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  • The Inria's Research Teams produce an annual Activity Report presenting their activities and their results of the year. These reports include the team members, the scientific program, the software developed by the team and the new results of the year. The report also describes the grants, contracts and the activities of dissemination and teaching. Finally, the report gives the list of publications of the year.

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Section: New Results

Knowledge Discovery in Healthcare and Life Sciences

Participants : Miguel Couceiro, Adrien Coulet, Nicolas Jay, Joël Legrand, Pierre Monnin, Amedeo Napoli, Abdelkader Ouali, Chedy Raïssi, Malika Smaïl-Tabbone, Yannick Toussaint.

Ontology-based Clustering of Biological Data

Biomedical objects can be characterized by ontology annotations. For example, Gene Ontology annotations provide information on the functions of genes, while Human Phenotype Ontology (HPO) annotations provide information about phenotypes associated with diseases. It is usual to consider such annotations in the analysis of biomedical data, most of the time annotations from only one single ontology. However, complex objects such as diseases can be annotated at the same time w.r.t. different ontologies, making clear distinct dimensions. We are investigating how annotations from several ontologies may be cooperating in disease classification. In particular, we classified Genetic Intellectual Disabilities (GID), on the basis of their HPO annotations and of GO annotations of genes known for being responsible for these diseases [43]. We used clustering algorithms based on semantic similarities and enabling to compare sets of annotations. This experiment illustrates the fact that considering several ontologies provides better results, while selecting the best set of ontologies to combine is dependent on the dataset and on the classification task.

Validation of Pharmacogenomic Knowledge

State of the art knowledge in pharmacogenomics is heterogeneous w.r.t. validation. A part is well validated, observed on a large population and already used in clinical practice, while a large majority of this knowledge is lacking validation and reproducibility, mainly because of scarce observation. Accordingly, validating state of the art knowledge in pharmacogenomics by mining Electronic Health Records (EHRs) is one objective of the ANR project “PractiKPharma” initiated in 2016 (http://practikpharma.loria.fr/).

To lead this validation, we define a minimal data schema for pharmacogenomic knowledge units (PGxO ontology), which is instantiated with data of various provenance (e.g. biomedical databases, literature and EHR). Such an instantiation produces a unique knowledge graph named PGxLOD (https://pgxlod.loria.fr/). We defined and applied a first set of reconciliation rules that compare and align whenever possible knowledge elements of various provenance. A journal article on the construction of PGxLOD and its use in knowledge comparison is currently under evaluation. We are continuing this effort by studying methods which enable a more flexible knowledge comparison.

In addition, we took part to the Biohackathon 2018 Paris (https://bh2018paris.info/) during which we worked on two tasks. Firstly we updated PGxLOD for improving its quality, completeness and interconnection with other resources. Secondly we mined PGxLOD and searched for explanations of the molecular mechanism of adverse drug responses. PGxLOD is under evaluation for being registered as a resource of the IBF (French Institute for Bioinformatics) and Elixir (an international organization that supports and structures bioinformatics efforts in Europe).

Mining Electronic Health Records

In the context of the Snowball Inria Associate Team, we developed an approach based on pattern structures to identify frequently associated ADRs (Adverse Drug Reactions) from patient data either in the form of EHR or ADR spontaneous reports. Pattern structures provide an expressive representation of ADR, taking into account the multiplicity of drugs and phenotypes involved in such reactions. Additionally, pattern structures allow considering diverse biomedical ontologies used to represent or annotate patient data, enabling a “semantic” comparison of ADRs. Up to now, this is one of the first research attempts considering such representations to mine rules between frequently associated ADRs. We illustrated the generality of the approach on two patient datasets, each of them linked to distinct biomedical ontologies. The first dataset corresponds to anonymized EHRs, extracted from “STRIDE”, the EHR data warehouse of Stanford Hospital and Clinics. The second dataset is extracted from the U.S. FDA (for Food & Drug Administration) “Adverse Event Reporting System” (FAERS). Several significant association rules have been extracted, analyzed and may be used as a basis for a recommendation system.

In collaboration with Stanford University and the CHRU Nancy, we studied the use of Electronic Health Records to predict at first prescription the need for a patient to be prescribed with a reduced drug dose [4]. We particularly focused on drugs whose dosage is known to be sensitive and variable. We used data from the Stanford Hospital to construct cohorts of patients that either did or did not need a dose change for each considered drug. After feature selection, we trained Random Forest models which successfully predict whether a new patient will or not require a dose change after being prescribed one of 23 drugs among 22 drug classes. Several of these drugs are related to clinical guidelines that recommend dose reduction exclusively in the case of adverse reaction. For these cases, a reduction in dosage may be considered as a surrogate for an adverse reaction, which our system could help predicting and preventing.