Dieterle Frank, Ross Alfred, Schlotterbeck Götz, Senn Hans
Pharmaceuticals Division, F. Hoffman La Roche Ltd., PRBD-E, Building 065/512, 4070-Basel, Switzerland.
Anal Chem. 2006 Jun 1;78(11):3551-61. doi: 10.1021/ac0518351.
The assignment of significantly changed NMR signals, which were identified with the help of multivariate models, to individual metabolites in biofluids is a manual and tedious task requiring knowledge in chemometrics and NMR spectroscopy. Metabolite projection analysis, introduced in this work, allows automatic linking of multivariate models with metabolites by skipping the level of manual NMR signal identification. The method depends on the projection of sets of metabolite NMR spectra from a database into PCA or PLS models of NMR spectra of biofluid samples. Metabolites that are significantly changed can be identified graphically in metabolite projection plots or numerically as projected virtual concentration. The method is demonstrated together with a newly introduced algorithm for refined nonequidistant binning using a metabonomics study with amiodarone as administered drug. Amiodarone can induce phospholipidosis in the lung and liver, which is accompanied by associated organ toxicity in these organs. It is shown how metabolite projection analysis allows easy and fast tentative assignment of all structures of metabolites whose concentrations in the urine samples significantly changed upon dosage. These metabolites had also been identified previously by manually interpreting the multivariate models and spectra. Among these metabolites, phenylacetylglycine was also identified as being significantly increased. This metabolite has recently been proposed as urinary biomarker for phospholipidosis.
借助多变量模型识别出的生物流体中显著变化的核磁共振信号与各个代谢物的对应关系，是一项需要化学计量学和核磁共振光谱知识的手工且繁琐的任务。本文介绍的代谢物投影分析，通过跳过手工核磁共振信号识别这一步骤，实现了多变量模型与代谢物的自动关联。该方法依赖于将数据库中代谢物核磁共振光谱集投影到生物流体样本核磁共振光谱的主成分分析（PCA）或偏最小二乘法（PLS）模型中。显著变化的代谢物可以在代谢物投影图中以图形方式识别，或以投影虚拟浓度的数值形式识别。使用以胺碘酮作为给药药物的代谢组学研究，结合新引入的用于精细非等距分箱的算法，对该方法进行了演示。胺碘酮可在肺部和肝脏诱导磷脂沉着症，并伴有这些器官的相关毒性。展示了代谢物投影分析如何轻松快速地初步确定尿液样本中浓度在给药后显著变化的所有代谢物结构。这些代谢物此前也已通过人工解读多变量模型和光谱得以识别。在这些代谢物中，苯乙酰甘氨酸也被确定为显著增加。这种代谢物最近被提议作为磷脂沉着症的尿液生物标志物。
