VPatho: a deep learning-based two-stage approach for accurate prediction of gain-of-function and loss-of-function variants

Fang Ge, Chen Li, Shahid Iqbal, Arif Muhammad, Fuyi Li, Maha A. Thafar, Zihao Yan, Apilak Worachartcheewan, Xiaofeng Xu, Jiangning Song, Dong-Jun Yu

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Determining the pathogenicity and functional impact (i.e. gain-of-function; GOF or loss-of-function; LOF) of a variant is vital for unraveling the genetic level mechanisms of human diseases. To provide a 'one-stop' framework for the accurate identification of pathogenicity and functional impact of variants, we developed a two-stage deep-learning-based computational solution, termed VPatho, which was trained using a total of 9619 pathogenic GOF/LOF and 138 026 neutral variants curated from various databases. A total number of 138 variant-level, 262 protein-level and 103 genome-level features were extracted for constructing the models of VPatho. The development of VPatho consists of two stages: (i) a random under-sampling multi-scale residual neural network (ResNet) with a newly defined weighted-loss function (RUS-Wg-MSResNet) was proposed to predict variants' pathogenicity on the gnomAD_NV + GOF/LOF dataset; and (ii) an XGBOD model was constructed to predict the functional impact of the given variants. Benchmarking experiments demonstrated that RUS-Wg-MSResNet achieved the highest prediction performance with the weights calculated based on the ratios of neutral versus pathogenic variants. Independent tests showed that both RUS-Wg-MSResNet and XGBOD achieved outstanding performance. Moreover, assessed using variants from the CAGI6 competition, RUS-Wg-MSResNet achieved superior performance compared to state-of-the-art predictors. The fine-trained XGBOD models were further used to blind test the whole LOF data downloaded from gnomAD and accordingly, we identified 31 nonLOF variants that were previously labeled as LOF/uncertain variants. As an implementation of the developed approach, a webserver of VPatho is made publicly available at http://csbio.njust.edu.cn/bioinf/vpatho/ to facilitate community-wide efforts for profiling and prioritizing the query variants with respect to their pathogenicity and functional impact.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalBriefings in Bioinformatics
Volume24
Issue number1
DOIs
Publication statusPublished - 19 Jan 2023

Keywords

  • 1D-ResNet
  • 2D-ResNet
  • gnomAD variants
  • pathogenic GOF/LOF
  • random under-sampling
  • weighted-loss function

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