{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:44:55Z","timestamp":1790819095377,"version":"4.1.0"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000892","name":"Prostate Cancer Foundation","doi-asserted-by":"publisher","award":["18PILO02"],"award-info":[{"award-number":["18PILO02"]}],"id":[{"id":"10.13039\/100000892","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Prostate cancer is the second leading cause of cancer death in men in the developed world. A more sensitive and specific detection strategy for lethal prostate cancer beyond serum prostate specific antigen (PSA) population screening is urgently needed. Diagnosis by canine olfaction, using dogs trained to detect cancer by smell, has been shown to be both specific and sensitive. While dogs themselves are impractical as scalable diagnostic sensors, machine olfaction for cancer detection is testable. However, studies bridging the divide between clinical diagnostic techniques, artificial intelligence, and molecular analysis remains difficult due to the significant divide between these disciplines. We tested the clinical feasibility of a cross-disciplinary, integrative approach to early prostate cancer biosensing in urine using trained canine olfaction, volatile organic compound (VOC) analysis by gas chromatography-mass spectroscopy (GC-MS) artificial neural network (ANN)-assisted examination, and microbial profiling in a double-blinded pilot study. Two dogs were trained to detect Gleason 9 prostate cancer in urine collected from biopsy-confirmed patients. Biopsy-negative controls were used to assess canine specificity as prostate cancer biodetectors. Urine samples were simultaneously analyzed for their VOC content in headspace via GC-MS and urinary microbiota content via 16S rDNA Illumina sequencing. In addition, the dogs\u2019 diagnoses were used to train an ANN to detect significant peaks in the GC-MS data. The canine olfaction system was 71% sensitive and between 70\u201376% specific at detecting Gleason 9 prostate cancer. We have also confirmed VOC differences by GC-MS and microbiota differences by 16S rDNA sequencing between cancer positive and biopsy-negative controls. Furthermore, the trained ANN identified regions of interest in the GC-MS data, informed by the canine diagnoses. Methodology and feasibility are established to inform larger-scale studies using canine olfaction, urinary VOCs, and urinary microbiota profiling to develop machine olfaction diagnostic tools. Scalable multi-disciplinary tools may then be compared to PSA screening for earlier, non-invasive, more specific and sensitive detection of clinically aggressive prostate cancers in urine samples.<\/jats:p>","DOI":"10.1371\/journal.pone.0245530","type":"journal-article","created":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T13:29:13Z","timestamp":1613568553000},"page":"e0245530","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":49,"title":["Feasibility of integrating canine olfaction with chemical and microbial profiling of urine to detect lethal prostate cancer"],"prefix":"10.1371","volume":"16","author":[{"given":"Claire","family":"Guest","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7015-3059","authenticated-orcid":true,"given":"Karen S.","family":"Sfanos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Shrestha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan W.","family":"Partin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Trock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Mangold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Bader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Kozak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Mclean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Simons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Soule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0835-6418","authenticated-orcid":true,"given":"Thomas","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patritsia Maria","family":"Stathatou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Thaler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simmie","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Mershin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,17]]},"reference":[{"issue":"2","key":"pone.0245530.ref001","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.juro.2013.04.119","article-title":"Early detection of prostate cancer: AUA Guideline","volume":"190","author":"HB Carter","year":"2013","journal-title":"The Journal of urology"},{"issue":"1","key":"pone.0245530.ref002","doi-asserted-by":"crossref","first-page":"012001","DOI":"10.1088\/1752-7163\/aa5524","article-title":"Canine