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PgmNr 1173: Insights from applying ClinGen framework in evaluating the clinical validity of 30 published studies of gene-disease relationship of monogenic disorders.

Authors:
R. Attali; O. Farchy; A. Rafaeli; S. Tzur

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Affiliation: Genomic Research Department, Emedgene Technologies, Tel Aviv, Israel.


The Clinical Genome Resource (ClinGen) has recently developed a framework for evaluating the clinical validity of gene-disease relationship in monogenic disorders. Using this semi-quantitative measurement framework, a scientist can evaluate the relevant genetic and experimental evidence for supporting a certain gene-disease relationship, and to calculate the strength of evidence based on qualitative classifications: ‘‘Definitive’’, ‘‘Strong’’, ‘‘Moderate’’, ‘‘Limited’’, ‘‘No Reported Evidence’’, or ‘‘Conflicting Evidence’’.
In an attempt to assay this framework, we evaluated 30 studies (in journals with impact factor greater than 5) that described new gene-disease connections. The aim of our work was twofold: to evaluate the usability of the ClinGen framework and to estimate its power when applied to a single first gene-disease article.
Overall, we confirm the usability and the importance of this framework approach in clinical validation of new gene-disease connections. The evaluation process is well detailed and accurate and therefore can be used as a powerful source for gene-disease validity assessment by multiple users. Potential drawbacks are the frequent inconsistencies between curators that will often require ClinGen expert decision, and the technical calculation of the segregation Lod-score for non-experts.
Interestingly, in our review 40% of the evaluated articles were scored with “Strong” strength of evidences, whereas 42% were “moderate”, and only 18% with “Limited” strength. This tends to show the high standards demanded by most editors and peer-reviewers.
The generalized use of this framework will indescribably benefit scientists in building their research evidence, and it can also be used as a standard evaluation in peer reviewed journals for submitters and publishers. Particularly this framework could help defining a strict threshold for the recognition of a new gene-disease connection in databases such as OMIM.