners.org

Clinical cancer genotyping Our current approach Clinical genomics workflow Clinical NGS informatics

The New Paradigm in Cancer Treatment

EGFR: Erlotinib/ Gefitinib 20% Lung adenocarcinomas

ALK: Crizotinib 3-5% Lung adenocarcinoma

BRAF V600E: PLX4032 60% Melanoma

BRAF 1799 T>A

KRAS: Cetuximab resistance 36-50% Colon adenocarcinoma

Molecular Markers and Targeted Therapy

Complex Variants

copy number indels

epigenetics non-coding RNAs

proteomics

gene expression

rearrangements

Not So Common Recurrent Variants

Real Life in a Molecular Diagnostic Lab

More With Less

Increasing Throughput; Decreasing Cost

Next-Generation Sequencing: 1 tube to many reads

Next-Generation Sequencing

First Generation Sequencing

Illumina Sequencing by Synthesis

Cost of Next Generation Sequencing

Adapted from Nature 1 April 2010

Library Preparation Cost

MGH CID Tumor Profiling

copy number indels

epigenetics non-coding RNAs

proteomics

gene expression

rearrangements

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 ++++++++ +++++++++++ ++++++++

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

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)

Dr. Ignatius Ou, UC Irvine

Rapid Response to Crizotinib

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)

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

ROS1-translocated NSCLC Crizotinib Response

SQSTM1-NTRK1 Fusion

Farago et al. JTO in press

Clinical Response to Entrectinib

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

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

Clinical Genomics Workflow: The Laboratory

Molecular LIMS

Molecular Lab Asset Graph

Clinical Genomics Workflow

Primary Analysis

Variant Store

Variant Filtering

Variant Vetting

Variant Curation

Reporting Decision Support Action Outcome New

Knowledge

Molecular LIMS

Pipeline VarVault VarVetter WikiVar

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)

Bioinformatics

Collaborator

Cluster

• Takes days to prepare • Error-prone • Different versions • Unknown behaviors

CIDer2.0: MGH CID Bioinformatics Pipeline

From Seeds to Trees

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 . .

Clinical Genomics Workflow: Secondary Analysis

Primary Analysis

Variant Store

Variant Filtering

Variant Vetting

Variant Curation

Clinical Genomics Workflow: Tertiary Analysis

Primary Analysis

Variant Store

Variant Filtering

Variant Vetting

Variant Curation

Variant

Chromosome Position

Gene Coding Change Protein Change

Relevance Association

Evidence

Therapy

Reference

Tissue

Disease

Emerging

Other relevant variants Prognostic

Diagnostic

Therapeutic/Predictive Unknown

Actionable

Reportable

Consensus

Guidelines

Late trials

Early trials

Case Reports

Preclinical

Strong evidence

Variants in known oncogenes

Variants in known tumor suppressor

Other relevant genomic alterations

Pathways

Dienstmann R. et al, Molecular Oncology 2014

• 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

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

Universal case: Treating Cancer Patient with Precision Medicine

Cancer Patient

Genomics Diagnostics

Pathology

Public KB

Curated DB

Therapy

Targeted Therapy

Protocol 1

Protocol 2

Protocol 3Clinical Diagnostics

Compliant Data Lake

Searchable domain-specific data layer

Data Catalog

Governance / Access policies

Compliant Data Store (Externally certified

Secondary data

EMC Business Data Lake Foundation

Clinical

Sensors

Domain-specific tools, apps and services

Database indices

NLP indices BI indices

Associations

Text analytics

Termino logy

Bio informatics pipelines

Anoni mization

Community sharing

Data lake refactoring Research Sandboxes

Collaboration toolset

Compliancy For the Healthcare Data Lakes

Health and Genomic Data

Clinical Trial and Research results

Integrated Clinical Genomics Data Model

Unstructured Data

Ingest ETL

Take aways

Patient centric

Driven by clinicians

Regulation isn’t a

showstopper Data

accessibility

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ECD SERVICES

Genius Labs Garden Level

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Solution for growth

Persistent Data Vault

Inferred Data Vault

Data Lake Foundation

Platform Services

Platform Tools

Searchable Data Layer

Data Lake UI BI Analytical

Workbench

Governance / Access Policies Store

4Data Catalog

clinical research platform to enable precision medicine ... · in collaboration with emc’s...

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