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Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing
Predictive modeling of drug-induced gene expressions is a powerful tool for phenotype-based compound screening and drug repurposing. State-of-the-art machine learning methods use a small number of fixed cell lines as a surrogate for predicting actual expressions in a new cell type or tissue, althoug...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398009/ https://www.ncbi.nlm.nih.gov/pubmed/35951653 http://dx.doi.org/10.1371/journal.pcbi.1010367 |
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author | Wu, You Liu, Qiao Qiu, Yue Xie, Lei |
author_facet | Wu, You Liu, Qiao Qiu, Yue Xie, Lei |
author_sort | Wu, You |
collection | PubMed |
description | Predictive modeling of drug-induced gene expressions is a powerful tool for phenotype-based compound screening and drug repurposing. State-of-the-art machine learning methods use a small number of fixed cell lines as a surrogate for predicting actual expressions in a new cell type or tissue, although it is well known that drug responses depend on a cellular context. Thus, the existing approach has limitations when applied to personalized medicine, especially for many understudied diseases whose molecular profiles are dramatically different from those characterized in the training data. Besides the gene expression, dose-dependent cell viability is another important phenotype readout and is more informative than conventional summary statistics (e.g., IC50) for characterizing clinical drug efficacy and toxicity. However, few computational methods can reliably predict the dose-dependent cell viability. To address the challenges mentioned above, we designed a new deep learning model, MultiDCP, to predict cellular context-dependent gene expressions and cell viability on a specific dosage. The novelties of MultiDCP include a knowledge-driven gene expression profile transformer that enables context-specific phenotypic response predictions of novel cells or tissues, integration of multiple diverse labeled and unlabeled omics data, the joint training of the multiple prediction tasks, and a teacher-student training procedure that allows us to utilize unreliable data effectively. Comprehensive benchmark studies suggest that MultiDCP outperforms state-of-the-art methods with unseen cell lines that are dissimilar from the cell lines in the supervised training in terms of gene expressions. The predicted drug-induced gene expressions demonstrate a stronger predictive power than noisy experimental data for downstream tasks. Thus, MultiDCP is a useful tool for transcriptomics-based drug repurposing and compound screening that currently rely on noisy high-throughput experimental data. We applied MultiDCP to repurpose individualized drugs for Alzheimer’s disease in terms of efficacy and toxicity, suggesting that MultiDCP is a potentially powerful tool for personalized drug discovery. |
format | Online Article Text |
id | pubmed-9398009 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-93980092022-08-24 Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing Wu, You Liu, Qiao Qiu, Yue Xie, Lei PLoS Comput Biol Research Article Predictive modeling of drug-induced gene expressions is a powerful tool for phenotype-based compound screening and drug repurposing. State-of-the-art machine learning methods use a small number of fixed cell lines as a surrogate for predicting actual expressions in a new cell type or tissue, although it is well known that drug responses depend on a cellular context. Thus, the existing approach has limitations when applied to personalized medicine, especially for many understudied diseases whose molecular profiles are dramatically different from those characterized in the training data. Besides the gene expression, dose-dependent cell viability is another important phenotype readout and is more informative than conventional summary statistics (e.g., IC50) for characterizing clinical drug efficacy and toxicity. However, few computational methods can reliably predict the dose-dependent cell viability. To address the challenges mentioned above, we designed a new deep learning model, MultiDCP, to predict cellular context-dependent gene expressions and cell viability on a specific dosage. The novelties of MultiDCP include a knowledge-driven gene expression profile transformer that enables context-specific phenotypic response predictions of novel cells or tissues, integration of multiple diverse labeled and unlabeled omics data, the joint training of the multiple prediction tasks, and a teacher-student training procedure that allows us to utilize unreliable data effectively. Comprehensive benchmark studies suggest that MultiDCP outperforms state-of-the-art methods with unseen cell lines that are dissimilar from the cell lines in the supervised training in terms of gene expressions. The predicted drug-induced gene expressions demonstrate a stronger predictive power than noisy experimental data for downstream tasks. Thus, MultiDCP is a useful tool for transcriptomics-based drug repurposing and compound screening that currently rely on noisy high-throughput experimental data. We applied MultiDCP to repurpose individualized drugs for Alzheimer’s disease in terms of efficacy and toxicity, suggesting that MultiDCP is a potentially powerful tool for personalized drug discovery. Public Library of Science 2022-08-11 /pmc/articles/PMC9398009/ /pubmed/35951653 http://dx.doi.org/10.1371/journal.pcbi.1010367 Text en © 2022 Wu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Wu, You Liu, Qiao Qiu, Yue Xie, Lei Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing |
title | Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing |
title_full | Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing |
title_fullStr | Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing |
title_full_unstemmed | Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing |
title_short | Deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing |
title_sort | deep learning prediction of chemical-induced dose-dependent and context-specific multiplex phenotype responses and its application to personalized alzheimer’s disease drug repurposing |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398009/ https://www.ncbi.nlm.nih.gov/pubmed/35951653 http://dx.doi.org/10.1371/journal.pcbi.1010367 |
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