Case Study
TGX – Toxicogenomics-based prediction and mechanism identification

Summary

In this case study a transcriptomics-based hazard prediction model for identification of specific molecular initiating events (MIE) will be applied based on (A) top-down and (B) bottom-up approaches.

The MIEs can include, but are not limited to: (1) Genotoxicity (p53 activation), (2) Oxidative stress (Nrf2 activation), (3) Endoplasmic Reticulum Stress (unfolded protein response), (4) Dioxin-like activity (AhR receptor activation), (5) HIF1 alpha activation and (6) Nuclear receptor activation (e.g. for endocrine disruption).

Objectives

  • Creation of prediction models based on differentially regulated genes (top-down approach);
  • Using knowledge of stress response pathways to integrate data sets for their activation or inhibition (bottom-up approach).

Risk assessment framework

This case study is associated with all 3 tiers of the selected framework and in particular the following steps:

  • Collection of support data;
  • Identification of analogues / suitability assessment and existing data;
  • Mode of Action hypothesis generation.

Use Cases Associated

This case study is associated with UC1 - Merge existing data by a common structure identifier and UC2 - Building and using a prediction model.

These two use cases are relevant for the top-down approaches:

  • Reproducing the prediction models published by Herwig et al., 2016 using data from the EU-project carcinoGENOMICs;
  • Advanced predictions using as much data as possible from the diXa data warehouse and other repositories giving free access to the data.

Databases and tools

Databases:

  • diXa (carcinoGENOMICs, Predict-IV), TG-GATEs, EU-ToxRisk (nascent), HeCaToS (nascent), ArrayExpress/GEO BioStudies.

Tools:

  • top-down: Data normalisation tools, prediction tools such as Caret;
  • bottom-up: ToxPi.

Service integration

Service integration will be needed for the omics databases; knowledge bases and data mining; processing and analysis.

Currently available services:

  • Interactive computing and workflows sharing
    Service type: Helper tool, Visualisation tool, Processing tool, Analysis tool, Software, Workflow
  • Scientific workflows make simple
    Service type: Database / data source, Service, Workflow