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Applying knowledge-driven mechanistic inference to toxicogenomics.

ABSTRACT: When considering toxic chemicals in the environment, a mechanistic, causal explanation of toxicity may be preferred over a statistical or machine learning-based prediction by itself. Elucidating a mechanism of toxicity is, however, a costly and time-consuming process that requires the participation of specialists from a variety of fields, often relying on animal models. We present an innovative mechanistic inference framework (MechSpy), which can be used as a hypothesis generation aid to narrow the scope of mechanistic toxicology analysis. MechSpy generates hypotheses of the most likely mechanisms of toxicity, by combining a semantically-interconnected knowledge representation of human biology, toxicology and biochemistry with gene expression time series on human tissue. Using vector representations of biological entities, MechSpy seeks enrichment in a manually curated list of high-level mechanisms of toxicity, represented as biochemically- and causally-linked ontology concepts. Besides predicting the canonical mechanism of toxicity for many well-studied compounds, we experimentally validated some of our predictions for other chemicals without an established mechanism of toxicity. This mechanistic inference framework is an advantageous tool for predictive toxicology, and the first of its kind to produce a mechanistic explanation for each prediction. MechSpy can be modified to include additional mechanisms of toxicity, and is generalizable to other types of mechanisms of human biology.

SUBMITTER: Tripodi IJ

PROVIDER: S-EPMC7306473 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWhile in principle a seemingly infinite variety of combinations of mutations could result in tumor development, in practice it appears that most human cancers fall into a relatively small number of "sub-types," each characterized a roughly equivalent sequence of mutations by which it progresses in different patients. There is currently great interest in identifying the common sub-types and applying them to the development of diagnostics or therapeutics. Phylogenetic methods have shown great promise for inferring common patterns of tumor progression, but suffer from limits of the technologies available for assaying differences between and within tumors. One approach to tumor phylogenetics uses differences between single cells within tumors, gaining valuable information about intra-tumor heterogeneity but allowing only a few markers per cell. An alternative approach uses tissue-wide measures of whole tumors to provide a detailed picture of averaged tumor state but at the cost of losing information about intra-tumor heterogeneity.ResultsThe present work applies "unmixing" methods, which separate complex data sets into combinations of simpler components, to attempt to gain advantages of both tissue-wide and single-cell approaches to cancer phylogenetics. We develop an unmixing method to infer recurring cell states from microarray measurements of tumor populations and use the inferred mixtures of states in individual tumors to identify possible evolutionary relationships among tumor cells. Validation on simulated data shows the method can accurately separate small numbers of cell states and infer phylogenetic relationships among them. Application to a lung cancer dataset shows that the method can identify cell states corresponding to common lung tumor types and suggest possible evolutionary relationships among them that show good correspondence with our current understanding of lung tumor development.ConclusionsUnmixing methods provide a way to make use of both intra-tumor heterogeneity and large probe sets for tumor phylogeny inference, establishing a new avenue towards the construction of detailed, accurate portraits of common tumor sub-types and the mechanisms by which they develop. These reconstructions are likely to have future value in discovering and diagnosing novel cancer sub-types and in identifying targets for therapeutic development.

Project description:BackgroundToxicogenomics studies often profile gene expression from assays involving multiple doses and time points. The dose- and time-dependent pattern is of great importance to assess toxicity but computational approaches are lacking to effectively utilize this characteristic in toxicity assessment. Topic modeling is a text mining approach, but may be used analogously in toxicogenomics due to the similar data structures between text and gene dysregulation.ResultsTopic modeling was applied to a very large toxicogenomics dataset containing microarray gene expression data from >15,000 samples associated with 131 drugs tested in three different assay platforms (i.e., in vitro assay, in vivo repeated dose study and in vivo single dose experiment) with a design including multiple doses and time points. A set of "topics" which each consist of a set of genes was determined, by which the varying sensitivity of three assay systems was observed. We found that the drug-dependent effect was more pronounced in the two in vivo systems than the in vitro system, while the time-dependent effect was most strongly reflected in the in vitro system followed by the single dose study and lastly the repeated dose experiment. The dose-dependent effect was similar across three assay systems. Although the results indicated a challenge to extrapolate the in vitro results to the in vivo situation, we did notice that, for some drugs but not for all the drugs, the similarity in gene expression patterns was observed across all three assay systems, indicating a possibility of using in vitro systems with careful designs (such as the choice of dose and time point), to replace the in vivo testing strategy. Nonetheless, a potential to replace the repeated dose study by the single-dose short-term methodology was strongly implied.ConclusionsThe study demonstrated that text mining methodologies such as topic modeling provide an alternative method compared to traditional means for data reduction in toxicogenomics, enhancing researchers' capabilities to interpret biological information.

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Applying knowledge-driven mechanistic inference to toxicogenomics.

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