Accurately modeling LD in simulations is essential to correctly evaluate new and existing association methods. At present, there has been minimal research comparing the quality of existing gene region simulation methods to produce LD structures similar to an existing gene region. Here we compare the ability of three approaches to accurately simulate the LD within a gene region: HapSim (2005), Hapgen (2009), and a minor extension to simple haplotype resampling.
In order to observe the variation and bias for each method, we compare the simulated pairwise LD measures and minor allele frequencies to the original HapMap data in an extensive simulation study. When possible, we also evaluate the effects of changing parameters.
HapSim produces samples of haplotypes with lower LD, on average, compared to the original haplotype set while both our resampling method and Hapgen do not introduce this bias. The variation introduced across the replicates by our resampling method is quite small and may not provide enough sampling variability to make a generalizable simulation study.
We recommend using Hapgen to simulate replicate haplotypes from a gene region. Hapgen produces moderate sampling variation between the replicates while retaining the overall unique LD structure of the gene region.