Molecular biomarkers for the evaluation of indeterminate pulmonary nodules: a systematic review

Current risk prediction tools for indeterminate pulmonary nodules (IPNs) are imperfect and there is a growing body of research in biomarkers to aid management. We undertook this systematic review to evaluate the current landscape of molecular biomarkers designed for IPN risk stratification. PubMed, CINAHL Complete, and Scopus databases were searched through December 2024. Clinical validation or utility studies of non-invasive molecular biomarkers for IPNs (<30mm) were included. Risk of bias was assessed using QUADAS-2. Database and citation searching identified 1,577 studies from 2007-2024. After abstract and full-text screening, 106 studies were included in the systematic review. Of the 106 studies included, less than half validated the accuracy of the biomarker in an external cohort (n = 48, 45%), while most others (n = 47, 44%) used a split-validation design. The median size of the validation cohort was 112.5 (range: 29 to 1,679). Protein biomarkers were the most commonly evaluated (n = 73), followed by genetic/nucleic acid compounds (n = 40). Risk of bias assessment using the QUADAS-2 tool found 9 studies to be at low risk across all domains, and many studies had an unclear risk due to lack of reporting or clarity. This review highlights the growing and diverse field of molecular biomarker development for the evaluation of pulmonary nodules. The vast majority had no external validation in an intended use cohort. Improvements must be made to the completeness of reporting in the field to address issues with risk of bias and applicability of study results.