The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients: A Pilot Randomized Trial.

BACKGROUND

Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value.

OBJECTIVE

To describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care.

DESIGN

Pilot randomized trial. (ClinicalTrials.gov: NCT01736566).

SETTING

Academic primary care practices.

PARTICIPANTS

9 primary care physicians (PCPs) and 100 generally healthy patients recruited at ages 40 to 65 years.

INTERVENTION

Patients were randomly assigned to receive a family history report alone (FH group) or in combination with an interpreted WGS report (FH + WGS group), which included monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits. Each patient met with his or her PCP to discuss the report.

MEASUREMENTS

Clinical outcomes and health care use through 6 months were obtained from medical records and audio-recorded discussions between PCPs and patients. Patients' health behavior changes were surveyed 6 months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results.

RESULTS

Mean age was 55 years; 58% of patients were female. Eleven FH + WGS patients (22% [95% CI, 12% to 36%]) had new MDR results. Only 2 (4% [CI, 0.01% to 15%]) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). Primary care physicians recommended new clinical actions for 16% (CI, 8% to 30%) of FH patients and 34% (CI, 22% to 49%) of FH + WGS patients. Thirty percent (CI, 17% to 45%) and 41% (CI, 27% to 56%) of FH and FH + WGS patients, respectively, reported making a health behavior change after 6 months. Geneticists rated PCP management of 8 MDR results (73% [CI, 39% to 99%]) as appropriate and 2 results (18% [CI, 3% to 52%]) as inappropriate.

LIMITATION

Limited sample size and ancestral and socioeconomic diversity.

CONCLUSION

Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Nongeneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value.

PRIMARY FUNDING SOURCE

National Institutes of Health.