Publications

Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of "lookup tables" of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.

BACKGROUND

Missed or delayed follow-up of abnormal subcritical tests (tests that do not require immediate medical attention) can lead to poor patient outcomes. Safety-net health systems with limited resources and socially complex patients are vulnerable to safety gaps resulting from delayed management. Clinician perspectives to identify system challenges, vulnerable situations, and potential solutions were sought in focus groups.

METHODS

Five semistructured focus groups were conducted in 2015 with purposefully sampled clinicians from radiology, hospital medicine, emergency medicine, risk management, and ambulatory care from an urban, academic, integrated, safety-net health system. Thematic analysis identified challenges of current management of abnormal subcritical tests, vulnerable situations, and solution characteristics. A total of 43 clinicians participated.

RESULTS

Clinicians cited challenges in assigning responsibility for follow-up and identified tests pending at discharge and tests requiring delayed follow-up as vulnerable situations. The lack of tracking systems and missing contact information for patients and providers exacerbated these challenges. Proposed solution characteristics involved protocols to aid in assigning responsibility, reliable paths of communication, and systems to track the status of tests. Clinicians noted a strong desire for integration of the work flow and technology solutions into existing structures.

CONCLUSION

In an urban safety-net setting, clinicians recommended outlining clear chains of responsibility and communication in the management of subcritical test results, and employing simple, integrated technological solutions that allow for tracking and management of tests. Existing test management solutions should be adapted to work within safety-net systems, which often have fewer resources and more complex patients and may function in the absence of integrated technology systems.