PROJECT SUMMARY/ABSTRACT
Some of the most challenging diagnostic cases involve patients who present with complex phenotypes that
evolve over time and intersect multiple medical disciplines. The two primary clinical settings for diagnosing such
patients are undiagnosed disease clinics and neonatal intensive care unit rapid genome sequencing programs.
These clinics have adopted an approach where diagnostic analysis is based on comprehensive genomic
sequencing data; and analysis is carried out by a large, collaborative clinical team. This team-based
approach leverages the treating physician’s detailed understanding of the patient’s phenotype, the medical
geneticist’s deep knowledge of genetic diseases, the bioinformatic analyst’s expertise in adjudicating a variant’s
quality and predicted pathogenicity, as well as the diagnostic pathologist’s ability to synthesize all relevant
information and reach a conclusion regarding a given variant’s clinical significance. Diagnostic analysis of
patients in both of these environments is a long-term process that often continues for months or even years,
until new phenotypes in the patient are observed or novel gene-disease associations are reported in the literature
that provide the necessary insight for case solution. However, existing software tools typically only cater to the
bioinformatician expert or the diagnostic molecular pathologist, but not the treating physician or the genetic
counselor; focus on making a genetic diagnosis at a single timepoint, rather than following the patient over time
during a lengthy diagnostic process, and are therefore unable to adequately support team-based, longitudinal
genomic diagnostic care. Addressing this pressing need, here we propose to develop a comprehensive software
system, Calypso, to address this pressing need. Calypso will support team-based diagnostics via intuitive and
visual iobio web tools tailored for each team member’s specialized contribution to diagnostic analysis; and
facilitate long-term genomic care by keeping patient genomic data up-to-date via a systematic variant re-
annotation infrastructure. We will put Calypso into the hands of the clinical teams in our undiagnosed disease
clinic and our neonatal intensive care unit, ideal testing grounds for evaluating our tool’s impact on long-term
genome diagnostic care in the context of team-based medicine. We will also centrally deploy and evaluate our
tool in NHGRI’s Undiagnosed Disease Network to help realize the collaborative diagnostic opportunities
presented by a large, clinically focused research consortium.