Estimating information in time-varying signals

Abstract

Across diverse biological systems—ranging from neural networks to intracellular signaling and genetic regulatory networks—the information about changes in the environment is frequently encoded in the full temporal dynamics of the network nodes. A pressing data-analysis challenge has thus been to efficiently estimate the amount of information that these dynamics convey from experimental data. Here we develop and evaluate decoding-based estimation methods to lower bound the mutual information about a finite set of inputs, encoded in single-cell high-dimensional time series data. For biological reaction networks governed by the chemical Master equation, we derive model-based information approximations and analytical upper bounds, against which we benchmark our proposed model-free decoding estimators. In contrast to the frequently-used k-nearest-neighbor estimator, decoding-based estimators robustly extract a large fraction of the available information from high-dimensional trajectories with a realistic number of data samples. We apply these estimators to previously published data on Erk and Ca2+ signaling in mammalian cells and to yeast stress-response, and find that substantial amount of information about environmental state can be encoded by non-trivial response statistics even in stationary signals. We argue that these single-cell, decoding-based information estimates, rather than the commonly-used tests for significant differences between selected population response statistics, provide a proper and unbiased measure for the performance of biological signaling networks. Cells represent changes in their own state or in the state of their environment by temporally varying the concentrations of intracellular signaling molecules, mimicking in a simple chemical context the way we humans represent our thoughts and observations through temporally varying patterns of sounds that constitute speech. These time-varying concentrations are used as signals to regulate downstream molecular processes, to mount appropriate cellular responses for the environmental challenges, or to communicate with nearby cells. But how precise and unambiguous is such chemical communication, in theory and in data? On the one hand, intuition tells us that many possible environmental changes could be represented by variation in concentration patterns of multiple signaling chemicals; on the other, we know that chemical signals are inherently noisy at the molecular scale. Here we develop data analysis methodology that allows us to pose and answer these questions rigorously. Our decoding-based information estimators, which we test on simulated and real data from yeast and mammalian cells, measure how precisely individual cells can detect and report environmental changes, without making assumptions about the structure of the chemical communication and using only the amounts of data that is typically available in today’s experiments.