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Incorporating External Information in Tissue Subtyping: A Topic Modeling Approach.

ABSTRACT: Probabilistic topic models, have been widely deployed for various applications such as learning disease or tissue subtypes. Yet, learning the parameters of such models is usually an ill-posed problem and may result in losing valuable information about disease severity. A common approach is to add a discriminative loss term to the generative model's loss in order to learn a representation that is also predictive of disease severity. However, finding a balance between these two losses is not straightforward. We propose an alternative way in this paper. We develop a framework which allows for incorporating external covariates into the generative model's approximate posterior. These covariates can have more discriminative power for disease severity compared to the representation that we extract from the posterior distribution. For instance, they can be features extracted from a neural network which predicts disease severity from CT images. Effectively, we enforce the generative model's approximate posterior to reside in the subspace of these discriminative covariates. We illustrate our method's application on a large-scale lung CT study of Chronic Obstructive Pulmonary Disease (COPD), a highly heterogeneous disease. We aim at identifying tissue subtypes by using a variant of topic model as a generative model. We quantitatively evaluate the predictive performance of the inferred subtypes and demonstrate that our method outperforms or performs on par with some reasonable baselines. We also show that some of the discovered subtypes are correlated with genetic measurements, suggesting that the identified subtypes may characterize the disease's underlying etiology.

SUBMITTER: Saeedi A

PROVIDER: S-EPMC8797254 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:High Content Screening (HCS) has become an important tool for toxicity assessment, partly due to its advantage of handling multiple measurements simultaneously. This approach has provided insight and contributed to the understanding of systems biology at cellular level. To fully realize this potential, the simultaneously measured multiple endpoints from a live cell should be considered in a probabilistic relationship to assess the cell's condition to response stress from a treatment, which poses a great challenge to extract hidden knowledge and relationships from these measurements. METHOD:In this work, we applied a text mining method of Latent Dirichlet Allocation (LDA) to analyze cellular endpoints from in vitro HCS assays and related to the findings to in vivo histopathological observations. We measured multiple HCS assay endpoints for 122 drugs. Since LDA requires the data to be represented in document-term format, we first converted the continuous value of the measurements to the word frequency that can processed by the text mining tool. For each of the drugs, we generated a document for each of the 4 time points. Thus, we ended with 488 documents (drug-hour) each having different values for the 10 endpoints which are treated as words. We extracted three topics using LDA and examined these to identify diagnostic topics for 45 common drugs located in vivo experiments from the Japanese Toxicogenomics Project (TGP) observing their necrosis findings at 6 and 24 hours after treatment. RESULTS:We found that assay endpoints assigned to particular topics were in concordance with the histopathology observed. Drugs showing necrosis at 6 hour were linked to severe damage events such as Steatosis, DNA Fragmentation, Mitochondrial Potential, and Lysosome Mass. DNA Damage and Apoptosis were associated with drugs causing necrosis at 24 hours, suggesting an interplay of the two pathways in these drugs. Drugs with no sign of necrosis we related to the Cell Loss and Nuclear Size assays, which is suggestive of hepatocyte regeneration. CONCLUSIONS:The evidence from this study suggests that topic modeling with LDA can enable us to interpret relationships of endpoints of in vitro assays along with an in vivo histological finding, necrosis. Effectiveness of this approach may add substantially to our understanding of systems biology.

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Incorporating External Information in Tissue Subtyping: A Topic Modeling Approach.

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