Table 2.
Top Three Nonredundant Pathways for Association With Toxicity Phenotype
| Tox Phenotype a | Time b | Top-Ranked Pathways c |
|---|---|---|
| Adverse at 29 days | 1d | GO: cellular amino acid metabolic process (−0.7), GO: drug metabolic process (−0.6), GO: unsaturated fatty acid metabolic process (0.8) |
| Bile duct hyperplasia | 1d | GO: positive regulation of leukocyte apoptotic process (1.2), GO: cofactor metabolic process (−0.6), KEGG: Cell adhesion molecules (0.6) |
| C | REACTOME: Genes involved in Apoptotic execution phase (1.8), GO: positive regulation of extrinsic apoptotic signaling pathway in absence of ligand (1.7), GO: regulation of triglyceride metabolic process (−1.7) | |
| Cholesterol decrease | 1d | GO: regulation of membrane potential (−0.9), GO: germ cell nucleus (1), GO: regulation of feeding behavior (−1) |
| C | REACTOME: Genes involved in Cell surface interactions at the vascular wall (−0.8), GO: extracellular matrix (−0.5), REACTOME: Genes involved in Association of TriC/CCT with target proteins during biosynthesis (1.2) | |
| Cholesterol increase | C | REACTOME: Genes involved in Ethanol oxidation (0.7), GO: ethanol catabolic process (0.6), GO: canalicular bile acid transport (0.5) |
| Hematopoiesis | 1d | GO: negative regulation of programed cell death (1.3), REACTOME: Genes involved in Sulfur amino acid metabolism (−1.4), GO: dicarboxylic acid metabolic process (−1.1) |
| C | GO: apoptotic cell clearance (2.3), GO: complement activation, classical pathway (2.2), GO: blood coagulation (2.2) | |
| Hypertrophy | 1d | REACTOME: Genes involved in Orc1 removal from chromatin (0.6), REACTOME: Genes involved in SCF(Skp2)-mediated degradation of p27/p21 (0.7), GO: ribosomal large subunit export from nucleus (1.5) |
| C | GO: protein homotetramerization (1.2), GO: sterol esterification (−1.1), REACTOME: Genes involved in Recycling of bile acids and salts (1.1) | |
| Increased glycogen | C | PID: TNF receptor signaling pathway PMID: 18832364 (−1.6), GO: cellular response to lipoprotein particle stimulus (−0.9), GO: intrinsic apoptotic signaling pathway in response to DNA damage (−1.5) |
| Increased mitosis | 1d | KEGG: Pyruvate metabolism (1.4), KEGG: Propanoate metabolism (1), GO: single-organism catabolic process (0.6) |
| Increased mitosis | C | GO: nuclear ubiquitin ligase complex (1.6), PID: Aurora A signaling PMID: 18832364 (1.1), GO: homologous chromosome segregation (1) |
| Necrosis | C | GO: macrophage chemotaxis (0.8), GO: myeloid leukocyte migration (0.5), GO: monocarboxylic acid catabolic process (−0.8) |
| Single cell necrosis | C | REACTOME: Genes involved in Activation of Genes by ATF4 (1), GO: endoplasmic reticulum unfolded protein response (1.1), PID: ATF-2 transcription factor network PMID: 18832364 (0.6) |
| Trigs decrease | C | BIOCARTA: Apoptotic DNA fragmentation and tissue homeostasis (−1.3), GO: pronucleus (−1), GO: protein depolymerization (−0.9) |
| Trigs increase | C | KEGG: Steroid biosynthesis (−0.3), GO: sterol esterification (0.7), GO: response to drug (−0.4) |
| Vacuolation | C | KEGG: Steroid biosynthesis (0.7), GO: isoprenoid biosynthetic process (0.7), GO: extracellular matrix assembly (−0.8) |
Representative toxicity phenotype as defined in methods; “adverse at 29 days” is an aggregate endpoint and included any treatments that produced 1 or more adverse morphologic changes at 29 days of dosing; only relationships at 1 day (1d) were evaluated.
Whether expression analysis is performed from samples collected after 1 day (1d) or concurrent with the observed toxicity phenotype (C).
Showing the top 3-ranked pathways for the toxicity phenotype and time, ranked using p-adj per (Sutherland et al., 2018), selecting only the most highly ranked pathway within each cluster. The value in parentheses is the pathway’s coefficient in the logistic regression model, interpreted as the natural log of odds-ratio for observing toxicity given a 1 unit increase in the pathway score. The sign indicates whether induction (positive) or repression (negative) associates with increased odds of toxicity. A coefficient value of 0.69 corresponds to 2× odds of toxicity, 1.1 corresponds to 3×, etc. The full results are provided in Supplementary Dataset 2.