Computation and measurement of cell decision making errors using single cell data

In this study a new computational method is developed to quantify decision making errors in cells, caused by noise and signaling failures. Analysis of tumor necrosis factor (TNF) signaling pathway which regulates the transcription factor Nuclear Factor κB (NF-κB) using this method identifies two types of incorrect cell decisions called false alarm and miss. These two events represent, respectively, declaring a signal which is not present and missing a signal that does exist. Using single cell experimental data and the developed method, we compute false alarm and miss error probabilities in wild-type cells and provide a formulation which shows how these metrics depend on the signal transduction noise level. We also show that in the presence of abnormalities in a cell, decision making processes can be significantly affected, compared to a wild-type cell, and the method is able to model and measure such effects. In the TNF—NF-κB pathway, the method computes and reveals changes in false alarm and miss probabilities in A20-deficient cells, caused by cell’s inability to inhibit TNF-induced NF-κB response. In biological terms, a higher false alarm metric in this abnormal TNF signaling system indicates perceiving more cytokine signals which in fact do not exist at the system input, whereas a higher miss metric indicates that it is highly likely to miss signals that actually exist. Overall, this study demonstrates the ability of the developed method for modeling cell decision making errors under normal and abnormal conditions, and in the presence of transduction noise uncertainty. Compared to the previously reported pathway capacity metric, our results suggest that the introduced decision error metrics characterize signaling failures more accurately. This is mainly because while capacity is a useful metric to study information transmission in signaling pathways, it does not capture the overlap between TNF-induced noisy response curves.Author summary: Cell continuously receives signals from the surrounding environment and is supposed to make correct decisions, i.e., respond properly to various signals and initiate certain cellular functions. Modeling and quantification of decision making processes in a cell have emerged as important areas of research in recent years. Due to signal transduction noise, cells respond differently to similar inputs, which may result in incorrect cell decisions. Here we develop a novel method for characterization of decision making processes in cells, using statistical signal processing and decision theory concepts. To demonstrate the utility of the method, we apply it to an important signaling pathway that regulates molecules which play key roles in cell survival. Our method reveals that cells can make two types of incorrect decisions, namely, false alarm and miss events. We measure the likelihood of these decisions using single cell experimental data, and demonstrate how these incorrect decisions are related to the signal transduction noise or absence of certain molecular functions. Using our method, decision making errors in other molecular systems can be modeled. Such models are useful for understanding and developing treatments for pathological processes such as inflammation, various cancers and autoimmune diseases.