Real-world clinical impact of plasma cell-free DNA metagenomic next-generation sequencing assay

Abstract

Objective: To describe the real-world clinical impact of a commercially available plasma cell-free DNA metagenomic next-generation sequencing assay, the Karius test (KT).

Methods: We retrospectively evaluated the clinical impact of KT by clinical panel adjudication. Descriptive statistics were used to study associations of diagnostic indications, host characteristics, and KT-generated microbiologic patterns with the clinical impact of KT. Multivariable logistic regression modeling was used to further characterize predictors of higher positive clinical impact.

Results: We evaluated 1000 unique clinical cases of KT from 941 patients between January 1, 2017-August 31, 2023. The cohort included adult (70%) and pediatric (30%) patients. The overall clinical impact of KT was positive in 16%, negative in 2%, and no clinical impact in 82% of the cases. Among adult patients, multivariable logistic regression modeling showed that culture-negative endocarditis (OR 2.3; 95% CI, 1.11-4.53; P .022) and concern for fastidious/zoonotic/vector-borne pathogens (OR 2.1; 95% CI, 1.11-3.76; P .019) were associated with positive clinical impact of KT. Host immunocompromised status was not reliably associated with a positive clinical impact of KT (OR 1.03; 95% CI, 0.83-1.29; P .7806). No significant predictors of KT clinical impact were found in pediatric patients. Microbiologic result pattern was also a significant predictor of impact.

Conclusions: Our study highlights that despite the positive clinical impact of KT in select situations, most testing results had no clinical impact. We also confirm diagnostic indications where KT may have the highest yield, thereby generating tools for diagnostic stewardship.

Figure 1.

Demographics of the study population. Figure 1a, age distribution of the study cohort at the time of Karius testing; Figure 1b, distribution of comorbidities of the pediatric and adult cohort at the time of Karius testing; Figure 1c, distribution of diagnostic indications for Karius test in the pediatric and adult patient cohort.

Figure 2.

Microbiologic results of Karius testing. Figure 2a, Microbiologic result patterns of Karius test. Figure 2b, causative pathogens detected exclusively/earlier by Karius test in comparison with standard microbiological tests in more than one case. Figure 2c, causative pathogens missed by the Karius test in comparison with standard microbiological tests in more than one case.