The invention provides methods for processing tissue-derived spectral data for use in a tissue classification algorithm. Methods of the invention comprise application of spectral and/or image masks for automatically separating ambiguous or unclassifiable spectral data from valid spectral data. The invention improves the accuracy of tissue classification, in part, by properly identifying and accounting for spectral data from tissue regions that are affected by an obstruction and/or regions that lie outside a diagnostic zone of interest.