tranSMART Community Meeting 5-7 Nov 13 - Session 3: Characterization of the cell phenotypes involved in metastasis Characterization of the cell phenotypes involved in metastasis: Using tranSMART to enable high-throughput heterogeneous data integration and analysis Brian Athey, University of Michigan

1. tranSMART Overview
University of MichiganJohns Hopkins UniversityCollaboration
Brian D. Athey UM
Kenneth J. Pienta JHU
Kevin A. Smith UM
Terry E. Weymouth UM
6 November 2013
Sanofi tranSMART Paris Meeting

2. Presentation Outline
• Motivating & Conceptual Background
• tranSMART at Johns Hopkins University
– Overall Scope
– Scope of Pienta-Athey Lab Collaborative Demonstration Project
• Digital Microscopy Service, NCIBI tools and data, EMT-MET
Transformation
• Future: Establishing and harmonizing databases across The Brady
Institute
• Future: Evaluating PE or IDBS Electronic Laboratory Notebook (ELN)
integration; Institutional level
• tranSMART at Michigan
– PerkinElmer (PE) Spotfire Collaboration
– Current and Future

3. UMHS Data Architecture Unifying the Three Missions:
Education, Research, & Patient Care
Brian Athey
& ECRIT
1/11/11
Admissions
Research Pre,
Post- Award
Education
IT Security
IT SERCUIRTY
Ctools/Saki 3
Visiting Student
Application Service(VSAS)
M-Pathways
Research
Proteomics
Core
Metabolomics
Facilities/
‘Omics’
eThority
(billing)
Tissue
Biorepositories
Collexis
ULAM
Research
Administration
Data Warehouse
RedCAP
Populations
Research Individuals
Research &
BioDBX
Data
Quality
Velos
Management Diseases
Metrics
Systems
Data Marts
Demographics
OpenClinica
Others …
Registries
Research Data Warehouse
CareLink/
Eclipsys
Clinical
Quality
Analysis
Metrics
Database
Reporting
(CAD)
&
Peer
Others
Review
Pharmacy
Radiology
Scheduling
HIM/
Documentation
Others…
CDR
Epic Clarity
HSDW
i2b2
Emergency Med.
Patient Care Revenue Cycle
Systems
Pathology
Legacy+/Epic EHR
Enterprise Federated Data Warehouse
CAD
Historical
SPORES
Ambulatory
Data
Biomedical
Engineering
HIPAA/IRB Services (Honest Broker, DE-ID Consent Management, …)
Common Identifier Services (Patient, Provider, Information Bus
Service-Oriented Research, Specimens, External Mappings)
Vocabulary & Terminology Mapping Services (ICD-9/10 SNOMED, IMO, caDSR, ...)
ITIT Security
Security
Campus Systems
Curriculum Eval.
System
Bioinformatics
Research
Click
Administration
Commerce
Systems
(IRB)
Clinical Scheduling
& Grading System
Education
Knowledge
Repository
Next-Gen
Sequencing
Portals / Providers, Payors, P. Health Databases / HIEs / NHIN
Comprehensive
Clinical Assessment Exam
Messaging Bus, ETL & External Collaboration Services (SOA, caGRID, SHRINE, ...)
Health
Sciences
Library
Resources
NIH-Specific &
External Data
Resources
(PubMed, GenBank,
KEGG, GO, etc.)
High
Performance
Cloud
Computing &
Data Storage
Bioinformatics and Systems
Biology Workbenches
• Reporting
• Visualization
• Analysis &
• Data Mining
Data Sharing
with External
Collaborators
International
Industry:
Pharma/
caBIG
I2b2/ CTSAs Biotech
TCGA SHRINE

4. UMHS Data Architecture Unifying the Three Missions:
Education, Research, & Patient Care
Education
Admissions
Clinical Scheduling
Metabolomics
BioDBX
Individuals
Tissue
Biorepositories
Diseases
M-Pathways
eThority
(billing)
Velos
Others…
Collexis
ULAM
CTools/Sakai 3
IT Security
IT SERCUIRTY
Campus Systems
Curriculum
Evaluation System
Education
Knowledge
Repository
Research
Administration
Data Warehouse
CIDSS
Analytics
& Reporting
Tools
Populations
Pharmacy
Ambulatory
Emergency Med.
Pathology
Revenue Cycle
Demographics
Registries
Others …
Research Data Warehouse
CAD
i2b2
Others
Radiology
Scheduling
Centricity
Documentation
OpenClinica
SPORES
CareLink/
Eclipsys
Others…
CDR
HSDW
Historical
Data
HIM
Epic Clarity
Biomedical
Engineering
HIPAA/IRB Services (Honest Broker, De-ID Consent Management, …)
Common Identifier Services (Patient, Provider, Research, Specimens, External Mappings)
Vocabulary & Terminology Mapping Services (ICD-9/10 SNOMED, IMO, caDSR, ...)
ITIT Security
Security
Click
Commerce
(IRB)
Proteomics
RedCAP
Patient Care Systems
Legacy + Epic Epic EHR
Portals / Providers, Payors, P. Health Databases / HIEs / NHIN
Comprehensive
Clinical Assessment
Exam
Research
Research Core
AdministrationFacilities/‘Omics’
Quality
Systems
Metrics
Research &
Research
Quality Metrics Reporting
Data
Next-Gen
&
Management Data Marts
Sequencing
Research Pre,
Peer
Systems
Post- Award
Bioinformatics
Review
Brian Athey
& ECRIT
1/11/11
Messaging Bus, ETL & External Collaboration Services (SOA, caGRID, SHRINE, ...)
Health
Sciences
Library
Resources
NIH-Specific &
External Data
Resources
(PubMed, GenBank,
KEGG, GO, etc.)
High
Performance
Cloud
Computing &
Data Storage
Bioinformatics and Systems
Biology Workbenches
• Reporting
• Visualization
• Analysis &
• Data Mining
Data Sharing
with External
Collaborators
International
Industry:
Pharma/
caBIG
I2b2/ CTSAs Biotech
TCGA SHRINE

