Prediction of hemophilia A severity using a small-input machine-learning framework
| Autor: | Tiago J. S. Lopes, Rodrigo Fernandes de Mello, Ricardo Araújo Rios, Tatiane C.A. Nogueira |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities QH301-705.5 In silico 030204 cardiovascular system & hematology Machine learning computer.software_genre Hemophilia A General Biochemistry Genetics and Molecular Biology Article Machine Learning 03 medical and health sciences 0302 clinical medicine Protein structure Disease severity Coagulation cascade hemic and lymphatic diseases Drug Discovery Medicine Humans Biology (General) Coagulation Disorder Biochemical networks business.industry Applied Mathematics Protein structure analysis Inhibitory antibodies PROTEÍNAS Computer Science Applications 030104 developmental biology Modeling and Simulation Joint damage Mutation Artificial intelligence Protein engineering business Structural biology computer |
| Zdroj: | npj Systems Biology and Applications, Vol 7, Iss 1, Pp 1-8 (2021) Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP NPJ Systems Biology and Applications |
| ISSN: | 2056-7189 |
| Popis: | Hemophilia A is a relatively rare hereditary coagulation disorder caused by a defective F8 gene resulting in a dysfunctional Factor VIII protein (FVIII). This condition impairs the coagulation cascade, and if left untreated, it causes permanent joint damage and poses a risk of fatal intracranial hemorrhage in case of traumatic events. To develop prophylactic therapies with longer half-lives and that do not trigger the development of inhibitory antibodies, it is essential to have a deep understanding of the structure of the FVIII protein. In this study, we explored alternative ways of representing the FVIII protein structure and designed a machine-learning framework to improve the understanding of the relationship between the protein structure and the disease severity. We verified a close agreement between in silico, in vitro and clinical data. Finally, we predicted the severity of all possible mutations in the FVIII structure – including those not yet reported in the medical literature. We identified several hotspots in the FVIII structure where mutations are likely to induce detrimental effects to its activity. The combination of protein structure analysis and machine learning is a powerful approach to predict and understand the effects of mutations on the disease outcome. |
| Databáze: | OpenAIRE |
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