Methods and systems for measuring values of one or more parameters of interest, including changes in values of one or more parameters of interest, based on measured spectral differences are presented herein. A trained spectral difference based measurement model determines changes in the values of one or more parameters of interest based on a measure of differences in spectra measured before and after one or more process steps. In some examples, a measure of spectral difference is determined based on a difference in measured intensity, a difference in harmonic signal values, or a difference in value of one or more Mueller Matrix elements. A measure of spectral difference may be expressed as a set of difference values, a scalar value, or coefficients of a functional fit to difference values. A measure of spectral difference may be determined based on a weighting of spectral differences according to wavelength.