Browsing by Author "Kossinna, Thalagala Kossinnage Pathum Subhashana"

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    Novel stabilized models to characterize gene-gene interactions by utilizing transcriptome data
    (2022-09-28) Kossinna, Thalagala Kossinnage Pathum Subhashana; Long, Quan; Zhang, Qingrun; Arnold, Paul Daniel; De Leon, Alexander
    Machine learning models employed in genetics often grapple with issues related to the "curse of dimensionality". Furthermore, due to the inherent noisy nature of most -omics data, most methods suffer from the problem of "stability": i.e., even slight perturbations of the original data may result in wholly different outcomes. This becomes particularly true when dealing with interactions as the number of potential interactions are usually astronomical. In this thesis, we present two novel methods: 1) Stabilized COre gene and Pathway Election (SCOPE) and 2) Interaction Bridged Association Study (IBAS) that uses two differing approaches in analyzing biological interactions. SCOPE employs a stabilized form of the LASSO that is better able to handle highly correlated expression data and a co-expression network analysis that identifies "core" genes that may be of interest as well as the underlying biological pathways or mechanisms by which they interact. Stabilizing these results across six cancers of The Cancer Genome Atlas uncovered hallmark cancer pathways as well as a novel potential therapeutic target of kidney cancer, CD63. IBAS utilizes a "data-bridge" composed of dimensionality reduced pathway level interactions of the transcriptome to identify genes associated with a phenotype of interest using the Sequence Kernel Association Test (SKAT), in a disentangled form of the Transcriptome Wide Association Study. Application to the Wellcome Trust Case Control Consortium reveals novel gene candidates with literature reviews highlighting their potential for further study. In conclusion, we have developed two novel methodologies in analyzing complex interaction patterns in -omics data using stabilized machine learning methods, paving the way to further understand the biological interactions underlying complex disease.