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However, understanding these mechanisms is hindered by the growing complexity of single-cell data and the difficulty in unmasking meaningful differential gene signatures among HF types. Machine learning, particularly deep neural networks (NNs), address these challenges by learning transcriptional patterns, reconstructing expression profiles and effectively classifying cells but often lacks interpretability. Recent advances in explainable AI (XAI) offer tools to clarify model decisions. Yet pinpointing differentially regulated genes with these tools remains challenging. We introduce a novel method to identify differentially explained genes (DXGs) based on importance scores derived from custom-built NNs. We highlight the superiority of DXGs in identifying HF subtypes-specific pathways that provide new insights into different types of HF. Offering a robust foundation for future research and therapeutic exploration in expanding transcriptome atlases.<\/jats:p>","DOI":"10.1093\/bib\/bbaf581","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:27:15Z","timestamp":1762957635000},"source":"Crossref","is-referenced-by-count":1,"title":["Decoding heart failure subtypes with neural networks via differential explanation analysis"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5354-5336","authenticated-orcid":false,"given":"Mariano","family":"Ruz Jurado","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Regeneration, Theodor-Stern-Kai 7, Goethe University Frankfurt , Frankfurt am Main 60590, Hessen, Germany"},{"name":"German Centre for Cardiovascular Research (DZHK) , Theodor-Stern-Kai 7, Frankfurt am Main 60590 ,","place":["Germany"]},{"name":"Cardio-Pulmonary Institute (CPI), funded by the German Research Foundation (DFG) , Hessen ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1819-6991","authenticated-orcid":false,"given":"David","family":"Rodriguez Morales","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Regeneration, Theodor-Stern-Kai 7, Goethe University Frankfurt , Frankfurt am Main 60590, Hessen ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research (DZHK) , Theodor-Stern-Kai 7, Frankfurt am Main 60590 ,","place":["Germany"]},{"name":"Cardio-Pulmonary Institute (CPI), funded by the German Research Foundation (DFG) , Hessen ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4381-7268","authenticated-orcid":false,"given":"Elijah","family":"Genetzakis","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Regeneration, Theodor-Stern-Kai 7, Goethe University Frankfurt , Frankfurt am Main 60590, Hessen, 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University Hospital Frankfurt , Theodor-Stern-Kai 7, Frankfurt am Main 60590, Hessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariane","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Regeneration, Theodor-Stern-Kai 7, Goethe University Frankfurt , Frankfurt am Main 60590, Hessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5587-6761","authenticated-orcid":false,"given":"Florian","family":"Buettner","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ) , Heidelberg 69120, Baden-W\u00fcrttemberg ,","place":["Germany"]},{"name":"German Cancer Consortium (DKTK), Goethe University Hospital , Frankfurt am Main 60590, Hessen ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1252-3656","authenticated-orcid":false,"given":"Marcel H","family":"Schulz","sequence":"additional","affiliation":[{"name":"German Centre for Cardiovascular Research (DZHK) , Theodor-Stern-Kai 7, Frankfurt am Main 60590 ,","place":["Germany"]},{"name":"Cardio-Pulmonary Institute (CPI), funded by the German Research Foundation (DFG ), Hessen ,","place":["Germany"]},{"name":"Institute for Computational Genomic Medicine, Goethe University Frankfurt , Theodor-Stern-Kai 7, Frankfurt am Main 60590, Hessen ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1045-2436","authenticated-orcid":false,"given":"Stefanie","family":"Dimmeler","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Regeneration, Theodor-Stern-Kai 7, Goethe University Frankfurt , Frankfurt am Main 60590, Hessen ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research (DZHK) , Theodor-Stern-Kai 7, Frankfurt am Main 60590 ,","place":["Germany"]},{"name":"Cardio-Pulmonary 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