A penalized mixture model approach in genotype/phenotype association analysis for quantitative phenotypes.
A mixture normal model has been developed to partition genotypes in predicting quantitative phenotypes. Its estimation and inference are performed through an EM algorithm. This approach can conduct simultaneous genotype clustering and hypothesis testing. It is a valuable method for predicting the distribution of quantitative phenotypes among multi-locus genotypes across genes or within a gene. This mixture model's performance is evaluated in data analyses for two pharmacogenetics studies. In one example, thirty five CYP2D6 genotypes were partitioned into three groups to predict pharmacokinetics of a breast cancer drug, Tamoxifen, a CYP2D6 substrate (p-value = 0.04). In a second example, seventeen CYP2B6 genotypes were categorized into three clusters to predict CYP2B6 protein expression (p-value = 0.002). The biological validities of both partitions are examined using established function of CYP2D6 and CYP2B6 alleles. In both examples, we observed genotypes clustered in the same group to have high functional similarities. The power and recovery rate of the true partition for the mixture model approach are investigated in statistical simulation studies, where it outperforms another published method.
Li
Lang
L
Division of Biostatistics, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, USA. lali@iupui.edu
Borges
Silvana
S
Jason
Robarge D
RD
Shen
Changyu
C
Desta
Zeruesenay
Z
Flockhart
David
D
Genet Epidemiol. 2004 Sep;27(2):141-52
15305330
J Clin Oncol. 2005 Oct 10;23(29):7342-9
16145062
Clin Pharmacol Ther. 1992 Jan;51(1):12-7
1346258
Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):23-37
14618296
J Pharmacol Exp Ther. 2004 Oct;311(1):34-43
15190123
Gene. 1999 Jan 21;226(2):327-38
9931507
Am J Hum Genet. 1997 Feb;60(2):284-95
9012401
Pharmacogenetics. 2003 Oct;13(10):619-26
14515060
Pharmacogenetics. 2001 Jul;11(5):399-415
11470993
Pharmacogenomics. 2007 Jun;8(6):547-58
17559344
Pharmacogenet Genomics. 2005 Dec;15(12):861-73
16272958
AIDS. 2004 Dec 3;18(18):2391-400
15622315
Mol Pharmacol. 2005 May;67(5):1772-82
15722458
Stat Methods Med Res. 1996 Jun;5(2):155-78
8817796
Biochem Biophys Res Commun. 2004 Jul 9;319(4):1322-6
15194512
J Pharmacol Exp Ther. 1995 Jul;274(1):516-20
7616439