TY - JOUR A1 - Kraus, Sara Milena A1 - Mathew-Stephen, Mariet A1 - Schapranow, Matthieu-Patrick T1 - Eatomics BT - Shiny exploration of quantitative proteomics data JF - Journal of proteome research N2 - Quantitative proteomics data are becoming increasingly more available, and as a consequence are being analyzed and interpreted by a larger group of users. However, many of these users have less programming experience. Furthermore, experimental designs and setups are getting more complicated, especially when tissue biopsies are analyzed. Luckily, the proteomics community has already established some best practices on how to conduct quality control, differential abundance analysis and enrichment analysis. However, an easy-to-use application that wraps together all steps for the exploration and flexible analysis of quantitative proteomics data is not yet available. For Eatomics, we utilize the R Shiny framework to implement carefully chosen parts of established analysis workflows to (i) make them accessible in a user-friendly way, (ii) add a multitude of interactive exploration possibilities, and (iii) develop a unique experimental design setup module, which interactively translates a given research hypothesis into a differential abundance and enrichment analysis formula. In this, we aim to fulfill the needs of a growing group of inexperienced quantitative proteomics data analysts. Eatomics may be tested with demo data directly online via https://we.analyzegenomes.com/now/eatomics/or with the user's own data by installation from the Github repository at https://github.com/Millchmaedchen/Eatomics. KW - R Shiny KW - application KW - label-free KW - proteomics KW - analysis KW - differential KW - abundance KW - experimental design Y1 - 2021 U6 - https://doi.org/10.1021/acs.jproteome.0c00398 SN - 1535-3893 SN - 1535-3907 VL - 20 IS - 1 SP - 1070 EP - 1078 PB - American Chemical Society CY - Washington ER - TY - GEN A1 - Perscheid, Cindy A1 - Faber, Lukas A1 - Kraus, Milena A1 - Arndt, Paul A1 - Janke, Michael A1 - Rehfeldt, Sebastian A1 - Schubotz, Antje A1 - Slosarek, Tamara A1 - Uflacker, Matthias T1 - A tissue-aware gene selection approach for analyzing multi-tissue gene expression data T2 - 2018 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) N2 - High-throughput RNA sequencing (RNAseq) produces large data sets containing expression levels of thousands of genes. The analysis of RNAseq data leads to a better understanding of gene functions and interactions, which eventually helps to study diseases like cancer and develop effective treatments. Large-scale RNAseq expression studies on cancer comprise samples from multiple cancer types and aim to identify their distinct molecular characteristics. Analyzing samples from different cancer types implies analyzing samples from different tissue origin. Such multi-tissue RNAseq data sets require a meaningful analysis that accounts for the inherent tissue-related bias: The identified characteristics must not originate from the differences in tissue types, but from the actual differences in cancer types. However, current analysis procedures do not incorporate that aspect. As a result, we propose to integrate a tissue-awareness into the analysis of multi-tissue RNAseq data. We introduce an extension for gene selection that provides a tissue-wise context for every gene and can be flexibly combined with any existing gene selection approach. We suggest to expand conventional evaluation by additional metrics that are sensitive to the tissue-related bias. Evaluations show that especially low complexity gene selection approaches profit from introducing tissue-awareness. KW - RNAseq KW - gene selection KW - tissue-awareness KW - TCGA KW - GTEx Y1 - 2018 SN - 978-1-5386-5488-0 U6 - https://doi.org/10.1109/BIBM.2018.8621189 SN - 2156-1125 SN - 2156-1133 SP - 2159 EP - 2166 PB - IEEE CY - New York ER - TY - JOUR A1 - Nordmeyer, Sarah A1 - Kraus, Milena A1 - Ziehm, Matthias A1 - Kirchner, Marieluise A1 - Schafstedde, Marie A1 - Kelm, Marcus A1 - Niquet, Sylvia A1 - Stephen, Mariet Mathew A1 - Baczko, Istvan A1 - Knosalla, Christoph A1 - Schapranow, Matthieu-Patrick A1 - Dittmar, Gunnar A1 - Gotthardt, Michael A1 - Falcke, Martin A1 - Regitz-Zagrosek, Vera A1 - Kuehne, Titus A1 - Mertins, Philipp T1 - Disease- and sex-specific differences in patients with heart valve disease BT - a proteome study JF - Life Science Alliance N2 - Pressure overload in patients with aortic valve stenosis and volume overload in mitral valve regurgitation trigger specific forms of cardiac remodeling; however, little is known about similarities and differences in myocardial proteome regulation. We performed proteome profiling of 75 human left ventricular myocardial biopsies (aortic stenosis = 41, mitral regurgitation = 17, and controls = 17) using high-resolution tandem mass spectrometry next to clinical and hemodynamic parameter acquisition. In patients of both disease groups, proteins