Avec la révolution récente de la génomique et la médecine stratifiée, le développement de signatures moléculaires devient de plus en plus important pour prédire le pronostic (biomarqueurs pronostiques) ou l’effet d’un traitement (biomarqueurs prédictifs) de chaque patient. Cependant, la grande quantité d’information disponible rend la découverte de faux positifs de plus en plus fréquente dans la recherche biomédicale. La présence de données de grande dimension (nombre de biomarqueurs ≫ taille d’échantillon) soulève de nombreux défis statistiques tels que la non-identifiabilité des modèles, l’instabilité des biomarqueurs sélectionnés ou encore la multiplicité des tests.L’objectif de cette thèse a été de proposer et d’évaluer des méthodes statistiques pour l’identification de ces biomarqueurs et l’élaboration d’une prédiction individuelle des probabilités de survie pour des nouveaux patients à partir d’un modèle de régression de Cox. Pour l’identification de biomarqueurs en présence de données de grande dimension, la régression pénalisée lasso est très largement utilisée. Dans le cas de biomarqueurs pronostiques, une extension empirique de cette pénalisation a été proposée permettant d’être plus restrictif sur le choix du paramètre λ dans le but de sélectionner moins de faux positifs. Pour les biomarqueurs prédictifs, l’intérêt s’est porté sur les interactions entre le traitement et les biomarqueurs dans le contexte d’un essai clinique randomisé. Douze approches permettant de les identifier ont été évaluées telles que le lasso (standard, adaptatif, groupé ou encore ridge+lasso), le boosting, la réduction de dimension des effets propres et un modèle implémentant les effets pronostiques par bras. Enfin, à partir d’un modèle de prédiction pénalisé, différentes stratégies ont été évaluées pour obtenir une prédiction individuelle pour un nouveau patient accompagnée d’un intervalle de confiance, tout en évitant un éventuel surapprentissage du modèle. La performance des approches ont été évaluées au travers d’études de simulation proposant des scénarios nuls et alternatifs. Ces méthodes ont également été illustrées sur différents jeux de données, contenant des données d’expression de gènes dans le cancer du sein. / With the recent revolution in genomics and in stratified medicine, the development of molecular signatures is becoming more and more important for predicting the prognosis (prognostic biomarkers) and the treatment effect (predictive biomarkers) of each patient. However, the large quantity of information has rendered false positives more and more frequent in biomedical research. The high-dimensional space (i.e. number of biomarkers ≫ sample size) leads to several statistical challenges such as the identifiability of the models, the instability of the selected coefficients or the multiple testing issue.The aim of this thesis was to propose and evaluate statistical methods for the identification of these biomarkers and the individual predicted survival probability for new patients, in the context of the Cox regression model. For variable selection in a high-dimensional setting, the lasso penalty is commonly used. In the prognostic setting, an empirical extension of the lasso penalty has been proposed to be more stringent on the estimation of the tuning parameter λ in order to select less false positives. In the predictive setting, focus has been given to the biomarker-by-treatment interactions in the setting of a randomized clinical trial. Twelve approaches have been proposed for selecting these interactions such as lasso (standard, adaptive, grouped or ridge+lasso), boosting, dimension reduction of the main effects and a model incorporating arm-specific biomarker effects. Finally, several strategies were studied to obtain an individual survival prediction with a corresponding confidence interval for a future patient from a penalized regression model, while limiting the potential overfit.The performance of the approaches was evaluated through simulation studies combining null and alternative scenarios. The methods were also illustrated in several data sets containing gene expression data in breast cancer.

This thesis studies, implements and experiments with specific application-oriented approaches for exploring and querying multi-dimensional datasets. The first part of the thesis scrutinizes indexing of the complex space of chemical compounds, and details a design of high-performance retrieval system for small molecules. The resulting system is then utilized within a wider context of federated search in heterogeneous data and metadata related to the chemical datasets. In the second part, the thesis focuses on fast visualization and exploration of many-dimensional data that originate from single- cell cytometry. Self-organizing maps are used to derive fast methods for analysis of the datasets, and used as a base for a novel data visualization algorithm. Finally, a similar approach is utilized for highly interactive exploration of multimedia datasets. The main contributions of the thesis comprise the advancement in optimization and methods for querying the chemical data implemented in the Sachem database cartridge, the federated, SPARQL-based interface to Sachem that provides the heterogeneous search support, dimensionality reduction algorithm EmbedSOM, design and implementation of the specific EmbedSOM-backed analysis tool for flow and mass cytometry, and design and implementation of the multimedia...

