The Inferred Cardiogenic Gene Regulatory Network in the Mammalian Heart

Cardiac development is a complex, multiscale process encompassing cell fate adoption, differentiation and morphogenesis. To elucidate pathways underlying this process, a recently developed algorithm to reverse engineer gene regulatory networks was applied to time-course microarray data obtained from the developing mouse heart. Approximately 200 genes of interest were input into the algorithm to generate putative network topologies that are capable of explaining the experimental data via model simulation. To cull specious network interactions, thousands of putative networks are merged and filtered to generate scale-free, hierarchical networks that are statistically significant and biologically relevant. The networks are validated with known gene interactions and used to predict regulatory pathways important for the developing mammalian heart. Area under the precision-recall curve and receiver operator characteristic curve are 9% and 58%, respectively. Of the top 10 ranked predicted interactions, 4 have already been validated. The algorithm is further tested using a network enriched with known interactions and another depleted of them. The inferred networks contained more interactions for the enriched network versus the depleted network. In all test cases, maximum performance of the algorithm was achieved when the purely data-driven method of network inference was combined with a data-independent, functional-based association method. Lastly, the network generated from the list of approximately 200 genes of interest was expanded using gene-profile uniqueness metrics to include approximately 900 additional known mouse genes and to form the most likely cardiogenic gene regulatory network. The resultant network supports known regulatory interactions and contains several novel cardiogenic regulatory interactions. The method outlined herein provides an informative approach to network inference and leads to clear testable hypotheses related to gene regulation

Hybrid Approach of Relation Network and Localized Graph Convolutional Filtering for Breast Cancer Subtype Classification

Network biology has been successfully used to help reveal complex mechanisms of disease, especially cancer. On the other hand, network biology requires in-depth knowledge to construct disease-specific networks, but our current knowledge is very limited even with the recent advances in human cancer biology. Deep learning has shown a great potential to address the difficult situation like this. However, deep learning technologies conventionally use grid-like structured data, thus application of deep learning technologies to the classification of human disease subtypes is yet to be explored. Recently, graph based deep learning techniques have emerged, which becomes an opportunity to leverage analyses in network biology. In this paper, we proposed a hybrid model, which integrates two key components 1) graph convolution neural network (graph CNN) and 2) relation network (RN). We utilize graph CNN as a component to learn expression patterns of cooperative gene community, and RN as a component to learn associations between learned patterns. The proposed model is applied to the PAM50 breast cancer subtype classification task, the standard breast cancer subtype classification of clinical utility. In experiments of both subtype classification and patient survival analysis, our proposed method achieved significantly better performances than existing methods. We believe that this work is an important starting point to realize the upcoming personalized medicine.Comment: 8 pages, To be published in proceeding of IJCAI 201

Refining interaction search through signed iterative Random Forests

Advances in supervised learning have enabled accurate prediction in biological systems governed by complex interactions among biomolecules. However, state-of-the-art predictive algorithms are typically black-boxes, learning statistical interactions that are difficult to translate into testable hypotheses. The iterative Random Forest algorithm took a step towards bridging this gap by providing a computationally tractable procedure to identify the stable, high-order feature interactions that drive the predictive accuracy of Random Forests (RF). Here we refine the interactions identified by iRF to explicitly map responses as a function of interacting features. Our method, signed iRF, describes subsets of rules that frequently occur on RF decision paths. We refer to these rule subsets as signed interactions. Signed interactions share not only the same set of interacting features but also exhibit similar thresholding behavior, and thus describe a consistent functional relationship between interacting features and responses. We describe stable and predictive importance metrics to rank signed interactions. For each SPIM, we define null importance metrics that characterize its expected behavior under known structure. We evaluate our proposed approach in biologically inspired simulations and two case studies: predicting enhancer activity and spatial gene expression patterns. In the case of enhancer activity, s-iRF recovers one of the few experimentally validated high-order interactions and suggests novel enhancer elements where this interaction may be active. In the case of spatial gene expression patterns, s-iRF recovers all 11 reported links in the gap gene network. By refining the process of interaction recovery, our approach has the potential to guide mechanistic inquiry into systems whose scale and complexity is beyond human comprehension

Identification of a selective G1-phase benzimidazolone inhibitor by a senescence-targeted virtual screen using artificial neural networks

Cellular senescence is a barrier to tumorigenesis in normal cells and tumour cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. 147 virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase (SA-β-gal) assays. Among the found hits a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced SA-β-gal activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1 and CDC25C. Additionally, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long term treatments. Preliminary structure-activity and structure clustering analyses are reported and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells

An agent-based hybrid system for microarray data analysis

This article reports our experience in agent-based hybrid construction for microarray data analysis. The contributions are twofold: We demonstrate that agent-based approaches are suitable for building hybrid systems in general, and that a genetic ensemble system is appropriate for microarray data analysis in particular. Created using an agent-based framework, this genetic ensemble system for microarray data analysis excels in both sample classification accuracy and gene selection reproducibility.<br /