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TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data

BACKGROUND: Locus heterogeneity is one of the most documented phenomena in genetics. To date, relatively little work had been done on the development of methods to address locus heterogeneity in genetic association analysis. Motivated by Zhou and Pan's work, we present a mixture model of linked...

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Autores principales: Londono, Douglas, Buyske, Steven, Finch, Stephen J, Sharma, Swarkar, Wise, Carol A, Gordon, Derek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292499/
https://www.ncbi.nlm.nih.gov/pubmed/22264315
http://dx.doi.org/10.1186/1471-2105-13-13
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author Londono, Douglas
Buyske, Steven
Finch, Stephen J
Sharma, Swarkar
Wise, Carol A
Gordon, Derek
author_facet Londono, Douglas
Buyske, Steven
Finch, Stephen J
Sharma, Swarkar
Wise, Carol A
Gordon, Derek
author_sort Londono, Douglas
collection PubMed
description BACKGROUND: Locus heterogeneity is one of the most documented phenomena in genetics. To date, relatively little work had been done on the development of methods to address locus heterogeneity in genetic association analysis. Motivated by Zhou and Pan's work, we present a mixture model of linked and unlinked trios and develop a statistical method to estimate the probability that a heterozygous parent transmits the disease allele at a di-allelic locus, and the probability that any trio is in the linked group. The purpose here is the development of a test that extends the classic transmission disequilibrium test (TDT) to one that accounts for locus heterogeneity. RESULTS: Our simulations suggest that, for sufficiently large sample size (1000 trios) our method has good power to detect association even the proportion of unlinked trios is high (75%). While the median difference (TDT-HET empirical power - TDT empirical power) is approximately 0 for all MOI, there are parameter settings for which the power difference can be substantial. Our multi-locus simulations suggest that our method has good power to detect association as long as the markers are reasonably well-correlated and the genotype relative risk are larger. Results of both single-locus and multi-locus simulations suggest our method maintains the correct type I error rate. Finally, the TDT-HET statistic shows highly significant p-values for most of the idiopathic scoliosis candidate loci, and for some loci, the estimated proportion of unlinked trios approaches or exceeds 50%, suggesting the presence of locus heterogeneity. CONCLUSIONS: We have developed an extension of the TDT statistic (TDT-HET) that allows for locus heterogeneity among coded trios. Benefits of our method include: estimates of parameters in the presence of heterogeneity, and reasonable power even when the proportion of linked trios is small. Also, we have extended multi-locus methods to TDT-HET and have demonstrated that the empirical power may be high to detect linkage. Last, given that we obtain PPBs, we conjecture that the TDT-HET may be a useful method for correctly identifying linked trios. We anticipate that researchers will find this property increasingly useful as they apply next-generation sequencing data in family based studies.
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spelling pubmed-32924992012-03-05 TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data Londono, Douglas Buyske, Steven Finch, Stephen J Sharma, Swarkar Wise, Carol A Gordon, Derek BMC Bioinformatics Methodology Article BACKGROUND: Locus heterogeneity is one of the most documented phenomena in genetics. To date, relatively little work had been done on the development of methods to address locus heterogeneity in genetic association analysis. Motivated by Zhou and Pan's work, we present a mixture model of linked and unlinked trios and develop a statistical method to estimate the probability that a heterozygous parent transmits the disease allele at a di-allelic locus, and the probability that any trio is in the linked group. The purpose here is the development of a test that extends the classic transmission disequilibrium test (TDT) to one that accounts for locus heterogeneity. RESULTS: Our simulations suggest that, for sufficiently large sample size (1000 trios) our method has good power to detect association even the proportion of unlinked trios is high (75%). While the median difference (TDT-HET empirical power - TDT empirical power) is approximately 0 for all MOI, there are parameter settings for which the power difference can be substantial. Our multi-locus simulations suggest that our method has good power to detect association as long as the markers are reasonably well-correlated and the genotype relative risk are larger. Results of both single-locus and multi-locus simulations suggest our method maintains the correct type I error rate. Finally, the TDT-HET statistic shows highly significant p-values for most of the idiopathic scoliosis candidate loci, and for some loci, the estimated proportion of unlinked trios approaches or exceeds 50%, suggesting the presence of locus heterogeneity. CONCLUSIONS: We have developed an extension of the TDT statistic (TDT-HET) that allows for locus heterogeneity among coded trios. Benefits of our method include: estimates of parameters in the presence of heterogeneity, and reasonable power even when the proportion of linked trios is small. Also, we have extended multi-locus methods to TDT-HET and have demonstrated that the empirical power may be high to detect linkage. Last, given that we obtain PPBs, we conjecture that the TDT-HET may be a useful method for correctly identifying linked trios. We anticipate that researchers will find this property increasingly useful as they apply next-generation sequencing data in family based studies. BioMed Central 2012-01-20 /pmc/articles/PMC3292499/ /pubmed/22264315 http://dx.doi.org/10.1186/1471-2105-13-13 Text en Copyright ©2012 Londono 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 Methodology Article
Londono, Douglas
Buyske, Steven
Finch, Stephen J
Sharma, Swarkar
Wise, Carol A
Gordon, Derek
TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data
title TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data
title_full TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data
title_fullStr TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data
title_full_unstemmed TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data
title_short TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data
title_sort tdt-het: a new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data
topic Methodology Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292499/
https://www.ncbi.nlm.nih.gov/pubmed/22264315
http://dx.doi.org/10.1186/1471-2105-13-13
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