The technical advancements in genomics, functional magnetic-resonance and other areas of scientific research seen in the last two decades have led to a burst of interest in multiple testing procedures. A driving factor for innovations in the field of multiple testing has been the problem of large scale simultaneous testing. There, the goal is to uncover lower--dimensional signals from high--dimensional data. Mathematically speaking, this means that the dimension d is usually in the thousands while the sample size n is relatively small (max. 100 in general, often due to cost constraints) --- a characteristic commonly abbreviated as d >> n. In my thesis I look at several multiple testing problems and corresponding procedures from a false discovery rate (FDR) perspective, a methodology originally introduced in a seminal paper by Benjamini and Hochberg (2005). FDR analysis starts by fitting a two--component mixture model to the observed test statistics. This mixture consists of a null model density and an alternative component density from which the interesting cases are assumed to be drawn. In the thesis I proposed a new approach called log--FDR to the estimation of false discovery rates. Specifically, my new approach to truncated maximum likelihood estimation yields accurate null model estimates. This is complemented by constrained maximum likelihood estimation for the alternative density using log--concave density estimation. A recent competitor to the FDR is the method of \"Higher Criticism\". It has been strongly advocated in the context of variable selection in classification which is deeply linked to multiple comparisons. Hence, I also looked at variable selection in class prediction which can be viewed as a special signal identification problem. Both FDR methods and Higher Criticism can be highly useful for signal identification. This is discussed in the context of variable selection in linear discriminant analysis (LDA), a popular classification method. FDR methods are not only useful for multiple testing situations in the strict sense, they are also applicable to related problems. I looked at several kinds of applications of FDR in linear classification. I present and extend statistical techniques related to effect size estimation using false discovery rates and showed how to use these for variable selection. The resulting fdr--effect method proposed for effect size estimation is shown to work as well as competing approaches while being conceptually simple and computationally inexpensive. Additionally, I applied the fdr--effect method to variable selection by minimizing the misclassification rate and showed that it works very well and leads to compact and interpretable feature sets.

Motivée par les récentes avancées dans l'analyse théorique des performances des algorithmes d'apprentissage automatisé, cette thèse s'intéresse à l'analyse de performances et à l'amélioration de la classification nonsupervisée de données et graphes en grande dimension. Spécifiquement, dans la première grande partie de cette thèse, en s'appuyant sur des outils avancés de la théorie des grandes matrices aléatoires, nous analysons les performances de méthodes spectrales sur des modèles de graphes réalistes et denses ainsi que sur des données en grandes dimensions en étudiant notamment les valeurs propres et vecteurs propres des matrices d'affinités de ces données. De nouvelles méthodes améliorées sont proposées sur la base de cette analyse théorique et démontrent à travers de nombreuses simulations que leurs performances sont meilleures comparées aux méthodes de l'état de l'art. Dans la seconde partie de la thèse, nous proposons un nouvel algorithme pour la détection de communautés hétérogènes entre plusieurs couches d'un graphe à plusieurs types d'interaction. Une approche bayésienne variationnelle est utilisée pour approximer la distribution apostériori des variables latentes du modèle. Toutes les méthodes proposées dans cette thèse sont utilisées sur des bases de données synthétiques et sur des données réelles et présentent de meilleures performances en comparaison aux approches standard de classification dans les contextes susmentionnés. / Spurred by recent advances on the theoretical analysis of the performances of the data-driven machine learning algorithms, this thesis tackles the performance analysis and improvement of high dimensional data and graph clustering. Specifically, in the first bigger part of the thesis, using advanced tools from random matrix theory, the performance analysis of spectral methods on dense realistic graph models and on high dimensional kernel random matrices is performed through the study of the eigenvalues and eigenvectors of the similarity matrices characterizing those data. New improved methods are proposed and are shown to outperform state-of-the-art approaches. In a second part, a new algorithm is proposed for the detection of heterogeneous communities from multi-layer graphs using variational Bayes approaches to approximate the posterior distribution of the sought variables. The proposed methods are successfully applied to synthetic benchmarks as well as real-world datasets and are shown to outperform standard approaches to clustering in those specific contexts.

