Department of Surgery, Virginia Commonwealth University, Richmond, Virginia, USA.
Mol Med. 2011;17(7-8):824-33. doi: 10.2119/molmed.2011.00072. Epub 2011 Apr 20.
Acute cellular rejection (ACR) and hepatitis C virus (HCV) recurrence (HCVrec) are common complications after liver transplantation (LT) in HCV patients, who share common clinical and histological features, making a differential diagnosis difficult. Fifty-three liver allograft samples from unique HCV LT recipients were studied using microarrays, including a training set (n = 32) and a validation set (n = 19). Two no-HCV-ACR samples from LT recipients were also included. Probe set intensity values were obtained using the robust multiarray average method (RMA) method. Analysis of variance identified statistically differentially expressed genes (P ≤ 0.005). The limma package was used to fit the mixed-effects models using a restricted maximum likelihood procedure. The last absolute shrinkage and selection operator (LASSO) model was fit with HCVrec versus ACR as the dependent variable predicted. N-fold cross-validation was performed to provide an unbiased estimate of generalization error. A total of 179 probe sets were differentially expressed among groups, with 71 exclusive genes between HCVrec and HCV-ACR. No differences were found within ACR group (HCV-ACR vs. no-HCV-ACR). Supervised clustering analysis displayed two clearly independent groups, and no-HCV-ACR clustered within HCV-ACR. HCVrec-related genes were associated with a cytotoxic T-cell profile, and HCV-ACR-related genes were associated with the inflammatory response. The best-fitting LASSO model classifier accuracy, including 15 genes, has an accuracy of 100% in the training set. N-fold cross-validation accuracy was 78.1%, and sensitivity, specificity and positive and negative predictive values were 50.0%, 90.9%, 71.4% and 80.0%, respectively. Arginase type II (ARG2), ethylmalonic encephalopathy 1 (ETHE1), transmembrane protein 176A (TMEM176A) and TMEM176B genes were significantly confirmed in the validation set. A molecular signature capable of distinguishing HCVrec and ACR in HCV LT recipients was identified and validated.
急性细胞排斥反应 (ACR) 和丙型肝炎病毒 (HCV) 复发 (HCVrec) 是丙型肝炎病毒患者肝移植 (LT) 后的常见并发症，这些患者具有共同的临床和组织学特征，使得鉴别诊断变得困难。使用微阵列研究了 53 个来自独特 HCV LT 受者的肝移植物样本，包括一个训练集 (n = 32) 和一个验证集 (n = 19)。还包括来自 LT 受者的两个无 HCV-ACR 样本。使用稳健多阵列平均方法 (RMA) 方法获得探针集强度值。方差分析确定了统计学上差异表达的基因 (P ≤ 0.005)。使用受限最大似然程序的 limma 包拟合混合效应模型。使用 HCVrec 与 ACR 作为因变量预测的最后绝对收缩和选择算子 (LASSO) 模型进行拟合。进行 N 折交叉验证以提供无偏估计的泛化误差。共有 179 个探针组在组间差异表达，HCVrec 与 HCV-ACR 之间有 71 个独特基因。ACR 组内未发现差异 (HCV-ACR 与无 HCV-ACR)。监督聚类分析显示了两个明显独立的组，无 HCV-ACR 聚类在 HCV-ACR 内。与 HCVrec 相关的基因与细胞毒性 T 细胞表型相关，与 HCV-ACR 相关的基因与炎症反应相关。最佳拟合 LASSO 模型分类器准确率，包括 15 个基因，在训练集中准确率为 100%。N 折交叉验证准确率为 78.1%，敏感性、特异性和阳性预测值和阴性预测值分别为 50.0%、90.9%、71.4%和 80.0%。精氨酸酶 II (ARG2)、乙基丙二酸脑病 1 (ETHE1)、跨膜蛋白 176A (TMEM176A) 和 TMEM176B 基因在验证集中得到了显著验证。鉴定并验证了一种能够区分 HCV LT 受者中 HCVrec 和 ACR 的分子特征。
