Quantitatively identifying direct dependencies between variables is an important task in data analysis, in particular for reconstructing various types of networks and causal relations in science and engineering. One of the most widely used criteria is partial correlation, but it can only measure linearly direct association and miss nonlinear associations. However, based on conditional independence, conditional mutual information (CMI) is able to quantify nonlinearly direct relationships among variables from the observed data, superior to linear measures, but suffers from a serious problem of underestimation, in particular for those variables with tight associations in a network, which severely limits its applications. In this work, we propose a new concept, "partial independence," with a new measure, "part mutual information" (PMI), which not only can overcome the problem of CMI but also retains the quantification properties of both mutual information (MI) and CMI. Specifically, we first defined PMI to measure nonlinearly direct dependencies between variables and then derived its relations with MI and CMI. Finally, we used a number of simulated data as benchmark examples to numerically demonstrate PMI features and further real gene expression data from Escherichia coli and yeast to reconstruct gene regulatory networks, which all validated the advantages of PMI for accurately quantifying nonlinearly direct associations in networks.conditional mutual information | systems biology | network inference | conditional independence B ig data provide unprecedented information and opportunities to uncover ambiguous correlations among measured variables, but how to further infer direct associations, which means two variables are dependent given all of the remaining variables (1), quantitatively from those correlations or data remains a challenging task, in particular in science and engineering. For instance, distinguishing dependencies or direct associations between molecules is of great importance in reconstructing gene regulatory networks in biology (2-4), which can elucidate the molecular mechanisms of complex biological processes at a network level. Traditionally, correlation [e.g., the Pearson correlation coefficient (PCC)] is widely used to evaluate linear relations between the measured variables (2, 5), but it cannot distinguish indirect and direct associations due to only relying on the information of co-occurring events. Partial correlation (PC) avoids this problem by considering additional information of conditional events and can detect the direct associations. Thus, PC becomes one of the most widely used criteria to infer direct associations in various areas. As applications of PC to network reconstruction (6), recently Barzel and Barabási (7) proposed a dynamical correlation-based method to discriminate direct and indirect associations by silencing indirect effects in networks, and Feizi et al. (8) developed a network deconvolution method to distinguish direct dependencies by removing the combined effect of al...