Annotating Adverse Outcome Pathways to Organize Toxicological Information for Risk Assessment

The Adverse Outcome Pathway (AOP) framework connects molecular perturbations with organism and population level endpoints used for regulatory decision-making by providing a conceptual construct of the mechanistic basis for toxicity. Development of an AOP typically begins with the adverse outcome, and intermediate effects connect the outcome with a molecular initiating event amenable to high-throughput toxicity testing (HTT). Publicly available controlled vocabularies were used to provide terminology supporting AOP’s at all levels of biological organization. The resulting data model contains terms from 22 ontologies and controlled vocabularies annotating currently existing AOP’s. The model provides the ability to attach evidence in support of the AOP, supports data aggregation, and promotes the development of AOP networks. Long term, this structured description of the AOP will enable logical reasoning for hazard identification and for dose-response assessment. Case studies showcase how the model informs AOP development in the context of chemical risk assessment.Master of Scienc

CASSANDRA: drug gene association prediction via text mining and ontologies

The amount of biomedical literature has been increasing rapidly during the last decade. Text mining techniques can harness this large-scale data, shed light onto complex drug mechanisms, and extract relation information that can support computational polypharmacology. In this work, we introduce CASSANDRA, a fully corpus-based and unsupervised algorithm which uses the MEDLINE indexed titles and abstracts to infer drug gene associations and assist drug repositioning. CASSANDRA measures the Pointwise Mutual Information (PMI) between biomedical terms derived from Gene Ontology (GO) and Medical Subject Headings (MeSH). Based on the PMI scores, drug and gene profiles are generated and candidate drug gene associations are inferred when computing the relatedness of their profiles. Results show that an Area Under the Curve (AUC) of up to 0.88 can be achieved. The algorithm can successfully identify direct drug gene associations with high precision and prioritize them over indirect drug gene associations. Validation shows that the statistically derived profiles from literature perform as good as (and at times better than) the manually curated profiles. In addition, we examine CASSANDRA’s potential towards drug repositioning. For all FDA-approved drugs repositioned over the last 5 years, we generate profiles from publications before 2009 and show that the new indications rank high in these profiles. In summary, co-occurrence based profiles derived from the biomedical literature can accurately predict drug gene associations and provide insights onto potential repositioning cases

Contribution à la construction d’ontologies et à la recherche d’information : application au domaine médical

This work aims at providing efficient access to relevant information among the increasing volume of digital data. Towards this end, we studied the benefit from using ontology to support an information retrieval (IR) system.We first described a methodology for constructing ontologies. Thus, we proposed a mixed method which combines natural language processing techniques for extracting knowledge from text and the reuse of existing semantic resources for the conceptualization step. We have also developed a method for aligning terms in English and French in order to enrich terminologically the resulting ontology. The application of our methodology resulted in a bilingual ontology dedicated to Alzheimer’s disease.We then proposed algorithms for supporting ontology-based semantic IR. Thus, we used concepts from ontology for describing documents automatically and for query reformulation. We were particularly interested in: 1) the extraction of concepts from texts, 2) the disambiguation of terms, 3) the vectorial weighting schema adapted to concepts and 4) query expansion. These algorithms have been used to implement a semantic portal about Alzheimer’s disease. Further, because the content of documents are not always fully available, we exploited incomplete information for identifying the concepts, which are relevant for indexing the whole content of documents. Toward this end, we have proposed two classification methods: the first is based on the k nearest neighbors’ algorithm and the second on the explicit semantic analysis. The two methods have been evaluated on large standard collections of biomedical documents within an international challenge.Ce travail vise à permettre un accès efficace à des informations pertinentes malgré le volume croissant des données disponibles au format électronique. Pour cela, nous avons étudié l’apport d’une ontologie au sein d’un système de recherche d'information (RI).Nous avons tout d’abord décrit une méthodologie de construction d’ontologies. Ainsi, nous avons proposé une méthode mixte combinant des techniques de traitement automatique des langues pour extraire des connaissances à partir de textes et la réutilisation de ressources sémantiques existantes pour l’étape de conceptualisation. Nous avons par ailleurs développé une méthode d’alignement de termes français-anglais pour l’enrichissement terminologique de l’ontologie. L’application de notre méthodologie a permis de créer une ontologie bilingue de la maladie d’Alzheimer.Ensuite, nous avons élaboré des algorithmes pour supporter la RI sémantique guidée par une ontologie. Les concepts issus d’une ontologie ont été utilisés pour décrire automatiquement les documents mais aussi pour reformuler les requêtes. Nous nous sommes intéressés à : 1) l’identification de concepts représentatifs dans des corpus, 2) leur désambiguïsation, 3), leur pondération selon le modèle vectoriel, adapté aux concepts et 4) l’expansion de requêtes. Ces propositions ont permis de mettre en œuvre un portail de RI sémantique dédié à la maladie d’Alzheimer. Par ailleurs, le contenu des documents à indexer n’étant pas toujours accessible dans leur ensemble, nous avons exploité des informations incomplètes pour déterminer les concepts pertinents permettant malgré tout de décrire les documents. Pour cela, nous avons proposé deux méthodes de classification de documents issus d’un large corpus, l’une basée sur l’algorithme des k plus proches voisins et l’autre sur l’analyse sémantique explicite. Ces méthodes ont été évaluées sur de larges collections de documents biomédicaux fournies lors d’un challenge international