1. Visualization of Adverse effect pathways
Hristo Aladjov

2. 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

3. What are Adverse Effect Pathways
Overview
Generalized Estrogen Receptor (ER) Adverse Effect Pathway
MOLECULAR
Initiating Event
CELLULAR
Response
TISSUE/ORGAN
Response
INDIVIDUAL
Response
POPULATION
Response
ER Binding
Altered
Protein
Expression
Altered proteins
Ova-testis
Sex Reversal,
Altered Behavior,
↓Repro.
Skewed
Sex Ratios,
↓Year Class
Adverse Effect Pathway of Developmental Neurotoxicity in Humans
MOLECULAR
Initiating Event
CELLULAR
Response
CELLULAR
Response
TISSUE/ORGAN
Response
INDIVIDUAL
Response
AChE Binding
Altered
Intra-cellular
Signaling
Altered Cell Structure
Brain:
Loss of synaptic connect.
Behavior:
Impaired cognitive function

4. Challenges of the Adverse Effect Pathways
Complexity
Multidisciplinary
Lack of unified pathway representation language
Accessibility to the scientific community and the public

5. Existing Solutions Existing Solutions System biology models advantages
Systematic description of the complex interactions in biological systems
Integrate and analyze complex data from multiple experimental sources
System biology models disadvantages
Exhaustive complexity not focused by the subject of study
Focus on molecular level
Investigating the continuous uncompensated dysfunction
ToxRefDB
Collection of endpoints
ToxCast
Collection of in-vitro cellular assays

6. QSAR models and Adverse Effect Pathways
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
Inspiring the Next Generation QSAR Models,
based on classic rules

7. The online encyclopedia of Adverse effect pathways

8. Effectopedia – Adverse Effect Pathways Representation System
Efectopedia.qsari.org
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

9. Pathway Building Blocks
Use Simple Building Blocks
Pathway Building Blocks
Cause
Effect
Link
Chemical
Molecular Initiating Event
Effect
Threshold
Dose-Response
Reversible or not
Specific or not
Duration
Molecular Initiating Event
Effect
Endpoint

10. Coordinates in Pathway Space
Effect: …
male
adult
human
Liver
Gender
Life Stage
Taxonomy
Level of Biological Organization

11. Start form both ends Efectopedia.qsari.org MIE 1 Effect 1 Chemical
Effect n1
MIE 1
Effect 1
Chemical
Effect 1
Effect 2
Effect n1
Endpoint
MIE 2
Effect 2
Effect 1
Effect 2
Effect n1
MIE n
Effect n

12. What Other Downstream effects you know?
Breaking Complexity with simple Questions
Efectopedia.qsari.org
Effect 1
Effect 2
Effect
What Other Downstream effects you know?

13. What other causes you know can lead to this effect?
Breaking Complexity with simple Questions
Efectopedia.qsari.org
Cause 1
Effect
Cause 2
What other causes you know can lead to this effect?

14. Dysfunction Duration as a Cause
Effectopedia.qsari.org
Link conditions:
Duration 1
Endpoint 1
Effect
Link conditions:
Duration 2
Endpoint 2

15. Demo
Effectopedia.qsari.org

16. Free, Platform Independent, Open Source
Technology
Free, Platform Independent, Open Source
Based entirely on open source platform independent solutions
<? XML ?>
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

17. Benefits
Conclusions
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