visualization of adverse effect pathways hristo aladjov
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VISUALIZATION OF ADVERSE EFFECT PATHWAYSHristo Aladjov
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OVERVIEW
Overview
What are adverse effect pathways ?
Challenges of the Adverse Effect Pathways ?
What are some of the existing solutions for representing pathways ?
Why Adverse Effect Pathways are important for QSAR models ?
The Solution
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OVERVIEW
What are Adverse Effect Pathways
Generalized Estrogen Receptor (ER) Adverse Effect Pathway
ER BindingAlteredProtein
Expression
Sex Reversal,Altered
Behavior,↓Repro.
Skewed Sex Ratios,
↓Year Class
MOLECULARInitiating Event
CELLULARResponse
TISSUE/ORGANResponse
INDIVIDUALResponse
POPULATIONResponse
Altered proteins
Ova-testis
MOLECULARInitiating Event
CELLULARResponse
TISSUE/ORGANResponse
INDIVIDUALResponse
AChEBinding
AlteredIntra-
cellularSignaling
Brain: Loss of
synaptic connect.
Behavior:Impaired cognitive function
Altered Cell
Structure
CELLULARResponse
Adverse Effect Pathway of Developmental Neurotoxicity in Humans
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CHALLEN
GES O
F THE ADVERSE EFFECT PATH
WAYS
Challenges of the Adverse Effect Pathways
Complexity
Multidisciplinary
Lack of unified pathway representation language
Accessibility to the scientific community and the public
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EXISTING
SOLU
TION
S Existing Solutions
System biology models advantages
o Systematic description of the complex interactions in biological systems
o Integrate and analyze complex data from multiple experimental sources
System biology models disadvantages
o Exhaustive complexity not focused by the subject of study
o Focus on molecular level
o Investigating the continuous uncompensated dysfunction
ToxRefDB
o Collection of endpoints
ToxCast
o Collection of in-vitro cellular assays
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First Rule of QSAR: Select well defined Endpoint
Model different mechanisms/modes of action separately
Separate chemical models from biological effects
Use transparent mechanistically interpretable methods
Use good quality data
QSAR M
OD
ELS AND
ADVERSE EFFECT PATHW
AYS QSAR models and Adverse Effect Pathways
Inspiring the Next Generation QSAR Models,
based on classic rules
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THE ONLINE ENCYCLOPEDIA OF ADVERSE EFFECT PATHWAYS
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EFECTOPED
IA.QSARI.O
RGEffectopedia – Adverse Effect Pathways Representation System
Simple enough to make it manageable, complex enough to be useful
Build the pathways from both ends
Brake the complexity with simple questions
Provide organized slots and global context for integrating individual experts knowledge
Create efficient way of expert collaboration
Create open standard for pathway presentation
Make all data freely accessible online
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PATHW
AY BUILD
ING
BLOCKS
Use Simple Building Blocks
Cause Link Effect
Chemical Molecular Initiating Event Effect
Molecular Initiating Event Effect Endpoint
Threshold Dose-Response Reversible or not Specific or not Duration
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Coordinates in Pathway Space
Effect:…
maleadult
humanLiver
…Level of Biological Organization
TaxonomyG
ende
r
Life
Stag
e
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EFECTOPED
IA.QSARI.O
RGStart form both ends
Chemical Endpoint
MIE 1
MIE 2
MIE n
Effect 1
Effect 2
Effect n1
Effect 1
Effect 2
Effect n1
Effect 1
Effect 2
Effect n1
Effect 1
Effect 2
Effect n
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EFECTOPED
IA.QSARI.O
RGBreaking Complexity with simple Questions
Effect
Effect 1
What Other Downstream effects you
know?
Effect 2
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EFECTOPED
IA.QSARI.O
RGBreaking Complexity with simple Questions
Effect
Cause 1
What other causes you
know can lead to this effect?
Cause 2
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EFFECTOPED
IA.QSARI.O
RGDysfunction Duration as a Cause
Effect
Endpoint1
Endpoint2
Link conditions:
Duration 1
Link conditions:
Duration 2
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EFFECTOPED
IA.QSARI.O
RGDemo
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FREE, PLATFORM
IND
EPEND
ENT, O
PEN SO
URCE
Technology
<? XML ?>
Based entirely on open source platform independent solutions
Accessible with standard web browser
Creates search engine optimized static HTML pages for higher visibility
Standard XML based language for direct data import / export
Modular, Plug-in architecture
Open source
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CON
CLUSIO
NS
Benefits
QSAR models can be used for what they are good for – predicting molecular initiating events and identifying chemicals with similar behavior without additional animal testing
Provide a global context and new applications of existing experimental data
Create public knowledge repository that stimulate research and modeling efforts
Outline the most frequently used tests in regulatory decision making process to facilitate the search for alternative methods.
Help indentify missing information and facilitate experiment design.
Create focused and effective discussion environment