Andrea Fernandez Valledor,Cathrine M Moeller,Daniel Oren,Julia Baranowska,Salwa Rahman,Adi Hertz,Afsana Rahman,Carolyn Hennecken,Gal Rubinstein,Boaz Elad,Ilan Richter,Dor Lotan,Matthew Regan,Brian LaBarre,Adil Yunis,Justin Fried,Ersilia M DeFilippis,Paolo C Colombo,Melana Yuzefpolskaya,Jayant Raihkelkar,Farhana Latif,Kevin D Clerkin,David T Majure,Gabriel T Sayer,Nir Uriel
{"title":"供体来源的无细胞DNA和组织基因表达在心脏移植患者接受因故心肌活检的相关性。","authors":"Andrea Fernandez Valledor,Cathrine M Moeller,Daniel Oren,Julia Baranowska,Salwa Rahman,Adi Hertz,Afsana Rahman,Carolyn Hennecken,Gal Rubinstein,Boaz Elad,Ilan Richter,Dor Lotan,Matthew Regan,Brian LaBarre,Adil Yunis,Justin Fried,Ersilia M DeFilippis,Paolo C Colombo,Melana Yuzefpolskaya,Jayant Raihkelkar,Farhana Latif,Kevin D Clerkin,David T Majure,Gabriel T Sayer,Nir Uriel","doi":"10.1016/j.healun.2025.04.019","DOIUrl":null,"url":null,"abstract":"INTRODUCTION\r\nThe introduction of donor-derived cell-free DNA (dd-cfDNA) and the Molecular Microscope (MMDx) is changing how we diagnose rejection following heart transplantation (HT). This study aims to assess the accuracy of dd-cfDNA in detecting rejection as identified by MMDx and histology, with a focus on determining an optimal dd-cfDNA threshold to improve diagnostic performance.\r\n\r\nMETHODS\r\nSingle-center prospective study of HT recipients undergoing for-cause biopsies with paired MMDx results and dd-cfDNA levels. We employed a Receiver Operator Curve (ROC) to evaluate the performance of dd-cfDNA levels to detect rejection assessed by both histology and MMDx. We also assessed the correlation between dd-cfDNA levels and MMDx rejection scores. A mixed-effects model was applied to account for repeated dependent samples when appropriate.\r\n\r\nRESULTS\r\n247 for-cause biopsies were identified with a median of 21 months from HT and a median of 11 days between dd-cfDNA and biopsy. 56.7% of the samples had dd-cfDNA levels ≥0.20%. MMDx identified rejection in 27.1% of biopsies, compared to 7.7% identified by histology. Elevated dd-cfDNA levels were associated with a fourfold increase in rejection rates by MMDx, mainly driven by a fivefold increase in ABMR detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (AUC of 0.77; optimal cut-off dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further, (AUC of 0.89; optimal cut-off value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64. The correlation between dd-cfDNA levels and MMDx rejection scores was moderate (r=0.51; p<0.001).\r\n\r\nCONCLUSIONS\r\nIn a for-cause biopsy population, elevated dd-cfDNA levels were more predictive of rejection on MMDx than on histology, suggesting that molecular techniques may detect rejection at earlier stages than traditional histological methods. A dd-cfDNA cutoff of 0.26% provided the highest predictive accuracy for rejection by MMDx when applied within a mixed-effects model for repeated measures.","PeriodicalId":22654,"journal":{"name":"The Journal of Heart and Lung Transplantation","volume":"4 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Correlation between Donor-Derived Cell-free DNA and Tissue Gene Expression in Heart Transplant Patients Undergoing for-cause Endomyocardial Biopsies.\",\"authors\":\"Andrea Fernandez Valledor,Cathrine M Moeller,Daniel Oren,Julia Baranowska,Salwa Rahman,Adi Hertz,Afsana Rahman,Carolyn Hennecken,Gal Rubinstein,Boaz Elad,Ilan Richter,Dor Lotan,Matthew Regan,Brian LaBarre,Adil Yunis,Justin Fried,Ersilia M DeFilippis,Paolo C Colombo,Melana Yuzefpolskaya,Jayant Raihkelkar,Farhana Latif,Kevin D Clerkin,David T Majure,Gabriel T Sayer,Nir Uriel\",\"doi\":\"10.1016/j.healun.2025.04.019\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"INTRODUCTION\\r\\nThe introduction of donor-derived cell-free DNA (dd-cfDNA) and the Molecular Microscope (MMDx) is changing how we diagnose rejection following heart transplantation (HT). This study aims to assess the accuracy of dd-cfDNA in detecting rejection as identified by MMDx and histology, with a focus on determining an optimal dd-cfDNA threshold to improve diagnostic performance.