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Approaches to analyse and interpret biological profile dataScholz, Matthias January 2006 (has links)
Advances in biotechnologies rapidly increase the number of molecules of a cell which can be observed simultaneously. This includes expression levels of thousands or ten-thousands of genes as well as concentration levels of metabolites or proteins.
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Such Profile data, observed at different times or at different experimental conditions (e.g., heat or dry stress), show how the biological experiment is reflected on the molecular level. This information is helpful to understand the molecular behaviour and to identify molecules or combination of molecules that characterise specific biological condition (e.g., disease).
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This work shows the potentials of component extraction algorithms to identify the major factors which influenced the observed data. This can be the expected experimental factors such as the time or temperature as well as unexpected factors such as technical artefacts or even unknown biological behaviour.
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Extracting components means to reduce the very high-dimensional data to a small set of new variables termed components. Each component is a combination of all original variables. The classical approach for that purpose is the principal component analysis (PCA).
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It is shown that, in contrast to PCA which maximises the variance only, modern approaches such as independent component analysis (ICA) are more suitable for analysing molecular data. The condition of independence between components of ICA fits more naturally our assumption of individual (independent) factors which influence the data. This higher potential of ICA is demonstrated by a crossing experiment of the model plant <i>Arabidopsis thaliana</i> (Thale Cress). The experimental factors could be well identified and, in addition, ICA could even detect a technical artefact.
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However, in continuously observations such as in time experiments, the data show, in general, a nonlinear distribution. To analyse such nonlinear data, a nonlinear extension of PCA is used. This nonlinear PCA (NLPCA) is based on a neural network algorithm. The algorithm is adapted to be applicable to incomplete molecular data sets. Thus, it provides also the ability to estimate the missing data. The potential of nonlinear PCA to identify nonlinear factors is demonstrated by a cold stress experiment of <i>Arabidopsis thaliana</i>.
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The results of component analysis can be used to build a molecular network model. Since it includes functional dependencies it is termed functional network. Applied to the cold stress data, it is shown that functional networks are appropriate to visualise biological processes and thereby reveals molecular dynamics. / Fortschritte in der Biotechnologie ermöglichen es, eine immer größere Anzahl von Molekülen in einer Zelle gleichzeitig zu erfassen. Das betrifft sowohl die Expressionswerte tausender oder zehntausender Gene als auch die Konzentrationswerte von Metaboliten oder Proteinen.
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Diese Profildaten verschiedener Zeitpunkte oder unterschiedlicher experimenteller Bedingungen (z.B. unter Stressbedingungen wie Hitze oder Trockenheit) zeigen, wie sich das biologische Experiment auf molekularer Ebene widerspiegelt. Diese Information kann genutzt werden, um molekulare Abläufe besser zu verstehen und um Moleküle oder Molekül-Kombinationen zu bestimmen, die für bestimmte biologische Zustände (z.B.: Krankheit) charakteristisch sind.
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Die Arbeit zeigt die Möglichkeiten von Komponenten-Extraktions-Algorithmen zur Bestimmung der wesentlichen Faktoren, die einen Einfluss auf die beobachteten Daten ausübten. Das können sowohl die erwarteten experimentellen Faktoren wie Zeit oder Temperatur sein als auch unerwartete Faktoren wie technische Einflüsse oder sogar unerwartete biologische Vorgänge.
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Unter der Extraktion von Komponenten versteht man die Reduzierung dieser stark hoch-dimensionalen Daten auf wenige neue Variablen, die eine Kombination aus allen ursprünglichen Variablen darstellen und als Komponenten bezeichnet werden. Die Standard-Methode für diesen Zweck ist die Hauptkomponentenanalyse (PCA).
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Es wird gezeigt, dass - im Vergleich zur nur die Varianz maximierenden PCA - moderne Methoden wie die Unabhängige Komponentenanalyse (ICA) für die Analyse molekularer Datensätze besser geeignet sind. Die Unabhängigkeit von Komponenten in der ICA entspricht viel besser unserer Annahme individueller (unabhängiger) Faktoren, die einen Einfluss auf die Daten ausüben. Dieser Vorteil der ICA wird anhand eines Kreuzungsexperiments mit der Modell-Pflanze <i>Arabidopsis thaliana</i> (Ackerschmalwand) demonstriert. Die experimentellen Faktoren konnten dabei gut identifiziert werden und ICA erkannte sogar zusätzlich einen technischen Störfaktor.