related to ECM and cytoskeleton were more abundant, whereas those related to energy metabolism and proteostasis were less abundant compared with controls. In addition, disease group-specific and sex-specific differences have been observed. Male patients with aortic stenosis showed more proteins related to fibrosis and less to energy metabolism, whereas female patients showed strong reduction in proteostasis-related proteins. Clinical imaging was in line with proteomic findings, showing elevation of fibrosis in both patient groups and sex differences. Disease-and sex-specific proteomic profiles provide insight into cardiac remodeling in patients with heart valve disease and might help improve the understanding of molecular mechanisms and the development of individualized treatment strategies. Y1 - 2023 U6 - https://doi.org/10.26508/lsa.202201411 SN - 2575-1077 VL - 6 IS - 3 PB - EMBO Press CY - Heidelberg ER - TY - THES A1 - Kraus, Sara Milena T1 - A Systems Medicine approach for heart valve diseases BT - addressing the proteomic landscape and differential expression software N2 - In Systems Medicine, in addition to high-throughput molecular data (*omics), the wealth of clinical characterization plays a major role in the overall understanding of a disease. Unique problems and challenges arise from the heterogeneity of data and require new solutions to software and analysis methods. The SMART and EurValve studies establish a Systems Medicine approach to valvular heart disease -- the primary cause of subsequent heart failure. With the aim to ascertain a holistic understanding, different *omics as well as the clinical picture of patients with aortic stenosis (AS) and mitral regurgitation (MR) are collected. Our task within the SMART consortium was to develop an IT platform for Systems Medicine as a basis for data storage, processing, and analysis as a prerequisite for collaborative research. Based on this platform, this thesis deals on the one hand with the transfer of the used Systems Biology methods to their use in the Systems Medicine context and on the other hand with the clinical and biomolecular differences of the two heart valve diseases. To advance differential expression/abundance (DE/DA) analysis software for use in Systems Medicine, we state 21 general software requirements and features of automated DE/DA software, including a novel concept for the simple formulation of experimental designs that can represent complex hypotheses, such as comparison of multiple experimental groups, and demonstrate our handling of the wealth of clinical data in two research applications DEAME and Eatomics. In user interviews, we show that novice users are empowered to formulate and test their multiple DE hypotheses based on clinical phenotype. Furthermore, we describe insights into users' general impression and expectation of the software's performance and show their intention to continue using the software for their work in the future. Both research applications cover most of the features of existing tools or even extend them, especially with respect to complex experimental designs. Eatomics is freely available to the research community as a user-friendly R Shiny application. Eatomics continued to help drive the collaborative analysis and interpretation of the proteomic profile of 75 human left myocardial tissue samples from the SMART and EurValve studies. Here, we investigate molecular changes within the two most common types of valvular heart disease: aortic valve stenosis (AS) and mitral valve regurgitation (MR). Through DE/DA analyses, we explore shared and disease-specific protein alterations, particularly signatures that could only be found in the sex-stratified analysis. In addition, we relate changes in the myocardial proteome to parameters from clinical imaging. We find comparable cardiac hypertrophy but differences in ventricular size, the extent of fibrosis, and cardiac function. We find that AS and MR show many shared remodeling effects, the most prominent of which is an increase in the extracellular matrix and a decrease in metabolism. Both effects are stronger in AS. In muscle and cytoskeletal adaptations, we see a greater increase in mechanotransduction in AS and an increase in cortical cytoskeleton in MR. The decrease in proteostasis proteins is mainly attributable to the signature of female patients with AS. We also find relevant therapeutic targets. In addition to the new findings, our work confirms several concepts from animal and heart failure studies by providing the largest collection of human tissue from in vivo collected biopsies to date. Our dataset contributing a resource for isoform-specific protein expression in two of the most common valvular heart diseases. Apart from the general proteomic landscape, we demonstrate the added value of the dataset by showing proteomic and transcriptomic evidence for increased expression of the SARS-CoV-2- receptor at pressure load but not at volume load in the left ventricle and also provide the basis of a newly developed metabolic model of the heart. N2 - In der Systemmedizin spielt zusätzlich zu den molekularen Hochdurchsatzdaten (*omics) die Fülle an klinischer Charakterisierung eine große Rolle im Gesamtverständnis einer Krankheit. Hieraus ergeben sich Probleme und Herausforderungen unter anderem in Bezug auf Softwarelösungen und Analysemethoden. Die SMART- und EurValve-Studien etablieren einen systemmedizinischen Ansatz für Herzklappenerkrankungen -- die Hauptursache für eine spätere Herzinsuffizienz. Mit dem Ziel ein ganzheitliches Verständnis zu etablieren, werden verschiedene *omics sowie das klinische Bild von Patienten mit Aortenstenosen (AS) und Mitralklappeninsuffizienz (MR) erhoben. Unsere Aufgabe innerhalb des SMART Konsortiums bestand in der Entwicklung einer IT-Plattform für Systemmedizin als Grundlage für die Speicherung, Verarbeitung und Analyse von Daten als Voraussetzung für gemeinsame Forschung. Ausgehend von dieser Plattform beschäftigt sich diese Arbeit einerseits mit dem Transfer der genutzten systembiologischen Methoden hin zu einer Nutzung im systemmedizinischen Kontext und andererseits mit den klinischen und biomolekularen Unterschieden der beiden Herzklappenerkrankungen. Um die Analysesoftware für differenzielle Expression/Abundanz, eine häufig genutzte Methode der System Biologie, für die Nutzung in der Systemmedizin voranzutreiben, erarbeiten wir 21 allgemeine Softwareanforderungen und Funktionen einer automatisierten DE/DA Software. Darunter ist ein neuartiges Konzept für die einfache Formulierung experimenteller Designs, die auch komplexe Hypothesen wie den Vergleich mehrerer experimenteller Gruppen abbilden können und demonstrieren unseren Umgang mit der Fülle klinischer Daten in zwei Forschungsanwendungen -- DEAME und Eatomics. In Nutzertests zeigen wir, dass Nutzer befähigt werden, ihre vielfältigen Hypothesen zur differenziellen Expression basierend auf dem klinischen Phänotyp zu formulieren und zu testen, auch ohne einen dedizierten Hintergrund in Bioinformatik. Darüber hinaus beschreiben wir Einblicke in den allgemeinen Eindruck der Nutzer, ihrer Erwartung an die Leistung der Software und zeigen ihre Absicht, die Software auch in der Zukunft für ihre Arbeit zu nutzen. Beide Forschungsanwendungen decken die meisten Funktionen bestehender Tools ab oder erweitern sie sogar, insbesondere im Hinblick auf komplexe experimentelle Designs. Eatomics steht der Forschungsgemeinschaft als benutzerfreundliche R Shiny-Anwendung frei zur Verfügung. \textit{Eatomics} hat weiterhin dazu beigetragen, die gemeinsame Analyse und Interpretation des Proteomprofils von 75 menschlichen linken Myokardgewebeproben aus den SMART- und EurValve-Studien voran zu treiben. Hier untersuchen wir die molekularen Veränderungen innerhalb der beiden häufigsten Arten von Herzklappenerkrankungen: AS und MR. Durch DE/DA Analysen erarbeiten wir gemeinsame und krankheitsspezifische Proteinveränderungen, insbesondere Signaturen, die nur in einer geschlechtsstratifizierten Analyse gefunden werden konnten. Darüber hinaus beziehen wir Veränderungen des Myokardproteoms auf Parameter aus der klinischen Bildgebung. Wir finden eine vergleichbare kardiale Hypertrophie, aber Unterschiede in der Ventrikelgröße, dem Ausmaß der Fibrose und der kardialen Funktion. Wir stellen fest, dass AS und MR viele gemeinsame Remodelling-Effekte zeigen, von denen die wichtigsten die Zunahme der extrazellulären Matrix und eine Abnahme des Metabolismus sind. Beide Effekte sind bei AS stärker. Zusätzlich zeigt sich eine größere Variabilität zwischen den einzelnen Patienten mit AS. Bei Muskel- und Zytoskelettanpassungen sehen wir einen stärkeren Anstieg der Mechanotransduktion bei AS und einen Anstieg des kortikalen Zytoskeletts bei MR. Die Abnahme von Proteinen der Proteostase ist vor allem der Signatur von weiblichen Patienten mit AS zuzuschreiben. Außerdem finden wir therapierelevante Proteinveränderungen. Zusätzlich zu den neuen Erkenntnissen bestätigt unsere Arbeit mehrere Konzepte aus Tierstudien und Studien zu Herzversagen durch die bislang größte Kollektion von humanem Gewebe aus in vivo Biopsien. Mit unserem Datensatz stellen wir eine Ressource für die isoformspezifische Proteinexpression bei zwei der häufigsten Herzklappenerkrankungen zur Verfügung. Abgesehen von der allgemeinen Proteomlandschaft zeigen wir den Mehrwert des Datensatzes, indem wir proteomische und transkriptomische Beweise für eine erhöhte Expression des SARS-CoV-2- Rezeptors bei Drucklast, jedoch nicht bei Volumenlast im linken Ventrikel aufzeigen und außerdem die Grundlage eines neu entwickelten metabolischen Modells des Herzens liefern. KW - Systems Medicine KW - Systemmedizin KW - Proteomics KW - Proteom KW - Heart Valve Diseases KW - Herzklappenerkrankungen KW - Differential Expression Analysis KW - Software KW - Software Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-522266 ER -