The inference of gene regulatory networks (GRN) is of great importance to medical research, as causal mechanisms responsible for phenotypes are unravelled and potential therapeutical targets identified. In type 1 diabetes, insulin producing pancreatic beta-cells are the target of an auto-immune attack leading to apoptosis (cell suicide). Although key genes and regulations have been identified, a precise characterization of the process leading to beta-cell apoptosis has not been achieved yet. The inference of relevant molecular pathways in type 1 diabetes is then a crucial research topic. GRN inference from gene expression data (obtained from microarrays and RNA-seq technology) is a causal inference problem which may be tackled with well-established statistical and machine learning concepts. In particular, the use of time series facilitates the identification of the causal direction in cause-effect gene pairs. However, inference from gene expression data is a very challenging problem due to the large number of existing genes (in human, over twenty thousand) and the typical low number of samples in gene expression datasets. In this context, it is important to correctly assess the accuracy of network inference methods. The contributions of this thesis are on three distinct aspects. The first is on inference assessment using precision-recall curves, in particular using the area under the curve (AUPRC). The typical approach to assess AUPRC significance is using Monte Carlo, and a parametric alternative is proposed. It consists on deriving the mean and variance of the null AUPRC and then using these parameters to fit a beta distribution approximating the true distribution. The second contribution is an investigation on network inference from time series. Several state of the art strategies are experimentally assessed and novel heuristics are proposed. One is a fast approximation of first order Granger causality scores, suited for GRN inference in the large variable case. Another identifies co-regulated genes (ie. regulated by the same genes). Both are experimentally validated using microarray and simulated time series. The third contribution of this thesis is on the context of type 1 diabetes and is a study on beta cell gene expression after exposure to cytokines, emulating the mechanisms leading to apoptosis. 8 datasets of beta cell gene expression were used to identify differentially expressed genes before and after 24h, which were functionally characterized using bioinformatics tools. The two most differentially expressed genes, previously unknown in the type 1 Diabetes literature (RIPK2 and ELF3) were found to modulate cytokine induced apoptosis. A regulatory network was then inferred using a dynamic adaptation of a state of the art network inference method. Three out of four predicted regulations (involving RIPK2 and ELF3) were experimentally confirmed, providing a proof of concept for the adopted approach. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished
| Identifer | oai:union.ndltd.org:ulb.ac.be/oai:dipot.ulb.ac.be:2013/216729 |
| Date | 04 September 2015 |
| Creators | Lopes, Miguel |
| Contributors | Bontempi, Gianluca, Lenaerts, Tom, Eizirik, Decio L., Jansen, Maarten, Laukens, Kris K. |
| Publisher | Universite Libre de Bruxelles, Université libre de Bruxelles, Faculté des Sciences – Informatique, Bruxelles |
| Source Sets | Université libre de Bruxelles |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:ulb-repo/semantics/doctoralThesis, info:ulb-repo/semantics/openurl/vlink-dissertation |
| Format | No full-text files |
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