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Due to the inherent noise of the data, computational techniques often rely on dimensionality reduction (DR) as both a pre-processing step and an analysis tool. Ideally, DR should preserve the biological information while discarding the noise. However, if the DR is to be used directly to gain biological insight it must also be interpretable\u2014that is the individual dimensions of the reduction should correspond to specific biological variables such as cell-type identity or pathway activity. Maximizing biological interpretability necessitates making assumption about the data structures and the choice of the model is critical.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We present a new probabilistic single-cell factor analysis model, Non-negative Independent Factor Analysis (NIFA), that incorporates different interpretability inducing assumptions into a single modeling framework. The key advantage of our NIFA model is that it simultaneously models uni- and multi-modal latent factors, and thus isolates discrete cell-type identity and continuous pathway activity into separate components. We apply our approach to a range of datasets where cell-type identity is known, and we show that NIFA-derived factors outperform results from ICA, PCA, NMF and scCoGAPS (an NMF method designed for single-cell data) in terms of disentangling biological sources of variation. Studying an immunotherapy dataset in detail, we show that NIFA is able to reproduce and refine previous findings in a single analysis framework and enables the discovery of new clinically relevant cell states.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>NFIA is a R package which is freely available at GitHub (https:\/\/github.com\/wgmao\/NIFA). The test dataset is archived at https:\/\/zenodo.org\/record\/6286646.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btac136","type":"journal-article","created":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T00:24:03Z","timestamp":1647563043000},"page":"2749-2756","source":"Crossref","is-referenced-by-count":1,"title":["Non-negative Independent Factor Analysis disentangles discrete and continuous sources of variation in scRNA-seq data"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5288-4309","authenticated-orcid":false,"given":"Weiguang","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15260, USA"},{"name":"Joint Carnegie Mellon-University of Pittsburgh Ph.D. Program in Computational Biology , Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maziyar Baran","family":"Pouyan","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1460-5487","authenticated-orcid":false,"given":"Dennis","family":"Kostka","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15260, USA"},{"name":"Joint Carnegie Mellon-University of Pittsburgh Ph.D. Program in Computational Biology , Pittsburgh, PA 15260, USA"},{"name":"Department of Developmental Biology, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15260, USA"},{"name":"Center for Evolutionary Biology and Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Chikina","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh , Pittsburgh, PA 15260, USA"},{"name":"Joint Carnegie Mellon-University of Pittsburgh Ph.D. Program in Computational Biology , Pittsburgh, PA 15260, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,3,18]]},"reference":[{"key":"2023031800054138600_","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xcell: digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol"},{"key":"2023031800054138600_","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1080\/01621459.2017.1285773","article-title":"Variational inference: a review for statisticians","volume":"112","author":"Blei","year":"2017","journal-title":"J. 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