We employ noise spectroscopy and transconductance measurements to establish the optimal regimes of operation for our fabricated silicon nanowire field-effect transistors (Si NW FETs) sensors. A strong coupling between the liquid gate and back gate (the substrate) has been revealed and used for optimization of signal-to-noise ratio in subthreshold as well as above-threshold regimes. Increasing the sensitivity of Si NW FET sensors above the detection limit has been predicted and proven by direct experimental measurements.