stephen friend mit 2011-10-20
DESCRIPTION
Stephen Friend, Oct 20, 2011. Massachusetts Institute of Technology, Cambridge, MATRANSCRIPT
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Novel Structures (and Non-Structures) to Facilitate Translational Research
Integrating layers of omics data models and compute spaces needed to build a “Knowledge Expert”
Stephen Friend MD PhD
Sage Bionetworks (Non-Profit Organization) Seattle/ Beijing/ Amsterdam
MIT/Whitehead October 10th, 2011
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Why not use data intensive science to build models of disease
Organizational Structures and Tools
How not What
Six Pilots
Opportunities
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Alzheimer’s Diabetes
Cancer Obesity Treating Symptoms v.s. Modifying Diseases
Will it work for me? Biomarkers?
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Personalized Medicine 101: Capturing Single bases pair mutations = ID of responders
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Reality: Overlapping Pathways
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The value of appropriate representations/ maps
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Equipment capable of generating massive amounts of data
“Data Intensive” Science- Fourth Scientific Paradigm
Open Information System
IT Interoperability
Host evolving Models in a Compute Space- Knowledge Expert
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WHY NOT USE“DATA INTENSIVE” SCIENCE
TO BUILD BETTER DISEASE MAPS?
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what will it take to understand disease?
DNA RNA PROTEIN (dark ma>er)
MOVING BEYOND ALTERED COMPONENT LISTS
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2002 Can one build a “causal” model?
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trait
How is genomic data used to understand biology?
“Standard” GWAS Approaches Profiling Approaches
“Integrated” Genetics Approaches
Genome scale profiling provide correlates of disease Many examples BUT what is cause and effect?
Identifies Causative DNA Variation but provides NO mechanism
Provide unbiased view of molecular physiology as it
relates to disease phenotypes
Insights on mechanism
Provide causal relationships and allows predictions
RNA amplification Microarray hybirdization
Gene Index
Tum
ors
Tum
ors
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Integration of Genotypic, Gene Expression & Trait Data
Causal Inference
Schadt et al. Nature Genetics 37: 710 (2005) Millstein et al. BMC Genetics 10: 23 (2009)
Chen et al. Nature 452:429 (2008) Zhang & Horvath. Stat.Appl.Genet.Mol.Biol. 4: article 17 (2005)
Zhu et al. Cytogenet Genome Res. 105:363 (2004) Zhu et al. PLoS Comput. Biol. 3: e69 (2007)
“Global Coherent Datasets” • population based
• 100s-1000s individuals
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SNP rs599839 in the 1p13.3 locus associated with CAD: PSRC1highlighted as candidate suscepUbility gene
Association of SNPs at 1p13.3 with Coronary Artery Disease
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Schadt et al, PLoS Biol. 2008
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Mouse network around Sort1, Psrc1, and Celsr2
Schadt et al, PLoS Biol. 2008
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Human network around Sort1, Psrc1, and Celsr2
Schadt et al, PLoS Biol. 2008
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Map compound signatures to disease networks
Sub-network contains
genes associated
with toxicities
Sub-network contains genes associated with diabetes
traits
Sub-network contains genes associated with obesity traits
1
2
3
Compound 1: Drug signature significantly enriched in subnetwork associated with diabetes traits
Compound 2: Drug signature significantly enriched in subnetwork associated with obesity traits
Compound 3: Drug signature significantly enriched in subnetwork associated with obesity traits BUT also in subnetwork associated with toxicities
Compound Gene expression signatures
Tissue Disease Networks
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Case Study – Target A/Drug B
Identified compound whose signature significantly intersected with Islet module
