Journal
TRANSPLANTATION
Volume 106, Issue 5, Pages 1004-1011Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TP.0000000000003895
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Funding
- Northwestern University Comprehensive Transplant Center
- Northwestern and Eurofins-Viracor-Transplant Genomics Inc.
- National Institute of Allergy and Infectious Disease [14 U01AI084146]
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The study developed a blood-based biomarker that can detect acute rejection in liver transplant recipients before it occurs, providing guidance for reducing immunosuppression.
Background. Noninvasive biomarkers distinguishing early immune activation before acute rejection (AR) could more objectively inform immunosuppression management in liver transplant recipients (LTRs). We previously reported a genomic profile distinguishing LTR with AR versus stable graft function. This current study includes key phenotypes with other causes of graft dysfunction and uses a novel random forest approach to augment the specificity of predicting and diagnosing AR. Methods. Gene expression results in LTRs with AR versus non-AR (combination of other causes of graft dysfunction and normal function) were analyzed from single and multicenter cohorts. A 70:30 approach (61 ARs; 162 non-ARs) was used for training and testing sets. Microarray data were normalized using a LT-specific vector. Results. Random forest modeling on the training set generated a 59-probe classifier distinguishing AR versus non-AR (area under the curve 0.83; accuracy 0.78, sensitivity 0.70, specificity 0.81, positive predictive value 0.54, negative predictive value [NPV] 0.89; F-score 0.61). Using a locked threshold, the classifier performed well on the testing set (accuracy 0.72, sensitivity 0.67, specificity 0.73, positive predictive value 0.48, NPV 0.86; F-score 0.56). Probability scores increased in samples preceding AR versus non-AR, when liver function tests were normal, and decreased following AR treatment (P < 0.001). Ingenuity pathway analysis of the genes revealed a high percentage related to immune responses and liver injury. Conclusions. We have developed a blood-based biologically relevant biomarker that can be detected before AR-associated graft injury distinct from LTR never developing AR. Given its high NPV (rule out AR), the biomarker has the potential to inform precision-guided immunosuppression minimization in LTRs.
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