GenomeDiver: a platform for phenotype-guided medical genomic diagnosis

Abstract

Purpose: Making a diagnosis from clinical genomic sequencing requires well-structured phenotypic data to guide genotype interpretation. A patient's phenotypic features can be documented using the Human Phenotype Ontology (HPO), generating terms used to prioritize genes potentially causing the patient's disease. We have developed GenomeDiver to provide a user interface for clinicians that allows more effective collaboration with the clinical diagnostic laboratory, with the goal of improving the success of the diagnostic process.

Methods: GenomeDiver uses genomic data to prompt reverse phenotyping of patients undergoing genetic testing, enriching the amount and quality of structured phenotype data for the diagnostic laboratory, and helping clinicians to explore and flag diseases potentially causing their patient's presentation.

Results: We show how GenomeDiver communicates the clinician's informed insights to the diagnostic lab in the form of HPO terms for interpretation of genomic sequencing data. We describe our user-driven design process, the engineering of the software for efficiency, security and portability, and examples of the performance of GenomeDiver using genomic testing data.

Conclusion: GenomeDiver is a first step in a new approach to genomic diagnostics that enhances laboratory-clinician interactions, with the goal of directly engaging clinicians to improve the outcome of genomic diagnostic testing.

FIGURE 1:

The clinician interface for GenomeDiver. HPO terms can be added in the ‘Add Phenotype Feature’ field by entering text which will bring up a list of HPO terms from which the appropriate term can be chosen. The HPO terms generated by GenomeDiver are shown in the ‘Classify all phenotype features’ section. These can be dragged into each of the categories underneath, ‘Present’, ‘Absent’ or ‘Unknown’. Three terms have been moved into the ‘Present’ category as an example.

FIGURE 2:

Following the categorization of the HPO terms, a second Exomiser run re-prioritizes variants, genes and associated diseases. The clinician is presented with a shortlist of genes, ranked by the Exomiser combined_score which is shown, as well as the change in score (green positive, red negative) resulting from the HPO term categorization. We list the disease and a link that allows the clinician to explore whether a disease description resembles their patient, allowing them to flag one or more as being candidates for causing the patient’s presentation. Free text can be used in the ‘Add comment’ box, finalizing the process by clicking ‘Confirm analysis’ to return the information to the diagnostic laboratory.