* * *
* * *
Fasting Insulin
Fasting Glucose
• Test carried out in a Diet-Induced Obesity model on the B6 background
• Model for obesity and insulin resistance • Animals treated with compound over an 8 week
interval, starting at 8 weeks of age • No significant Adverse Events in 30 day human
clinical trial for another indication
HF-DRUG
HF-DRUG
NO CELL DYNAMICS NEEDED
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db/db mouse (p~10E(-30))
AVANDIA in db/db mouse
= up regulated = down regulated
Our ability to integrate compound data into our network analyses
db/db mouse (p~10E(-20) p~10E(-100))
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"Genetics of gene expression surveyed in maize, mouse and man." Nature. (2003)
"Variations in DNA elucidate molecular networks that cause disease." Nature. (2008)
"Genetics of gene expression and its effect on disease." Nature. (2008)
"Validation of candidate causal genes for obesity that affect..." Nat Genet. (2009) ….. Plus 10 additional papers in Genome Research, PLoS Genetics, PLoS Comp.Biology, etc
"Identification of pathways for atherosclerosis." Circ Res. (2007)
"Mapping the genetic architecture of gene expression in human liver." PLoS Biol. (2008)
…… Plus 5 additional papers in Genome Res., Genomics, Mamm.Genome
"Integrating genotypic and expression data …for bone traits…" Nat Genet. (2005)
“..approach to identify candidate genes regulating BMD…" J Bone Miner Res. (2009)
"An integrative genomics approach to infer causal associations ...” Nat Genet. (2005)
"Increasing the power to detect causal associations… “PLoS Comput Biol. (2007)
"Integrating large-scale functional genomic data ..." Nat Genet. (2008)
…… Plus 3 additional papers in PLoS Genet., BMC Genet.
Metabolic Disease
CVD
Bone
Methods
Extensive Publications now Substantiating Scientific Approach Probabilistic Causal Bionetwork Models
• >80 Publications from Rosetta Genetics Group (~30 scientists) over 5 years including high profile papers in PLoS Nature and Nature Genetics
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50 network papers http://sagebase.org/research/resources.php
List of Influential Papers in Network Modeling
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(Eric Schadt)
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Recognition that the benefits of bionetwork based molecular models of diseases are powerful but that they require significant resources
Appreciation that it will require decades of evolving representations as real complexity emerges and needs to be integrated with therapeutic interventions
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Sage Mission
Sage Bionetworks is a non-profit organization with a vision to create a “commons” where integrative bionetworks are evolved by
contributor scientists with a shared vision to accelerate the elimination of human disease
Sagebase.org
Data Repository
Discovery Platform
Building Disease Maps
Commons Pilots
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Lee Hartwell Hans Wizgell WangJun Jeff Hammerbacher
Ex President FHCRC Co-Founder Rosetta
ExPresident Karolinska Head SAB Rosetta
Executive Director BGI
CEO Cloudera Built and Headed
Facebook Data Architecture
Board of Directors- Sage Bionetworks
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Sage Bionetworks Collaborators
Pharma Partners Merck, Pfizer, Takeda, Astra Zeneca, Amgen, Johnson &Johnson
28
Foundations Kauffman CHDI, Gates Foundation
Government NIH, LSDF
Academic Levy (Framingham) Rosengren (Lund) Krauss (CHORI)
Federation Ideker, Califarno, Butte, Schadt
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RULES GOVERN
PLAT
FORM
NEW
MAP
S PLATFORM
Sage Platform and Infrastructure Builders- ( Academic Biotech and Industry IT Partners...)
PILOTS= PROJECTS FOR COMMONS Data Sharing Commons Pilots-
(Federation, CCSB, Inspire2Live....)
NEW TOOLS Data Tool and Disease Map Generators- (Global coherent data sets, Cytoscape,
Clinical Trialists, Industrial Trialists, CROs…)
NEW MAPS Disease Map and Tool Users-
( Scientists, Industry, Foundations, Regulators...)
RULES AND GOVERNANCE Data Sharing Barrier Breakers-
(Patients Advocates, Governance and Policy Makers, Funders...)
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Why not share clinical /genomic data and model building in the ways currently used by the software industry (power of tracking workflows and versioning
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Evolution of a Software Project
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Biology Tools Support Collaboration
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Potential Supporting Technologies
Taverna
Addama
tranSMART
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Platform for Modeling
SYNAPSE
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Watch What I Do, Not What I Say Reduce, Reuse, Recycle
Most of the People You Need to Work with Don’t Work with You
My Other Computer is Amazon
sage bionetworks synapse project
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-‐-‐ Implement customTrain() andcustomPredict() funcUons-‐-‐ Everything else handled instandardized workflow(performance evaluaUon,biomarker outputs, evaluaUonagainst other methods, loading ofdifferent datasets, etc).
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INTEROPERABILITY
INTEROPERABILITY
Genome Pattern CYTOSCAPE tranSMART I2B2
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NOT JUST WHAT BUT HOW
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“hunter gathers”- not sharing
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TENURE FEUDAL STATES
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Clinical/genomic data are accessible but minimally usable
Little incentive to annotate and curate data for other scientists to use
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Mathematical models of disease are not built to be
reproduced or versioned by others
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Assumption that genetic alterations in human conditions should be owned
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Lack of standard forms for sharing data and lack of forms for future rights and consentss
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Publication Bias- Where can we find the (negative) clinical data?
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sharing as an adoption of common standards.. Clinical Genomics Privacy IP
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CTCAP Non-Responders Arch2POCM The Federation Portable Legal Consent Sage Congress Project
Six Pilots at Sage Bionetworks
RULES GOVERN
PLAT
FORM
NEW
MAP
S
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Clinical Trial Comparator Arm Partnership “CTCAP” Strategic Opportunities For Regulatory Science
Leadership and Action
FDA September 27, 2011
CTCAP
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Clinical Trial Comparator Arm Partnership (CTCAP)
Description: Collate, Annotate, Curate and Host Clinical Trial Data with Genomic Information from the Comparator Arms of Industry and Foundation Sponsored Clinical Trials: Building a Site for Sharing Data and Models to evolve better Disease Maps.
Public-Private Partnership of leading pharmaceutical companies, clinical trial groups and researchers.
Neutral Conveners: Sage Bionetworks and Genetic Alliance [nonprofits].
Initiative to share existing trial data (molecular and clinical) from non-proprietary comparator and placebo arms to create powerful new tool for drug development.
Started Sept 2010
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Shared clinical/genomic data sharing and analysis will maximize clinical impact and enable discovery
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Non-‐Responders Project
To identify Non-Responders to approved Oncology drug regimens in order to improve
outcomes, spare patients unnecessary toxicities from treatments that have no benefit to them, and
reduce healthcare costs
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The Non-‐Responder Cancer Project Leadership Team
11
Garry Nolan, PhD Professor, Baxter Laboratory of Stem Cell Biology, Department of Microbiology and Immunology, Stanford University Director, Proteomics Center at Stanford University
Richard Schilsky, MD Chief, Hematology- Oncology, Deputy Director, Comprehensive Cancer Center, University of Chicago; Chair, National Cancer Institute Board of Scientific Advisors; past-President ASCO, past Chairman CALGB clinical trials group
Todd Golub, MD Founding Director Cancer Biology Program Broad Institute, Charles Dana Investigator Dana-Farber Cancer Institute, Professor of Pediatrics Harvard Medical School, Investigator, Howard Hughes Medical Institute
Stephen Friend, MD, PhD President and Co-Founder of Sage Bionetworks, Head of Merck Oncology 01-08, Founder of Rosetta Inpharmatics 97-01, co-Founder of the Seattle Project
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The Non-‐Responder Project is an internaUonal iniUaUve with funding for 6 iniUal cancers anUcipated from both the public and private sectors
5
Ovarian Renal Breast AML Colon Lung
United States China
Seeking private sector and philanthropic funding for
