Development of pathogenicity predictors specific for variants that do not comply with clinical guidelines for the use of computational evidence
de la Campa, Elena Álvarez (Institut de Biologia Molecular de Barcelona)
Padilla Sirera, Natàlia (Hospital Universitari Vall d'Hebron)
de la Cruz, Xavier (Institució Catalana de Recerca i Estudis Avançats)
Universitat Autònoma de Barcelona

Fecha:	2017
Resumen:	Strict guidelines delimit the use of computational information in the clinical setting, due to the still moderate accuracy of in silico tools. These guidelines indicate that several tools should always be used and that full coincidence between them is required if we want to consider their results as supporting evidence in medical decision processes. Application of this simple rule certainly decreases the error rate of in silico pathogenicity assignments. However, when predictors disagree this rule results in the rejection of potentially valuable information for a number of variants. In this work, we focus on these variants of the protein sequence and develop specific predictors to help improve the success rate of their annotation. We have used a set of 59,442 protein sequence variants (15,723 pathological and 43,719 neutral) from 228 proteins to identify those cases for which pathogenicity predictors disagree. We have repeated this process for all the possible combinations of five known methods (SIFT, PolyPhen-2, PON-P2, CADD and MutationTaster2). For each resulting subset we have trained a specific pathogenicity predictor. We find that these specific predictors are able to discriminate between neutral and pathogenic variants, with a success rate different from random. They tend to outperform the constitutive methods but this trend decreases as the performance of the constitutive predictor improves (e. g. with PON-P2 and PolyPhen-2). We also find that specific methods outperform standard consensus methods (Condel and CAROL). Focusing development efforts on the case of variants for which known methods disagree we may obtain pathogenicity predictors with improved performances. Although we have not yet reached the success rate that allows the use of this computational evidence in a clinical setting, the simplicity of the approach indicates that more advanced methods may reach this goal in a close future. The online version of this article (doi:10. 1186/s12864-017-3914-0) contains supplementary material, which is available to authorized users.
Ayudas:	Ministerio de Economía y Competitividad BIO2012-40133 Agencia Estatal de Investigación SAF2016-80255-R
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	In silico pathogenicity predictors ; Protein sequence variants ; Molecular diagnostics ; Missense variants ; Next-generation sequencing
Publicado en:	BMC genomics, Vol. 18 (august 2017) , ISSN 1471-2164

DOI: 10.1186/s12864-017-3914-0
PMID: 28812538

14 p, 1.3 MB

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