Machine Learning Enabled Prediction of Biologically Relevant Gene Expression Using CT‐Based Radiomic Features in Non‐Small Cell Lung Cancer

ABSTRACT Background Non‐small‐cell lung cancer (NSCLC) remains a global health challenge, driving morbidity and mortality. The emerging field of radiogenomics utilizes statistical methods to correlate radiographic tumor features with genomic characteristics from biopsy samples. Radiomic techniques automate the precise extraction of imaging features from tumor regions in radiographic scans, which are subjected to machine learning (ML) to predict genomic attributes. Methods In a retrospective study of two NSCLC patient cohorts separated by 5 years, we performed a radiogenomic analysis of previously disseminated data from 2018 (n = 116) and newly acquired data from 2023 (n = 44) using RNA sequencing and lung CT images. Combining the data from two cohorts post binarization (of gene expression) or batch normalization (of radiomic features) in each cohort proved to be a better approach as compared to training the model on one cohort and validating on the other. Results Our ML‐based radiogenomic modeling identified specific imaging features—wavelet, three‐dimensional local binary patterns, and logarithmic sigma of gray‐level variance—as predictive indicators for high (1) vs. low (0) gene expression of pivotal NSCLC‐related genes: SLC35C1, BCL2L1, and MAPK1. These genes have recognized implications in a variety of biological pathways and mechanisms of drug resistance pertinent to NSCLC. Conclusion The successful integration of heterogeneous radiogenomic datasets underscores the potential of imaging biomarkers in uncovering NSCLC biological processes through gene expression profiles. In the present study, we used two heterogeneous NSCLC cohorts to make two substantial advances in the field of radiogenomics: (1) we successfully combined two temporally distinct cohorts, thereby addressing a long‐standing problem in radiogenomics, and (2) we show that radiomic features extracted from tumor regions of interest from SOC images can be used as surrogate biomarkers for the individual expression of several genes known to play key roles in NSCLC and other human malignancies. We believe that our study makes a significant contribution to the literature because it represents substantial advances in the field of radiogenomics and provides a blueprint for homogenizing temporally distinct patient cohorts and using predictions of individual gene expression as surrogate biomarkers in clinical oncology workflows.