A classification and characterization of two-locus, pure, strict, epistatic models for simulation and detection

BioData Mining

Ryan J Urbanowicz¹  Ambrose LS Granizo-Mackenzie¹  Jeff Kiralis¹  Jason H Moore¹ 

[1] Department of Genetics, Dartmouth College, 1 Medical Center Dr., Lebanon, NH 05001, USA

关键词: Convex hull;    Computational geometry;    GAMETES;    Genetics;    Simulation;    Models;    Epistasis;   

Others  :  1084070
DOI  :  10.1186/1756-0381-7-8

 received in 2013-11-05, accepted in 2014-05-23,  发布年份 2014

【 摘 要 】

Background

The statistical genetics phenomenon of epistasis is widely acknowledged to confound disease etiology. In order to evaluate strategies for detecting these complex multi-locus disease associations, simulation studies are required. The development of the GAMETES software for the generation of complex genetic models, has provided the means to randomly generate an architecturally diverse population of epistatic models that are both pure and strict, i.e. all n loci, but no fewer, are predictive of phenotype. Previous theoretical work characterizing complex genetic models has yet to examine pure, strict, epistasis which should be the most challenging to detect. This study addresses three goals: (1) Classify and characterize pure, strict, two-locus epistatic models, (2) Investigate the effect of model ‘architecture’ on detection difficulty, and (3) Explore how adjusting GAMETES constraints influences diversity in the generated models.

Results

In this study we utilized a geometric approach to classify pure, strict, two-locus epistatic models by “shape”. In total, 33 unique shape symmetry classes were identified. Using a detection difficulty metric, we found that model shape was consistently a significant predictor of model detection difficulty. Additionally, after categorizing shape classes by the number of edges in their shape projections, we found that this edge number was also significantly predictive of detection difficulty. Analysis of constraints within GAMETES indicated that increasing model population size can expand model class coverage but does little to change the range of observed difficulty metric scores. A variable population prevalence significantly increased the range of observed difficulty metric scores and, for certain constraints, also improved model class coverage.

Conclusions

These analyses further our theoretical understanding of epistatic relationships and uncover guidelines for the effective generation of complex models using GAMETES. Specifically, (1) we have characterized 33 shape classes by edge number, detection difficulty, and observed frequency (2) our results support the claim that model architecture directly influences detection difficulty, and (3) we found that GAMETES will generate a maximally diverse set of models with a variable population prevalence and a larger model population size. However, a model population size as small as 1,000 is likely to be sufficient.

【 授权许可】

   
2014 Urbanowicz et al.; licensee BioMed Central Ltd.

【 图 表 】

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