olfaction as an alternative to analytical instruments for disease diagnosis: understanding 'dog personality' to achieve reproducible results","volume":"11","author":"K Hackner","year":"2017","journal-title":"J Breath Res"},{"issue":"8640","key":"pone.0245530.ref003","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/S0140-6736(89)92257-5","article-title":"Sniffer dogs in the melanoma clinic?","volume":"1","author":"H Williams","year":"1989","journal-title":"Lancet (London, England)"},{"issue":"9285","key":"pone.0245530.ref004","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/S0140-6736(01)06065-2","article-title":"Another sniffer dog for the clinic?","volume":"358","author":"J Church","year":"2001","journal-title":"The Lancet"},{"key":"pone.0245530.ref005","doi-asserted-by":"crossref","first-page":"bcr2013008566","DOI":"10.1136\/bcr-2013-008566","article-title":"Canine olfactory detection of malignant melanoma","volume":"2013","author":"LF Campbell","year":"2013","journal-title":"BMJ Case Reports"},{"issue":"1","key":"pone.0245530.ref006","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.applanim.2004.04.008","article-title":"Evidence for canine olfactory detection of melanoma","volume":"89","author":"D Pickel","year":"2004","journal-title":"Applied Animal Behaviour Science"},{"issue":"7468","key":"pone.0245530.ref007","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1136\/bmj.329.7468.712","article-title":"Olfactory detection of human bladder cancer by dogs: proof of principle study","volume":"329","author":"CM Willis","year":"2004","journal-title":"BMJ (Clinical research ed)"},{"issue":"1","key":"pone.0245530.ref008","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1177\/1534735405285096","article-title":"Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers","volume":"5","author":"M McCulloch","year":"2006","journal-title":"Integr Cancer Ther"},{"key":"pone.0245530.ref009","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1186\/1471-2407-13-396","article-title":"Cancer odor in the blood of ovarian cancer patients: a retrospective study of detection by dogs during treatment, 3 and 6 months afterward","volume":"13","author":"G Horvath","year":"2013","journal-title":"BMC cancer"},{"issue":"2","key":"pone.0245530.ref010","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1177\/1534735408319058","article-title":"Human ovarian carcinomas detected by specific odor","volume":"7","author":"G Horvath","year":"2008","journal-title":"Integr Cancer Ther"},{"key":"pone.0245530.ref011","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1186\/1471-2407-10-643","article-title":"Characteristic odour in the blood reveals ovarian carcinoma","volume":"10","author":"G Horvath","year":"2010","journal-title":"BMC cancer"},{"issue":"3","key":"pone.0245530.ref012","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3233\/CBM-2011-0208","article-title":"Volatile organic compounds as biomarkers of bladder cancer: Sensitivity and specificity using trained sniffer dogs","volume":"8","author":"CM Willis","year":"2010","journal-title":"Cancer biomarkers: section A of Disease markers"},{"issue":"2","key":"pone.0245530.ref013","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.eururo.2010.10.006","article-title":"Olfactory detection of prostate cancer by dogs sniffing urine: a step forward in early diagnosis","volume":"59","author":"JN Cornu","year":"2011","journal-title":"European urology"},{"issue":"6","key":"pone.0245530.ref014","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1136\/gut.2010.218305","article-title":"Colorectal cancer screening with odour material by canine scent detection","volume":"60","author":"H Sonoda","year":"2011","journal-title":"Gut"},{"issue":"2","key":"pone.0245530.ref015","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1159\/000492895","article-title":"A new transcutaneous method for breast cancer detection with dogs","volume":"96","author":"A Thuleau","year":"2019","journal-title":"Oncology"},{"key":"pone.0245530.ref016","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jveb.2019.10.006","article-title":"How dogs learn to detect colon cancer\u2014Optimizing the use of training aids","volume":"35","author":"GAA Schoon","year":"2020","journal-title":"Journal of Veterinary Behavior"},{"key":"pone.0245530.ref017","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jveb.2019.04.010","article-title":"Testing ovarian cancer cell lines to train dogs to detect ovarian cancer from blood plasma: A pilot study","volume":"32","author":"M Murarka","year":"2019","journal-title":"Journal of Veterinary