An optimized measurement model is determined based a model of parameter variations across a semiconductor wafer. A global, cross-wafer model characterizes a structural parameter as a function of location on the wafer. A measurement model is optimized by constraining the measurement model with the cross-wafer model of process variations. In some examples, the cross-wafer model is itself a parameterized model. However, the cross-wafer model characterizes the values of a structural parameter at any location on the wafer with far fewer parameters than a measurement model that treats the structural parameter as unknown at every location. In some examples, the cross-wafer model gives rise to constraints among unknown structural parameter values based on location on the wafer. In one example, the cross-wafer model relates the values of structural parameters associated with groups of measurement sites based on their location on the wafer.