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Systems ReconstructionTM Technology
CONFIDENTIAL
Analysis of Proteomics Data in the Context of Human Systems Biology
Tatiana Nikolskaya, PhD
SCO & President, GeneGo, Inc
April 22, 2004
Workshop II: Medical Applications and Protein Networks
Copyright GeneGo 2000-2003
Why Systems Reconstruction?
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Avalanche of genomic, gene expression, proteomic, metabolomic data on
one hand
Complex human diseases and patient’s data on the other
Understanding of the actual cause of complex diseases on molecular
level is still at its infancy
To the HT data mining boils down to statistical analysis
Integration, visualization and data mining of each and every type of HT
remains a BIG problem
How to bring different types of molecular and clinical data together?
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Systems Reconstruction Technology
Pathway-centered database
Clean and comprehensive content: human cellular pathways
Necessary tools to manipulate each and every type of molecular data
Identified links between pathway elements and human diseases
Ability to retrieve disease-specific pathways
Ability to identify and propose missing/unknown pathways from HT data
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Copyright GeneGo 2000-2003
CONFIDENTIAL
MetaCore™ Platform
SNP
Analysis
Tools
Importing
Tools
Gene Expression Tools:
Affy, Agilent, Resolver parsers
Pathway
Editor
Network
Tools
SAGE
analysis tools
Visualization
Tools
Proteomics
Tools
Metabolomics
Tools
Proprietary Content of 23,000 curated pathway building blocks
Novel Database Architecture
Oracle Based
150 relational tables
Copyright GeneGo 2000-2003
What makes MC special?
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CONFIDENTIAL
The most comprehensive DB of human pathways:
– 23,000 human 1-step pathway blocks, rat and mouse orthologs
– Vertical integration of pathways: from receptors to core effectors
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Extensive manual pathway curation:
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Associations with human diseases/conditions
Tissue specificity, sub-cellular localization, effects, mechanisms
>270,000 synonyms resolved
Custom pathway editor to add/change the pathways
Unique database architecture:
– Pathways is the backbone for experimental data, literature info
– Concurrent mapping of different types of HT data on maps and networks
– Multiple time points, treatments/dosages, custom colors, custom ranges
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Flexible visualization tools and options:
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Mapping of customer’s data on maps and computer-generated networks
Disease- and tissue-specific filters
Tools for expanding and collapsing pathways on networks
User’s choice between data sets and algorithms for generating networks
Tools for reducing overall network’s complexity and expanding it
Copyright GeneGo 2000-2003
MetaCoreTM: Content and Capabilities
MetaCoreTM, a database of human
metabolism and its regulation
CONFIDENTIAL
MetaCoreTM, data-mining tools,
algorithms and visualization
23,000 pathway building blocks
Metabolic and signaling networks
>300 expert-curated maps
Rat and Mouse orthologs
270,000 synonyms resolved
Pathway editor
32,000 pathway/disease links
3,250 human diseases
Transcriptional factors and sites
1,200 journals/37,000 unique ref
Concurrent visualization of HT data
Affymetrix and Agilent array parsers
Proteomic and metabonomic parsers
Custom and NCBI SAGE data parser
Copyright GeneGo 2000-2003
CONFIDENTIAL
MC: The Most Comprehensive Database on Human Biology
Affymetrix
chip ID
U95Av2
HG-U133A
HG-U133B
GeneGo
MetaCore
~82 %
~40 %
GeneLogic
GeneExpress
~20 %
~8 %
SpotFire
~16%
~5%
75% of known human proteins can be visualized on maps and
networks
Copyright GeneGo 2000-2003
Pathways in MetaCore: Maps and Networks
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Interactive, static maps
– >300 maps
– Signaling, receptors,
metabolism
– Backbone of formalized “state of
art” in the field
Networks of protein interactions
– Dynamic; built “on-the-fly”
– Exploratory tool
– Build new pathways for genes
of interest
Copyright GeneGo 2000-2003
CONFIDENTIAL
Why Manual Curation?
Microarray
A
Source of interaction
NLP associations
MC curated networks
Two hybrid
screen
2D gel
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C
D
P interaction
Confidence in a 4 step
pathway
.25
.4%
.5
6%
.75
30%
.99
96 %
Copyright GeneGo 2000-2003
Projected number of 5-step pathways
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5
More than 2,000,000,000 5-step pathways
Copyright GeneGo 2000-2003
Maps and Networks Legend
CONFIDENTIAL
Copyright GeneGo 2000-2003
MetaCoreTM: Depth and precision…
CONFIDENTIAL
1. transcription
2. processing RNA
3. transport PNA
from nucleus
4. stabilization of
RNA
5. translation
6. Protein transport
7. Folding &
stabilization
8. allosteric
modification
9. covalent
modification
Copyright GeneGo 2000-2003
MC: Reconstruction of “Vertical” Pathways from
Receptors to Core Effectors
CONFIDENTIAL
adenosine
Copyright GeneGo 2000-2003
Unique Capabilities: Visualization of Different
Types of HT Data within the Same System
Gene
expression
CONFIDENTIAL
Protein
levels
Protein
Interactions
Metabolite
concentrations
Data parsers link user’s data to relevant
molecular objects in MetaCore DB
Copyright GeneGo 2000-2003
Concurrent Visualization of Different HT data
Agilent
Affymetrix
Proteomic
CONFIDENTIAL
SAGE
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CONFIDENTIAL
MC : Relevance to Human Diseases
Breast cancer
Alzheimer disease
lung carcinoma
Alzheimer disease
chronic
Leukemia
breast cancer
Cancer
Breast cancer
Brain tumors
adenocarcinoma
Tangier disease
breast cancer
Alzheimer disease
neuroblastoma
T cell lymphoma
Breast cancer
bladder transitional cell
carcinoma
bladder cancer
lung cancer
squamous cell carcinoma
Alzheimer disease
diabetes mellitus
Alzheimer disease
colorectal carcinoma
breast cancer
Parkinson disease
pancreatic cancer
glioblastoma
Alzheimer disease
chronic
myelogenous
leukemia
Wiskott-Aldrich syndrome
Friedreich ataxia
Alzheimer disease
Parkinson disease
Prostate cancer
nephronophthisis 1
Alzheimer disease
Alzheimer disease
Parkinson disease
B-cell chronic
lymphocytic leukemia
Friedreich ataxia
BorjesonForsmanLehmann
syndromecondent
ial cerebellar
hypoplasia
Acute myelogenous leukemia
Creutzfeldt-Jakob disease
Parkinson disease
bladder cancer
Lupus erythematosus
polycystic kidney disease
cystic fibrosis
Alzheimer disease
squamous cell carcinoma
hepatocellular carcinoma
Bladder cancer
Copyright GeneGo 2000-2003
MC Value: HT Data Mining. Maps
Inhibitors upregulated in
Down-regulated
Glaucoma
in Glaucoma
CONFIDENTIAL
Copyright GeneGo 2000-2003
MC value: HT Data Mining. Networks
CONFIDENTIAL
Copyright GeneGo 2000-2003
CONFIDENTIAL
MC value: Identify Novel Pathways for Your Genes
Copyright GeneGo 2000-2003
User Chooses Network-creating Algorithms
CONFIDENTIAL
Copyright GeneGo 2000-2003
Generate Networks From the List of
Genes/Proteins.
CONFIDENTIAL
Through
Internal
transcriptional
database
Copyright GeneGo 2000-2003
Generate Networks around Single Gene/Protein
CONFIDENTIAL
Copyright GeneGo 2000-2003
Custom Ranges and Colors
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1. Select experiment
2. Show all descriptions
3. Add ranges
4. Switch to indicator state
5. Select ranges to visualize
Copyright GeneGo 2000-2003
Pathway Editor: view/edit Interactions
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1. Search for a protein class
2. View its interactions
3. Edit interactions
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Edit effect
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Edit mechanism
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Insert references
Copyright GeneGo 2000-2003
Pathway editor: adding new interactions
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1. Search for new interaction’s
vertices and their existing
interactions
2. Edit existing existing interactions
(if any) or add a new one
3. Use pull-down menus to specify
effect and mechanism (if known)
4. Add references
Copyright GeneGo 2000-2003
Hardware requirement,
Maintenance and Upgrades
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Server
– Oracle 8 DBMS or higher, Apache web server with mod_perl
– 2 or more P4/XEON CPU’s with 512-1024 MB of RAM recommended
– SCSI HDD is recommended
– Linux OS 7.3 (RedHat)
– MetaCore™ takes about 300MB of space
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Client:
– Internet Explorer 6.0 or higher is required
– Macromedia Flash 6 (MX) Plug-In is required
– P4 CPU and 256MB of RAM is recommended
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Maintenance is included in the annual fee
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Updates will be shipped quarterly
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Web based, easy to use and access
Copyright GeneGo 2000-2003