Determining the structure of dependencies among a set of variables is a common task in many signal and image processing applications, including multitarget tracking and computer vision. In this paper, we present an information-theoretic, machine learning approach to problems of this type. We cast this problem as a hypothesis test between factorizations of variables into mutually independent subsets. We show that the likelihood ratio can be written as sums of two sets of Kullback-Leibler (KL) divergence terms. The first set captures the structure of the statistical dependencies within each hypothesis, whereas the second set measures the details of model differences between hypotheses. We then consider the case when the signal prior models are unknown, so that the distributions of interest must be estimated directly from data, showing that the second set of terms is (asymptotically) negligible and quantifying the loss in hypothesis separability when the models are completely unknown. We demonstrate the utility of nonparametric estimation methods for such problems, providing a general framework for determining and distinguishing between dependency structures in highly uncertain environments. Additionally, we develop a machine learning approach for estimating lower bounds on KL divergence and mutual information from samples of high-dimensional random variables for which direct density estimation is infeasible. We present empirical results in the context of three prototypical applications: association of signals generated by sources possessing harmonic behavior, scene correspondence using video imagery, and detection of coherent behavior among sets of moving objects.