VISUALIZATION OF ADVERSE EFFECT PATHWAYSHristo Aladjov

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

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

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

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

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

THE ONLINE ENCYCLOPEDIA OF ADVERSE EFFECT PATHWAYS

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

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

Coordinates in Pathway Space

Effect:…

maleadult

humanLiver

…Level of Biological Organization

TaxonomyG

ende

r

Life

Stag

e

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

EFECTOPED

IA.QSARI.O

RGBreaking Complexity with simple Questions

Effect

Effect 1

What Other Downstream effects you

know?

Effect 2

EFECTOPED

IA.QSARI.O

RGBreaking Complexity with simple Questions

Effect

Cause 1

What other causes you

know can lead to this effect?

Cause 2

EFFECTOPED

IA.QSARI.O

RGDysfunction Duration as a Cause

Effect

Endpoint1

Endpoint2

Link conditions:

Duration 1

Link conditions:

Duration 2

EFFECTOPED

IA.QSARI.O

RGDemo

FREE, PLATFORM

IND

EPEND

ENT, O

PEN SO

URCE

Technology

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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

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