Identification of probable genotyping errors by consideration of haplotypes

Abstract

Undetected genotyping errors pose a problem in genetic epidemiological studies, as they may invalidate statistical analysis or reduce its power. Haplotype analysis requires an improved standard of the data, because a haplotype can be inferred correctly only if the genotypes of all its markers are correct. Here, we present a method that identifies probable genotyping errors in trio samples with the help of the estimated haplotype frequency distribution of the sample. If the likelihood of the most likely haplotype explanation depends strongly on just one genotype, in the sense that setting the genotype to be missing leads to a much more likely haplotype explanation, this genotype is considered as a potential genotyping error. We describe a method that systematically searches the whole data set for such potential errors. Based on the haplotype distribution of a real data set, we carry out a simulation study to estimate the sensitivity and specifity of the method. In addition, we apply our approach to the real data set itself. Potentially erroneous genotypes are re-determined via sequencing. The results of both the simulation study and of the application to the real data set show that a considerable proportion of true genotyping errors is detected and that the number of false-positive signals is acceptable. We conclude that it is indeed possible to identify probable genotyping errors by considering haplotypes. The method described here will be part of the next release of our FAMHAP software.

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

“…Hardy-Weinberg equilibrium was checked on parental genotypes by w 2 -tests as implemented in Pedstats. 51 We checked for likely genotyping errors (e.g., manifesting as close double recombinants) using FAM-HAP 52 and set unlikely genotypes on missing for the respective individuals.…”

Incorporating Genotyping Uncertainty in Haplotype Frequency Estimation in Pedigree Studies

“…However, almost all existing algorithms estimate haplotype frequencies under the assumption that all of the genotype data are correct. In fact, large genotype data sets often have errors, though some genotyping errors can be partly detected using Mendel's laws as a check using trio design for pedigree data [33,34] . Furthermore, several studies have shown that even a small quantity of genotyping errors can have enormous impact on haplotype frequency estimates [1,24] , and then markedly affect haplotype-based linkage and association studies [31,32] .…”

“…Although some genotyping errors can be detected using Mendel's laws as a check for pedigree data, Gordon and coworkers [33] showed that the error-detection rate that has been estimated using trio designs does not exceed 30% for one diallelic marker. As Becker and coworkers [34] pointed out, the effect of undetected genotype errors may be exaggerated when haplotypes instead of single-marker loci are analyzed. Furthermore, they presented a method that detect genotyping errors in trios through using the estimated haplotype frequency distribution.…”

“…Furthermore, they presented a method that detect genotyping errors in trios through using the estimated haplotype frequency distribution. Although some additional genotyping errors can be detected using the method of Becker and coworkers [34] , this methods needs to estimate the haplotype frequency distribution in advance, and the reliability of their method in detecting genotyping errors depends on the accuracy of estimation of true haplotype frequency distribution. So it is important to develop methods that incorporate genotyping errors into haplotype frequency estimation for pedigree data.…”

Genotype Error Detection Using Hidden Markov Models of Haplotype Diversity

“…Unfortunately, these methods have very limited power to detect errors in genotype data from small pedigrees such as mother-father-child trios, and do not apply at all to genotype data from unrelated individuals. (Becker et al, 2006) have recently introduced the use of population level haplotype frequency information for genotype error detection in trio data via a simple likelihood ratio test. However, detection accuracy of their method is severely limited by the reliance on explicit enumeration of most frequent haplotypes within short blocks of consecutive SNP loci.…”