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With the increase of the number of drugs, artificial intelligence techniques, especially machine learning methods, have become applicable for the discovery of synergistic drug combinations to significantly reduce the experimental workload. In this study, in order to predict novel synergistic drug combinations in various cancer cell lines, the cell line-specific drug-induced gene expression profile (GP) is added as a new feature type to capture the cellular response of drugs and reveal the biological mechanism of synergistic effect. Then, an enhanced cascade-based deep forest regressor (EC-DFR) is innovatively presented to apply the new small-scale drug combination dataset involving chemical, physical and biological (GP) properties of drugs and cells. Verified by the dataset, EC-DFR outperforms two state-of-the-art deep neural network-based methods and several advanced classical machine learning algorithms. Biological experimental validation performed subsequently on a set of previously untested drug combinations further confirms the performance of EC-DFR. What is more prominent is that EC-DFR can distinguish the most important features, making it more interpretable. By evaluating the contribution of each feature type, GP feature contributes 82.40%, showing the cellular responses of drugs may play crucial roles in synergism prediction. The analysis based on the top contributing genes in GP further demonstrates some potential relationships between the transcriptomic levels of key genes under drug regulation and the synergism of drug combinations.<\/jats:p>","DOI":"10.1093\/bib\/bbab562","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T20:12:53Z","timestamp":1639080773000},"source":"Crossref","is-referenced-by-count":41,"title":["An enhanced cascade-based deep forest model for drug combination prediction"],"prefix":"10.1093","volume":"23","author":[{"given":"Weiping","family":"Lin","sequence":"first","affiliation":[{"name":"School of Informatics, Xiamen University, Xiamen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9611-4488","authenticated-orcid":false,"given":"Lianlian","family":"Wu","sequence":"additional","affiliation":[{"name":"Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 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