ToxAssay: a hierarchical model-driven tool for advanced toxicogenomics biomarker discovery

Abstract Motivation Understanding the genetic basis of drug-induced toxicity is crucial for drug development. In-silico analysis of toxicogenomics datasets facilitates early detection of toxicity biomarkers. However, existing tools struggle with the complex interdependencies among hierarchically structured variables, leading to inaccurate biomarker identification. To address this limitation, we developed a Hierarchical Linear Model (HLM) and implemented it in the R package ToxAssay, offering extensive functionality for comprehensive toxicity assessment. Results ToxAssay outperforms existing methods by improving biomarker detection and computational efficiency. Applied to glutathione depletion-induced toxicity, it prioritized 71 key genes and identified 26 core genes with high discriminative accuracy (AUC = 0.97) and strong cross-correlation (Pearson’s r = 0.88) with external datasets. Additionally, our advance outcome pathway (AOP) analysis algorithm uncovered disease outcomes linked to glutathione depletion. These findings provide precise insights into the molecular mechanisms driving drug-induced toxicity. Availability and implementation ToxAssay is available as an open-source R package at https://github.com/Fun-Gene/toxassay.

• Publication year

  2025

• Venue

  Bioinform.

• Publication date

  2025-10-01

• Fields of study

  Biology, Medicine, Chemistry, Computer Science

• Identifiers
  DOI 10.1093/bioinformatics/btaf561PMID 41075158PMCID 12571508
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Dynamic association rules for gene expression data analysis

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• Current status and future prospects of toxicogenomics in drug discovery.

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• Open TG-GATEs: a large-scale toxicogenomics database

  2014cited by this paper
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• Glutathione synthesis.

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  2010cited by this paper
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• Glutathione: overview of its protective roles, measurement, and biosynthesis.

  2009cited by this paper
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  2004cited by this paper
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• Cellular glutathione and thiols metabolism.

  2002cited by this paper
• Community structure in social and biological networks

  2001influential reference
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