Comprehensive Serum Glycopeptide Spectra Analysis Combined with Machine Learning for Early Detection of Lung Cancer: A Case–Control Study

Abstract

Background: Lung cancer is among the most prevalent and fatal cancers worldwide. Traditional diagnostic methods, such as computed tomography, are not ideal for screening due to their high cost and radiation exposure. In contrast, blood-based diagnostics, as non-invasive approaches, are expected to reduce patient burden, thereby increasing screening participation and ultimately improving survival rates. However, conventional tumor markers have shown limited effectiveness in early detection. Methods: We recruited 199 patients with lung cancer and 590 healthy volunteers. Nine tumor markers (CEA, CA19-9, CYFRA, AFP, PSA, CA125, CA15-3, SCC antigen, and NCC-ST439) were analyzed, along with enriched glycopeptides (EGPs) derived from serum proteins using liquid chromatography–mass spectrometry. Machine learning models, including decision trees and deep learning approaches, were employed to develop a predictive model for accurately distinguishing lung cancer from healthy controls based on tumor markers and EGP profiles. Results: We found that α1-antitrypsin with fully sialylated biantennary glycan, attached to asparagine 271 (AT271-FSG), and α2-macroglobulin with fully sialylated biantennary glycan, attached to asparagine 70 (MG70-FSG), could significantly distinguish between patients with lung cancer and healthy individuals. Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA), integrating nine conventional tumor markers and 1688 EGPs using a machine learning model, enhanced diagnostic accuracy and achieved an ROC-AUC score of 0.935. It also identified stage I cases with an ROC-AUC of 0.914, indicating the possibility of early-stage detection. The PPV reached 2.8%, which was sufficient for practical application. Conclusions: This method represents a significant advancement in cancer diagnostics, combining multiple biomarkers with cutting-edge machine learning to improve the early detection of lung cancer.