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In this paper, we present the design of a clinical decision support system (CDSS) for monitoring comorbid conditions. Specifically, we address the architecture of a CDSS by characterizing it from three layers and discuss the algorithms in each layer. Also we address the applications of CDSSs in a few real scenarios and analyze the accuracy of a CDSS in consideration of the potential conflicts when using multiple clinical practice guidelines concurrently. Finally, we compare the system performance in our design with that in the other design schemes. Our study shows that our proposed design can achieve a clinical decision in a shorter time than the other designs, while ensuring a high level of system accuracy.