Integrative pathway-centric modeling of ventricular dysfunction after myocardial infarction.
Integrative pathway-centric modeling of ventricular dysfunction after myocardial infarction.
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DOI：
10.1371/journal.pone.0009661
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发表时间：
2010-03-11
期刊：
影响因子：
3.7
通讯作者：
Wagner DR
中科院分区：
文献类型：
--
作者：
Azuaje F;Devaux Y;Wagner DR
相当比例的心肌梗死（MI）患者在分子水平上经历复杂的、协调的扰动，最终可能导致心室功能障碍和心力衰竭的发生。尽管在阐明与这种疾病相关的关键过程方面取得了进展，但传统的方法依赖于基因表达数据和单个生物标志物的分离鉴定，这不仅在提高预测能力方面存在重大限制，而且在模型的可解释性方面也存在很大限制。心肌梗死后临床反应的机制仍然难以捉摸，也没有能够准确预测心肌梗死后心室功能障碍的生物标志物。这就需要探索心肌梗死后患者心室功能障碍的系统水平建模。在这一发现框架内，关键扰动和预测模式的特征是在途径中观察到的综合生物活性水平，而不是在单个基因中。在这里，我们报告了一种综合方法来识别与心肌梗死后心室功能障碍相关的通路，具有潜在的预后和治疗价值。我们发现，在心肌梗死后心室功能障碍患者的样本中，存在多种途径水平的扰动，其中大多数代表基因表达的主要减少。高度干扰的途径包括那些涉及抗原依赖性b细胞活化和亮氨酸合成的途径。通过分析由来自高度扰动通路的信息编码的患者特异性样本，可以可视化不同的预后模式，并对接受者工作特征曲线下的面积大于0.75的患者进行计算分类。我们还展示了如何整合由不同通路分析模型产生的结果可以提高心室功能障碍的预测性能。这项研究提供了一个替代的，全面的观点，关键关系和干扰，可能引发心肌梗死后心室功能障碍的出现或预防。
A significant proportion of myocardial infarction (MI) patients undergo complex, coordinated perturbations at the molecular level that may eventually drive the occurrence of ventricular dysfunction and heart failure. Despite advances in the elucidation of key processes implicated in this condition, traditional methods relying on gene expression data and the identification of individual biomarkers in isolation pose major limitations not only for improving prediction power, but also for model interpretability. Mechanisms underlying clinical responses after MI remain elusive and there is no biomarker with the capacity to accurately predict ventricular dysfunction after MI. This calls for the exploration of system-level modeling of ventricular dysfunction in post-MI patients. Within this discovery framework key perturbations and predictive patterns are characterized by the integrated biological activity levels observed in pathways, rather than in individual genes. Here we report an integrative approach to identifying pathways related with ventricular dysfunction post MI with potential prognostic and therapeutic value. We found that a diversity of pathway-level perturbations can be profiled in samples of patients with ventricular dysfunction post MI, most of which represent major reductions of gene expression. Highly perturbed pathways included those implicated in antigen-dependent B-cell activation and the synthesis of leucine. By analyzing patient-specific samples encoded with information derived from highly-perturbed pathways, it is possible to visualize differential prognostic patterns and to perform computational classification of patients with areas under the receiver operating characteristic curve above 0.75. We also demonstrate how the integration of the outcomes generated by different pathway-based analysis models may improve ventricular dysfunction prediction performance. This research offers an alternative, comprehensive view of key relationships and perturbations that may trigger the emergence or prevention of ventricular dysfunction post-MI.
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