Behavior"},{"issue":"4","key":"pone.0245530.ref018","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1016\/j.juro.2014.09.099","article-title":"Olfactory system of highly trained dogs detects prostate cancer in urine samples","volume":"193","author":"G Taverna","year":"2015","journal-title":"J Urol"},{"issue":"10","key":"pone.0245530.ref019","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/s41416-019-0585-4","article-title":"Identification of a biomarker panel for improvement of prostate cancer diagnosis by volatile metabolic profiling of urine","volume":"121","author":"AR Lima","year":"2019","journal-title":"British Journal of Cancer"},{"issue":"3","key":"pone.0245530.ref020","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1128\/CMR.00020-13","article-title":"Clinical application of volatile organic compound analysis for detecting infectious diseases","volume":"26","author":"S Sethi","year":"2013","journal-title":"Clinical microbiology reviews"},{"issue":"7815","key":"pone.0245530.ref021","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/s41586-020-2451-1","article-title":"Structure and flexibility in cortical representations of odour space","volume":"583","author":"SL Pashkovski","year":"2020","journal-title":"Nature"},{"key":"pone.0245530.ref022","first-page":"109","article-title":"Perceptual convergence of multi-component mixtures in olfaction implies an olfactory white","author":"T Weiss","year":"2012","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"pone.0245530.ref023","article-title":"The quest to make a bot that can smell as well as a dog","author":"S Harrison","year":"2019","journal-title":"Wired"},{"issue":"5","key":"pone.0245530.ref024","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1111\/j.1467-9868.2008.00674.x","article-title":"Sure independence screening for ultrahigh dimensional feature space","volume":"70","author":"J Fan","year":"2008","journal-title":"Journal of the Royal Statistical Society: Series B (Statistical Methodology)"},{"key":"pone.0245530.ref025","doi-asserted-by":"crossref","unstructured":"Kleinbaum DaK, M. Logistic Regression, A Self-Learning Text. 3rd Edition.2010.","DOI":"10.1007\/978-1-4419-1742-3"},{"issue":"1","key":"pone.0245530.ref026","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/biomet\/80.1.27","article-title":"Bias reduction of maximum likelihood estimates","volume":"80","author":"D Firth","year":"1993","journal-title":"Biometrika"},{"key":"pone.0245530.ref027","volume-title":"R: A language and environment for statistical computing","author":"RC Team","year":"2017"},{"issue":"1","key":"pone.0245530.ref028","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.juro.2017.08.001","article-title":"Profiling the urinary microbiome in men with positive versus negative biopsies for prostate cancer","volume":"199","author":"E Shrestha","year":"2018","journal-title":"The Journal of Urology"},{"issue":"5","key":"pone.0245530.ref029","first-page":"335","article-title":"QIIME allows analysis of high-throughput community sequencing data.","volume":"7","author":"JG Caporaso","year":"2010"},{"issue":"19","key":"pone.0245530.ref030","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1093\/bioinformatics\/btq461","article-title":"Search and clustering orders of magnitude faster than BLAST","volume":"26","author":"RC Edgar","year":"2010","journal-title":"Bioinformatics"},{"issue":"4","key":"pone.0245530.ref031","first-page":"357","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"B Langmead","year":"2012"},{"issue":"3","key":"pone.0245530.ref032","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/AOG.0000000000001892","article-title":"Urinary microbiome and cytokine levels in women with interstitial cystitis","volume":"129","author":"MG Abernethy","year":"2017","journal-title":"Obstetrics and gynecology"},{"issue":"1","key":"pone.0245530.ref033","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1186\/s12866-016-0894-1","article-title":"Enrichment dynamics of Listeria monocytogenes and the associated microbiome from naturally contaminated ice cream linked to a listeriosis outbreak","volume":"16","author":"A Ottesen","year":"2016","journal-title":"BMC Microbiol"},{"key":"pone.0245530.ref034","first-page":"2103","article-title":"Early recovery of Salmonella from food using a 6-hour non-selective pre-enrichment and reformulation of tetrathionate broth","volume":"7","author":"N Daquigan","year":"2016","journal-title":"Frontiers in Microbiology"},{"issue":"1","key":"pone.0245530.ref035","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0925-8388(98)00611-2","article-title":"Predicting ultra-hard binary compounds via cascaded auto- and