caa a22 4500 378925857 CHVBK 20180305123617.0 cr unu---uuuuu 161128e20041006xx s 000 0 eng 10.2202/1544-6115.1085 doi (NATIONALLICENCE)gruyter-10.2202/1544-6115.1085 Increasing Power for Tests of Genetic Association in the Presence of Phenotype and/or Genotype Error by Use of Double-Sampling [Elektronische Daten] [Derek Gordon, Yaning Yang, Chad Haynes, Stephen J Finch, Nancy R Mendell, Abraham M Brown, Vahram Haroutunian] Phenotype and/or genotype misclassification can: significantly increase type II error probabilities for genetic case/control association, causing decrease in statistical power; and produce inaccurate estimates of population frequency parameters. We present a method, the likelihood ratio test allowing for errors (LRTae) that incorporates double-sample information for phenotypes and/or genotypes on a sub-sample of cases/controls. Population frequency parameters and misclassification probabilities are determined using a double-sample procedure as implemented in the Expectation-Maximization (EM) method. We perform null simulations assuming a SNP marker or a 4-allele (multi-allele) marker locus. To compare our method with the standard method that makes no adjustment for errors (LRTstd), we perform power simulations using a 2^k factorial design with high and low settings of: case/control samples, phenotype/genotype costs, double-sampled phenotypes/genotypes costs, phenotype/genotype error, and proportions of double-sampled individuals. All power simulations are performed fixing equal costs for the LRTstd and LRTae methods. We also consider case/control ApoE genotype data for an actual Alzheimer's study. The LRTae method maintains correct type I error proportions for all null simulations and all significance level thresholds (10%, 5%, 1%). LRTae average estimates of population frequencies and misclassification probabilities are equal to the true values, with variances of 10e-7 to 10e-8. For power simulations, the median power difference LRTae-LRTstd at the 5% significance level is 0.06 for multi-allele data and 0.01 for SNP data. For the ApoE data example, the LRTae and LRTstd p-values are 5.8 x 10e-5 and 1.6 x 10e-3, respectively. The increase in significance is due to adjustment in the LRTae for misclassification of the most commonly reported risk allele. We have developed freely available software that performs our LRTae statistic. ©2011 Walter de Gruyter GmbH & Co. KG, Berlin/Boston Statistical Theory and Methods nationallicence General Biostatistics nationallicence Computational Biology/Bioinformatics nationallicence misclassification nationallicence case nationallicence control nationallicence likelihood ratio nationallicence study design nationallicence cost-benefits nationallicence Gordon Derek Rockefeller University aut Yang Yaning Rockefeller University aut Haynes Chad Rockefeller University aut Finch Stephen J. Stony Brook University aut Mendell Nancy R. Stony Brook University aut Brown Abraham M. Burke Medical Research Institute aut Haroutunian Vahram Mount Sinai School of Medicine aut Statistical Applications in Genetics and Molecular Biology De Gruyter 3/1(2004-10-06), 1-32 3:1<1 2004 3 sagmb https://doi.org/10.2202/1544-6115.1085 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.2202/1544-6115.1085 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gordon Derek Rockefeller University aut NATIONALLICENCE 700 1- Yang Yaning Rockefeller University aut NATIONALLICENCE 700 1- Haynes Chad Rockefeller University aut NATIONALLICENCE 700 1- Finch Stephen J. Stony Brook University aut NATIONALLICENCE 700 1- Mendell Nancy R. Stony Brook University aut NATIONALLICENCE 700 1- Brown Abraham M. Burke Medical Research Institute aut NATIONALLICENCE 700 1- Haroutunian Vahram Mount Sinai School of Medicine aut NATIONALLICENCE 773 0- Statistical Applications in Genetics and Molecular Biology De Gruyter 3/1(2004-10-06), 1-32 3:1<1 2004 3 sagmb CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter