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EDISON-WMW: Exact Dynamic Programing Solution of the Wilcoxon–Mann–Whitney Test

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Genomics, Proteomics & Bioinformatics 2016年第1期14卷 55-61页

作者： Alexander Marx christina backes Eckart Meese Hans-Peter Lenhof Andreas Keller Chair for Clinical Bioinformatics Medical Faculty Saarland University Department of Human Genetics Saarland University University Hospital Chair for Bioinformatics Saarland University

In many research disciplines, hypothesis tests are applied to evaluate whether findings are statistically significant or could be explained by chance. The Wilcoxon-Mann-Whitney （WMW） test is among the most popular hypothesis tests in medicine and life science to analyze if two groups of samples are equally distributed. This nonparametric statistical homogeneity test is commonly applied in molecular diagnosis. Generally, the solution of the WMW test takes a high combinatorial effort for large sample cohorts containing a significant number of ties. Hence, P value is frequently approximated by a normal distribution. We developed EDISON-WMW, a new approach to calcu- late the exact permutation of the two-tailed unpaired WMW test without any corrections required and allowing for ties. The method relies on dynamic programing to solve the combinatorial problem of the WMW test efficiently. Beyond a straightforward implementation of the algorithm, we pre- sented different optimization strategies and developed a parallel solution. Using our program, the exact P value for large cohorts containing more than 1000 samples with ties can be calculated within minutes. We demonstrate the performance of this novel approach on randomly-generated data, benchmark it against 13 other commonly-applied approaches and moreover evaluate molec- ular biomarkers for lung carcinoma and chronic obstructive pulmonary disease （COPD）. We foundthat approximated P values were generally higher than the exact solution provided by EDISON- WMW. Importantly, the algorithm can also be applied to high-throughput omics datasets, where hundreds or thousands of features are included. To provide easy access to the multi-threaded version of EDISON-WMW, a web-based solution of our algorithm is freely available at http：// ***/software/wtest/.

关键词： Wilcoxon-Mann-Whitneytest:Wilcoxon rank-sum test Dynamic programing Exact permutation Parallel optimization

Whole miRNome-wide Differential Co-expression of MicroRNAs

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Genomics, Proteomics & Bioinformatics 2012年第5期10卷 285-294页

作者： Cord F.Stehler Andreas Keller Petra Leidinger christina backes Anoop Chandran Jerg Wischhusen Benjamin Meder Eckart Meese Siemens Healthcare Strategy Department of Human Genetics Saarland University Interdisciplinary Center for Clinical Research University of Wuerzburg Department of Internal Medicine III Heidelberg University

Co-regulation of genes has been extensively analyzed, however, rather limited knowledge is available on co-regulations within the miRNome. We investigated differential co-expression of microRNAs （miRNAs） based on miRNome profiles of whole blood from 540 individuals. These include patients suffering from different cancer and non-cancer diseases, and unaffected controls. Using hierarchi- cal clustering, we found 9 significant clusters of co-expressed miRNAs containing 2-36 individual miRNAs. Through analyzing multiple sequencing alignments in the clusters, we found that co-expression of miRNAs is associated with both sequence similarity and genomic co-localization. We calculated correlations for all 371,953 pairs of miRNAs for all 540 individuals and identified 184 pairs of miRNAs with high correlation values. Out of these 184 pairs of miRNAs, 16 pairs （8.7%） were differentially co-expressed in unaffected controls, cancer patients and patients with non-cancer diseases. By computing correlated and anti-correlated miRNA pairs, we constructed a net- work with 184 putative co-regulations as edges and 100 miRNAs as nodes. Thereby, we detected specific clusters of miRNAs with high and low correlation values. Our approach represents the most comprehensive co-regulation analysis based on whole miRNome-wide expression profiling. Our findings further decrypt the interactions of miRNAs in normal and human pathological processes.

关键词： Co-expression Microarray MicroRNA Network analysis

Genome-wide MicroRNA Expression Profiles in COPD: Early Predictors for Cancer Development

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Genomics, Proteomics & Bioinformatics 2018年第3期16卷 162-171页

作者： Andreas Keller Tobias Fehlmann Nicole Ludwig Mustafa Kahraman Thomas Laufer christina backes Claus Vogelmeier Caroline Diener Frank Biertz Christian Herr Rudolf A. Jorres Hans-Peter Lenhof Eckart Meese Robert Bals Clinical Bioinformatics Saarland University 66123 Saarbriieken Germany Department of Human Genetics Saarland University Hospital 66421 Homburg Germany Hummingbird Diagnostics GmbH 69120 Heidelberg Germany Department of Internal Medicine Division for Pulmonary Diseases Philipps University of Marburg 35043 Marburg Germany Institute for Biostatistics Hannover Medical School 30625 Hanover Germany Department of Internal Medicine V- Pulmonology AlIergology Intensive Care Medicine Saarland University Hospital 66421 Homburg Germany Institute and Outpatient Clinic for Occupational Social and Environmental Medicine Comprehensive Pneumology Center Munich (CPC-M) Ludwig-Maximilians-University Munich Member of the German Center for Lung Research ( DZL) 80539 Munich Germany Bioinformatics Saarland University 66123 Saarbrucken Germany Center for Bioinformatics Saarland University 66123 Saarbrucken Germany

Chronic obstructive pulmonary disease （COPD） significantly increases the risk of developing cancer. Biomarker studies frequently follow a case-control set-up in which patients diagnosed with a disease are compared to controls. Longitudinal cohort studies such as the COPD-centered German COPD and SYstemic consequences-COmorbidities NETwork （COSYCONET） study provide the patient and biomaterial base for discovering predictive molecular markers. We asked whether microRNA （miRNA） profiles in blood collected from COPD patients prior to a tumor diagnosis could support an early diagnosis of tumor development independent of the tumor type. From 2741 participants of COSYCONET diagnosed with COPD, we selected 534 individuals including 33 patients who developed cancer during the follow-up period of 54 months and 501 patients who did not develop cancer, but had similar age, gender and smoking history. Genome-wide miRNA profiles were generated and evaluated using machine learning techniques. For patients developing cancer we identified nine miRNAs with significantly decreased abundance （two-tailed unpaired t-test adjusted for multiple testing P 〈 0.05）, including members of the miR-320 family. The identified miRNAs regulate different cancer-related pathways including the MAPK pathway （P - 2.3 × 10 -5）. We also observed the impact of confounding factors on the generated miRNA profiles, underlining the value of our matched analysis. For selected miRNAs, qRT-PCR analysis was applied to validate the results. In conclusion, we identified several miRNAs in blood of COPD patients, which could serve as candidates for biomarkers to help identify COPD patients at risk of developing cancer.

关键词： microRNA Cancer COPD Lung Biomarker COSYCONET

Integrating Culture-based Antibiotic Resistance Profiles with Whole-genome Sequencing Data for 11,087 Clinical Isolates

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Genomics, Proteomics & Bioinformatics 2019年第2期17卷 169-182页

作者： Valentina Galata Cédric C. Laczny christina backes Georg Hemmrich-Stanisak Susanne Schmolke Andre Franke Eckart Meese Mathias Herrmann Lutz von Müller Achim Plum Rolf Mü ller Cord Stahler Andreas E. Posch Andreas Keller Chair for Clinical Bioinformatics Saarland University 66123 Saarbrücken Germany Helmholtz Center for Infection Research and Pharmaceutical Biotechnology (HZI) Saarland University 66123 Saarbrücken Germany Institute of Clinical Molecular Biology Christian-Albrechts University of Kiel 24105 Kiel Germany Siemens Healthcare GmbH Strategy and Innovation 91052 Erlangen Germany Department of Human Genetics Saarland University 66421 Homburg Germany Institute of Medical Microbiology and Hygiene Saarland University 66421 Homburg Germany Ares Genetics GmbH 1030 Vienna Austria Curetis GmbH 71088 Holzgerlingen Germany Department of Pharmacy Pharmaceutical Biotechnology Saarland University 66123 Saarbrücken Germany Department of Microbial Natural Products Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) Saarland University 66123 Saarbrücken Germany

