Lost in translation: On the problem of data coding in penalized whole genome regression with interactions

Mixed models can be considered as a type of penalized regression and are everyday tools in statistical genetics. The standard mixed model for whole genome regression (WGR) is ridge regression best linear unbiased prediction (RRBLUP) which is based on an additive marker effect model. Many publications have extended the additive WGR approach by incorporating interactions between loci or between genes and environment. In this context of penalized regressions with interactions, it has been reported that translating the coding of single nucleotide polymorphisms -for instance from -1,0,1 to 0,1,2- has an impact on the prediction of genetic values and interaction effects. In this work, we identify the reason for the relevance of variable coding in the general context of penalized polynomial regression. We show that in many cases, predictions of the genetic values are not invariant to translations of the variable coding, with an exception when only the sizes of the coefficients of monomials of highest total degree are penalized. The invariance of RRBLUP can be considered as a special case of this setting, with a polynomial of total degree 1, penalizing additive effects (total degree 1) but not the fixed effect (total degree 0). The extended RRBLUP (eRRBLUP), which includes interactions, is not invariant to translations because it does not only penalize interactions (total degree 2), but also additive effects (total degree 1). This observation implies that translation-invariance can be maintained in a pair-wise epistatic WGR if only interaction effects are penalized, but not the additive effects. In this regard, approaches of pre-selecting loci may not only reduce computation time, but can also help to avoid the variable coding issue. To illustrate the practical relevance, we compare different regressions on a publicly available wheat data set. We show that for an eRRBLUP, the relevance of the marker coding for interaction effect estimates increases with the number of variables included in the model. A biological interpretation of estimated interaction effects may therefore become more difficult. Consequently, comparing reproducing kernel Hilbert space (RKHS) approaches to WGR approaches modeling effects explicitly, the supposed advantage of an increased interpretability of the latter may not be real. Our theoretical results are generally valid for penalized regressions, for instance also for the least absolute shrinkage and selection operator (LASSO). Moreover, they apply to any type of interaction modeled by products of predictor variables in a penalized regression approach or by Hadamard products of covariance matrices in a mixed model.