Differential metabolic network construction for personalized medicine: Study of type 2 diabetes mellitus patients' response to gliclazide-modified-release-treated

Abstract

Individual variation in genetic and environmental factors can cause the differences in metabolic phenotypes, which may have an effect on drug responses of patients. Deep exploration of patients’ responses to therapeutic agents is a crucial and urgent event in the personalized treatment study. Using machine learning methods for the discovery of suitability evaluation biomarkers can provide deep insight into the mechanism of disease therapy and facilitate the development of personalized medicine. To find important metabolic network signals for the prediction of patients’ drug responses, a novel method referred to as differential metabolic network construction (DMNC) was proposed. In DMNC, concentration changes in metabolite ratios between different pathological states are measured to construct differential metabolic networks, which can be used to advance clinical decision-making. In this study, DMNC was applied to characterize type 2 diabetes mellitus (T2DM) patients’ responses against gliclazide modified-release (MR) therapy. Two T2DM metabolomics datasets from different batches of subjects treated by gliclazide MR were analyzed in depth. A network biomarker was defined to assess the patients’ suitability for gliclazide MR. It can be effective in the prediction of significant responders from nonsignificant responders, achieving area under the curve values of 0.893 and 1.000 for the discovery and validation sets, respectively. Compared with the metabolites selected by the other methods, the network biomarker selected by DMNC was more stable and precise to reflect the metabolic responses in patients to gliclazide MR therapy, thereby contributing for the personalized medicine of T2DM patients. The better performance of DMNC validated its potential for the identification of network biomarkers to characterize the responses against therapeutic treatments and provide valuable information for personalized medicine.