PredictiveNetwork: predictive gene network estimation with application to gastric cancer drug response-predictive...

Gene regulatory networks have garnered a large amount of attention to understand disease mechanisms caused by complex molecular network interactions. These networks have been applied to predict specific clinical characteristics, e.g., cancer, pathogenicity, and anti-cancer drug sensitivity. However, in most previous studies using network-based prediction, the gene networks were estimated first, and predicted clinical characteristics based on pre-estimated networks. Thus, the estimated networks cannot describe clinical characteristic-specific gene regulatory systems. Furthermore, existing computational methods were developed from algorithmic and mathematics viewpoints, without considering network biology.

To effectively predict clinical characteristics and estimate gene networks that provide critical insights into understanding the biological mechanisms involved in a clinical characteristic, we propose a novel strategy for predictive gene network estimation. The proposed strategy simultaneously performs gene network estimation and prediction of the clinical characteristic. In this strategy, the gene network is estimated with minimal network estimation and prediction errors. We incorporate network biology by assuming that neighboring genes in a network have similar biological functions, while hub genes play key roles in biological processes. Thus, the proposed method provides interpretable prediction results and enables us to uncover biologically reliable marker identification. Monte Carlo simulations shows the effectiveness of our method for feature selection in gene estimation and prediction with excellent prediction accuracy. We applied the proposed strategy to construct gastric cancer drug-responsive networks.

We identified gastric drug response predictive markers and drug sensitivity/resistance-specific markers, AKR1B10, AKR1C3, ANXA10, and ZNF165, based on GDSC data analysis. Our results for identifying drug sensitive and resistant specific molecular interplay are strongly supported by previous studies. We expect that the proposed strategy will be a useful tool for uncovering crucial molecular interactions involved a specific biological mechanism, such as cancer progression or acquired drug resistance.