MPVNN: Mutated Pathway Visible Neural Network architecture for interpretable prediction of cancer-specific survival risk.

MOTIVATION: Survival risk prediction using gene expression data is important in making treatment decisions in cancer. Standard neural network (NN) survival analysis models are black boxes with a lack of interpretability. More interpretable visible neural network architectures are designed using biological pathway knowledge. But they do not model how pathway structures can change for particular cancer types. RESULTS: We propose a novel Mutated Pathway Visible Neural Network (MPVNN) architecture, designed using prior signaling pathway knowledge and random replacement of known pathway edges using gene mutation data simulating signal flow disruption. As a case study, we use the PI3K-Akt pathway and demonstrate overall improved cancer-specific survival risk prediction of MPVNN over other similar-sized NN and standard survival analysis methods. We show that trained MPVNN architecture interpretation, which points to smaller sets of genes connected by signal flow within the PI3K-Akt pathway that is important in risk prediction for particular cancer types, is reliable. AVAILABILITY AND IMPLEMENTATION: The data and code are available at https://github.com/gourabghoshroy/MPVNN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PoLoBag: Polynomial Lasso Bagging for signed gene regulatory network inference from expression data.

MOTIVATION: Inferring gene regulatory networks (GRNs) from expression data is a significant systems biology problem. A useful inference algorithm should not only unveil the global structure of the regulatory mechanisms but also the details of regulatory interactions such as edge direction (from regulator to target) and sign (activation/inhibition). Many popular GRN inference algorithms cannot infer edge signs, and those that can infer signed GRNs cannot simultaneously infer edge directions or network cycles. RESULTS: To address these limitations of existing algorithms, we propose Polynomial Lasso Bagging (PoLoBag) for signed GRN inference with both edge directions and network cycles. PoLoBag is an ensemble regression algorithm in a bagging framework where Lasso weights estimated on bootstrap samples are averaged. These bootstrap samples incorporate polynomial features to capture higher-order interactions. Results demonstrate that PoLoBag is consistently more accurate for signed inference than state-of-the-art algorithms on simulated and real-world expression datasets. AVAILABILITY AND IMPLEMENTATION: Algorithm and data are freely available at https://github.com/gourabghoshroy/PoLoBag. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Bow-tie architecture of gene regulatory networks in species of varying complexity.

The gene regulatory network (GRN) architecture plays a key role in explaining the biological differences between species. We aim to understand species differences in terms of some universally present dynamical properties of their gene regulatory systems. A network architectural feature associated with controlling system-level dynamical properties is the bow-tie, identified by a strongly connected subnetwork, the core layer, between two sets of nodes, the in and the out layers. Though a bow-tie architecture has been observed in many networks, its existence has not been extensively investigated in GRNs of species of widely varying biological complexity. We analyse publicly available GRNs of several well-studied species from prokaryotes to unicellular eukaryotes to multicellular organisms. In their GRNs, we find the existence of a bow-tie architecture with a distinct largest strongly connected core layer. We show that the bow-tie architecture is a characteristic feature of GRNs. We observe an increasing trend in the relative core size with species complexity. Using studied relationships of the core size with dynamical properties like robustness and fragility, flexibility, criticality, controllability and evolvability, we hypothesize how these regulatory system properties have emerged differently with biological complexity, based on the observed differences of the GRN bow-tie architectures.