The present application discloses methods, systems and devices for using charged particle beam tools to pattern and inspect a substrate. The inventors have discovered that it is highly advantageous to use patterns generated using the Hadamard transform as alignment and registration marks (Hadamard targets) for multiple-column charged particle beam lithography and inspection tools. Further, superior substrate alignment and layer-to-layer pattern registration accuracy can be achieved using Hadamard targets patterned in edge-proximal portions of the substrate that are typically stripped bare of resist prior to lithography, in addition to Hadamard targets patterned in inner substrate portions. High-order Hadamard targets can also be patterned and imaged to obtain superior column performance metrics for applications such as super-rapid beam calibration DOE, column matching, and column performance tracking. Superior alignment and registration, and column parameter optimization, allow significant yield gains.