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Bei kontinuierlichen Beobachtungen wie in Zeitexperimenten zeigen die Daten jedoch häufig eine nichtlineare Verteilung. Für die Analyse dieser nichtlinearen Daten wird eine nichtlinear erweiterte Methode der PCA angewandt. Diese nichtlineare PCA (NLPCA) basiert auf einem neuronalen Netzwerk-Algorithmus. Der Algorithmus wurde für die Anwendung auf unvollständigen molekularen Daten erweitert. Dies ermöglicht es, die fehlenden Werte zu schätzen. Die Fähigkeit der nichtlinearen PCA zur Bestimmung nichtlinearer Faktoren wird anhand eines Kältestress-Experiments mit <i>Arabidopsis thaliana</i> demonstriert.
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Die Ergebnisse aus der Komponentenanalyse können zur Erstellung molekularer Netzwerk-Modelle genutzt werden. Da sie funktionelle Abhängigkeiten berücksichtigen, werden sie als Funktionale Netzwerke bezeichnet. Anhand der Kältestress-Daten wird demonstriert, dass solche funktionalen Netzwerke geeignet sind, biologische Prozesse zu visualisieren und dadurch die molekularen Dynamiken aufzuzeigen.
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A signal transduction score flow algorithm for cyclic cellular pathway analysis, which combines transcriptome and ChIP-seq dataIsik, Zerrin, Ersahin, Tulin, Atalay, Volkan, Aykanat, Cevdet, Cetin-Atalay, Rengul 08 April 2014 (has links) (PDF)
Determination of cell signalling behaviour is crucial for understanding the physiological response to a specific stimulus or drug treatment. Current approaches for large-scale data analysis do not effectively incorporate critical topological information provided by the signalling network. We herein describe a novel model- and data-driven hybrid approach, or signal transduction score flow algorithm, which allows quantitative visualization of cyclic cell signalling pathways that lead to ultimate cell responses such as survival, migration or death. This score flow algorithm translates signalling pathways as a directed graph and maps experimental data, including negative and positive feedbacks, onto gene nodes as scores, which then computationally traverse the signalling pathway until a pre-defined biological target response is attained. Initially, experimental data-driven enrichment scores of the genes were computed in a pathway, then a heuristic approach was applied using the gene score partition as a solution for protein node stoichiometry during dynamic scoring of the pathway of interest. Incorporation of a score partition during the signal flow and cyclic feedback loops in the signalling pathway significantly improves the usefulness of this model, as compared to other approaches. Evaluation of the score flow algorithm using both transcriptome and ChIP-seq data-generated signalling pathways showed good correlation with expected cellular behaviour on both KEGG and manually generated pathways. Implementation of the algorithm as a Cytoscape plug-in allows interactive visualization and analysis of KEGG pathways as well as user-generated and curated Cytoscape pathways. Moreover, the algorithm accurately predicts gene-level and global impacts of single or multiple in silico gene knockouts. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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A signal transduction score flow algorithm for cyclic cellular pathway analysis, which combines transcriptome and ChIP-seq dataIsik, Zerrin, Ersahin, Tulin, Atalay, Volkan, Aykanat, Cevdet, Cetin-Atalay, Rengul January 2012 (has links)
Determination of cell signalling behaviour is crucial for understanding the physiological response to a specific stimulus or drug treatment. Current approaches for large-scale data analysis do not effectively incorporate critical topological information provided by the signalling network. We herein describe a novel model- and data-driven hybrid approach, or signal transduction score flow algorithm, which allows quantitative visualization of cyclic cell signalling pathways that lead to ultimate cell responses such as survival, migration or death. This score flow algorithm translates signalling pathways as a directed graph and maps experimental data, including negative and positive feedbacks, onto gene nodes as scores, which then computationally traverse the signalling pathway until a pre-defined biological target response is attained. Initially, experimental data-driven enrichment scores of the genes were computed in a pathway, then a heuristic approach was applied using the gene score partition as a solution for protein node stoichiometry during dynamic scoring of the pathway of interest. Incorporation of a score partition during the signal flow and cyclic feedback loops in the signalling pathway significantly improves the usefulness of this model, as compared to other approaches. Evaluation of the score flow algorithm using both transcriptome and ChIP-seq data-generated signalling pathways showed good correlation with expected cellular behaviour on both KEGG and manually generated pathways. Implementation of the algorithm as a Cytoscape plug-in allows interactive visualization and analysis of KEGG pathways as well as user-generated and curated Cytoscape pathways. Moreover, the algorithm accurately predicts gene-level and global impacts of single or multiple in silico gene knockouts. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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