Emerging antibiotic resistance is a major global health threat. The analysis of nucleic acid sequences linked to susceptibility phenotypes facilitates the study of genetic antibiotic resistance determinants to inform molecular diagnostics and drug development. We collected genetic data (11,087 newly-sequenced whole genomes) and culture-based resistance profiles (10,991 out of the 11,087 isolates comprehensively tested against 22 antibiotics in total) of clinical isolates including 18 main species spanning a time period of 30 years. Species and drug specific resistance patterns were observed including increased resistance rates for Acinetobacter baumannii to carbapenems and for Escherichia coli to fluoroquinolones. Species-level pan-genomes were constructed to reflect the genetic repertoire of the respective species,including conserved essential genes and known resis-tance factors. Integrating phenotypes and genotypes through species-level pan-genomes allowed to infer gene–drug resistance associations using statistical testing. The isolate collection and the analysis results have been integrated into GEAR-base,a resource available for academic research use free of charge at https://***.

关键词： Antibiotic resistance Whole-genome sequencing Bacteria Pan-genome

Machine Learning to Detect Alzheimer’s Disease from Circulating Non-coding RNAs

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Genomics, Proteomics & Bioinformatics 2019年第4期17卷 430-440页

作者： Nicole Ludwig Tobias Fehlmann Fabian Kern Manfred Gogol Walter Maetzler Stephanie Deutscher Simone Gurlit Claudia Schulte Anna-Katharina von Thaler Christian Deuschle Florian Metzger Daniela Berg Ulrike Suenkel Verena Keller christina backes Hans-Peter Lenhof Eckart Meese Andreas Keller Department of Human Genetics Saarland University66421 Homburg/SaarGermany Chair for Clinical Bioinformatics Saarland University66123 Saarbru¨ckenGermany Institut fur Gerontologie Universitat Heidelberg69047 HeidelbergGermany Department of Neurology Christian-Albrechts-University of Kiel24118 KielGermany Center for Neurology and Hertie Institute for Clinical Brain Research Department of NeurodegenerationUniversity of Tuebingen72074 TuebingenGermany German Center for Neurodegenerative Diseases(DZNE) 72076 TuebingenGermany Department of Anesthesiology and Intensive Care St.Franziskus Hospital Muenster48145 MuensterGermany Department of Psychiatry and Psychotherapy University Hospital Tuebingen72016 TuebingenGermany Department of Medicine II Saarland University Medical Center66421 Homburg/SaarGermany Center for Bioinformatics Saarland Informatics Campus66123 SaarbruckenGermany

Blood-borne small non-coding(snc RNAs)are among the prominent candidates for blood-based diagnostic ***,high-throughput approaches are applied to discover biomarker *** have to be validated in larger cohorts and evaluated by adequate statistical learning ***,we published high-throughput sequencing based microRNA(miRNA)signatures in Alzheimer’s disease(AD)patients in the United States(US)and ***,we determined abundance levels of 21 known circulating miRNAs in 465 individuals encompassing AD patients and controls by *** computed models to assess the relation between miRNA expression and phenotypes,gender,age,or disease severity(Mini-Mental State Examination;MMSE).Of the 21 miRNAs,expression levels of 20 miRNAs were consistently de-regulated in the US and German cohorts.18 miRNAs were significantly correlated with neurodegeneration(Benjamini-Hochberg adjusted P<0.05)with highest significance for miR-532-5 p(BenjaminiHochberg adjusted P=4.8×10^-30).Machine learning models reached an area under the curve(AUC)value of 87.6%in differentiating AD patients from ***,ten miRNAs were significantly correlated with MMSE,in particular miR-26a/26b-5p(adjusted P=0.0002).Interestingly,the miRNAs with lower abundance in AD were enriched in monocytes and T-helper cells,while those up-regulated in AD were enriched in serum,exosomes,cytotoxic t-cells,and *** study represents the next important step in translational research for a miRNA-based AD test.

关键词： miRNAs Neurodegeneration Alzheimer’s disease Biomarker Non-coding RNAs Gene regulation