VISUALIZATION OF ADVERSE EFFECT PATHWAYS Hristo Aladjov

O VERVIEW 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

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

C HALLENGES OF THE A DVERSE E FFECT P ATHWAYS Challenges of the Adverse Effect Pathways  Complexity  Multidisciplinary  Lack of unified pathway representation language  Accessibility to the scientific community and the public

E XISTING S OLUTIONS 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

 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 MODELS AND A DVERSE E FFECT P ATHWAYS QSAR models and Adverse Effect Pathways Inspiring the Next Generation QSAR Models, based on classic rules Inspiring the Next Generation QSAR Models, based on classic rules

THE ONLINE ENCYCLOPEDIA OF ADVERSE EFFECT PATHWAYS

E FECTOPEDIA. QSARI. ORG Effectopedia – 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

P ATHWAY B UILDING B LOCKS 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

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

E FECTOPEDIA. QSARI. ORG Start 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

E FECTOPEDIA. QSARI. ORG Breaking Complexity with simple Questions Effect Effect 1 What Other Downstream effects you know? Effect 2

E FECTOPEDIA. QSARI. ORG Breaking Complexity with simple Questions Effect Cause 1 What other causes you know can lead to this effect? Cause 2

E FFECTOPEDIA. QSARI. ORG Dysfunction Duration as a Cause Effect Endpoint 1 Endpoint 1 Endpoint 2 Endpoint 2 Link conditions: Duration 1 Link conditions: Duration 1 Link conditions: Duration 2 Link conditions: Duration 2

E FFECTOPEDIA. QSARI. ORG Demo

F REE, P LATFORM I NDEPENDENT, O PEN S OURCE Technology  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

C ONCLUSIONS 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