hetero-associative neural networks","volume":"279","author":"SL Thaler","year":"1998","journal-title":"Journal of Alloys and Compounds"},{"key":"pone.0245530.ref036","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.proeng.2013.05.006","article-title":"Artificial neural networks for characterizing whipple shield performance","volume":"58","author":"S Ryan","year":"2013","journal-title":"Procedia Engineering"},{"key":"pone.0245530.ref037","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.eswa.2015.09.038","article-title":"Machine learning methods for predicting the outcome of hypervelocity impact events","volume":"45","author":"S Ryan","year":"2016","journal-title":"Expert Systems with Applications"},{"key":"pone.0245530.ref038","unstructured":"Thaler S, inventor Non-algorithmically implemented artificial neural networks and components thereof. USA patent 6,014,653. 2000."},{"key":"pone.0245530.ref039","first-page":"26","article-title":"The semiotic canine: Scent processing dogs as research assistants in biomedical and environmental research","volume":"2","author":"S Gadbois","year":"2016","journal-title":"Dog Behavior"},{"issue":"3","key":"pone.0245530.ref040","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.clgc.2019.02.003","article-title":"Application of urinary volatile organic compounds (VOCs) for the diagnosis of prostate cancer","volume":"17","author":"Q Gao","year":"2019","journal-title":"Clinical genitourinary cancer"},{"issue":"15","key":"pone.0245530.ref041","doi-asserted-by":"crossref","first-page":"4796","DOI":"10.1039\/C6AN00825A","article-title":"Quantification of selected volatile organic compounds in human urine by gas chromatography selective reagent ionization time of flight mass spectrometry (GC-SRI-TOF-MS) coupled with head-space solid-phase microextraction (HS-SPME)","volume":"141","author":"P Mochalski","year":"2016","journal-title":"Analyst"},{"issue":"2","key":"pone.0245530.ref042","first-page":"40","article-title":"Discerning the mauve factor, Part 1","volume":"14","author":"WR McGinnis","year":"2008","journal-title":"Alternative therapies in health and medicine"},{"key":"pone.0245530.ref043","article-title":"A prospective study of the urinary and gastrointestinal microbiota in male children with or without prior antibiotic exposure","author":"B Kassiri","year":"2019","journal-title":"Submitted"},{"issue":"10","key":"pone.0245530.ref044","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1128\/JCM.01373-07","article-title":"Dolosigranulum pigrum causing nosocomial pneumonia and septicemia","volume":"45","author":"H L\u00e9cuyer","year":"2007","journal-title":"Journal of clinical microbiology"},{"key":"pone.0245530.ref045","article-title":"inventors; Massachusetts Institute of Technology, assignee","author":"A Mershin","year":"2013","journal-title":"Methods and apparatus for artificial olfaction"},{"issue":"11","key":"pone.0245530.ref046","doi-asserted-by":"crossref","first-page":"e0143283","DOI":"10.1371\/journal.pone.0143283","article-title":"Urinary volatile organic compounds for the detection of prostate cancer","volume":"10","author":"T Khalid","year":"2015","journal-title":"PLoS One"},{"issue":"1","key":"pone.0245530.ref047","doi-asserted-by":"crossref","first-page":"10219","DOI":"10.1038\/s41598-017-10080-z","article-title":"Odorant-odorant metabolic interaction, a novel actor in olfactory perception and behavioral responsiveness","volume":"7","author":"H-I Hanser","year":"2017","journal-title":"Scientific Reports"},{"issue":"4","key":"pone.0245530.ref048","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/sj.bjc.6605810","article-title":"Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors","volume":"103","author":"G Peng","year":"2010","journal-title":"British Journal of Cancer"},{"key":"pone.0245530.ref049","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1002\/rcm.3466","article-title":"Investigation of volatile biomarkers in liver cancer blood using solid-phase microextraction and gas chromatography\/mass spectrometry","volume":"22","author":"R Xue","year":"2008","journal-title":"Rapid Communications in Mass Spectrometry"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245530","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T13:30:00Z","timestamp":1613568600000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245530"}},"subtitle":[],"editor":[{"given":"Zoran","family":"Culig","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,2,17]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0245530","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.09.09.288258","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,17]]}}}