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Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem
Rare variants are becoming the new candidates in the search for genetic variants that predispose individuals to a phenotype of interest. Their low prevalence in a population requires the development of dedicated detection and analytical methods. A family-based approach could greatly enhance their de...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287918/ https://www.ncbi.nlm.nih.gov/pubmed/22373261 http://dx.doi.org/10.1186/1753-6561-5-S9-S78 |
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author | Alfonso de Almeida, Marcio Augusto Vançan Russo Horimoto, Andrea Roseli Lopes de Oliveira, Paulo Sérgio Krieger, José Eduardo da Costa Pereira, Alexandre |
author_facet | Alfonso de Almeida, Marcio Augusto Vançan Russo Horimoto, Andrea Roseli Lopes de Oliveira, Paulo Sérgio Krieger, José Eduardo da Costa Pereira, Alexandre |
author_sort | Alfonso de Almeida, Marcio Augusto |
collection | PubMed |
description | Rare variants are becoming the new candidates in the search for genetic variants that predispose individuals to a phenotype of interest. Their low prevalence in a population requires the development of dedicated detection and analytical methods. A family-based approach could greatly enhance their detection and interpretation because rare variants are nearly family specific. In this report, we test several distinct approaches for analyzing the information provided by rare and common variants and how they can be effectively used to pinpoint putative candidate genes for follow-up studies. The analyses were performed on the mini-exome data set provided by Genetic Analysis Workshop 17. Eight approaches were tested, four using the trait’s heritability estimates and four using QTDT models. These methods had their sensitivity, specificity, and positive and negative predictive values compared in light of the simulation parameters. Our results highlight important limitations of current methods to deal with rare and common variants, all methods presented a reduced specificity and, consequently, prone to false positive associations. Methods analyzing common variants information showed an enhanced sensibility when compared to rare variants methods. Furthermore, our limited knowledge of the use of biological databases for gene annotations, possibly for use as covariates in regression models, imposes a barrier to further research. |
format | Online Article Text |
id | pubmed-3287918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-32879182012-02-28 Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem Alfonso de Almeida, Marcio Augusto Vançan Russo Horimoto, Andrea Roseli Lopes de Oliveira, Paulo Sérgio Krieger, José Eduardo da Costa Pereira, Alexandre BMC Proc Proceedings Rare variants are becoming the new candidates in the search for genetic variants that predispose individuals to a phenotype of interest. Their low prevalence in a population requires the development of dedicated detection and analytical methods. A family-based approach could greatly enhance their detection and interpretation because rare variants are nearly family specific. In this report, we test several distinct approaches for analyzing the information provided by rare and common variants and how they can be effectively used to pinpoint putative candidate genes for follow-up studies. The analyses were performed on the mini-exome data set provided by Genetic Analysis Workshop 17. Eight approaches were tested, four using the trait’s heritability estimates and four using QTDT models. These methods had their sensitivity, specificity, and positive and negative predictive values compared in light of the simulation parameters. Our results highlight important limitations of current methods to deal with rare and common variants, all methods presented a reduced specificity and, consequently, prone to false positive associations. Methods analyzing common variants information showed an enhanced sensibility when compared to rare variants methods. Furthermore, our limited knowledge of the use of biological databases for gene annotations, possibly for use as covariates in regression models, imposes a barrier to further research. BioMed Central 2011-11-29 /pmc/articles/PMC3287918/ /pubmed/22373261 http://dx.doi.org/10.1186/1753-6561-5-S9-S78 Text en Copyright ©2011 Alfonso de Almeida et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Proceedings Alfonso de Almeida, Marcio Augusto Vançan Russo Horimoto, Andrea Roseli Lopes de Oliveira, Paulo Sérgio Krieger, José Eduardo da Costa Pereira, Alexandre Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem |
title | Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem |
title_full | Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem |
title_fullStr | Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem |
title_full_unstemmed | Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem |
title_short | Different approaches for dealing with rare variants in family-based genetic studies: application of a Genetic Analysis Workshop 17 problem |
title_sort | different approaches for dealing with rare variants in family-based genetic studies: application of a genetic analysis workshop 17 problem |
topic | Proceedings |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287918/ https://www.ncbi.nlm.nih.gov/pubmed/22373261 http://dx.doi.org/10.1186/1753-6561-5-S9-S78 |
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