Bias Characterization in Probabilistic Genotype Data and Improved Signal Detection with Multiple Imputation

Missing data are an unavoidable component of modern statistical genetics. Different array or sequencing technologies cover different single nucleotide polymorphisms (SNPs), leading to a complicated mosaic pattern of missingness where both individual genotypes and entire SNPs are sporadically absent....

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Bibliographic Details
Published in:PLoS genetics 2016-06, Vol.12 (6), p.e1006091-e1006091
Main Authors: Palmer, Cameron, Pe'er, Itsik
Format: Article
Language:English
Subjects:
Algorithms
Bias
Binomial distribution
Biology and Life Sciences
Confidence intervals
Estimates
Gene expression
Genome-Wide Association Study - methods
Genomes
Genotype
Genotype & phenotype
Genotypes
Haplotypes
Humans
Methods
Observations
Physical Sciences
Polymorphism, Single Nucleotide - genetics
Quality
Research and Analysis Methods
Statistics as Topic - methods
Studies
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Summary:Missing data are an unavoidable component of modern statistical genetics. Different array or sequencing technologies cover different single nucleotide polymorphisms (SNPs), leading to a complicated mosaic pattern of missingness where both individual genotypes and entire SNPs are sporadically absent. Such missing data patterns cannot be ignored without introducing bias, yet cannot be inferred exclusively from nonmissing data. In genome-wide association studies, the accepted solution to missingness is to impute missing data using external reference haplotypes. The resulting probabilistic genotypes may be analyzed in the place of genotype calls. A general-purpose paradigm, called Multiple Imputation (MI), is known to model uncertainty in many contexts, yet it is not widely used in association studies. Here, we undertake a systematic evaluation of existing imputed data analysis methods and MI. We characterize biases related to uncertainty in association studies, and find that bias is introduced both at the imputation level, when imputation algorithms generate inconsistent genotype probabilities, and at the association level, when analysis methods inadequately model genotype uncertainty. We find that MI performs at least as well as existing methods or in some cases much better, and provides a straightforward paradigm for adapting existing genotype association methods to uncertain data.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006091