 This paper proposes a new approach to detect the pre-disease state of complex diseases using a single sample. The authors propose a novel index called Single Sample Cullback Leibler Divergence, SKLD, to measure the disturbance caused by a case sample on the background. This index can be used to identify the critical state or tipping point of a biological system. The authors tested their method on several different types of cancer and found that it successfully identified the pre-disease state of these diseases. Furthermore, they also provided a set of SKLD signaling markers that could be used for further practical applications. This article was authored by Jiu Yun Zhong, Rui Liu, and Pei Chen.