Drug response prediction in patient-derived xenografts with data augmentation and multimodal deep learning.

Abstract

e13572 Background: Prediction of drug response is a critical research area in precision oncology and has been previously explored with large drug screening studies of cancer cell lines (CCLs). Patient-derived xenografts (PDXs) are an appealing platform for preclinical drug studies because the in vivo environment of PDXs helps preserve tumor heterogeneity and usually better mimics drug response of patients with cancer compared to CCLs. Methods: We investigate multimodal neural network (NN) and data augmentation for drug response prediction in PDXs. The multimodal NN learns to predict response using drug descriptors, gene expressions (GE), and histology whole-slide images (WSIs) where the multi-modality refers to tumor features only. The NN uses late integration where separate subnetworks are used to encode the input feature types before concatenation and prediction layers. Median tumor volume per treatment group is assessed relative to the control group to create a binary variable representing response. The data include twelve single-drug and 36 drug-pair treatments resulting in 2,556 single-drug and 2,203 drug-pair response values. Pathology and omics data from 487 PDXs from NCI's Patient Derived Models Repository are used as tumor feature model inputs. We explore whether the integration of WSIs with GE improves predictions as compared with models that use GE alone. We use two methods to address the limited number of response values in the dataset: 1) homogenize drug representations which allows to combine single-drug and drug-pairs into a single dataset, 2) augment drug-pair samples by switching the order of drug features which doubles the sample size of all drug-pair samples. These methods enable us to combine single-drug and drug-pair treatments which results in 6,962 responses, allowing us to train multimodal and unimodal NNs without changing architectures or the dataset. Results: Prediction performance of three unimodal NNs which use GE (um1, um2, and um3) are compared to assess the contribution of data augmentation methods. NN um1 that uses the full dataset which includes the original and the augmented drug-pair treatments as well as single-drug treatments significantly outperforms NNs (p-values < 0.01) that ignore either the augmented drug-pairs (um2) or the single-drug treatments (um3). In assessing the contribution of multimodal learning, results show that the multimodal NN (mm) outperforms both unimodal NNs that ignore either the GE (um4) or the WSIs (um1). However, the improvement of mm over um1 is not statistically significant (p-value < 0.26). Conclusions: Our results show that data augmentation and integration of histology images and GE can help improve prediction performance of drug response in PDXs.[Table: see text]