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      Diagnostic Performance of DNA Hypermethylation Markers in Peripheral Blood for the Detection of Colorectal Cancer: A Meta-Analysis and Systematic Review

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          Abstract

          DNA hypermethylation in blood is becoming an attractive candidate marker for colorectal cancer (CRC) detection. To assess the diagnostic accuracy of blood hypermethylation markers for CRC in different clinical settings, we conducted a meta-analysis of published reports. Of 485 publications obtained in the initial literature search, 39 studies were included in the meta-analysis. Hypermethylation markers in peripheral blood showed a high degree of accuracy for the detection of CRC. The summary sensitivity was 0.62 [95% confidence interval (CI), 0.56–0.67] and specificity was 0.91 (95% CI, 0.89–0.93). Subgroup analysis showed significantly greater sensitivity for the methylated Septin 9 gene ( SEPT9) subgroup (0.75; 95% CI, 0.67–0.81) than for the non-methylated SEPT9 subgroup (0.58; 95% CI, 0.52–0.64). Sensitivity and specificity were not affected significantly by target gene number, CRC staging, study region, or methylation analysis method. These findings show that hypermethylation markers in blood are highly sensitive and specific for CRC detection, with methylated SEPT9 being particularly robust. The diagnostic performance of hypermethylation markers, which have varied across different studies, can be improved by marker optimization. Future research should examine variation in diagnostic accuracy according to non-neoplastic factors.

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          Most cited references47

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          Meta-DiSc: a software for meta-analysis of test accuracy data

          Background Systematic reviews and meta-analyses of test accuracy studies are increasingly being recognised as central in guiding clinical practice. However, there is currently no dedicated and comprehensive software for meta-analysis of diagnostic data. In this article, we present Meta-DiSc, a Windows-based, user-friendly, freely available (for academic use) software that we have developed, piloted, and validated to perform diagnostic meta-analysis. Results Meta-DiSc a) allows exploration of heterogeneity, with a variety of statistics including chi-square, I-squared and Spearman correlation tests, b) implements meta-regression techniques to explore the relationships between study characteristics and accuracy estimates, c) performs statistical pooling of sensitivities, specificities, likelihood ratios and diagnostic odds ratios using fixed and random effects models, both overall and in subgroups and d) produces high quality figures, including forest plots and summary receiver operating characteristic curves that can be exported for use in manuscripts for publication. All computational algorithms have been validated through comparison with different statistical tools and published meta-analyses. Meta-DiSc has a Graphical User Interface with roll-down menus, dialog boxes, and online help facilities. Conclusion Meta-DiSc is a comprehensive and dedicated test accuracy meta-analysis software. It has already been used and cited in several meta-analyses published in high-ranking journals. The software is publicly available at .
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            Principles and challenges of genomewide DNA methylation analysis.

            Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. Therefore, profiling DNA methylation across the genome is vital to understanding the influence of epigenetics. There has been a revolution in DNA methylation analysis technology over the past decade: analyses that previously were restricted to specific loci can now be performed on a genome-scale and entire methylomes can be characterized at single-base-pair resolution. However, there is such a diversity of DNA methylation profiling techniques that it can be challenging to select one. This Review discusses the different approaches and their relative merits and introduces considerations for data analysis.
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              American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected].

              This document is the first update of the American College of Gastroenterology (ACG) colorectal cancer (CRC) screening recommendations since 2000. The CRC screening tests are now grouped into cancer prevention tests and cancer detection tests. Colonoscopy every 10 years, beginning at age 50, remains the preferred CRC screening strategy. It is recognized that colonoscopy is not available in every clinical setting because of economic limitations. It is also realized that not all eligible persons are willing to undergo colonoscopy for screening purposes. In these cases, patients should be offered an alternative CRC prevention test (flexible sigmoidoscopy every 5-10 years, or a computed tomography (CT) colonography every 5 years) or a cancer detection test (fecal immunochemical test for blood, FIT).
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 May 2016
                2016
                : 11
                : 5
                : e0155095
                Affiliations
                [1 ]Department of Gastroenterology, Huizhou First Hospital, Huizhou, 516003, China
                [2 ]Department of Gastroenterology, Hainan provincial people’s Hospital, Haikuo, 570100, China
                [3 ]Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
                [4 ]Huizhou Medicine Institute, Huizhou First Hospital, Huizhou, 516003, China
                [5 ]School of Public Health, Kunming Medical University, Kunming, 650500, China
                University Hospital Llandough, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BL AG AX. Performed the experiments: XC WH XZ RH SZ. Analyzed the data: XS BL XC XW RH. Contributed reagents/materials/analysis tools: AX AG XW XZ. Wrote the paper: BL XW XZ.

                Article
                PONE-D-15-54250
                10.1371/journal.pone.0155095
                4861294
                27158984
                6a6b4861-4ad0-4cab-b27f-d7f7454b15a1
                © 2016 Li et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 January 2016
                : 25 April 2016
                Page count
                Figures: 2, Tables: 3, Pages: 13
                Funding
                This study was supported by Natural Science Foundation of Guangdong Province (2015A030310057).
                Categories
                Research Article
                Biology and life sciences
                Cell biology
                Chromosome biology
                Chromatin
                Chromatin modification
                DNA methylation
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