无监督的心脏移植活检 mRNA-seq 分类。
Unsupervised mRNA-seq classification of heart transplant endomyocardial biopsies.
机构信息
Division of Cardiovascular Medicine, UC Davis Medical Center, Sacramento, California, USA.
Courant Institute of Mathematical Sciences, New York University, New York, New York, USA.
出版信息
Clin Transplant. 2023 Sep;37(9):e15011. doi: 10.1111/ctr.15011. Epub 2023 May 7.
BACKGROUND
Endomyocardial biopsy (EMB) is currently considered the gold standard for diagnosing cardiac allograft rejection. However, significant limitations related to histological interpretation variability are well-recognized. We sought to develop a methodology to evaluate EMB solely based on gene expression, without relying on histology interpretation.
METHODS
Sixty-four EMBs were obtained from 47 post-heart transplant recipients, who were evaluated for allograft rejection. EMBs were subjected to mRNA sequencing, in which an unsupervised classification algorithm was used to identify the molecular signatures that best classified the EMBs. Cytokine and natriuretic peptide peripheral blood profiling was also performed. Subsequently, we performed gene network analysis to identify the gene modules and gene ontology to understand their biological relevance. We correlated our findings with the unsupervised and histological classifications.
RESULTS
Our algorithm classifies EMBs into three categories based solely on clusters of gene expression: unsupervised classes 1, 2, and 3. Unsupervised and histological classifications were closely related, with stronger gene module-phenotype correlations for the unsupervised classes. Gene ontology enrichment analysis revealed processes impacting on the regulation of cardiac and mitochondrial function, immune response, and tissue injury response. Significant levels of cytokines and natriuretic peptides were detected following the unsupervised classification.
CONCLUSION
We have developed an unsupervised algorithm that classifies EMBs into three distinct categories, without relying on histology interpretation. These categories were highly correlated with mitochondrial, immune, and tissue injury response. Significant cytokine and natriuretic peptide levels were detected within the unsupervised classification. If further validated, the unsupervised classification could offer a more objective EMB evaluation.
背景
心肌内膜活检（EMB）目前被认为是诊断心脏移植物排斥反应的金标准。然而，组织学解释变异性相关的显著局限性是众所周知的。我们试图开发一种仅基于基因表达评估 EMB 的方法，而不依赖于组织学解释。
方法
从 47 名心脏移植受者中获得 64 份 EMB，对其进行移植物排斥评估。EMB 进行 mRNA 测序，其中使用无监督分类算法来识别最佳分类 EMB 的分子特征。还进行了细胞因子和利钠肽外周血分析。随后，我们进行了基因网络分析，以识别基因模块并了解其生物学相关性。我们将我们的发现与无监督和组织学分类相关联。
结果
我们的算法仅根据基因表达聚类将 EMB 分为三类：无监督类别 1、2 和 3。无监督和组织学分类密切相关，无监督类别具有更强的基因模块-表型相关性。基因本体富集分析显示，影响心脏和线粒体功能、免疫反应和组织损伤反应的过程。在无监督分类后检测到细胞因子和利钠肽的显著水平。
结论
我们已经开发了一种无监督算法，可将 EMB 分为三个不同类别，而不依赖于组织学解释。这些类别与线粒体、免疫和组织损伤反应高度相关。在无监督分类中检测到显著水平的细胞因子和利钠肽。如果进一步验证，无监督分类可以提供更客观的 EMB 评估。
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