A microfluidic system comprising: an electro-wetting on dielectric (EWOD) cartridge (105,152,163) comprising an element array (140,153, 200) configured to receive liquid droplets, the element array comprising a plurality of individual array elements (142, 201, 208, 210) each including array element circuity comprising sensing circuitry that is integrated into the array element circuitry; a microfluidic instrument (104, 154) that is configured to receive the EWOD cartridge (105,152,163) and having an electrically conductive locator (158,159,164, 206, LOC) that is external to the EWOD cartridge; and a control system configured to perform electrowetting operations by controlling actuation voltages applied to the element array (140,153, 200) to perform manipulation operations as to liquid droplets (144,202) present on the element array; wherein the control system further is configured to: read an output from the sensing circuitry; determine a position of the locator (158,159,164, 206) relative to the element array (140,153, 172, 200) based on the output; determine a misalignment of the EWOD cartridge (105,152,163) relative to the microfluidic instrument (104, 154) based on the determined position of the locator (158,159,164, 206); and adjust a manipulation operation of a liquid droplet (144,202) to compensate for the determined misalignment of the EWOD cartridge (105,152,163) relative to the microfluidic instrument (104, 154). an electro-wetting on dielectric (EWOD) cartridge (105,152,163) comprising an element array (140,153, 200) configured to receive liquid droplets, the element array comprising a plurality of individual array elements (142, 201, 208, 210) each including array element circuity comprising sensing circuitry that is integrated into the array element circuitry; a microfluidic instrument (104, 154) that is configured to receive the EWOD cartridge (105,152,163) and having an electrically conductive locator (158,159,164, 206, LOC) that is external to the EWOD cartridge; and a control system configured to perform electrowetting operations by controlling actuation voltages applied to the element array (140,153, 200) to perform manipulation operations as to liquid droplets (144,202) present on the element array; wherein the control system further is configured to: read an output from the sensing circuitry; determine a position of the locator (158,159,164, 206) relative to the element array (140,153, 172, 200) based on the output; determine a misalignment of the EWOD cartridge (105,152,163) relative to the microfluidic instrument (104, 154) based on the determined position of the locator (158,159,164, 206); and adjust a manipulation operation of a liquid droplet (144,202) to compensate for the determined misalignment of the EWOD cartridge (105,152,163) relative to the microfluidic instrument (104, 154). read an output from the sensing circuitry; determine a position of the locator (158,159,164, 206) relative to the element array (140,153, 172, 200) based on the output; determine a misalignment of the EWOD cartridge (105,152,163) relative to the microfluidic instrument (104, 154) based on the determined position of the locator (158,159,164, 206); and adjust a manipulation operation of a liquid droplet (144,202) to compensate for the determined misalignment of the EWOD cartridge (105,152,163) relative to the microfluidic instrument (104, 154).