Abstract
Metabonomics methods have gradually become important auxiliary tools for screening disease biomarkers. However, recognition of metabolites or potential biomarkers closely related to either particular clinical symptoms or prognosis has been difficult. The current study aims to identify potential biomarkers of functional dyspepsia (FD) by a new strategy that combined hydrogen nuclear magnetic resonance (1H NMR)-based metabonomics techniques and an integrative multi-objective optimization (LPIMO) method. First, clinical symptoms of FD were evaluated using the Nepean Dyspepsia Index (NDI), and plasma metabolic profiles were measured by 1H NMR. Correlations between the key metabolites and the NDI scores were calculated. Then, LPIMO was developed to identify a multi-biomarker panel by maximizing diagnostic ability and correlation with the NDI score. Finally, a KEGG database search elicited the metabolic pathways in which the potential biomarkers are involved. The results showed that glutamine, alanine, proline, HDL, β-glucose, α-glucose and LDL/VLDL levels were significantly altered in FD patients. Among them, phosphatidycholine (PtdCho) and leucine/isoleucine (Leu/Ile) were positively and negatively correlated with the NDI Symptom Index (NDSI) respectively. Our procedure not only significantly improved the credibility of the biomarkers, but also demonstrated the potential of further explorations and applications to diagnosis and treatment of complex disease.
Highlights
Functional dyspepsia (FD) is a common gastrointestinal disease accompanied by epigastric pain, nausea, vomiting, abdominal distension, poor appetite, belching and other symptoms but no underlying organic changes in pathology[1]
Linear programming for integrate mulƟ-objecƟve opƟmizaƟon (LPIMO) uses three criteria to select a set of PPMs: 1) classification is minimized to attain the best accuracy based on nearest centroid classifier; 2) the number of selected PPMs is minimized to remove redundancy and reduce noise; 3) the PCCs between selected PPMs and the Nepean Dyspepsia Index (NDI) score in functional dyspepsia (FD) patients is maximized to select biomarkers correlating well with the NDI score
The present study suggests that conventional biochemistry test did not show significant changes in plasmatic blood sugar and blood lipid of FD, while our nuclear magnetic resonance (NMR) test revealed significant changes in the levels of glucose, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL) and other metabolites in the plasma samples of FD patients
Summary
A standardized questionnaire based on the Chinese version of the Nepean Dyspepsia Index (NDI), which had been already tested for validity and reliability in a previous study[14] was filled out by each patient. The NDI scores consist of three parts: a symptom checklist that measures the frequency, intensity, and level of discomfort of 15 upper gastrointestinal symptoms over the prior 14 days; 25 items designed to assess Quality of Life (QoL), and an 11-item questionnaire designed to measure the relevance or importance of the above items. Pattern recognition analysis of NMR data and permutation test. For CPMG spectra, each spectrum over the range of δ 0.4–4.4 was data-reduced into integrated regions of equal width (0.01 ppm). The data were preprocessed using orthogonal signal correction (OSC) to filter the unrelated variations not correlated to the group membership[19,20]
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