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The absence of reliable biomarkers complicates the accurate classification of LUTD subtypes with shared symptoms such as non-ulcerative Bladder Pain Syndrome (BPS) and overactive bladder caused by bladder outlet obstruction with Detrusor Overactivity (DO). This study introduces a machine learning (ML)-based approach for the identification of mRNA signatures specific to non-ulcerative BPS. Using next-generation sequencing (NGS) transcriptome data from bladder biopsies of patients with BPS, benign prostatic obstruction with DO, and controls, our statistical approach successfully identified 13 candidate genes capable of discerning BPS from control and DO patients. This set was validated using Quantitative Polymerase Chain Reaction (QPCR) in a larger patient cohort. To confirm our findings, we applied both supervised and unsupervised ML approaches to the QPCR dataset. A three-mRNA signature TPPP3, FAT1, and NCALD, emerged as a robust classifier for non-ulcerative BPS. The ML-based framework used to define BPS classifiers establishes a solid foundation for comprehending the gene expression changes in the bladder during BPS and serves as a valuable resource and methodology for advancing signature identification in other fields. The proposed ML pipeline demonstrates its efficacy in handling challenges associated with limited sample sizes, offering a promising avenue for applications in similar domains.<\/jats:p>","DOI":"10.3390\/ijms25031568","type":"journal-article","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T10:54:27Z","timestamp":1706266467000},"page":"1568","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Machine Learning-Based Classification of Transcriptome Signatures of Non-Ulcerative Bladder Pain Syndrome"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3186-7478","authenticated-orcid":false,"given":"Akshay","family":"Akshay","sequence":"first","affiliation":[{"name":"Functional Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, 3008 Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Besic","sequence":"additional","affiliation":[{"name":"Functional Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Department of Gynaecology, Inselspital University Hospital, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8271-014X","authenticated-orcid":false,"given":"Fiona C.","family":"Burkhard","sequence":"additional","affiliation":[{"name":"Functional Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Urology, Inselspital University Hospital, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Bigger-Allen","sequence":"additional","affiliation":[{"name":"Urological Diseases Research Center, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0943-6236","authenticated-orcid":false,"given":"Rosalyn M.","family":"Adam","sequence":"additional","affiliation":[{"name":"Urological Diseases Research Center, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Monastyrskaya","sequence":"additional","affiliation":[{"name":"Functional Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Urology, Inselspital University Hospital, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9625-6259","authenticated-orcid":false,"given":"Ali","family":"Hashemi Gheinani","sequence":"additional","affiliation":[{"name":"Functional Urology Research Laboratory, Department for BioMedical Research DBMR, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Urology, Inselspital University Hospital, University of Bern, 3012 Bern, Switzerland"},{"name":"Urological Diseases Research Center, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1111\/j.1464-410X.2010.09993.x","article-title":"Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction","volume":"108","author":"Irwin","year":"2011","journal-title":"BJU Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1002\/nau.23513","article-title":"The economic burden of overactive bladder (OAB) and its effects on the costs associated with other chronic, age-related comorbidities in the United States","volume":"37","author":"Durden","year":"2018","journal-title":"Neurourol. 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