Integrating Statistical and Machine-Learning Approach for Meta-Analysis of Bisphenol A-Exposure Datasets Reveals Effects on Mouse Gene Expression within Pathways of Apoptosis and Cell Survival.

Bisphenols are important environmental pollutants that are extensively studied due to different detrimental effects, while the molecular mechanisms behind these effects are less well understood. Like other environmental pollutants, bisphenols are being tested in various experimental models, creating large expression datasets found in open access storage. The meta-analysis of such datasets is, however, very complicated for various reasons. Here, we developed an integrating statistical and machine-learning model approach for the meta-analysis of bisphenol A (BPA) exposure datasets from different mouse tissues. We constructed three joint datasets following three different strategies for dataset integration: in particular, using all common genes from the datasets, uncorrelated, and not co-expressed genes, respectively. By applying machine learning methods to these datasets, we identified genes whose expression was significantly affected in all of the BPA microanalysis data tested; those involved in the regulation of cell survival include: Tnfr2, Hgf-Met, Agtr1a, Bdkrb2; signaling through Mapk8 (Jnk1)); DNA repair (Hgf-Met, Mgmt); apoptosis (Tmbim6, Bcl2, Apaf1); and cellular junctions (F11r, Cldnd1, Ctnd1 and Yes1). Our results highlight the benefit of combining existing datasets for the integrated analysis of a specific topic when individual datasets are limited in size.

SimVec: predicting polypharmacy side effects for new drugs.

Polypharmacy refers to the administration of multiple drugs on a daily basis. It has demonstrated effectiveness in treating many complex diseases , but it has a higher risk of adverse drug reactions. Hence, the prediction of polypharmacy side effects is an essential step in drug testing, especially for new drugs. This paper shows that the current knowledge graph (KG) based state-of-the-art approach to polypharmacy side effect prediction does not work well for new drugs, as they have a low number of known connections in the KG. We propose a new method , SimVec, that solves this problem by enhancing the KG structure with a structure-aware node initialization and weighted drug similarity edges. We also devise a new 3-step learning process, which iteratively updates node embeddings related to side effects edges, similarity edges, and drugs with limited knowledge. Our model significantly outperforms existing KG-based models. Additionally, we examine the problem of negative relations generation and show that the cache-based approach works best for polypharmacy tasks.