5. Supporting Academic Health Centers is beyond ‘just Epic’ :
Translational Biomedical Knowledge Creation & tranSMART
 Gender
 Ethnicity
 Age
 Weight
 Diagnosis
 Medical History
 Biological Models
 Technologies
 Algorithms
Research
 Lab Tests
 Genes
 Proteins
 Literature
 Databases
 Terminologies
 Ontologies

6. Conceptual Vision: Building a Knowledge Network
“Towards Precision
Medicine”, Institute
of Medicine (IOM);
2011, NAS.org.

7. The Science in the Middle: Linking models and driving problems to
measurement core facilities, enabled by tranSMART
Lee Hood IOM February 27, 2012

8. tranSMART | JHU | Scaling to Johns Hopkins Medicine
Platform Development Collaboration
Pienta /
Athey
Collaboration
•
•
•
•
•
•
3-D Imaging Cell Lines
3-D Tissue Imaging
Genomics, Epigenomics
Proteomics
Metabolomics
Data and Metadata
concerning studies
Brady
Urological
Institute
Other
Johns Hopkins
Units
• Bio-specimen Repositories
• Next Generation
Sequencing Core
• Morphology Core
• Specified links to CRM and
EHR resources
• Oncology Dept.
• Cancer Center
• Others
• Broader enablement of
Personalized Medicine

9. Bioinformatics/tranSMART
Trans-Brady Datamart/tranSMART
Clinical studies
Preclinical therapeutics
Preclinical Studies
Modeling
Mathematical Modeling
Theory
Pienta lab: The etiology of cancer cell dormancy
in the cancer ecosystem

10. Bioinformatics/tranSMART
Trans-Brady Datamart/tranSMART
Clinical studies
‘omics
Metabolism
anti-CXCR4
3D
Cytoskeleton
In vivo Dispersion studies
2DCell morphology
CD44
RBM3
OVO-ZEB
RCI
EMT-MET
Modeling
Dormancy
Pienta lab: The etiology of cancer cell dormancy
Stem?

11. tranSMART | JHU | The Brady
• Datasets to be harmonized and loaded into tranSMART
(patients & samples including biorepositories)
–
–
–
–
–
–
–
–
Primary prostatectomy (>10,000)
Active surveillance (>1000)
Familial genetics (>1000)
Radiation Oncology (>5000)
Advanced prostate cancer (>100)
Kidney cancer (>100)
Bladder cancer (>100)
Pediatric bladder extrophy (>500)

12. Presentation Outline
• tranSMART – Brief History / Current Use/Demo
• tranSMART at Johns Hopkins University
– Scope of Pienta-Athey Lab Collaborative Demonstration
Project (EPI-EMT Transformation in PCa)
– National Center for Integrative Biomedical Informatics
(NCIBI) Tools, PerkinElmer (PE) Spotfire
– Establishing and Harmonizing databases across The Brady
Institute
– Currently: Evaluating PE or IDBS Electronic Laboratory
Notebook (ELN)
– Future: Scaling more broadly to Johns Hopkins Medicine
• tranSMART at University of Michigan

13. tranSMART | JHU | Pienta-Athey Lab Project
• Platform Development of 3D Microscopic
Imaging Technologies, Analytical Pipelines,
and Data and Information Reporting Services
– Integrative characterization of the cell phenotypes
involved in metastasis
– Re-engineering image processing pipeline
• Accommodate fluorescence Interphase FISH
• Tissue imaging replacing Feulgen with DAPI or other
appropriate DNA staining

14. Fundamental Microscopy Data Types
• Nuclear Morphometry
• Nuclear size
• Nuclear circularity and shape parameters
• DNA content via integrated fluorescent signal
• Chromosome Territories
• Position, shape, volume
• Sub-territory bodies (loci, collections of loci, chromosomal
segments e.g. TDs)
• Position, shape, volume
• Immunofluorescence of , e.g., epigenetic histone marks
• Localization to CTs, sub-territory bodies, morphometric nuclear
regions

