Network architecture for prediction of emergence in complex biological systems

Ghosh Roy, Gourab ORCID: 0000-0001-9420-5653 (2022). Network architecture for prediction of emergence in complex biological systems. University of Birmingham. Ph.D.

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Abstract

Emergence of properties at the system level, where these properties are not observed at the individual entity level, is an important feature of complex systems. Biological system emergent properties have critical roles in the functioning of organisms and the disruptions to normal functioning, and are relevant to the treatment of diseases like cancer. Complex biological systems can be modeled by abstractions in the form of molecular networks like gene regulatory networks (GRNs) and signaling networks with nodes representing molecules like genes and edges representing molecular interactions. The thesis aims at exploring the use of the architecture of these networks to predict emergence of system properties.

First, to better infer the network architecture with aspects that can be useful in predicting emergence, we propose a novel algorithm Polynomial Lasso Bagging or PoLoBag for signed GRN inference from gene expression data. The GRN edge signs represent the nature of the regulatory relationships, activating or inhibitory. Our algorithm gives more accurate signed inference compared to state-of-the-art algorithms, and overcomes their weaknesses by also inferring edge directions and cycles. We also show how combining signed GRN architecture with dynamical information in our proposed dynamical K-core method predicts emergent states of the gene regulatory system effectively.

Second, we investigate the existence of the bow-tie architectural organization in the GRNs of species of widely varying complexity. Prior work has shown the existence of this bow-tie feature in the GRNs of only some eukaryotes. Our investigation covers GRNs of prokaryotes to unicellular and multicellular eukaryotes. We find that the observed bow-tie architecture is a characteristic feature of GRNs. Based on differences that we observe in the bow-tie architectures across species, we predict a trend in the emergence of the dynamical gene regulatory system property of controllability with varying species complexity.

Third, from input genotype data we predict an emergent phenotype at the organism level -- the cancer-specific survival risk. We propose a novel Mutated Pathway Visible Neural Network or MPVNN, designed using prior knowledge of signaling network architecture and additional mutation data-based edge randomization. This randomization models how known signaling network architecture changes for a particular cancer type, which is not modeled by state-of-the-art visible neural networks. We suggest that MPVNN performs cancer-specific risk prediction better than other similar sized NN and non-NN survival analysis methods, while also providing reliable interpretations of the predictions.

These three research contributions taken together make significant advances towards our goal of using molecular network architecture for better prediction of emergence, which can inform treatment decisions and lead to novel therapeutic approaches and is of value to computational biologists and clinicians.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):