Computational translation of genomic responses from experimental model systems to humans

Douglas K Brubaker, Elizabeth A Proctor, Kevin M Haigis and Douglas A Lauffenburger

PLOS Computational Biology, 2019, vol. 15, issue 1, 1-19

Abstract: The high failure rate of therapeutics showing promise in mouse models to translate to patients is a pressing challenge in biomedical science. Though retrospective studies have examined the fidelity of mouse models to their respective human conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for inference of disease-associated human differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human biology from mouse datasets. We found that semi-supervised training of a neural network identified significantly more true human biological associations than interpreting mouse experiments directly. Evaluating the experimental design of mouse experiments where our model was most successful revealed principles of experimental design that may improve translational performance. Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches, combining mouse and human data for biological inference, provide the most accurate assessment of human in vivo disease processes. Finally, we proffer a delineation of four categories of model system-to-human “Translation Problems” defined by the resolution and coverage of the datasets available for molecular insight translation and suggest that the task of translating insights from model systems to human disease contexts may be better accomplished by a combination of translation-minded experimental design and computational approaches.Author summary: Empirical comparison of genomic responses in mouse models and human disease contexts is not sufficient for addressing the challenge of prospective translation from mouse models to human disease contexts. We address this challenge by developing a semi-supervised machine learning approach that combines supervised modeling of mouse datasets with unsupervised modeling of human disease-context datasets to predict human in vivo differentially expressed genes and enriched pathways. Semi-supervised training of a feed forward neural network was the most efficacious model for translating experimentally derived mouse biological associations to the human in vivo disease context. We find that computational generalization of signaling insights substantially improves upon direct generalization of mouse experimental insights and argue that such approaches can facilitate more clinically impactful translation of insights from preclinical studies in model systems to patients.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1006286

DOI: 10.1371/journal.pcbi.1006286

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