Early Screening and Subtype Identification of High-Risk Lung Nodules via Breathprint by Graphene eNose Platform: A Large Cohort Study

Early screening of individuals with high-risk lung nodules can significantly improve the prognosis of lung cancer patients, and accurate identification of lung nodule subtypes can provide guidance for medical treatment. Exhaled breath (EB) analysis via eNoses offers a quick and noninvasive approach, but current eNose technology lacks quality control and solid validation in large population studies. Herein, an eNose platform integrated with a metal ion-decorated graphene sensor array and a breath sampling accessory was established. EB samples from 427 healthy subjects and 2586 subjects with lung nodules, including various benign and malignant subtypes, were collected through the breath sampling accessory for quality control. The large-cohort clinical EB samples were analyzed by the eNose platform to acquire the cross-reactive resistance response. Breathprint analysis for high-risk lung nodules using SVM and age-matched training sets yielded strong and robust performance. Combined with baseline data, the model achieved an AUC of 0.93 (95% CI, 0.89-0.96) on the external test set, with 97% sensitivity and 73% specificity. Moreover, dimensionality reduction analysis of breathprints demonstrated separability across different lung nodule subtypes. This study demonstrates the reliability of the graphene eNose platform to identify high-risk lung nodules and classify lung nodule subtypes in a noninvasive and rapid method.