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While recent studies have shown that signatures of missing cell types persist in deconvolution residuals, existing approaches cannot automatically determine how many cell types are missing, estimate their specific proportions, or reconstruct their expression signatures. Here, we present DeconX, a computational framework that addresses these limitations by generating \u201cpseudo-cells\u201d from deconvolution residuals, enabling estimation of the number, proportions, and expression signatures of missing cell types. Through comprehensive evaluation on simulated datasets, we demonstrate that DeconX accurately recovers missing cell-type proportions and expression profiles across varying conditions, and systematically identifies key factors affecting performance, including expression similarity between missing and reference cell types and missing cell-type proportions. Application to high-grade serous ovarian cancer (HGSOC) samples reasonably identifies and quantifies adipocyte populations that are absent from matched single-cell references, recovering biologically interpretable expression signatures consistent with known adipocyte markers. We further demonstrate that DeconX can reasonably determine the number of missing cell types, supporting automated analysis of unknown tissue compositions. DeconX transforms residual-based missing cell-type inference from exploratory analysis into a complete computational framework, enabling accurate characterization of tissue heterogeneity from archival bulk RNA-seq data even when single-cell references are incomplete. The source code is available at https:\/\/github.com\/Seniorious123\/DeconX\/, and the documentation and tutorials are available at https:\/\/deconx.readthedocs.io.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btag412","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:23:38Z","timestamp":1781612618000},"source":"Crossref","is-referenced-by-count":0,"title":["Discovering reference-missing cell types in bulk transcriptomics"],"prefix":"10.1093","volume":"42","author":[{"given":"Yimin","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhua","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin Hei","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong, HKSAR , Hong Kong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqian","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Computer 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analysis","volume":"13","author":"Chen","year":"2022","journal-title":"Nat Commun"},{"key":"2026082407032789900_btag412-B2","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13059-023-03077-7","article-title":"Performance of computational algorithms to deconvolve heterogeneous bulk ovarian tumor tissue depends on experimental factors","volume":"24","author":"Hippen","year":"2023","journal-title":"Genome Biol"},{"key":"2026082407032789900_btag412-B3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13059-025-03506-9","article-title":"Missing cell types in single-cell references impact deconvolution of bulk data but are detectable","volume":"26","author":"Ivich","year":"2025","journal-title":"Genome Biol"},{"key":"2026082407032789900_btag412-B4","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41588-022-01100-4","article-title":"Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus 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