15. TMPRSS-ERG Fluorescence Micrograph
• Bracken, H,
et al,
Association
of SPINK1
Expression
and
TMPRSS2:E
RG Fusion
with
Prognosis in
EndocrineTreated
Prostate
Cancer.
Clin. Cancer
Res., 2010

16. Dataset Explorer – Images (prototype) 2

17. Athey Imaging Pipeline Service to tranSMART
Platform
Experiment
Cells, Prep, Features, Channels
Microscope Setup/Image
Full Image
Metadata
& DB
1K x 1K x Z x C
Grid Images
QC
C0 Nucleus Bounding Box
Spectral Unmixing …
1K x 1K x Z x C
Grid Images
Nucleus
BB
Raw
Raw C… Cn
Raw C1
Raw C0
Voxels and Clusters
For each BB
Voxel list file: x,y,z,v0, … vn
Image file: for each color
Stats: Min, Max, Stdev
Threshold: intensity and size
For each BB color cluster
Voxel list file: x,y,z,v
Voxels: count, centroid
Threshold: intensity and size
Electronic
Lab
Notebook
Outputs to
tranSMART
Tissue/Nuclear
Morphometry
Chromosome
Territories
Locus-specific
Immuno-fluor
Metadata for
above

18. tranSMART | JHU | Leveraging Global Initiatives
• NIH National Center for Integrative Biomedical
Informatics (NCIBI); Michigan-based
– Bioinformatics, Systems Biology Network Analysis,
Reference Data

19. NIH National Center for Integrative Biomedical
Informatics (NCIBI) integration with tranSMART
Tools
Data

20. NCIBI in tranSMART
Gene2MeSH
Metab2MeSH
The user can find Medical Subject
Headings (MeSH terms) enriched for a
particular gene with links to the
supporting PubMed publications.
The user can find Medical Subject
Headings (MeSH terms) enriched for a
particular compound with links to the
supporting PubMed publications.

21. NCIBI in tranSMART
Metscape
The user can visualize the interactions of
genes, enzymes, reactions and
compounds in human metabolomics
pathways.
ConceptGen
The user can find biomedical concepts
(pathways, MeSH terms, GO terms)
enriched for a list of genes or
associations between concepts based on
overlapping gene sets.

22. Demo Screenshots
Terry Weymouth
Tuesday, Nov 5, 2013

23. Demo Site Login

24. Dataset Explorer - Overview

25. Dataset Explorer – Summary Statistics

26. Dataset Explorer – Images (prototype) 1

27. Dataset Explorer – Hierarchical Clustering 1

28. Dataset Explorer – Hierarchical Clustering 2

29. Gene List Panel

30. NCIBI - Pubmed

31. NCIBI – Concept Explorer (ConceptGen)

32. NCIBI - Pubmed

33. NCIBI – Compound Network (MetScape)

34. NCIBI – Gene2Mesh

35. NCIBI – Metab2Mesh

36. Spotfire @ Michigan w/tranSMART

37. tranSMART Architecture – where Spotfire fits
Option 1 – as a Core Application with Information Links to the underlying Data Stores
Source: Stuart D, Harju J, Shi W, Hanauer D, Aronzon D, Liu J, Sharma R, Manion F, Xia H, Hutter C, Gruber S. tranSMART Supports a Post-GWAS Data Coordinating
Center. American Medical Informatics Association Annual Symposium, Chicago IL, November 4-7, 2012.

38. tranSMART Architecture – where Spotfire fits
Option 2 – as a Scientific Analysis Tool with capability to consume output from the
Core Applications
Source: Stuart D, Harju J, Shi W, Hanauer D, Aronzon D, Liu J, Sharma R, Manion F, Xia H, Hutter C, Gruber S. tranSMART Supports a Post-GWAS Data Coordinating
Center. American Medical Informatics Association Annual Symposium, Chicago IL, November 4-7, 2012.

39. Spotfire: Translational Data – Novel GEA analysis
Kruskal-Wallis test
of all significantly
differentially
expressed probes
vs. all clincal
response criteria
Overlay binned
gene expression
levels on time-ontrial plot
Embedded links out
to Entrez, Uniprot,
etc.

40. Spotfire: Translational Data – Merge NGS and GEA

41. tranSMART | UM | Scaling to U-Michigan Medicine
Platform Development Collaborations
Athey/
Burant
Collaboration
•
•
•
•
MRC2 NIH
Regional
Metabolomics
Center
Genomics, Epigenomics •
Proteomics
Metabolomics
•
Data and Metadata
•
concerning phenotypic
studies in investigational •
weight management clinic
•
Others
NIH National Metabolomics
DCC @ SDSC
Bio-specimen Repositories
Next Generation
Sequencing Core
Nutrition Core
Specified links to CRM and
EHR resources
•
•
•
•
Nephology
• Broader enablement of
Personalized Medicine
Cancer Center
Research IT
Others schools and colleges

42. Thank you/Questions/Discussion
Quiz: Which one is which?