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Whether compositional biases within reference datasets influence AI\u2010assisted cell identity assignment remains poorly understood. Here, we establish a harmonized single\u2010cell resource integrating 254\u00a0245 cells from five datasets of genetically engineered pig kidney grafts in human and non\u2010human primate (NHP) recipients. We evaluate representative annotation strategies, including the foundation model TranscriptFormer, the autonomous biomedical agent Biomni, and conventional approaches. Across frameworks, reference composition, represented as the empirical cell\u2010type composition, emerged as a major factor associated with inferred cell identity. In donor\u2010pig kidney grafts, abundant collecting\u2010duct (CD) references promoted widespread CD assignment and suppressed distal tubular identities. Under the empirical reference composition, 97.0% of cells carrying target\u2010native thick ascending limb (TAL) annotations and 97.2% of cells carrying target\u2010native distal convoluted tubule (DCT) annotations in a primary pig\u2010to\u2010NHP kidney xenograft dataset were reassigned to the CD compartment, revealing profound reference\u2010driven label collapse. This distortion extended to compartment\u2010level analyses, obscuring biological programs. Notably, an endothelial interferon\u2010stimulated gene signature in the primary target remained detectable under target\u2010native annotation but was masked by reference\u2010driven label transfer. We establish a harmonized xenotransplantation single\u2010cell resource and identify reference\u2010composition auditing as a general framework for evaluating AI\u2010assisted biological interpretation.<\/jats:p>","DOI":"10.1111\/xen.70171","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:18:52Z","timestamp":1790846332000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reference Composition Biases Automated Cell Annotation and Obscures Biological Signals in Xenotransplantation Single\u2010cell Atlases"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6232-8341","authenticated-orcid":false,"given":"Lisha","family":"Mou","sequence":"first","affiliation":[{"name":"Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital  Shenzhen China"},{"name":"MetaLife Lab, Shenzhen Institute of Translational Medicine  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Lu","sequence":"additional","affiliation":[{"name":"Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital  Shenzhen China"},{"name":"MetaLife Lab, Shenzhen Institute of Translational Medicine  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijing","family":"Wu","sequence":"additional","affiliation":[{"name":"Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital  Shenzhen China"},{"name":"MetaLife Lab, Shenzhen Institute of Translational Medicine  Shenzhen 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.16930"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2120238"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201038465\u2010x"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2024.05.003"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2412747"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010025\u201009846\u20107"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010025\u201009847\u20106"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat5031"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201005769\u20103"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20209620"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.66747"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010021\u201001001\u20107"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010018\u20100229\u20102"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006139\u20109"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","unstructured":"Y.Rosen 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