Development and user evaluation of a rare disease gene prioritization workflow based on cognitive ergonomics

OBJECTIVE: The clinical diagnosis of genetic disorders is undergoing transformation, driven by whole exome sequencing and whole genome sequencing (WES/WGS). However, such nucleotide-level resolution technologies create an interpretive challenge. Prior literature suggests that clinicians may employ characteristic cognitive processes during WES/WGS investigations to identify disruptions in genes causal for the observed disease. Based on cognitive ergonomics, we designed and evaluated a gene prioritization workflow that supported these cognitive processes. MATERIALS AND METHODS: We designed a novel workflow in which clinicians recalled known genetic diseases with similarity to patient phenotypes to inform WES/WGS data interpretation. This prototype-based workflow was evaluated against the common computational approach based on physician-specified sets of individual patient phenotypes. The evaluation was conducted as a web-based user study, in which 18 clinicians analyzed 2 simulated patient scenarios using a randomly assigned workflow. Data analysis compared the 2 workflows with respect to accuracy and efficiency in diagnostic interpretation, efficacy in collecting detailed phenotypic information, and user satisfaction. RESULTS: Participants interpreted genetic diagnoses faster using prototype-based workflows. The 2 workflows did not differ in other evaluated aspects. DISCUSSION: The user study findings indicate that prototype-based approaches, which are designed to model experts’ cognitive processes, can expedite gene prioritization and provide utility in synergy with common phenotype-driven variant/gene prioritization approaches. However, further research of the extent of this effect across diverse genetic diseases is required. CONCLUSION: The findings demonstrate potential for prototype-based phenotype description to accelerate computer-assisted variant/gene prioritization through complementation of skills and knowledge of clinical experts via human–computer interaction.