{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T21:49:56Z","timestamp":1757454596037,"version":"3.37.3"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"publisher","award":["R01CA222847","R01CA188575"],"award-info":[{"award-number":["R01CA222847","R01CA188575"]}],"id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wisconsin Breast Cancer Showhouse"},{"name":"Advancing a Healthier Wisconsin Endowment","award":["5520367"],"award-info":[{"award-number":["5520367"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Quantitative immunofluorescence is often used for immunohistochemistry quantification of proteins that serve as cancer biomarkers. Advanced image analysis systems for pathology allow capturing expression levels in each individual cell or subcellular compartment. However, only the mean signal intensity within the cancer tissue region of interest is usually considered as biomarker completely ignoring the issue of tumor heterogeneity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We propose using immunohistochemistry image-derived information on the spatial distribution of cellular signal intensity (CSI) of protein expression within the cancer cell population to quantify both mean expression level and tumor heterogeneity of CSI levels. We view CSI levels as marks in a marked point process of cancer cells in the tissue and define spatial indices based on conditional mean and conditional variance of the marked point process. The proposed methodology provides objective metrics of cell-to-cell heterogeneity in protein expressions that allow discriminating between different patterns of heterogeneity. The prognostic utility of new spatial indices is investigated and compared to the standard mean signal intensity biomarkers using the protein expressions in tissue microarrays incorporating tumor tissues from 1000+ breast cancer patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and Implementation: The R code for computing the proposed spatial indices is included as supplementary material<\/jats:title>\n                  <jats:p>\u2002<\/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\/btaa965","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T20:25:21Z","timestamp":1604521521000},"page":"1452-1460","source":"Crossref","is-referenced-by-count":16,"title":["Quantification of spatial tumor heterogeneity in immunohistochemistry staining images"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9104-4505","authenticated-orcid":false,"given":"Inna","family":"Chervoneva","sequence":"first","affiliation":[{"name":"Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University , Philadelphia, PA 19107, USA"}]},{"given":"Amy R","family":"Peck","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical College of Wisconsin , Milwaukee, WI 53226, USA"}]},{"given":"Misung","family":"Yi","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University , Philadelphia, PA 19107, USA"}]},{"given":"Boris","family":"Freydin","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University , Philadelphia, PA 19107, USA"}]},{"given":"Hallgeir","family":"Rui","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical College of Wisconsin , Milwaukee, WI 53226, USA"}]}],"member":"286","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"2023051709335867200_btaa965-B1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/1467-9574.00144","article-title":"Non- and semiparametric estimation of interaction in inhomogeneous point patterns","volume":"54","author":"Baddeley","year":"2000","journal-title":"Stat. Neerl"},{"key":"2023051709335867200_btaa965-B2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v012.i06","article-title":"Spatstat: an R package for analyzing spatial point patterns","volume":"12","author":"Baddeley","year":"2005","journal-title":"J. Stat. Softw"},{"key":"2023051709335867200_btaa965-B3","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1093\/bioinformatics\/btx723","article-title":"Identification of topological features in renal tumor microenvironment associated with patient survival","volume":"34","author":"Cheng","year":"2018","journal-title":"Bioinformatics"},{"first-page":"496","year":"2008","author":"Doyle","key":"2023051709335867200_btaa965-B4"},{"key":"2023051709335867200_btaa965-B5","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/nmeth.4634","article-title":"Identification of spatial expression trends in single-cell gene expression data","volume":"15","author":"Edsgard","year":"2018","journal-title":"Nat. Methods"},{"key":"2023051709335867200_btaa965-B6","first-page":"15","article-title":"State of the art and trends for digital pathology","volume":"179","author":"Garcia-Rojo","year":"2012","journal-title":"Stud. Health Technol. Inf"},{"key":"2023051709335867200_btaa965-B7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/labinvest.2014.155","article-title":"Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology","volume":"95","author":"Heindl","year":"2015","journal-title":"Lab. Invest"},{"key":"2023051709335867200_btaa965-B8","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.cell.2004.06.028","article-title":"Single cell profiling of potentiated phospho-protein networks in cancer cells","volume":"118","author":"Irish","year":"2004","journal-title":"Cell"},{"key":"2023051709335867200_btaa965-B9","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/sim.8046","article-title":"Identifying prognostic structural features in tissue sections of colon cancer patients using point pattern analysis","volume":"38","author":"Jones-Todd","year":"2019","journal-title":"Stat. Med"},{"key":"2023051709335867200_btaa965-B10","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.cell.2018.08.039","article-title":"A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging","volume":"174","author":"Keren","year":"2018","journal-title":"Cell"},{"key":"2023051709335867200_btaa965-B11","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/EDE.0000000000000018","article-title":"Net reclassification indices for evaluating risk-prediction instruments: a critical review","volume":"25","author":"Kerr","year":"2014","journal-title":"Epidemiol. (Cambridge, Mass.)"