Integrating Multiomics Information in Deep Learning Architectures for Joint Actuarial Outcome Prediction in Non-Small Cell Lung Cancer Patients After Radiation Therapy

Abstract

Novel actuarial deep learning neural network (ADNN) architectures are proposed for joint prediction of radiation therapy outcomes-radiation pneumonitis (RP) and local control (LC)-in stage III non-small cell lung cancer (NSCLC) patients. Unlike normal tissue complication probability/tumor control probability models that use dosimetric information solely, our proposed models consider complex interactions among multiomics information including positron emission tomography (PET) radiomics, cytokines, and miRNAs. Additional time-to-event information is also used in the actuarial prediction. Three architectures were investigated: ADNN-DVH considered dosimetric information only; ADNN-com integrated multiomics information; and ADNN-com-joint combined RP2 (RP grade ≥2) and LC prediction. In these architectures, differential dose-volume histograms (DVHs) were fed into 1D convolutional neural networks (CNN) for extracting reduced representations. Variational encoders were used to learn representations of imaging and biological data. Reduced representations were fed into Surv-Nets to predict time-to-event probabilities for RP2 and LC independently and jointly by incorporating time information into designated loss functions. Models were evaluated on 117 retrospective patients and were independently tested on 25 newly accrued patients prospectively. A multi-institutional RTOG0617 data set of 327 patients was used for external validation. ADNN-DVH yielded cross-validated c-indexes (95% confidence intervals) of 0.660 (0.630-0.690) for RP2 prediction and 0.727 (0.700-0.753) for LC prediction, outperforming a generalized Lyman model for RP2 (0.613 [0.583-0.643]) and a generalized log-logistic model for LC (0.569 [0.545-0.594]). The independent internal test and external validation yielded similar results. ADNN-com achieved an even better performance than ADNN-DVH on both cross-validation and independent internal test. Furthermore, ADNN-com-joint, which yielded performance similar to ADNN-com, realized joint prediction with c-indexes of 0.705 (0.676-0.734) for RP2 and 0.740 (0.714-0.765) for LC and achieved an area under a free-response receiving operator characteristic curve (AU-FROC) of 0.729 (0.697-0.773) for the joint prediction of RP2 and LC. Novel deep learning architectures that integrate multiomics information outperformed traditional normal tissue complication probability/tumor control probability models in actuarial prediction of RP2 and LC.