Abstract:Lung cancer is the leading cause of cancer-related mortality worldwide. Lung cancer screening (LCS) using annual low-dose computed tomography (CT) scanning has been proven to significantly reduce lung cancer mortality by detecting cancerous lung nodules at an earlier stage. Improving risk stratification of malignancy risk in lung nodules can be enhanced using machine/deep learning algorithms. However most existing algorithms: a) have primarily assessed single time-point CT data alone thereby failing to utilize the inherent advantages contained within longitudinal imaging datasets; b) have not integrated into computer models pertinent clinical data that might inform risk prediction; c) have not assessed algorithm performance on the spectrum of nodules that are most challenging for radiologists to interpret and where assistance from analytic tools would be most beneficial. Here we show the performance of our time-series deep learning model (DeepCAD-NLM-L) which integrates multi-model information across three longitudinal data domains: nodule-specific, lung-specific, and clinical demographic data. We compared our time-series deep learning model to a) radiologist performance on CTs from the National Lung Screening Trial enriched with the most challenging nodules for diagnosis; b) a nodule management algorithm from a North London LCS study (SUMMIT). Our model demonstrated comparable and complementary performance to radiologists when interpreting challenging lung nodules and showed improved performance (AUC=88\%) against models utilizing single time-point data only. The results emphasise the importance of time-series, multi-modal analysis when interpreting malignancy risk in LCS.