Identification of interactions using model-based multifactor dimensionality reduction

Common complex traits may involve multiple genetic and environmental factors and their interactions. Many methods have been proposed to identify these interaction effects, among them several machine learning and data mining methods. These are attractive for identifying interactions because they do not rely on specific genetic model assumptions. To handle the computational burden arising from an exhaustive search, including all possible combinations of factors, filter methods try to select promising factors in advance.

Model-based multifactor dimensionality reduction (MB-MDR), a semiparametric machine learning method allowing adjustment for confounding variables and lower level effects, is applied to Genetic Analysis Workshop 19 (GAW19) data to identify interaction effects on different traits. Several filtering methods based on the nearest neighbor algorithm are assessed in terms of compatibility with MB-MDR.

Single nucleotide polymorphism (SNP) rs859400 shows a significant interaction effect (corrected p value <0.05) with age on systolic blood pressure (SBP). We identified 23 SNP-SNP interaction effects on hypertension status (HS), 42 interaction effects on SBP, and 26 interaction effects on diastolic blood pressure (DBP). Several of these SNPs are in strong linkage disequilibrium (LD). Three of the interaction effects on HS are identified in filtered subsets.

The considered filtering methods seem not to be appropriate to use with MB-MDR. LD pruning is further quality control to be incorporated, which can reduce the combinatorial burden by removing redundant SNPs.