Biological Variation of Donor-Derived Cell-Free DNA in Stable Lung Transplant Recipients

Michael Keller, Cedric Mutebi, Pali Shah, Deborah Levine, Shambhu Aryal, Aldo Iacono, Irina Timofte, Joby Mathew, Anu Varghese, Cassandra Giner, Sean Agbor-Enoh

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


BACKGROUND: Prior studies demonstrate that donor-derived cell-free DNA (dd-cfDNA) in lung transplant recipients may serve as a marker of allograft injury for detecting allograft rejection and infection. Clinical interpretation of dd-cfDNA requires understanding its biological variation in stable lung transplant patients in order to identify abnormal results suggesting underlying allograft dysfunction. This study establishes the biological variation and reference change values (RCV) of dd-cfDNA in stable lung transplant recipients using an analytically validated assay with an established analytic coefficient of variation (CVA). METHODS: The AlloSure® assay, a targeted, sequencing-based approach, was used to measure plasma dd-cfDNA in a cohort of lung transplant patients at 4 centers that used dd-cfDNA to monitor for allograft dysfunction in preference to surveillance transbronchial biopsy. Patients with stable allograft function and ≥3 dd-cfDNA samples were included. Intraindividual coefficient of variation (CVI), interindividual CV (CVG), index of individuality (II) and the RCV were calculated. RESULTS: Thirty-five patients with a combined 124 dd-cfDNA samples were included in the final analysis. The median dd-cfDNA was 0.31% (interquartile range 0.18%-0.68%), the 97.5th percentile and 95th percentile were 1.3% and 1.0%, respectively. In 30 stable patients with an average of 3.7 tests, the CVI was 25%, CVG 19%, II 1.33, and RCV 70%. CONCLUSION: In stable lung transplant patients, fluctuations in dd-cfDNA levels of up to 70% or levels less than 1% are within normal biological variation. With further validation, these thresholds may be incorporated into surveillance monitoring algorithms to identify potentially abnormal results indicating allograft dysfunction.

Original languageEnglish (US)
Pages (from-to)901-909
Number of pages9
JournalThe journal of applied laboratory medicine
Issue number4
StatePublished - Jun 30 2022
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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