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Recent advances in interpretability of machine learning models\u00a0as applied to biomedical problems may enable discovery and prediction in clinical cancer genomics\n                    <jats:sup>3\u20135<\/jats:sup>\n                    . Here we developed P-NET\u2014a biologically informed deep learning model\u2014to stratify patients with\u00a0prostate cancer by treatment-resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modelling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as\n                    <jats:italic>MDM4<\/jats:italic>\n                    and\n                    <jats:italic>FGFR1<\/jats:italic>\n                    , which were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.\n                  <\/jats:p>","DOI":"10.1038\/s41586-021-03922-4","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:11:07Z","timestamp":1632715867000},"page":"348-352","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":414,"title":["Biologically informed deep neural network for prostate cancer discovery"],"prefix":"10.1038","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4315-4347","authenticated-orcid":false,"given":"Haitham A.","family":"Elmarakeby","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1686-7103","authenticated-orcid":false,"given":"Justin","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rand","family":"Arafeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jett","family":"Crowdis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Gang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saud H.","family":"AlDubayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyan","family":"Salari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Kregel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camden","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor E.","family":"Arnoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihye","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2840-9791","authenticated-orcid":false,"given":"William C.","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-4444","authenticated-orcid":false,"given":"Eliezer M.","family":"Van Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"3922_CR1","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/j.cell.2015.05.001","volume":"161","author":"D Robinson","year":"2015","unstructured":"Robinson, D., et al. 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