Dataset Information

Predicting variant deleteriousness in non-human species: applying the CADD approach in mouse.

ABSTRACT:

Background

Predicting the deleteriousness of observed genomic variants has taken a step forward with the introduction of the Combined Annotation Dependent Depletion (CADD) approach, which trains a classifier on the wealth of available human genomic information. This raises the question whether it can be done with less data for non-human species. Here, we investigate the prerequisites to construct a CADD-based model for a non-human species.

Results

Performance of the mouse model is competitive with that of the human CADD model and better than established methods like PhastCons conservation scores and SIFT. Like in the human case, performance varies for different genomic regions and is best for coding regions. We also show the benefits of generating a species-specific model over lifting variants to a different species or applying a generic model. With fewer genomic annotations, performance on the test set as well as on the three validation sets is still good.

Conclusions

It is feasible to construct species-specific CADD models even when annotations such as epigenetic markers are not available. The minimal requirement for these models is the availability of a set of genomes of closely related species that can be used to infer an ancestor genome and substitution rates for the data generation.

SUBMITTER: Groß C

PROVIDER: S-EPMC6186050 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Predicting variant deleteriousness in non-human species: applying the CADD approach in mouse.

Groß Christian C de Ridder Dick D Reinders Marcel M

BMC bioinformatics 20181012 1

<h4>Background</h4>Predicting the deleteriousness of observed genomic variants has taken a step forward with the introduction of the Combined Annotation Dependent Depletion (CADD) approach, which trains a classifier on the wealth of available human genomic information. This raises the question whether it can be done with less data for non-human species. Here, we investigate the prerequisites to construct a CADD-based model for a non-human species.<h4>Results</h4>Performance of the mouse model is ...[more]

PMID: 30314430

Similar Datasets

Project description: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: http://score.generesearch.ru/services/badmut/.

Project description:There is a growing desire to create computer systems that can collaborate with humans on complex, open-ended activities. These activities typically have no set completion criteria and frequently involve multimodal communication, extensive world knowledge, creativity, and building structures or compositions through multiple steps. Because these systems differ from question and answer (Q&A) systems, chatbots, and simple task-oriented assistants, new methods for evaluating such collaborative computer systems are needed. Here, we present a set of criteria for evaluating these systems, called Hallmarks of Human-Machine Collaboration. The Hallmarks build on the success of heuristic evaluation used by the user interface community and past evaluation techniques used in the spoken language and chatbot communities. They consist of observable characteristics indicative of successful collaborative communication, grouped into eight high-level properties: robustness; habitability; mutual contribution of meaningful content; context-awareness; consistent human engagement; provision of rationale; use of elementary concepts to teach and learn new concepts; and successful collaboration. We present examples of how we used these Hallmarks in the DARPA Communicating with Computers (CwC) program to evaluate diverse activities, including story and music generation, interactive building with blocks, and exploration of molecular mechanisms in cancer. We used the Hallmarks as guides for developers and as diagnostics, assessing systems with the Hallmarks to identify strengths and opportunities for improvement using logs from user studies, surveying the human partner, third-party review of creative products, and direct tests. Informal feedback from CwC technology developers indicates that the use of the Hallmarks for program evaluation helped guide development. The Hallmarks also made it possible to identify areas of progress and major gaps in developing systems where the machine is an equal, creative partner.

Dataset Information

Predicting variant deleteriousness in non-human species: applying the CADD approach in mouse.

Background

Results

Conclusions

Publications

Predicting variant deleteriousness in non-human species: applying the CADD approach in mouse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets