Whole-exome and genome sequencing are widely used to diagnose individual patients. However, despite its success, this approach leaves many patients undiagnosed. This could be due to the need to discover more disease genes and variants or because disease phenotypes are novel and arise from a combination of variants of multiple known genes related to the disease. Recent rapid increases in available genomic, biomedical, and phenotypic data enable computational analyses, reducing the search space for disease-causing genes or variants and facilitating the prediction of causal variants. Therefore, artificial intelligence, data mining, machine learning, and deep learning are essential tools that have been used to identify biological interactions, including protein-protein interactions, gene-disease predictions, and variant--disease associations. Predicting these biological associations is a critical step in diagnosing patients with rare or complex diseases. In recent years, computational methods have emerged to improve gene-disease prioritization by incorporating phenotype information. These methods evaluate a patient's phenotype against a database of gene-phenotype associations to identify the closest match. However, inadequate knowledge of phenotypes linked with specific genes in humans and model organisms limits the effectiveness of the prediction. Information about gene product functions and anatomical locations of gene expression is accessible for many genes and can be associated with phenotypes through ontologies and machine-learning models. Incorporating this information can enhance gene-disease prioritization methods and more accurately identify potential disease-causing genes. This dissertation aims to address key limitations in gene-disease prediction and variant prioritization by developing computational methods that systematically relate human phenotypes that arise as a consequence of the loss or change of gene function to gene functions and anatomical and cellular locations of activity. To achieve this objective, this work focuses on crucial problems in the causative variant prioritization pipeline and presents novel computational methods that significantly improve prediction performance by leveraging large background knowledge data and integrating multiple techniques. Therefore, this dissertation presents novel approaches that utilize graph-based machine-learning techniques to leverage biomedical ontologies and linked biological data as background knowledge graphs. The methods employ representation learning with knowledge graphs and introduce generic models that address computational problems in gene-disease associations and variant prioritization. I demonstrate that my approach is capable of compensating for incomplete information in public databases and efficiently integrating with other biomedical data for similar prediction tasks. Moreover, my methods outperform other relevant approaches that rely on manually crafted features and laborious pre-processing. I systematically evaluate our methods and illustrate their potential applications for data analytics in biomedicine. Finally, I demonstrate how our prediction tools can be used in the clinic to assist geneticists in decision-making. In summary, this dissertation contributes to the development of more effective methods for predicting disease-causing variants and advancing precision medicine.

Ces dernières années, le domaine de l’apprentissage profond a connu des progrès énormes dans des applications allant de la génération d’images, détection d’objets, modélisation du langage à la réponse aux questions visuelles. Les approches classiques telles que l’apprentissage supervisé nécessitent de grandes quantités de données étiquetées et spécifiques à la tâches. Cependant, celles-ci sont parfois coûteuses, peu pratiques, ou trop longues à collecter. La modélisation efficace en données, qui comprend des techniques comme l’apprentissage few-shot (à partir de peu d’exemples) et l’apprentissage self-supervised (auto-supervisé), tentent de remédier au manque de données spécifiques à la tâche en exploitant de grandes quantités de données plus “générales”. Les progrès de l’apprentissage profond, et en particulier de l’apprentissage few-shot, s’appuient sur les benchmarks (suites d’évaluation), les métriques d’évaluation et les jeux de données, car ceux-ci sont utilisés pour tester et départager différentes méthodes sur des tâches précises, et identifier l’état de l’art. Cependant, du fait qu’il s’agit de versions idéalisées de la tâche à résoudre, les benchmarks sont rarement équivalents à la tâche originelle, et peuvent avoir plusieurs limitations qui entravent leur rôle de sélection des directions de recherche les plus prometteuses. De plus, la définition de métriques d’évaluation pertinentes peut être difficile, en particulier dans le cas de sorties structurées et en haute dimension, telles que des images, de l’audio, de la parole ou encore du texte. Cette thèse discute des limites et des perspectives des benchmarks existants, des fonctions de coût (training losses) et des métriques d’évaluation (evaluation metrics), en mettant l’accent sur la modélisation générative - les Réseaux Antagonistes Génératifs (GANs) en particulier - et la modélisation efficace des données, qui comprend l’apprentissage few-shot et self-supervised. La première contribution est une discussion de la tâche de modélisation générative, suivie d’une exploration des propriétés théoriques et empiriques des fonctions de coût des GANs. La deuxième contribution est une discussion sur la limitation des few-shot classification benchmarks, certains ne nécessitant pas de généralisation à de nouvelles sémantiques de classe pour être résolus, et la proposition d’une méthode de base pour les résoudre sans étiquettes en phase de testing. La troisième contribution est une revue sur les méthodes few-shot et self-supervised de détection d’objets , qui souligne les limites et directions de recherche prometteuses. Enfin, la quatrième contribution est une méthode efficace en données pour la description de vidéo qui exploite des jeux de données texte et vidéo non supervisés. / In recent years, the field of deep learning has seen tremendous progress for applications ranging from image generation, object detection, language modeling, to visual question answering. Classic approaches such as supervised learning require large amounts of task-specific and labeled data, which may be too expensive, time-consuming, or impractical to collect. Data-efficient methods, such as few-shot and self-supervised learning, attempt to deal with the limited availability of task-specific data by leveraging large amounts of general data. Progress in deep learning, and in particular, few-shot learning, is largely driven by the relevant benchmarks, evaluation metrics, and datasets. They are used to test and compare different methods on a given task, and determine the state-of-the-art. However, due to being idealized versions of the task to solve, benchmarks are rarely equivalent to the original task, and can have several limitations which hinder their role of identifying the most promising research directions. Moreover, defining meaningful evaluation metrics can be challenging, especially in the case of high-dimensional and structured outputs, such as images, audio, speech, or text. This thesis discusses the limitations and perspectives of existing benchmarks, training losses, and evaluation metrics, with a focus on generative modeling—Generative Adversarial Networks (GANs) in particular—and data-efficient modeling, which includes few-shot and self-supervised learning. The first contribution is a discussion of the generative modeling task, followed by an exploration of theoretical and empirical properties of the GAN loss. The second contribution is a discussion of a limitation of few-shot classification benchmarks, which is that they may not require class semantic generalization to be solved, and the proposal of a baseline method for solving them without test-time labels. The third contribution is a survey of few-shot and self-supervised object detection, which points out the limitations and promising future research for the field. Finally, the fourth contribution is a data-efficient method for video captioning, which leverages unsupervised text and video datasets, and explores several multimodal pretraining strategies.