prospec:ve studies
RetrospecUve study; likely to be funded by the Federal Government
Funded by the Chinese government and private sector partners
GEOGRAPHY
TARGET CANCER
FUNDING SOURCE
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For each tumor-‐type, the non-‐responder project will follow a commonworkflow, with paUent idenUficaUon and sample collecUon the mostvariable across studies
7
IdenUficaUon andEnrollment
Data andSample
CollecUon
SampleProcessing
ClinicalData
ReporUng
DiseaseModeling
Feedbackand Results
Payment and Reimbursement
Project Management
Non-‐Responder Project Workflow
The remaining parts of the study will belargely similar, and potenUally shared, across
all projects
IdenUficaUon and enrollment, and dataand sample collecUon may differ by
tumor-‐type
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A consorUum of collaborators has been constructed to execute the non-‐responder project
8
Physicians &AMCs
PaUentAdvocacyGroups
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A consorUum of collaborators has been constructed to execute the non-‐responder project (conUnued)
9
PaUent Consent
Pathology
GenomeSequencing
CoreBioinformaUcs
Analysis andDiseaseModeling
TBD
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Arch2POCM
Restructuring Drug Discovery
How to potenUally De-‐RiskHigh-‐Risk TherapeuUc Areas
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What is the problem? • Regulatory hurdles too high? • Low hanging fruit picked? • Payers unwilling to pay? • Genome has not delivered? • Valley of death? • Companies not large enough to execute on strategy? • Internal research costs too high? • Clinical trials in developed countries too expensive?
In fact, all are true but none is the real problem
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What is the problem?
We need to rebuild the drug discovery process so that webeMer understand disease biology before tes:ngproprietary compounds on sick pa:ents
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The FederaUon
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2008 2009 2010 2011
How can we accelerate the pace of scientific discovery?
Ways to move beyond “traditional” collaborations?
Intra-lab vs Inter-lab Communication
Colrain/ Industrial PPPs Academic Unions
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Shared data tools models and prepublications
Conflict of interests
Intellectual property Authorship
Rules of the game: transparency & trust
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sage federation: human aging project
Justin Guinney Stephen Friend*
Greg Hannum Januz Dutkowski Trey Ideker* Kang Zhang*
Mariano Alvarez Celine Lefebrev Andrea Califano*
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sage federation: what is the impact of disease/environment on “biological age” ?
Chronological Age
Biol
ogic
al A
ge
2001
2009
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human aging: predicting bioage using whole blood methylation
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Training Cohort: San Diego (n=170)
Chronological Age
Bio
logic
al A
ge
RMSE=3.35
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Chronological Age
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logic
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RMSE=5.44
• Independent training (n=170) and validation (n=123) Caucasian cohorts • 450k Illumina methylation array • Exom sequencing • Clinical phenotypes: Type II diabetes, BMI, gender…
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sage federation: model of biological age
Faster Aging
Slower Aging
Clinical Association - Gender - BMI - Disease Genotype Association Gene Pathway Expression Pr
edic
ted
Age
(live
r exp
ress
ion)
Chronological Age (years)
Age Differential
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Reproducible science==shareable science
Sweave: combines programmatic analysis with narrative
Sweave.Friedrich Leisch. Sweave: Dynamic generation of statistical reports using literate data analysis. In Wolfgang Härdle and Bernd Rönz,editors, Compstat 2002 –
Proceedings in Computational Statistics,pages 575-580. Physica Verlag, Heidelberg, 2002. ISBN 3-7908-1517-9
Dynamic generation of statistical reports using literate data analysis
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Federated Aging Project : Combining analysis + narrative
=Sweave Vignette Sage Lab
Califano Lab Ideker Lab
Shared Data Repository
JIRA: Source code repository & wiki
R code + narrative
PDF(plots + text + code snippets)
Data objects
HTML
Submitted Paper
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Portable Legal Consent
(Activating Patients)
John Wilbanks
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Sage Congress Project April 20 2012
RA Parkinson’s
Asthma
(Responders Competitions)
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Why not use data intensive science to build models of disease
Organizational Structures and Tools
How not What
Six Pilots
Opportunities