{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T05:41:27Z","timestamp":1776577287468,"version":"3.51.2"},"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T00:00:00Z","timestamp":1724803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["NIH R01DK129469 and U01DK135017"],"award-info":[{"award-number":["NIH R01DK129469 and U01DK135017"]}]},{"DOI":"10.13039\/100007028","name":"The Leona M. and Harry B. Helmsley Charitable Trust","doi-asserted-by":"crossref","award":["G-2207-05399"],"award-info":[{"award-number":["G-2207-05399"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Recent studies show that cellular neighborhoods play an important role in evolving biological events such as cancer and diabetes. Therefore, it is critical to accurately and efficiently identify cellular neighborhoods from spatially-resolved single-cell transcriptomic data or single-cell resolution tissue imaging data. In this work, we develop CNTools, a computational toolbox for end-to-end cellular neighborhood analysis on annotated cell images, comprising both the identification and analysis steps. It includes state-of-the-art cellular neighborhood identification methods and post-identification smoothing techniques, with our newly proposed Cellular Neighbor Embedding (CNE) method and Naive Smoothing technique, as well as several established downstream analysis approaches. We applied CNTools on three real-world CODEX datasets and evaluated identification methods with smoothing techniques quantitatively and qualitatively. It shows that CNE with Naive Smoothing overall outperformed other methods and revealed more convincing biological insights. We also provided suggestions on how to choose proper identification methods and smoothing techniques according to input data.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012344","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T17:38:25Z","timestamp":1724866705000},"page":"e1012344","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["CNTools: A computational toolbox for cellular neighborhood analysis from multiplexed images"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9615-4976","authenticated-orcid":true,"given":"Yicheng","family":"Tao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1482-5359","authenticated-orcid":true,"given":"Conrad V.","family":"Reihsmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander L.","family":"Hopkirk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Philippe","family":"Cartailler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcela","family":"Brissova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen C. 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Nonnegative tucker decomposition. In: 2007 IEEE conference on computer vision and pattern recognition. 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