TDT-HET

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

Douglas Londono, Steven Buyske, Stephen J. Finch, Swarkar Sharma, Carol A. Wise, Derek Gordon

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number13
JournalBMC Bioinformatics
Volume13
Issue number1
DOIs
StatePublished - Jan 20 2012

Fingerprint

Data Association
Locus
Statistics
Proportion
Genetic Phenomena
Test Statistic
Genetic Heterogeneity
Family
Power transmission
Scoliosis
Statistical methods
Sample Size
Genetic Association
Simulation
Type I Error Rate
Relative Risk
Alleles
Genotype
Research Personnel
p-Value

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics
  • Structural Biology

Cite this

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.

In: BMC Bioinformatics, Vol. 13, No. 1, 13, 20.01.2012.

Research output: Contribution to journalArticle

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. In: BMC Bioinformatics. 2012 ; Vol. 13, No. 1.
@article{f5e4287516ed483fbadbe73b078b801d,
title = "TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data",
abstract = "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.",
author = "Douglas Londono and Steven Buyske and Finch, {Stephen J.} and Swarkar Sharma and Wise, {Carol A.} and Derek Gordon",
year = "2012",
month = "1",
day = "20",
doi = "10.1186/1471-2105-13-13",
language = "English (US)",
volume = "13",
journal = "BMC Bioinformatics",
issn = "1471-2105",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - TDT-HET

T2 - A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data

AU - Londono, Douglas

AU - Buyske, Steven

AU - Finch, Stephen J.

AU - Sharma, Swarkar

AU - Wise, Carol A.

AU - Gordon, Derek

PY - 2012/1/20

Y1 - 2012/1/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84856008086&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856008086&partnerID=8YFLogxK

U2 - 10.1186/1471-2105-13-13

DO - 10.1186/1471-2105-13-13

M3 - Article

VL - 13

JO - BMC Bioinformatics

JF - BMC Bioinformatics

SN - 1471-2105

IS - 1

M1 - 13

ER -