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      Development and Validation of a High-Throughput Mass Spectrometry Based Urine Metabolomic Test for the Detection of Colonic Adenomatous Polyps

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          Abstract

          Background: Colorectal cancer is one of the leading causes of cancer deaths worldwide. The detection and removal of the precursors to colorectal cancer, adenomatous polyps, is the key for screening. The aim of this study was to develop a clinically scalable (high throughput, low cost, and high sensitivity) mass spectrometry (MS)-based urine metabolomic test for the detection of adenomatous polyps. Methods: Prospective urine and stool samples were collected from 685 participants enrolled in a colorectal cancer screening program to undergo colonoscopy examination. Statistical analysis was performed on 69 urine metabolites measured by one-dimensional nuclear magnetic resonance spectroscopy to identify key metabolites. A targeted MS assay was then developed to quantify the key metabolites in urine. A MS-based urine metabolomic diagnostic test for adenomatous polyps was established using 67% samples (un-blinded training set) and validated using the remaining 33% samples (blinded testing set). Results: The MS-based urine metabolomic test identifies patients with colonic adenomatous polyps with an AUC of 0.692, outperforming the NMR based predictor with an AUC of 0.670. Conclusion: Here we describe a clinically scalable MS-based urine metabolomic test that identifies patients with adenomatous polyps at a higher level of sensitivity (86%) over current fecal-based tests (<18%).

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          Most cited references 25

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          HMDB: a knowledgebase for the human metabolome

          The Human Metabolome Database (HMDB, http://www.hmdb.ca) is a richly annotated resource that is designed to address the broad needs of biochemists, clinical chemists, physicians, medical geneticists, nutritionists and members of the metabolomics community. Since its first release in 2007, the HMDB has been used to facilitate the research for nearly 100 published studies in metabolomics, clinical biochemistry and systems biology. The most recent release of HMDB (version 2.0) has been significantly expanded and enhanced over the previous release (version 1.0). In particular, the number of fully annotated metabolite entries has grown from 2180 to more than 6800 (a 300% increase), while the number of metabolites with biofluid or tissue concentration data has grown by a factor of five (from 883 to 4413). Similarly, the number of purified compounds with reference to NMR, LC-MS and GC-MS spectra has more than doubled (from 380 to more than 790 compounds). In addition to this significant expansion in database size, many new database searching tools and new data content has been added or enhanced. These include better algorithms for spectral searching and matching, more powerful chemical substructure searches, faster text searching software, as well as dedicated pathway searching tools and customized, clickable metabolic maps. Changes to the user-interface have also been implemented to accommodate future expansion and to make database navigation much easier. These improvements should make the HMDB much more useful to a much wider community of users.
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            Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force.

            In 2002, the U.S. Preventive Services Task Force (USPSTF) recommended colorectal cancer screening for adults 50 years of age or older but concluded that evidence was insufficient to prioritize among screening tests or evaluate newer tests, such as computed tomographic (CT) colonography. To review evidence related to knowledge gaps identified by the 2002 recommendation and to consider community performance of screening endoscopy, including harms. MEDLINE, Cochrane Library, expert suggestions, and bibliographic reviews. Eligible studies reported performance of colorectal cancer screening tests or health outcomes in average-risk populations and were at least of fair quality according to design-specific USPSTF criteria, as determined by 2 reviewers. Two reviewers verified extracted data. Four fecal immunochemical tests have superior sensitivity (range, 61% to 91%), and some have similar specificity (97% to 98%), to the Hemoccult II fecal occult blood test (Beckman Coulter, Fullerton, California). Tradeoffs between superior sensitivity and reduced specificity occur with high-sensitivity guaiac tests and fecal DNA, with other important uncertainties for fecal DNA. In settings with sufficient quality control, CT colonography is as sensitive as colonoscopy for large adenomas and colorectal cancer. Uncertainties remain for smaller polyps and frequency of colonoscopy referral. We did not find good estimates of community endoscopy accuracy; serious harms occur in 2.8 per 1000 screening colonoscopies and are 10-fold less common with flexible sigmoidoscopy. The accuracy and harms of screening tests were reviewed after only a single application. Fecal tests with better sensitivity and similar specificity are reasonable substitutes for traditional fecal occult blood testing, although modeling may be needed to determine all tradeoffs. Computed tomographic colonography seems as likely as colonoscopy to detect lesions 10 mm or greater but may be less sensitive for smaller adenomas. Potential radiation-related harms, the effect of extracolonic findings, and the accuracy of test performance of CT colonography in community settings remain uncertain. Emphasis on quality standards is important for implementing any operator-dependent colorectal cancer screening test.
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              A new biometrical procedure for testing the equality of measurements from two different analytical methods. Application of linear regression procedures for method comparison studies in clinical chemistry, Part I.

              Procedures for the statistical evaluation of method comparisons and instrument tests often have a requirement for distributional properties of the experimental data, but this requirement is frequently not met. In our paper we propose a new linear regression procedure with no special assumptions regarding the distribution of the samples and the measurement errors. The result does not depend on the assignment of the methods (instruments) to X and Y. After testing a linear relationship between X and Y confidence limits are given for the slope beta and the intercept alpha; they are used to determine whether there is only a chance difference between beta and 1 and between alpha and 0. The mathematical background is amplified separately in an appendix.
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                Author and article information

                Journal
                Metabolites
                Metabolites
                metabolites
                Metabolites
                MDPI
                2218-1989
                22 June 2017
                September 2017
                : 7
                : 3
                Affiliations
                [1 ]Metabolomic Technologies Inc., Edmonton, AB T6N 1G1, Canada; david.chang@ 123456metabolomictechnologies.ca (D.C.); rae.foshaug@ 123456metabolomictechnologies.ca (R.R.F.); reisner@ 123456ualberta.ca (R.E.); vtso@ 123456ualberta.ca (V.K.T.)
                [2 ]Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada; david.wishart@ 123456ualberta.ca
                [3 ]Department of Medicine, University of Alberta, Edmonton, AB T6G 2G3, Canada; richard.fedorak@ 123456ualberta.ca
                Author notes
                [* ]Correspondence: lu.deng@ 123456metabolomictechnologies.ca ; Tel.: +1-587-772-1684; Fax: +1-780-492-8121
                Article
                metabolites-07-00032
                10.3390/metabo7030032
                5618317
                28640228
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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