Generalising better: Applying deep learning to integrate deleteriousness prediction scores for whole-exome SNV studies

PLoS One. 2018 Mar 14;13(3):e0192829. doi: 10.1371/journal.pone.0192829. eCollection 2018.


Many automatic classifiers were introduced to aid inference of phenotypical effects of uncategorised nsSNVs (nonsynonymous Single Nucleotide Variations) in theoretical and medical applications. Lately, several meta-estimators have been proposed that combine different predictors, such as PolyPhen and SIFT, to integrate more information in a single score. Although many advances have been made in feature design and machine learning algorithms used, the shortage of high-quality reference data along with the bias towards intensively studied in vitro models call for improved generalisation ability in order to further increase classification accuracy and handle records with insufficient data. Since a meta-estimator basically combines different scoring systems with highly complicated nonlinear relationships, we investigated how deep learning (supervised and unsupervised), which is particularly efficient at discovering hierarchies of features, can improve classification performance. While it is believed that one should only use deep learning for high-dimensional input spaces and other models (logistic regression, support vector machines, Bayesian classifiers, etc) for simpler inputs, we still believe that the ability of neural networks to discover intricate structure in highly heterogenous datasets can aid a meta-estimator. We compare the performance with various popular predictors, many of which are recommended by the American College of Medical Genetics and Genomics (ACMG), as well as available deep learning-based predictors. Thanks to hardware acceleration we were able to use a computationally expensive genetic algorithm to stochastically optimise hyper-parameters over many generations. Overfitting was hindered by noise injection and dropout, limiting coadaptation of hidden units. Although we stress that this work was not conceived as a tool comparison, but rather an exploration of the possibilities of deep learning application in ensemble scores, our results show that even relatively simple modern neural networks can significantly improve both prediction accuracy and coverage. We provide open-access to our finest model via the web-site:

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exome*
  • Internet*
  • Machine Learning*
  • Models, Genetic*
  • Polymorphism, Single Nucleotide*
  • Sequence Analysis, DNA / methods*

Grants and funding

The study was mainly funded by the 5top100 Russian Academic Excellence program Additionally, the Russian Science Foundation grant 14-26-00094 was used to fund computational resources at the Laboratory of microbiological monitoring and bioremediation of soils (ARRIAM), which were used in this study. ARRIAM played no role in designing and conducting this study. Ilia Korvigo (the corresponding author), being a former employee of iBinom Inc, has worked on this project before leaving the company. The specific role of this author is articulated in the ‘author contributions’ section. The project was initiated by Mr. Andrey Afanasyev (CEO at iBinom Inc), who provided it with data and computational resources at the early stages. The commercial funder supported the decision to publish the data and making all results openly accessible. The funder had no role in the preparation of this manuscript.