Improving the understanding of the oligogenic nature of diseases requires access to high-quality, well-curated Findable, Accessible, Interoperable, Reusable (FAIR) data. Although first steps were taken with the development of the Digenic Diseases Database, leading to novel computational advancements to assist the field, these were also linked with a number of limitations, for instance, the ad hoc curation protocol and the inclusion of only digenic cases. The OLIgogenic diseases DAtabase (OLIDA) presents a novel, transparent and rigorous curation protocol, introducing a confidence scoring mechanism for the published oligogenic literature. The application of this protocol on the oligogenic literature generated a new repository containing 916 oligogenic variant combinations linked to 159 distinct diseases. Information extracted from the scientific literature is supplemented with current knowledge support obtained from public databases. Each entry is an oligogenic combination linked to a disease, labelled with a confidence score based on the level of genetic and functional evidence that supports its involvement in this disease. These scores allow users to assess the relevance and proof of pathogenicity of each oligogenic combination in the database, constituting markers for reporting improvements on disease-causing oligogenic variant combinations. OLIDA follows the FAIR principles, providing detailed documentation, easy data access through its application programming interface and website, use of unique identifiers and links to existing ontologies. Database URL https://olida.ibsquare.be

Background The prediction of potentially pathogenic variant combinations in patients remains a key task in the field of medical genetics for the understanding and detection of oligogenic/multilocus diseases. Models tailored towards such cases can help shorten the gap of missing diagnoses and can aid researchers in dealing with the high complexity of the derived data. The predictor VarCoPP (Variant Combinations Pathogenicity Predictor) that was published in 2019 and identified potentially pathogenic variant combinations in gene pairs (bilocus variant combinations), was the first important step in this direction. Despite its usefulness and applicability, several issues still remained that hindered a better performance, such as its False Positive (FP) rate, the quality of its training set and its complex architecture. Results We present VarCoPP2.0: the successor of VarCoPP that is a simplified, faster and more accurate predictive model identifying potentially pathogenic bilocus variant combinations. Results from cross-validation and on independent data sets reveal that VarCoPP2.0 has improved in terms of both sensitivity (95% in cross-validation and 98% during testing) and specificity (5% FP rate). At the same time, its running time shows a significant 150-fold decrease due to the selection of a simpler Balanced Random Forest model. Its positive training set now consists of variant combinations that are more confidently linked with evidence of pathogenicity, based on the confidence scores present in OLIDA, the Oligogenic Diseases Database (https://olida.ibsquare.be). The improvement of its performance is also attributed to a more careful selection of up-to-date features identified via an original wrapper method. We show that the combination of different variant and gene pair features together is important for predictions, highlighting the usefulness of integrating biological information at different levels. Conclusions Through its improved performance and faster execution time, VarCoPP2.0 enables a more accurate analysis of larger data sets linked to oligogenic diseases. Users can access the ORVAL platform (https://orval.ibsquare.be) to apply VarCoPP2.0 on their data.

No abstract