Abundant datasets generated from various big science projects on diseases have presented great challenges and opportunities, which are contributed to unfold the complexity of diseases. The discovery of disease- associated molecular networks for each individual plays an important role in personalized therapy and precision treatment of cancer based on the reference networks. However, there are no effective ways to distinguish the consistency of different reference networks. In this study, we developed a statistical method, i.e. a sample-specific differential network (SSDN), to construct and analyze such networks based on gene expression of a single sample against a reference dataset. We proved that the SSDN is structurally consistent even with different reference datasets if the reference dataset can follow certain conditions. The SSDN also can be used to identify patient-specific disease modules or network biomarkers as well as predict the potential driver genes of a tumor sample.