Approaches for operating a memory device comprising memory cells are disclosed. Optimal values for one or more of programming voltages used to program memory cells of the memory device and read reference voltages used to read the memory cells are determined using a mutual information function, I(X; Y), where X represents data values programmed to the memory cells and Y represents data values read from the memory cells. The read reference and/or programming voltages used for reading and/or programming the memory cells are adjusted using the optimal values.