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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.

SUBMITTER: Hao L

PROVIDER: S-EPMC4977550 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms.

Hao Ling L Greer Tyler T Page David D Shi Yatao Y Vezina Chad M CM Macoska Jill A JA Marker Paul C PC Bjorling Dale E DE Bushman Wade W Ricke William A WA Li Lingjun L

Scientific reports 20160809

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 characteri ...[more]

PMID: 27502322

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Project description:OBJECTIVES: To evaluate the translation of the IPSS (Hong Kong Chinese version 1) and to assess the applicability, validity, reliability and sensitivity of the instrument in both males and females with LUTS in Chinese population. METHODS: The translation of the IPSS (Hong Kong Chinese version 1) was reviewed through back translation. Modifications were made, resulting in the development of The IPSS (Hong Kong Chinese version 2). The content validity was assessed by contend validity index. 233 subjects with LUTS were recruited in Hong Kong primary care settings for pilot psychometric testing. The construct validity was assessed by corrected item-total correlation and Pearson's correlation test against ICIQ-UI SF, IIQ-7 and SF-12 v2. The reliability was assessed by the internal consistency (Cronbach's Alpha coefficient) and test -retest reliability (Intraclass correlation coefficient). The Sensitivity was determined by performing known group comparisons by independent T-test. RESULTS: The content validity index for all items could reach 1. Corrected item-total correlation scores were ?0.4 for four symptom questions (feeling of incomplete bladder emptying, intermittency, weak stream and straining). Overall, the total symptom score moderately correlated with ICIQ-UI SF. The quality of life score moderately correlated with the IIQ-7 but weakly correlated with SF-12 v2. Overall, the reliability of the IPSS (Hong Kong Chinese version 2) was acceptable (Cronbach's Alpha coefficient?=?0.71, ICC of the symptom questions =0.8, ICC of the quality of life question =0.7). The symptoms questions and quality of life questions of the IPSS (Hong Kong Chinese versions 2) were sensitive in detecting differences between groups. CONCLUSIONS: The IPSS (Hong Kong Chinese version 2) is a valid, reliable and sensitive measure to assess Chinese females and males with lower urinary tract symptoms. The IPSS quality of life question is more sensitive than the generic quality of life measure to differentiate subgroups.

Project description:BackgroundIn men aged above 50 yr, lower urinary tract symptoms (LUTS), benign prostate hyperplasia, and prostate cancer are common urological conditions. Current guidelines for general practitioners frequently recommend prostate-specific antigen (PSA) testing in patients with LUTS for the detection of prostate cancer.ObjectiveTo assess the performance of PSA, PSA density, and the Stockholm3 blood test for identification of prostate cancer among men with LUTS.Design setting and participantsIn this post hoc analysis of a population-based diagnostic trial (STHLM3, n = 58 588), 4588 men aged 50-69 yr, without previous prostate cancer, with International Prostate Symptom Score (IPSS) data, and having PSA ≥ 3 ng/mL were identified. Men with at least moderate LUTS, defined as an IPSS score of ≥8, were included. PSA density and Stockholm3 scores were calculated.InterventionParticipants underwent 10-12-core systematic prostate biopsies.Outcome measurements and statistical analysisThe primary outcome was significant prostate cancer (sPCa) defined as International Society of Urological Pathology (ISUP) grade ≥2. Logistic regression analysis adjusted for age and previous biopsy status was performed. The area under the receiver operating characteristic curve (AUC) was calculated, and decision curve analysis was performed.Results and limitationsOut of 4588 men, 1544 (34%) reported at least moderate LUTS. The median age was 64 yr, and 11% had undergone a previous prostate biopsy. The Stockholm3 test showed superior discrimination for sPCa to PSA density, which in turn showed superior discrimination to PSA (AUC 0.77 vs 0.70 vs 0.61, p < 0.02). Calibration of the Stockholm3 test was adequate. Performing biopsy only in men with PSA ≥5 ng/mL saved 64% of biopsies, but resulted in missing 52% of detectable sPCa. Recommending biopsy for men with PSA density ≥0.07 resulted in sparing 26% of biopsy procedures and delaying the diagnosis of 12% of sPCa cases, with a 6.1% risk of sPCa among unbiopsied men. Recommending men with Stockholm3 ≥ 0.11 for biopsy resulted in sparing 53% of biopsy procedures and delaying the diagnosis of 20% of sPCa cases, with a 5.1% risk of finding sPCa in unbiopsied men.ConclusionsPSA density and the Stockholm3 blood test were superior to PSA for the identification of prostate cancer among men with LUTS.Patient summaryIn this analysis of a large Swedish study, we find that the use of prostate-specific antigen (PSA) density or the Stockholm3 blood test instead of only PSA might improve the detection of prostate cancer among men with lower urinary tract symptoms.

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In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms.

Publications

In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms.

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