title: In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms.
abstract: Lower urinary tract symptoms (LUTS) are a range of irritative or obstructive symptoms that commonly afflict aging population. The diagnosis is mostly based on patient-reported symptoms, and current medication often fails to completely eliminate these symptoms. There is a pressing need for objective non-invasive approaches to measure symptoms and understand disease mechanisms. We developed an in-depth workflow combining urine metabolomics analysis and machine learning bioinformatics to characterize metabolic alterations and support objective diagnosis of LUTS. Machine learning feature selection and statistical tests were combined to identify candidate biomarkers, which were statistically validated with leave-one-patient-out cross-validation and absolutely quantified by selected reaction monitoring assay. Receiver operating characteristic analysis showed highly-accurate prediction power of candidate biomarkers to stratify patients into disease or non-diseased categories. The key metabolites and pathways may be possibly correlated with smooth muscle tone changes, increased collagen content, and inflammation, which have been identified as potential contributors to urinary dysfunction in humans and rodents. Periurethral tissue staining revealed a significant increase in collagen content and tissue stiffness in men with LUTS. Together, our study provides the first characterization and validation of LUTS urinary metabolites and pathways to support the future development of a urine-based diagnostic test for LUTS.
authors: School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.
authors: Ling
authors: L
authors: Hao
authors: Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
authors: Tyler
authors: T
authors: Greer
authors: Department of Biostatistics &Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA.
authors: David
authors: D
authors: Page
authors: School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.
authors: Yatao
authors: Y
authors: Shi
authors: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, 53706, USA.|George M. O'Brien Urology research Center, University of Wisconsin-Madison, Madison, WI, USA.
authors: Chad M
authors: CM
authors: Vezina
authors: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, MA, 02125, USA.|George M. O'Brien Urology research Center, University of Wisconsin-Madison, Madison, WI, USA.
authors: Jill A
authors: JA
authors: Macoska
authors: School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.|George M. O'Brien Urology research Center, University of Wisconsin-Madison, Madison, WI, USA.
authors: Paul C
authors: PC
authors: Marker
authors: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, 53706, USA.|George M. O'Brien Urology research Center, University of Wisconsin-Madison, Madison, WI, USA.
authors: Dale E
authors: DE
authors: Bjorling
authors: Department of Urology, University of Wisconsin-Madison, Madison, WI, 53792, USA.|George M. O'Brien Urology research Center, University of Wisconsin-Madison, Madison, WI, USA.
authors: Wade
authors: W
authors: Bushman
authors: Department of Urology, University of Wisconsin-Madison, Madison, WI, 53792, USA.|George M. O'Brien Urology research Center, University of Wisconsin-Madison, Madison, WI, USA.
authors: William A
authors: WA
authors: Ricke
authors: School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.|Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
authors: Lingjun
authors: L
authors: Li
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D019540:Area Under Curve; D015415:Biomarkers / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000032:analysis / Q000378:metabolism; D006801:Humans; D059411:Lower Urinary Tract Symptoms / Q000378:metabolism / Q000473:pathology*; D000069550:Machine Learning; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000592:standards; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011786:Quality Control; D012372:ROC Curve; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D003094:Collagen