Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning approaches have been used to predict toxicity-related biological activities using chemical structure descriptors. However, toxicity-related proteomic features have not been fully investigated. In this study, we construct a computational pipeline using machine learning models for predicting the most important protein features responsible for the toxicity of compounds taken from the Tox21 dataset that is implemented within the multiscale Computational Analysis of Novel Drug Opportunities (CANDO) therapeutic discovery platform. Tox21 is a highly imbalanced dataset consisting of twelve in vitro assays, seven from the nuclear receptor (NR) signaling pathway and five from the stress response (SR) pathway, for more than 10,000 compounds. For the machine learning model, we employed a random forest with the combination of Synthetic Minority Oversampling Technique (SMOTE) and the Edited Nearest Neighbor (ENN) method (SMOTE+ENN), which is a resampling method to balance the activity class distribution. Within the NR and SR pathways, the activity of the aryl hydrocarbon receptor (NR-AhR) and the mitochondrial membrane potential (SR-MMP) were two of the top-performing twelve toxicity endpoints with AUCROCs of 0.90 and 0.92, respectively. The top extracted features for evaluating compound toxicity were analyzed for enrichment to highlight the implicated biological pathways and proteins. We validated our enrichment results for the activity of the AhR using a thorough literature search. Our case study showed that the selected enriched pathways and proteins from our computational pipeline are not only correlated with AhR toxicity but also form a cascading upstream/downstream arrangement. Our work elucidates significant relationships between protein and compound interactions computed using CANDO and the associated biological pathways to which the proteins belong for twelve toxicity endpoints. This novel study uses machine learning not only to predict and understand toxicity but also elucidates therapeutic mechanisms at a proteomic level for a variety of toxicity endpoints.

The important cues for a realistic lung nodule synthesis include the diversity in shape and background, controllability of semantic feature levels, and overall CT image quality. To incorporate these cues as the multiple learning targets, we introduce the Multi-Target Co-Guided Adversarial Mechanism , which utilizes the foreground and background mask to guide nodule shape and lung tissues, takes advantage of the CT lung and mediastinal window as the guidance of spiculation and texture control, respectively. Further, we propose a Multi-Target Co-Guided Synthesizing Network with a joint loss function to realize the co-guidance of image generation and semantic feature learning. The proposed network contains a Mask-Guided Generative Adversarial Sub-Network (MGGAN) and a Window-Guided Semantic Learning Sub-Network (WGSLN). The MGGAN generates the initial synthesis using the mask combined with the foreground and background masks, guiding the generation of nodule shape and background tissues. Meanwhile, the WGSLN controls the semantic features and refines the synthesis quality by transforming the initial synthesis into the CT lung and mediastinal window, and performing the spiculation and texture learning simultaneously. We validated our method using the quantitative analysis of authenticity under the Fréchet Inception Score, and the results show its state-of-the-art performance. We also evaluated our method as a data augmentation method to predict malignancy level on the LIDC-IDRI database, and the results show that the accuracy of VGG-16 is improved by 5.6%. The experimental results confirm the effectiveness of the proposed method.