Prediction of hemophilia A severity using a small-input machine-learning framework

Author(s)

Lopes, Tiago J. S. ^[1] ; Rios, Ricardo ^{[2, 3]} ; Nogueira, Tatiane ^{[2, 3]} ; Mello, Rodrigo F. ^{[3, 4]}

Affiliation

^[1] Natl Ctr Child Hlth & Dev Res Inst, Dept Reprod Biol, Tokyo - Japan

^[2] Univ Fed Bahia, Dept Comp Sci, Salvador, BA - Brazil

^[3] Univ Sao Paulo, Inst Math & Comp Sci, Sao Carlos - Brazil

^[4] Itau Unibanco, Av Eng Armando de Arruda Pereira, Sao Paulo - Brazil

• Document type: Journal article
• Source: NPJ SYSTEMS BIOLOGY AND APPLICATIONS; v. 7, n. 1 MAY 25 2021.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 13/07375-0 - CeMEAI - Center for Mathematical Sciences Applied to Industry
• Grantee: Francisco Louzada Neto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC