Power Loss for Linkage Analysis due to the Dichotomization of Trichotomous Phenotypes

Corbett, Jonathan; Gu, C. Charles; Rice, John P.; Reich, Theodore; Province, Michael A.; Rao, D. C.

doi:10.1159/000077386

Cited by 16 publications

(14 citation statements)

References 18 publications

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“…Previous studies have shown that treating a categorical trait as binary leads to a loss of power [3], [4]. Our results concur with this (Figure S3).…”

Section: Resultssupporting

confidence: 92%

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Bayesian Linkage Analysis of Categorical Traits for Arbitrary Pedigree Designs

et al. 2010

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BackgroundPedigree studies of complex heritable diseases often feature nominal or ordinal phenotypic measurements and missing genetic marker or phenotype data.MethodologyWe have developed a Bayesian method for Linkage analysis of Ordinal and Categorical traits (LOCate) that can analyze complex genealogical structure for family groups and incorporate missing data. LOCate uses a Gibbs sampling approach to assess linkage, incorporating a simulated tempering algorithm for fast mixing. While our treatment is Bayesian, we develop a LOD (log of odds) score estimator for assessing linkage from Gibbs sampling that is highly accurate for simulated data. LOCate is applicable to linkage analysis for ordinal or nominal traits, a versatility which we demonstrate by analyzing simulated data with a nominal trait, on which LOCate outperforms LOT, an existing method which is designed for ordinal traits. We additionally demonstrate our method's versatility by analyzing a candidate locus (D2S1788) for panic disorder in humans, in a dataset with a large amount of missing data, which LOT was unable to handle.ConclusionLOCate's accuracy and applicability to both ordinal and nominal traits will prove useful to researchers interested in mapping loci for categorical traits.

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“…Previous studies have shown that treating a categorical trait as binary leads to a loss of power [3], [4]. Our results concur with this (Figure S3).…”

Section: Resultssupporting

confidence: 92%

“…When performing linkage analysis of categorical traits, it is well appreciated that re-coding measurements as binary can lead to decreased power [3], [4]. Recoding measurements as continuous can lead to the same problem.…”

Section: Introductionmentioning

confidence: 99%

Bayesian Linkage Analysis of Categorical Traits for Arbitrary Pedigree Designs

et al. 2010

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“…It was also assumed that animals with IBK had the same levels of exposure to the genetic risk factors. In the two-category classification, however, some animals considered ‘affected’ could be in more severe states than other ‘affected’ animals [27]. This additional information could be used in the multiple-category classification of IBK, whereas it was lost upon two-category classification.…”

Section: Resultsmentioning

confidence: 99%

“…In the linkage analyses of two-, three- and multiple-categorical traits, Corbet el al. [27] indicated that two-category classification of multiple-categorical traits could lead to crippling power loss, especially in the case of many loci of small effects. In particular, if the underlying genetic factors for any trait confer not only IBK susceptibility but also IBK severity, treating IBK phenotypes as multi-categorical could provide additional information in genome-wide analysis.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association study of infectious bovine keratoconjunctivitis in Angus cattle

et al. 2013

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BackgroundInfectious Bovine Keratoconjunctivitis (IBK) in beef cattle, commonly known as pinkeye, is a bacterial disease caused by Moraxellabovis. IBK is characterized by excessive tearing and ulceration of the cornea. Perforation of the cornea may also occur in severe cases. IBK is considered the most important ocular disease in cattle production, due to the decreased growth performance of infected individuals and its subsequent economic effects. IBK is an economically important, lowly heritable categorical disease trait. Mass selection of unaffected animals has not been successful at reducing disease incidence. Genome-wide studies can determine chromosomal regions associated with IBK susceptibility. The objective of the study was to detect single-nucleotide polymorphism (SNP) markers in linkage disequilibrium (LD) with genetic variants associated with IBK in American Angus cattle.ResultsThe proportion of phenotypic variance explained by markers was 0.06 in the whole genome analysis of IBK incidence classified as two, three or nine categories. Whole-genome analysis using any categorisation of (two, three or nine) IBK scores showed that locations on chromosomes 2, 12, 13 and 21 were associated with IBK disease. The genomic locations on chromosomes 13 and 21 overlap with QTLs associated with Bovine spongiform encephalopathy, clinical mastitis or somatic cell count.ConclusionsResults of these genome-wide analyses indicated that if the underlying genetic factors confer not only IBK susceptibility but also IBK severity, treating IBK phenotypes as a two-categorical trait can cause information loss in the genome-wide analysis. These results help our overall understanding of the genetics of IBK and have the potential to provide information for future use in breeding schemes.

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“…Other researchers (15) have also observed loss of power for linkage analysis due to the dichotomization of trichotomous phenotypes.…”

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confidence: 97%

Linkage analysis of ordinal traits for pedigree data

Feng

Leckman

Zhang

2004

Proc. Natl. Acad. Sci. U.S.A.

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Linkage analysis is used routinely to map genes for human diseases and conditions. However, the existing linkage-analysis methods require that the diseases or conditions either be dichotomized or measured by a quantitative trait, such as blood pressure for hypertension. In the latter case, normality is generally assumed for the trait. However, many diseases and conditions, such as cancer and mental and behavioral conditions, are rated on ordinal scales. The objective of this study was to establish a framework to conduct linkage analysis for ordinal traits. We propose a latent-variable, proportional-odds logistic model that relates inheritance patterns to the distribution of the ordinal trait. We use the likelihood-ratio test for testing evidence of linkage. By means of simulation studies, we find that the power of our proposed model is substantially higher than that of the binary-trait-based linkage analysis and that our test statistic is robust with regard to certain parameter misspecifications. By using our proposed method, we performed a genome scan of the hoarding phenotype in a data set with 53 nuclear families, which were collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). Standard linkage scans using hoarding as a dichotomous trait were also performed by using GENEHUNTER and ALLEGRO. Both GENEHUNTER and ALLEGRO failed to reveal any marker significantly linked to the binary hoarding phenotypes. However, our method identified three markers at 4q34-35 (P ‫؍‬ 0.0009), 5q35.2-35.3 (P ‫؍‬ 0.0001), and 17q25 (P ‫؍‬ 0.0005) that manifest significant allele sharing.

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Power Loss for Linkage Analysis due to the Dichotomization of Trichotomous Phenotypes

Cited by 16 publications

References 18 publications

Bayesian Linkage Analysis of Categorical Traits for Arbitrary Pedigree Designs

Bayesian Linkage Analysis of Categorical Traits for Arbitrary Pedigree Designs

Genome-wide association study of infectious bovine keratoconjunctivitis in Angus cattle

Linkage analysis of ordinal traits for pedigree data

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