},{"key":"2023051709335867200_btaa965-B12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1471-2342-13-9","article-title":"Histological image classification using biologically interpretable shape-based features","volume":"13","author":"Kothari","year":"2013","journal-title":"BMC Med. Imaging"},{"key":"2023051709335867200_btaa965-B13","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth872","article-title":"Fluorescent cell barcoding in flow cytometry allows high-throughput drug screening and signaling profiling","volume":"3","author":"Krutzik","year":"2006","journal-title":"Nat. Methods"},{"key":"2023051709335867200_btaa965-B14","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1097\/PAS.0000000000000086","article-title":"A quantitative histomorphometric classifier (QuHbIC) identifies aggressive versus indolent p16-positive oropharyngeal squamous cell carcinoma","volume":"38","author":"Lewis","year":"2014","journal-title":"Am. J. Surg. Pathol"},{"key":"2023051709335867200_btaa965-B15","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13058-015-0638-4","article-title":"An ecological measure of immune-cancer colocalization as a prognostic factor for breast cancer","volume":"17","author":"Maley","year":"2015","journal-title":"Breast Cancer Res"},{"key":"2023051709335867200_btaa965-B16","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/biomet\/89.2.283","article-title":"A flexible additive multiplicative hazard model","volume":"89","author":"Martinussen","year":"2002","journal-title":"Biometrika"},{"key":"2023051709335867200_btaa965-B17","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.canlet.2015.11.018","article-title":"Computational pathology: exploring the spatial dimension of tumor ecology","volume":"380","author":"Nawaz","year":"2016","journal-title":"Cancer Lett"},{"key":"2023051709335867200_btaa965-B18","doi-asserted-by":"crossref","first-page":"e0186191","DOI":"10.1371\/journal.pone.0186191","article-title":"Prognostic and clinicopathological value of Twist expression in breast cancer: a meta-analysis","volume":"12","author":"Qiao","year":"2017","journal-title":"PLoS One"},{"volume-title":"Multiple Imputation for Nonresponse in Surveys","year":"2004","author":"Rubin","key":"2023051709335867200_btaa965-B19"},{"key":"2023051709335867200_btaa965-B20","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2307\/3318604","article-title":"On the second-order characteristics of marked point processes","volume":"7","author":"Schlather","year":"2001","journal-title":"Bernoulli"},{"key":"2023051709335867200_btaa965-B21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1046\/j.1369-7412.2003.05343.x","article-title":"Detecting dependence between marks and locations of marked point processes","volume":"66","author":"Schlather","year":"2004","journal-title":"J. R. Stat. Soc. Ser. B (Stat. Methodol.)"},{"key":"2023051709335867200_btaa965-B22","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/nmeth.4380","article-title":"Simultaneous epitope and transcriptome measurement in single cells","volume":"14","author":"Stoeckius","year":"2017","journal-title":"Nat. Methods"},{"volume-title":"Fractals, Random Shapes, and Point Fields: Methods of Geometrical Statistics","year":"1994","author":"Stoyan","key":"2023051709335867200_btaa965-B23"},{"key":"2023051709335867200_btaa965-B24","first-page":"309","article-title":"Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma","volume":"539","author":"Tirosh","year":"2016","journal-title":"Nat. Methods"},{"key":"2023051709335867200_btaa965-B25","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1002\/(SICI)1097-0258(19990330)18:6<681::AID-SIM71>3.0.CO;2-R","article-title":"Multiple imputation of missing blood pressure covariates in survival analysis","volume":"18","author":"Van Buuren","year":"1999","journal-title":"Stat. Med"},{"key":"2023051709335867200_btaa965-B26","first-page":"1","article-title":"MICE: multivariate imputation by chained equations in R","volume":"45","author":"Van Buuren","year":"2010","journal-title":"J. Stat. Softw"},{"key":"2023051709335867200_btaa965-B27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1471-2288-11-13","article-title":"One statistical test is sufficient for assessing new predictive markers","volume":"11","author":"Vickers","year":"2011","journal-title":"BMC Med. Res. Methodol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaa965\/36193809\/btaa965.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/10\/1452\/50360701\/btaa965.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/10\/1452\/50360701\/btaa965.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T09:48:11Z","timestamp":1684316891000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/37\/10\/1452\/6020255"}},"subtitle":[],"editor":[{"given":"Jinbo","family":"Xu","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2021,2,4]]},"references-count":27,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2021,6,16]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa965","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2021,5,15]]},"published":{"date-parts":[[2021,2,4]]}}}