Generalized linear models (GLMs) have a wide range of applications in systems neuroscience describing the encoding of stimulus and behavioral variables, as well as the dynamics of single neurons. However, in any given experiment, many variables that have an impact on neural activity are not observed or not modeled. Here we demonstrate, in both theory and practice, how these omitted variables can result in biased parameter estimates for the effects that are included. In three case studies, we estimate tuning functions for common experiments in motor cortex, hippocampus, and visual cortex. We find that including traditionally omitted variables changes estimates of the original parameters and that modulation originally attributed to one variable is reduced after new variables are included. In GLMs describing single-neuron dynamics, we then demonstrate how postspike history effects can also be biased by omitted variables. Here we find that omitted variable bias can lead to mistaken conclusions about the stability of single-neuron firing. Omitted variable bias can appear in any model with confounders—where omitted variables modulate neural activity and the effects of the omitted variables covary with the included effects. Understanding how and to what extent omitted variable bias affects parameter estimates is likely to be important for interpreting the parameters and predictions of many neural encoding models.

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