Project Summary Lung cancer remains to be a global public health priority. While low-dose computed tomography (LDCT) screening was shown to reduce lung cancer mortality by 20-30%, there remain to be unresolved challenges issues such as optimizing intervals for LDCT screening and how best to increase LDCT screening uptake and adherence. In addition, it has been shown previously that lung cancer risks for African Americans are higher than for Whites when having the same level of smoking exposure, while uptake of LDCT screening among African Americans has been one of the lowest. Moreover, the proportion of lung cancer among never smokers continues to rise across the world, particularly among Asians where over 50% of lung cancers are diagnosed among never smokers. None of these emerging issues are addressed under the recently expanded US Preventative Service Task Force criteria. The overall objective of this project is to establish a biomarker-informed LDCT screening pathway to maximize screening efficiency and benefit-harm ratio while accounting for racial disparity. Our research team is in the unique position to conduct this much-needed work as we have already established extensive resources for the data elements needed being the lead investigators of the major CT screening programs in the US, Canada, Europe and Asia along with international lung cancer consortia. Specifically, we will (i) Establish a biomarker-informed LDCT screening pathway accounting for racial disparity using data and samples from 3 ongoing LDCT screening programs in North America, with a total of 3500 participants and oversampling African Americans; (ii) Identify circulating biomarkers that predict lung cancer risk and differentiate nodule malignancy in Asian never smokers, using data and samples from the Taiwan Lung Cancer Screening for Never Smoker Trial (TALENT) with 12,011 high-risk Asian never smokers and 311 lung cancer cases detected by LDCT screening; (iii) Assess the prognostic values of biomarkers for lung cancer mortality based on multi-omics approaches using data and samples from 6 LDCT screening studies from US, Canada, Europe and Asia with a total of 1267 lung cancer cases. The results from this Project will shift the paradigm of what is considered an optimal CT screening pathway and address the need of under-represented populations and potential over-diagnosis by investigating mortality. It will provide necessary information toward the implementation of individual risk- profile based screening strategies that will increase efficiency, improve patient management, and reduce lung cancer mortality in an ethnically diverse population.