Building Multivariate Systems Biology Models
Building Multivariate Systems Biology Models
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DOI：
10.1021/ac301269r
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发表时间：
2012-08-21
影响因子：
7.4
通讯作者：
Wheelock, Craig E.
中科院分区：
文献类型：
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作者：
Kirwan, Gemma M.;Johansson, Erik;Wheelock, Craig E.
使用大规模“组学”数据集的系统生物学方法面临着独特的挑战：整合和分析近乎无限的数据空间，同时识别和消除系统变异或噪音。在此，我们提出了一个互补的多变量分析工作流程，既可以整合来自不同来源的“组学”数据，又可以分析结果以获取特定且独特的样本相关性。该工作流程结合了主成分分析 (PCA)、潜在结构正交投影判别分析 (OPLS-DA)、潜在结构正交 2 投影 (O2PLS) 以及共享和独特结构 (SUS) 图。使用一项研究的数据证明了工作流程，其中 ApoE3Leiden 小鼠被喂食致动脉粥样硬化饮食，其中包括增加胆固醇水平，然后进行治疗干预（非诺贝特、瑞舒伐他汀和 LXR 激活剂 T-0901317）。通过液相色谱质谱法 (LC-MS) 对肝脏中的结构脂质（脂质组学）和游离脂肪酸水平进行定量。补充工作流程将甘油二酯确定为受膳食胆固醇和药物干预影响的关键肝脏代谢物。对喂食高胆固醇饮食的小鼠的三种疗法的建模进一步强调了甘油二酯作为动脉粥样硬化形成中感兴趣的代谢物，表明其在引发慢性肝脏炎症中发挥作用。特别是，基于 O2PLS 的 SUS2 图显示，用 T-0901317 或瑞舒伐他汀治疗可使高胆固醇喂养小鼠的甘油二酯分布恢复到对照动物的水平。
Systems biology methods using large-scale "omics" data sets face unique challenges: integrating and analyzing near limitless data space, while recognizing and removing systematic variation or noise. Herein we propose a complementary multivariate analysis workflow to both integrate "omics" data from disparate sources and analyze the results for specific and unique sample correlations. This workflow combines principal component analysis (PCA), orthogonal projections to latent structures discriminate analysis (OPLS-DA), orthogonal 2 projections to latent structures (O2PLS), and shared and unique structures (SUS) plots. The workflow is demonstrated using data from a study in which ApoE3Leiden mice were fed an atherogenic diet consisting of increasing cholesterol levels followed by therapeutic intervention (fenofibrate, rosuvastatin, and LXR activator T-0901317). The levels of structural lipids (lipidomics) and free fatty acids in liver were quantified via liquid chromatography mass spectrometry (LC-MS). The complementary workflow identified diglycerides as key hepatic metabolites affected by dietary cholesterol and drug intervention. Modeling of the three therapeutics for mice fed a high-cholesterol diet further highlighted diglycerides as metabolites of interest in atherogenesis, suggesting a role in eliciting chronic liver inflammation. In particular, O2PLS-based SUS2 plots showed that treatment with T-0901317 or rosuvastatin returned the diglyceride profile in high-cholesterol-fed mice to that of control animals.