\\r\\n\\r\\nMETHODS\\r\\nSingle-center prospective study of HT recipients undergoing for-cause biopsies with paired MMDx results and dd-cfDNA levels. We employed a Receiver Operator Curve (ROC) to evaluate the performance of dd-cfDNA levels to detect rejection assessed by both histology and MMDx. We also assessed the correlation between dd-cfDNA levels and MMDx rejection scores. A mixed-effects model was applied to account for repeated dependent samples when appropriate.\\r\\n\\r\\nRESULTS\\r\\n247 for-cause biopsies were identified with a median of 21 months from HT and a median of 11 days between dd-cfDNA and biopsy. 56.7% of the samples had dd-cfDNA levels ≥0.20%. MMDx identified rejection in 27.1% of biopsies, compared to 7.7% identified by histology. Elevated dd-cfDNA levels were associated with a fourfold increase in rejection rates by MMDx, mainly driven by a fivefold increase in ABMR detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (AUC of 0.77; optimal cut-off dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further, (AUC of 0.89; optimal cut-off value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64. The correlation between dd-cfDNA levels and MMDx rejection scores was moderate (r=0.51; p<0.001).\\r\\n\\r\\nCONCLUSIONS\\r\\nIn a for-cause biopsy population, elevated dd-cfDNA levels were more predictive of rejection on MMDx than on histology, suggesting that molecular techniques may detect rejection at earlier stages than traditional histological methods. A dd-cfDNA cutoff of 0.26% provided the highest predictive accuracy for rejection by MMDx when applied within a mixed-effects model for repeated measures.\",\"PeriodicalId\":22654,\"journal\":{\"name\":\"The Journal of Heart and Lung Transplantation\",\"volume\":\"4 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-05-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Heart and Lung Transplantation\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.healun.2025.04.019\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Heart and Lung Transplantation","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.healun.2025.04.019","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Correlation between Donor-Derived Cell-free DNA and Tissue Gene Expression in Heart Transplant Patients Undergoing for-cause Endomyocardial Biopsies.
INTRODUCTION
The introduction of donor-derived cell-free DNA (dd-cfDNA) and the Molecular Microscope (MMDx) is changing how we diagnose rejection following heart transplantation (HT). This study aims to assess the accuracy of dd-cfDNA in detecting rejection as identified by MMDx and histology, with a focus on determining an optimal dd-cfDNA threshold to improve diagnostic performance.
METHODS
Single-center prospective study of HT recipients undergoing for-cause biopsies with paired MMDx results and dd-cfDNA levels. We employed a Receiver Operator Curve (ROC) to evaluate the performance of dd-cfDNA levels to detect rejection assessed by both histology and MMDx. We also assessed the correlation between dd-cfDNA levels and MMDx rejection scores. A mixed-effects model was applied to account for repeated dependent samples when appropriate.
RESULTS
247 for-cause biopsies were identified with a median of 21 months from HT and a median of 11 days between dd-cfDNA and biopsy. 56.7% of the samples had dd-cfDNA levels ≥0.20%. MMDx identified rejection in 27.1% of biopsies, compared to 7.7% identified by histology. Elevated dd-cfDNA levels were associated with a fourfold increase in rejection rates by MMDx, mainly driven by a fivefold increase in ABMR detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (AUC of 0.77; optimal cut-off dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further, (AUC of 0.89; optimal cut-off value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64. The correlation between dd-cfDNA levels and MMDx rejection scores was moderate (r=0.51; p<0.001).
CONCLUSIONS
In a for-cause biopsy population, elevated dd-cfDNA levels were more predictive of rejection on MMDx than on histology, suggesting that molecular techniques may detect rejection at earlier stages than traditional histological methods. A dd-cfDNA cutoff of 0.26% provided the highest predictive accuracy for rejection by MMDx when applied within a mixed-effects model for repeated measures.