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Tandem affinity purification coupled with mass-spectrometry (TAP/MS) analysis has been increasingly used to identify novel endogenous protein-protein interactions (PPIs) in a high-throughput manner. Computational analysis of TAP/MS data is critical, however, and remains challenging because of the noisy nature of the data. We developed an advanced method for identifying PPIs from TAP/MS data. Our approach APPIC, which stands for Advanced Protein-Protein Interactions Capturing, incorporates an improved statistical method and is more powerful than existing tools.