Many biological problems involve the response to multiple perturbations. Examples include response to combinations of many drugs, and the effects of combinations of many mutations. Such problems have an exponentially large space of combinations, which makes it infeasible to cover the entire space experimentally. To overcome this problem, several formulae that predict the effect of drug combinations or fitness landscape values have been proposed. These formulae use the effects of single perturbations and pairs of perturbations to predict triplets and higher order combinations. Interestingly, different formulae perform best on different datasets. Here we use Pareto optimality theory to quantitatively explain why no formula is optimal for all datasets, due to an inherent bias-variance (noise-precision) tradeoff. We calculate the Pareto front of log-linear formulae and find that the optimal formula depends on properties of the dataset: the typical interaction strength and the experimental noise. This study provides an approach to choose a suitable prediction formula for a given dataset, in order to best overcome the combinatorial explosion problem.