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Abstract Background Adverse drug reactions (ADRs) are statistically characterized within randomized clinical trials and postmarketing pharmacovigilance, but their molecular mechanism remains unknown in most cases. This is true even for hepatic or skin toxicities, which are classically monitored during drug design. Aside from clinical trials, many elements of knowledge about drug ingredients are available in open-access knowledge graphs, such as their properties, interactions, or involvements in pathways. In addition, drug classifications that label drugs as either causative or not for several ADRs, have been established. Methods We propose in this paper to mine knowledge graphs for identifying biomolecular features that may enable automatically reproducing expert classifications that distinguish drugs causative or not for a given type of ADR. In an Explainable AI perspective, we explore simple classification techniques such as Decision Trees and Classification Rules because they provide human-readable models, which explain the classification itself, but may also provide elements of explanation for molecular mechanisms behind ADRs. In summary, (1) we mine a knowledge graph for features; (2) we train classifiers at distinguishing, on the basis of extracted features, drugs associated or not with two commonly monitored ADRs: drug-induced liver injuries (DILI) and severe cutaneous adverse reactions (SCAR); (3) we isolate features that are both efficient in reproducing expert classifications and interpretable by experts (i.e., Gene Ontology terms, drug targets, or pathway names); and (4) we manually evaluate in a mini-study how they may be explanatory. Results Extracted features reproduce with a good fidelity classifications of drugs causative or not for DILI and SCAR (Accuracy = 0 .74 and 0 .81, respectively). Experts fully agreed that 7 3% and 3 8% of the most discriminative features are possibly explanatory for DILI and SCAR, respectively; and partially agreed (2/3) for 9 0% and 7 7% of them. Conclusion Knowledge graphs provide sufficiently diverse features to enable simple and explainable models to distinguish between drugs that are causative or not for ADRs. In addition to explaining classifications, most discriminative features appear to be good candidates for investigating ADR mechanisms further.

Abstract Background Medical terminologies are commonly used in medicine. For instance, to answer a pharmacovigilance question, pharmacovigilance specialists (PVS) search in a pharmacovigilance database for reports in relation to a given drug. To do that, they first need to identify all MedDRA terms that might have been used to code an adverse reaction in the database, but terms may be numerous and difficult to select as they may belong to different parts of the hierarchy. In previous studies, three tools have been developed to help PVS identify and group all relevant MedDRA terms using three different approaches: forms, structured query-builder, and icons. Yet, a poor usability of the tools may increase PVS’ workload and reduce their performance. This study aims to evaluate, compare and improve the three tools during two rounds of formative usability evaluation. Methods First, a cognitive walkthrough was performed. Based on the design recommendations obtained from this evaluation, designers made modifications to their tools to improve usability. Once this re-engineering phase completed, six PVS took part in a usability test: difficulties, errors and verbalizations during their interaction with the three tools were collected. Their satisfaction was measured through the System Usability Scale. The design recommendations issued from the tests were used to adapt the tools. Results All tools had usability problems related to the lack of guidance in the graphical user interface (e.g., unintuitive labels). In two tools, the use of the SNOMED CT to find MedDRA terms hampered their use because French PVS were not used to it. For the most obvious and common terms, the icons-based interface would appear to be more useful. For the less frequently used MedDRA terms or those distributed in different parts of the hierarchy, the structured query-builder would be preferable thanks to its great power and flexibility. The form-based tool seems to be a compromise. Conclusion These evaluations made it possible to identify the strengths of each tool but also their weaknesses to address them before further evaluation. Next step is to assess the acceptability of tools and the expressiveness of their results to help identify and group MedDRA terms.