Apprentissage de graphes causaux à partir de données continues ou mixtes d’intérêt biologique ou clinique

The work in this thesis follows the theory primarily developed by Judea Pearl on causal diagrams; graphical models that allow all causal quantities of interest to be derived formally and intuitively. We address the problem of causal network inference from observational data alone, i.e., without any intervention from the experimenter. In particular, we propose to improve existing methods to make them more suitable for analyzing real-world data, by freeing them as much as possible from constraints on data distributions, and by making them more interpretable. We propose an extension of MIIC, a constraint-based information-theoretic approach to recover the equivalence class of the causal graph from observations. Our contribution is an optimal discretization algorithm based on the minimum description length principle to simultaneously estimate the value of mutual (and multivariate) information and evaluate its significance between samples of variables of any nature: continuous, categorical or mixed. We use these developments to analyze mixed datasets of clinical (medical records of patients with cognitive disorders; or breast cancer and being treated by neoadjuvant chemotherapy) or biological interest (gene regulation networks of hematopoietic stem and precursor cells).Les travaux de cette thèse s’inscrivent dans la théorie principalement développée par Judea Pearl sur les diagrammes causaux; des modèles graphiques qui permettent de dériver toutes les quantités causales d’intérêt formellement et intuitivement. Nous traitons le problème de l’inférence de réseau causal à partir uniquement de données d’observation, c’est-à-dire sans aucune intervention de la part de l’expérimentateur. En particulier, nous proposons d’améliorer les méthodes existantes pour les rendre plus aptes à analyser des données issues du monde réel, en nous affranchissant le plus possible des contraintes sur les distributions des données, et en les rendant plus interprétables. Nous proposons une extension de MIIC, une approche basée sur les contraintes et la théorie de l’information pour retrouver la classe d’équivalence du graphe causal à partir d’observations. Notre contribution est un algorithme de discrétisation optimale basé sur le principe de description minimale pour simultanément estimer la valeur de l’information mutuelle (et multivariée) et évaluer sa significativité entre des échantillons de variables de n’importe quelle nature : continue, catégorique ou mixte. Nous mettons à profit ces développements pour analyser des jeux de données mixtes d'intérêt clinique (dossiers médicaux de patients atteints de troubles cognitifs; ou du cancer du sein) ou biologique (réseaux de régulation génique de cellules précurseur hématopoïétiques)

Apprentissage de graphes causaux à partir de données continues ou mixtes d’intérêt biologique ou clinique

Les travaux de cette thèse s’inscrivent dans la théorie principalement développée par Judea Pearl sur les diagrammes causaux; des modèles graphiques qui permettent de dériver toutes les quantités causales d’intérêt formellement et intuitivement. Nous traitons le problème de l’inférence de réseau causal à partir uniquement de données d’observation, c’est-à-dire sans aucune intervention de la part de l’expérimentateur. En particulier, nous proposons d’améliorer les méthodes existantes pour les rendre plus aptes à analyser des données issues du monde réel, en nous affranchissant le plus possible des contraintes sur les distributions des données, et en les rendant plus interprétables. Nous proposons une extension de MIIC, une approche basée sur les contraintes et la théorie de l’information pour retrouver la classe d’équivalence du graphe causal à partir d’observations. Notre contribution est un algorithme de discrétisation optimale basé sur le principe de description minimale pour simultanément estimer la valeur de l’information mutuelle (et multivariée) et évaluer sa significativité entre des échantillons de variables de n’importe quelle nature : continue, catégorique ou mixte. Nous mettons à profit ces développements pour analyser des jeux de données mixtes d'intérêt clinique (dossiers médicaux de patients atteints de troubles cognitifs; ou du cancer du sein) ou biologique (réseaux de régulation génique de cellules précurseur hématopoïétiques).The work in this thesis follows the theory primarily developed by Judea Pearl on causal diagrams; graphical models that allow all causal quantities of interest to be derived formally and intuitively. We address the problem of causal network inference from observational data alone, i.e., without any intervention from the experimenter. In particular, we propose to improve existing methods to make them more suitable for analyzing real-world data, by freeing them as much as possible from constraints on data distributions, and by making them more interpretable. We propose an extension of MIIC, a constraint-based information-theoretic approach to recover the equivalence class of the causal graph from observations. Our contribution is an optimal discretization algorithm based on the minimum description length principle to simultaneously estimate the value of mutual (and multivariate) information and evaluate its significance between samples of variables of any nature: continuous, categorical or mixed. We use these developments to analyze mixed datasets of clinical (medical records of patients with cognitive disorders; or breast cancer and being treated by neoadjuvant chemotherapy) or biological interest (gene regulation networks of hematopoietic stem and precursor cells)

Learning clinical networks from medical records based on information estimates in mixed-type data

International audienceThe precise diagnostics of complex diseases require to integrate a large amount of information from heterogeneous clinical and biomedical data, whose direct and indirect interdependences are notoriously difficult to assess. To this end, we propose an efficient computational approach to simultaneously compute and assess the significance of multivariate information between any combination of mixed-type (continuous/categorical) variables. The method is then used to uncover direct, indirect and possibly causal relationships between mixed-type data from medical records, by extending a recent machine learning method to reconstruct graphical models beyond simple categorical datasets. The method is shown to outperform existing tools on benchmark mixed-type datasets, before being applied to analyze the medical records of eldery patients with cognitive disorders from La Pitié-Salpêtrière Hospital, Paris. The resulting clinical network visually captures the global interdependences in these medical records and some facets of clinical diagnosis practice, without specific hypothesis nor prior knowledge on any clinically relevant information. In particular, it provides some physiological insights linking the consequence of cerebrovascular accidents to the atrophy of important brain structures associated to cognitive impairment

Inferring Gene Networks in Bone Marrow Hematopoietic Stem Cell-Supporting Stromal Niche Populations

International audienceThe cardinal property of bone marrow (BM) stromal cells is their capacity to contribute to hematopoietic stem cell (HSC) niches by providing mediators assisting HSC functions. In this study we first contrasted transcriptomes of stromal cells at different developmental stages and then included large number of HSC-supportive and non-supportive samples. Application of a combination of algorithms, comprising one identifying reliable paths and potential causative relationships in complex systems, revealed gene networks characteristic of the BM stromal HSC-supportive capacity and of defined niche populations of perivascular cells, osteoblasts, and mesenchymal stromal cells. Inclusion of single-cell transcriptomes enabled establishing for the perivascular cell subset a partially oriented graph of direct gene-to-gene interactions. As proof of concept we showed that R-spondin-2, expressed by the perivascular subset, synergized with Kit ligand to amplify ex vivo hematopoietic precursors. This study by identifying classifiers and hubs constitutes a resource to unravel candidate BM stromal mediators

Metabolically Primed Multipotent Hematopoietic Progenitors Fuel Innate Immunity

Following infection, hematopoietic stem and progenitor cells (HSPCs) support immunity by increasing the rate of innate immune cell production but the metabolic cues that guide this process are unknown. To address this question, we developed MetaFate, a method to trace the metabolic expression state and developmental fate of single cells in vivo . Using MetaFate we identified a gene expression program of metabolic enzymes and transporters that confers differences in myeloid differentiation potential in a subset of HSPCs that express CD62L. Using single-cell metabolic profiling, we confirmed that CD62L high myeloid-biased HSPCs have an increased dependency on oxidative phosphorylation and glucose metabolism. Importantly, metabolism actively regulates immune-cell production, with overexpression of the glucose-6-phosphate dehydrogenase enzyme of the pentose phosphate pathway skewing MPP output from B-lymphocytes towards the myeloid lineages, and expansion of CD62L high HSPCs occurring to support emergency myelopoiesis. Collectively, our data reveal the metabolic cues that instruct innate immune cell development, highlighting a key role for the pentose phosphate pathway. More broadly, our results show that HSPC metabolism can be manipulated to alter the cellular composition of the immune system