Identification of metabolomics-based biomarker discovery in individuals with down syndrome utilizing kernel-tree model-enhanced explainable artificial intelligence methodology.

objectiveThis study aims to develop an explainable artificial intelligence (XAI) model integrated with machine learning (ML) to comprehensively investigate metabolic differences between individuals with Down syndrome (T21) and healthy controls (D21) and to identify novel/pathway-specific biomarkers. In this study, ML classifiers including AdaBoost, LightGBM, Random Forest, KTBoost, and XGBoost are applied to metabolomics data obtained from metabolomic analyses by high-resolution liquid chromatography-mass spectrometry (LC-MS) using blood plasma samples of 316 T21 and 103 D21 individuals, and the importance of metabolites is evaluated by XAI-based SHAP analysis. The KTBoost model shows the highest classification performance with an accuracy of 90.4% and area under the curve (AUC) of 95.9%, outperforming AdaBoost, LightGBM, Random Forest, and XGBoost. Significant downregulation and upregulation of some metabolites were observed in the T21 group compared to the D21 group. Metabolites such as vitamin C, taurolithocholic acid, sphingosine, and prostaglandin A2/B2/J2 are observed at low levels in the T21 group. In contrast, metabolites such as thymidine, tau-roursodeoxycholic acid, serine, and nervonic acid are elevated. SHAP analysis revealed that L-Citrulline, Kynurenin, Prostaglandin A2/B2/J2, Urate, and Pantothenate metabolites could be novel/pathway-specific biomarkers to differentiate the T21 group. This study revealed significant metabolic alterations in individuals with T21 and demonstrated the effectiveness of the combination of ML and XAI methods to identify novel/pathway-specific biomarkers. The findings may contribute to a better understanding of Down syndrome's molecular mechanisms and the development of future diagnostic and therapeutic strategies.