Preclinical validation of therapeutic targets predicted by tensor factorization on heterogeneous graphs.
Sci Rep
; 10(1): 18250, 2020 10 26.
Article
em En
| MEDLINE
| ID: mdl-33106501
ABSTRACT
Incorrect drug target identification is a major obstacle in drug discovery. Only 15% of drugs advance from Phase II to approval, with ineffective targets accounting for over 50% of these failures1-3. Advances in data fusion and computational modeling have independently progressed towards addressing this issue. Here, we capitalize on both these approaches with Rosalind, a comprehensive gene prioritization method that combines heterogeneous knowledge graph construction with relational inference via tensor factorization to accurately predict disease-gene links. Rosalind demonstrates an increase in performance of 18%-50% over five comparable state-of-the-art algorithms. On historical data, Rosalind prospectively identifies 1 in 4 therapeutic relationships eventually proven true. Beyond efficacy, Rosalind is able to accurately predict clinical trial successes (75% recall at rank 200) and distinguish likely failures (74% recall at rank 200). Lastly, Rosalind predictions were experimentally tested in a patient-derived in-vitro assay for Rheumatoid arthritis (RA), which yielded 5 promising genes, one of which is unexplored in RA.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
/
Gráficos por Computador
/
Simulação por Computador
/
Biologia Computacional
/
Avaliação Pré-Clínica de Medicamentos
/
Descoberta de Drogas
/
Desenvolvimento de Medicamentos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos