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Biology subjects

Rawls, K. D.

Publications and source records attributed to Rawls, K. D..

3 recordsLinked to original sources

Local graph-motif features improve gene interaction network prediction

Gene interaction networks specify how genes interact to produce an organisms phenotype. These networks are often incomplete due to absent or unobserved information. Predicting these missing links is critical for many applications, including genome-wide association studies and phenotype prediction. Efforts have previously applied graph neural networks (GNNs) to this missing-link prediction problem, but these techniques too have limitations when the sparsity of the networks is very high. Here, we apply a novel feature engineering technique that uses local graph motif incidence to enhance the feature set for variational graph autoencoders (VGAE). We compare the performance of our technique against state-of-the-art approaches, and then progressively hide more and more of the original graph edges. Our results show that VGAEs with our local-area motif prevalence (LAMP) features outperform state-of-the-art node embeddings for a wide range of missing edges on both a benchmark and a biological dataset. We also observe that this combined VGAE and LAMP technique has the potential to facilitate the search for novel genetic interactions in an experimental adaptive sampling context with far fewer samples. Improvements to gene interaction imputation can lower the barrier to new pharmaceutical and epidemiological discoveries by revealing hidden gene interactions that steer the development of potential drug targets.

bioinformatics↗

Identifying metabolic adaptations during cardiotoxicity using paired transcriptomics andmetabolomics data integrated with a model of heart metabolism

Improvements in the diagnosis and treatment of cancer has revealed the long-term side effects of chemotherapeutics, particularly cardiotoxicity. Here, we present paired transcriptomics and metabolomics data characterizing in vitro cardiotoxicity to three compounds: 5-fluorouracil, acetaminophen, and doxorubicin. Standard gene enrichment and metabolomics approaches identify some commonly affected pathways and metabolites but are not able to readily identify metabolic adaptations in response to cardiotoxicity. The paired data was integrated with a genome-scale metabolic network reconstruction (GENRE) of the heart to identify shifted metabolic functions, unique metabolic reactions, and changes in flux in metabolic reactions in response to these compounds. Using this approach, we confirm known mechanisms of doxorubicin-induced cardiotoxicity and provide hypotheses for metabolic adaptations in cardiotoxicity for 5-fluorouracil, doxorubicin, and acetaminophen.

bioengineering↗

Identifying functional metabolic shifts in heart failure with the integration of omics data and a cardiomyocyte-specific, genome-scale model

The heart is a metabolic omnivore, known to consume many different carbon substrates in order to maintain function. In diseased states, the hearts metabolism can shift between different carbon substrates; however, there is some disagreement in the field as to the metabolic shifts seen in end-stage heart failure and whether all heart failure converges to a common metabolic phenotype. Here, we present a new, validated cardiomyocyte-specific GEnome-scale metabolic Network REconstruction (GENRE), iCardio, and use the model to identify common shifts in metabolic functions across heart failure omics datasets. We demonstrate the utility of iCardio in interpreting heart failure gene expression data by identifying Tasks Inferred from Differential Expression (TIDEs) which represent metabolic functions associated with changes in gene expression. We identify decreased NO and Neu5Ac synthesis as common metabolic markers of heart failure across datasets. Further, we highlight the differences in metabolic functions seen across studies, further highlighting the complexity of heart failure. The methods presented for constructing a tissue-specific model and identifying TIDEs can be extended to multiple tissue and diseases of interest.

bioengineering↗