{"doi":"10.1016/j.ajt.2025.04.021","title":"A two-threshold algorithm using donor-derived cell-free DNA fraction and quantity to detect acute rejection after heart transplantation","abstract":"Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker of acute rejection (AR) after heart transplantation (HTx). dd-cfDNA measured as a fraction of total cfDNA can be affected by changes in total cfDNA whereas dd-cfDNA quantity can mitigate this impact. This study investigates the performance of a two-threshold algorithm (2TA) that combines dd-cfDNA fraction (dd-cfDNA%) and donor-quantity score (DQS). A total of 808 plasma samples were prospectively collected for dd-cfDNA testing from 187 adult HTx patients with contemporaneous endomyocardial biopsies. cfDNA was analyzed by a single nucleotide polymorphism (SNP)-based next-generation sequencing workflow; dd-cfDNA% and DQS were measured using the sequencing reads and SNP genotypes. Both dd-cfDNA% and DQS were significantly higher in AR compared to non-AR samples (p<10 -14 ). Considering samples exceeding either dd-cfDNA%=0.26% or DQS=18 cp/mL as positive, the 2TA demonstrated 86.5% sensitivity and 83.6% specificity for AR detection and an AUC of 0.881. Compared to dd-cfdNA% alone, performance improved with a mean net reclassification index (NRI) of 16.4% (SD: 4.0%; p=0.015) and a 37.3% reduction of the false positive rate compared to the previously established cutoff of 0.15%. Combining dd-cfDNA fraction and quantity estimate in a 2TA may improve AR detection accuracy in HTx recipients compared to dd-cfDNA% alone.","journal":"American Journal of Transplantation","year":2025,"id":511274,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9641,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1369900,"name":"M. 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A. Barnes","orcid":null,"position":11,"is_corresponding":false},{"id":855642,"name":"Ebad Ahmed","orcid":null,"position":12,"is_corresponding":false},{"id":1369151,"name":"Jing Xie","orcid":"0000-0001-7293-2753","position":13,"is_corresponding":false},{"id":1369904,"name":"Adam Prewett","orcid":null,"position":14,"is_corresponding":false},{"id":1016438,"name":"Matthew Rabinowitz","orcid":"0009-0006-3109-4232","position":15,"is_corresponding":false},{"id":228243,"name":"Bernhard Zimmermann","orcid":"0000-0002-5275-4571","position":16,"is_corresponding":false},{"id":331616,"name":"Michelle S. Bloom","orcid":"0000-0002-5755-3955","position":17,"is_corresponding":false},{"id":57606,"name":"Zachary P. Demko","orcid":"0000-0001-8796-2381","position":18,"is_corresponding":false},{"id":367214,"name":"Eric Adler","orcid":"0000-0002-4765-0188","position":19,"is_corresponding":false},{"id":240845,"name":"Josef Stehlik","orcid":"0000-0002-7362-0513","position":20,"is_corresponding":false},{"id":854965,"name":"Paul Kim","orcid":"0000-0002-1755-6182","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:47:55.918021Z","pmid":"40334845","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}