The goal of this application is to test the clinical utility of a biomarker-informed approach to the evaluation and management of indeterminate pulmonary nodules (IPNs). The study is designed to address this major and growing unmet need given the adoption of lung cancer screening in the US and abroad and the common occurrence of incidentally identified IPNs. We have developed and validated in external cohorts a high sensitivity hs-CYFRA 21-1 biomarker assay and quantitative imaging features that together improve the current noninvasive assessment of IPNs. In this proposal we hypothesize that a prediction model that integrates clinical variables, hs-CYFRA 21-1 serum concentration, and quantitative imaging signature will show clinical utility by reducing costly and invasive procedures while shortening time to diagnosis. To test this hypothesis, we propose the following specific aims: First, we will test the clinical utility of a biomarker-informed strategy in a first of its kind randomized clinical trial of IPN management. We will enroll 440 individuals with intermediate risk IPNs (1070% risk for cancer) at four institutions with the goal of reducing the number of invasive procedures and time to diagnosis. In the control arm, participants will follow the standard of care and in the intervention arm the biomarker results, expressed as a post-test probability for lung cancer, will be given to providers and participants to inform nodule management. Second, to further our work in identifying new candidate biomarkers for better risk stratification, we will apply a workflow for evaluation of candidates and validate the best candidates for entry into a similar future trial to that proposed in Aim 1. In a set of prospectively collected specimens, evaluated retrospectively in a blinded fashion (ProBE design), we will test the improvement in diagnostic accuracy of candidate biomarkers in patients with IPNs of intermediate risk for lung cancer based on the Mayo risk model. A blood biomarker signature from Abbott laboratories will be tested alone and in combination with a validated radiomics score to determine if together they reclassify at least 20% of those at intermediate risk (10-70%) based on the Mayo risk model alone into either a lower risk (<10%) or higher risk (>70%) group. We will determine the optimal and most cost-effective Mayo model + biomarker combination or sequence needed to achieve the critical decision thresholds in the management of IPNs. At the end of this project, we will have: a) demonstrated for the first time the clinical utility of a biomarker informed approach to IPN management and acquired additional outcomes data for a larger follow-on randomized multicenter trial, b) validated the incremental diagnostic accuracy of new candidate biomarkers for the management of IPNs, and c) opened a new avenue for rapid testing of the most effective combination(s) of candidates.