Viewpoint on donor-derived cell-free DNA: Context of use and clinical utility are key

Recently, the Sensitization in Transplantation: Assessment of Risk (STAR) group of the American Society of Transplantation and the American Society for Histocompatibility and Immunogenetics published a position on donor-derived cell-free DNA (dd-cfDNA), followed by a letter emphasizing its specificity for rejection and a response. We aim to add personal and methodological perspectives on diagnostic metrics to an ongoing discussion focusing on the context of use and clinical utility of dd-cfDNA across different clinical scenarios. Particularly, we discuss the implications of the overall moderate specificity of the overall moderate specificity (approximately 80%) in publications. We argue that the transplant community would benefit by shifting descriptive diagnostic metrics to clinical utility within well-defined contexts of use. Consequently, we consider predictive values and likelihood ratios, which incorporate sensitivity as well-more conclusive measures for clinical medicine. To guide clinicians in adopting this emerging biomarker, we provide a broader overview of the literature focused on kidney transplantation, discuss diagnostic test metrics and society positions, and discuss its added value for detecting graft injury within routine decisional frameworks. We emphasize the need for rigorous cost-benefit assessments across different prevalence scenarios and graft pathologies, necessary for assigning the correct diagnostic interpretation and for aiding in the optimal treatment. We firmly believe that more studies, preferentially interventional, with clear outcome endpoints should be initiated to clarify the full potential of dd-cfDNA.