Segregation and linkage analyses of dopamine‐β‐hydroxylase activity in a six‐generation pedigree

Asamoah, Alexander; Af, Wilson; Rc, Elston; Dalferes, Edward R.; Gs, Berenson

doi:10.1002/ajmg.1320270314

Cited by 17 publications

(13 citation statements)

References 18 publications

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“…Transformation has been shown to increase the power of segregation analysis even in the presence of admixture [26][27][28][29]. Power transformations have been used to increase power to detect genetic linkage [30][31][32][33]. We applied the Box-Cox family of power transformations and found that power to detect linkage increased for skewed and kurtic phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Effect of Box-Cox Transformation on Power of Haseman-Elston and Maximum-Likelihood Variance Components Tests to Detect Quantitative Trait Loci

Etzel¹,

Shete²,

Beasley³

et al. 2003

Hum Hered

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Non-normality of the phenotypic distribution can affect power to detect quantitative trait loci in sib pair studies. Previously, we observed that Winsorizing the sib pair phenotypes increased the power of quantitative trait locus (QTL) detection for both Haseman-Elston (HE) least-squares tests [Hum Hered 2002;53:59–67] and maximum likelihood-based variance components (MLVC) analysis [Behav Genet (in press)]. Winsorizing the phenotypes led to a slight increase in type 1 error in H-E tests and a slight decrease in type I error for MLVC analysis. Herein, we considered transforming the sib pair phenotypes using the Box-Cox family of transformations. Data were simulated for normal and non-normal (skewed and kurtic) distributions. Phenotypic values were replaced by Box-Cox transformed values. Twenty thousand replications were performed for three H-E tests of linkage and the likelihood ratio test (LRT), the Wald test and other robust versions based on the MLVC method. We calculated the relative nominal inflation rate as the ratio of observed empirical type 1 error divided by the set α level (5, 1 and 0.1% α levels). MLVC tests applied to non-normal data had inflated type I errors (rate ratio greater than 1.0), which were controlled best by Box-Cox transformation and to a lesser degree by Winsorizing. For example, for non-transformed, skewed phenotypes (derived from a χ² distribution with 2 degrees of freedom), the rates of empirical type 1 error with respect to set α level = 0.01 were 0.80, 4.35 and 7.33 for the original H-E test, LRT and Wald test, respectively. For the same α level = 0.01, these rates were 1.12, 3.095 and 4.088 after Winsorizing and 0.723, 1.195 and 1.905 after Box-Cox transformation. Winsorizing reduced inflated error rates for the leptokurtic distribution (derived from a Laplace distribution with mean 0 and variance 8). Further, power (adjusted for empirical type 1 error) at the 0.01 α level ranged from 4.7 to 17.3% across all tests using the non-transformed, skewed phenotypes, from 7.5 to 20.1% after Winsorizing and from 12.6 to 33.2% after Box-Cox transformation. Likewise, power (adjusted for empirical type 1 error) using leptokurtic phenotypes at the 0.01 α level ranged from 4.4 to 12.5% across all tests with no transformation, from 7 to 19.2% after Winsorizing and from 4.5 to 13.8% after Box-Cox transformation. Thus the Box-Cox transformation apparently provided the best type 1 error control and maximal power among the procedures we considered for analyzing a non-normal, skewed distribution (χ²) while Winzorizing worked best for the non-normal, kurtic distribution (Laplace). We repeated the same simulations using a larger sample size (200 sib pairs) and found similar results.

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Section: Discussionmentioning

confidence: 99%

Effect of Box-Cox Transformation on Power of Haseman-Elston and Maximum-Likelihood Variance Components Tests to Detect Quantitative Trait Loci

Etzel¹,

Shete²,

Beasley³

et al. 2003

Hum Hered

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“…Lemons et al (HGM9) isolated a cDNA sequence encoding 80% of the C5 pro-molecule and mapped the locus to 9q34. Linkage between the ABO blood group and dopamine-beta-hydroxylase (DBH) has been suggested (Elston et al 1979) and confirmed (Asamoah et al 1987;Goldin et al 1982). Keats et al (HGM9) report the lod scores summed over four published reports giving the best map order as ABO-DBH-AK1-ORM and a total lod score for DBH with this group of 6.9.…”

Section: Chromosomementioning

confidence: 97%

Report of the committee on the genetic constitution of chromosomes 7, 8 and 9

Spence¹,

Tsui²

1987

Cytogenet Genome Res

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“…2 ), the model using a square-root transformation produced the highest linkage signal, while the model using the estimated transformation power 1 , which converged to a low-value recessive model, produced the lowest linkage signal. Thus, restricting the model to be dominant for low values, as found in previous studies [17,18] , was necessary to obtain a segregation model useful for linkage analysis. …”

Section: Model-based Linkage Analysismentioning

confidence: 99%

Some Capabilities for Model-Based and Model-Free Linkage Analysis using the Program Package S.A.G.E. (Statistical Analysis for Genetic Epidemiology)

Schnell¹,

Sun²,

Igo³

et al. 2011

Hum Hered

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For both model-free and model-based linkage analysis the S.A.G.E. (Statistical Analysis for Genetic Epidemiology) program package has some unique capabilities in analyzing both continuous traits and binary traits with variable age of onset. Here we highlight model-based linkage analysis of a quantitative trait (plasma dopamine β hydroxylase) that is known to be largely determined by monogenic inheritance, using a prior segregation analysis to produce the best fitting model for the trait. For a binary trait with variable age of onset (schizophrenia), we illustrate how using age of onset information to obtain a quantitative susceptibility trait leads to more statistically significant linkage signals, suggesting better power.

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Segregation and linkage analyses of dopamine‐β‐hydroxylase activity in a six‐generation pedigree

Cited by 17 publications

References 18 publications

Effect of Box-Cox Transformation on Power of Haseman-Elston and Maximum-Likelihood Variance Components Tests to Detect Quantitative Trait Loci

Effect of Box-Cox Transformation on Power of Haseman-Elston and Maximum-Likelihood Variance Components Tests to Detect Quantitative Trait Loci

Report of the committee on the genetic constitution of chromosomes 7, 8 and 9

Some Capabilities for Model-Based and Model-Free Linkage Analysis using the Program Package S.A.G.E. (Statistical Analysis for Genetic Epidemiology)

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