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Collected data may simultaneously be of low sample size and high dimension. Such data exhibit some geometric regularities consisting of a single observation being a rotation on a sphere, and a pair of observations being orthogonal. This thesis investigates these geometric properties in some detail. Background is provided and various approaches to the result are discussed. An approach based on the mean value theorem is eventually chosen, being the only candidate investigated that gives explicit convergence bounds. The bounds are tested employing Monte Carlo simulation and found to be adequate. / Data som insamlas kan samtidigt ha en liten stickprovsstorlek men vara högdimensionell. Sådan data uppvisar vissa geometriska mönster som består av att en enskild observation är en rotation på en sfär, och att ett par av observationer är rätvinkliga. Den här uppsatsen undersöker dessa geometriska egenskaper mer detaljerat. En bakgrund ges och olika typer av angreppssätt diskuteras. Till slut väljs en metod som baseras på medelvärdessatsen eftersom detta är den enda av de undersökta metoderna som ger explicita konvergensgränser. Gränserna testas sedermera med Monte Carlo-simulering och visar sig stämma.

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<p><strong>Background:</strong> Through unprecedented advances in technology, high-dimensional datasets have exploded into many fields of observational research. For example, it is now common to expect thousands or millions of genetic variables (p) with only a limited number of study participants (n). Determining the important features proves statistically difficult, as multivariate analysis techniques become flooded and mathematically insufficient when n < p. Principal Component Analysis (PCA) is a commonly used multivariate method for dimension reduction and data visualization but suffers from these issues. A collection of Sparse PCA methods have been proposed to counter these flaws but have not been tested in comparative detail. <strong>Methods:</strong> Performances of three Sparse PCA methods were evaluated through simulations. Data was generated for 56 different data-structures, ranging p, the number of underlying groups and the variance structure within them. Estimation and interpretability of the principal components (PCs) were rigorously tested. Sparse PCA methods were also applied to a real gene expression dataset. <strong>Results:</strong> All Sparse PCA methods showed improvements upon classical PCA. Some methods were best at obtaining an accurate leading PC only, whereas others were better for subsequent PCs. There exist different optimal choices of Sparse PCA methods when ranging within-group correlation and across-group variances; thankfully, one method repeatedly worked well under the most difficult scenarios. When applying methods to real data, concise groups of gene expressions were detected with the most sparse methods. <strong>Conclusions:</strong> Sparse PCA methods provide a new insightful way to detect important features amidst complex high-dimension data.</p> / Master of Science (MSc)

<p>Recent advances in technology have allowed researchers to collect high-dimensional biological data simultaneously. In genomic studies, for instance, measurements from tens of thousands of genes are taken from individuals across several experimental groups. In time course microarray experiments, gene expression is measured at several time points for each individual across the whole genome resulting in massive amount of data. In such experiments, researchers are faced with two types of high-dimensionality. The first is global high-dimensionality, which is common to all genomic experiments. The global high-dimensionality arises because inference is being done on tens of thousands of genes resulting in multiplicity. This challenge is often dealt with statistical methods for multiple comparison, such as the Bonferroni correction or false discovery rate (FDR). We refer to the second type of high-dimensionality as gene specific high-dimensionality, which arises in time course microarry experiments due to the fact that, in such experiments, sample size is often smaller than the number of time points ($n</p> <p>In this thesis, we use the growth curve model (GCM), which is a generalized multivariate analysis of variance (GMANOVA) model, and propose a moderated test statistic for testing a special case of the general linear hypothesis, which is specially useful for identifying genes that are expressed. We use the trace test for the GCM and modify it so that it can be used in high-dimensional situations. We consider two types of moderation: the Moore-Penrose generalized inverse and Stein's shrinkage estimator of $ S $. We performed extensive simulations to show performance of the moderated test, and compared the results with original trace test. We calculated empirical level and power of the test under many scenarios. Although the focus is on hypothesis testing, we also provided moderated maximum likelihood estimator for the parameter matrix and assessed its performance by investigating bias and mean squared error of the estimator and compared the results with those of the maximum likelihood estimators. Since the parameters are matrices, we consider distance measures in both power and level comparisons as well as when investigating bias and mean squared error. We also illustrated our approach using time course microarray data taken from a study on Lung Cancer. We were able to filter out 1053 genes as non-noise genes from a pool of 22,277 genes which is approximately 5\% of the total number of genes. This is in sync with results from most biological experiments where around 5\% genes are found to be differentially expressed.</p> / Master of Science (MSc)