Strain elastography (SE) is a technique in which images of localized tissue strains are used to detect the relative stiffness of tissues. The application of SE in differentiating malignant breast lesions from benign ones has been broadly investigated. The strain ratio (SR) between the background and the breast tumor has been used and its results have been mixed. Due to the complex nature of tissue elasticity and how it relates to the strain fields measured in SE, the exact reason is not known. In this study, we apply a novel design-of-experiments-based metamodeling approach to mechanical simulation of SE in the human breast. To our knowledge, such a study has not been reported in the ultrasound SE literature. More specifically, we first conduct a screening study to identify the biomechanical factors/simulation inputs that most strongly determine SR. We then apply a response surface experimental design to these factors to produce a metamodel of SR as a function of said factors. Results from the screening study suggest that the SR measurements are primarily influenced by three factors: the initial shear modulus of the lesion, the elastic nonlinearity of the lesion, and the precompression applied during acquisition. In order to investigate the implications of these results, stochastic inputs for these three factors associated with the malignant and benign cases were applied to the resulting response surface. The resulting optimal cutoffs, sensitivity, and specificity were generally in line with a majority (>60%) of 19 clinical trials in the literature.