title: Proof-of-Concept Workflow for Establishing Reference Intervals of Human Urine Proteome for Monitoring Physiological and Pathological Changes.
abstract: Urine as a true non-invasive sampling source holds great potential for biomarker discovery. While approximately 2000 proteins can be detected by mass spectrometry in urine from healthy people, the amount of these proteins vary considerably. A systematic evaluation of a large number of samples is needed to determine the range of the variations. Current biomarker studies often measure limited number of urine samples in the discovery phase, which makes it difficult to determine whether proteins differentially expressed between control and disease groups represent actual difference, or are just physiological variations among the individuals, leads to failures in the validation phase with the increased sample numbers. Here, we report a streamlined workflow with capacity of measuring 8 urine proteomes per day at the coverage of >1500 proteins. With this workflow, we evaluated variations in 497 urine proteomes from 167 healthy donors, establishing reference intervals (RIs) that covered urine protein variations. We demonstrated that RIs could be used to monitor physiological changes by detecting transient outlier proteins. Furthermore, we provided a RIs-based algorithm for biomarker discovery and validation to screen for diseases such as cancer. This study provided a proof-of-principle workflow for the use of urine proteome for health monitoring and disease screening.
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China.
authors.forename: Wenchuan
authors.initials: W
authors.lastname: Leng
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China; Center for Bioinformatics, East China Normal University, Shanghai 200241, China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Ni
authors.affiliation: Joint Center for Translational Medicine, Tianjin Baodi Hospital, Tianjin 301800, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Lu
authors.affiliation: Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Malovannaya
authors.affiliation: Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Jung
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China; School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China.
authors.forename: Guannan
authors.initials: G
authors.lastname: Sun
authors.affiliation: Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Holt
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China; Joint Center for Translational Medicine, Tianjin Baodi Hospital, Tianjin 301800, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Joint Center for Translational Medicine, Tianjin Baodi Hospital, Tianjin 301800, China.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Men
authors.affiliation: Center for Bioinformatics, East China Normal University, Shanghai 200241, China.
authors.forename: Tieliu
authors.initials: T
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China; Joint Center for Translational Medicine, Tianjin Baodi Hospital, Tianjin 301800, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China.
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China; Joint Center for Translational Medicine, Tianjin Baodi Hospital, Tianjin 301800, China. Electronic address: zp1963@sina.com.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhen
authors.affiliation: Joint Center for Translational Medicine, Tianjin Baodi Hospital, Tianjin 301800, China. Electronic address: wgsTMUBH@163.com.
authors.forename: Guangshun
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing 102206, China; Joint Center for Translational Medicine, Tianjin Baodi Hospital, Tianjin 301800, China; Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jqin@bcm.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
mesh_terms: D000465:Algorithms; D019540:Area Under Curve; D015415:Biomarkers / Q000652:urine*; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D005188:False Negative Reactions; D005189:False Positive Reactions; D006801:Humans; D013058:Mass Spectrometry / Q000592:standards; D008991:Monitoring, Physiologic; D036103:Nanotechnology / Q000592:standards; D009369:Neoplasms / Q000175:diagnosis; D020543:Proteome / Q000032:analysis* / Q000378:metabolism / Q000592:standards; D012372:ROC Curve; D012016:Reference Values
chemical_list: D015415:Biomarkers; D020543:Proteome
keywords: Biomarker; Cancer; Mass spectrometry; Reference intervals; Urine proteome