1. A method of developing a multi-tiered calibration model for estimating concentration of a target blood analyte from measured tissue spectra, comprising the steps of: providing a calibration set, wherein said calibration set comprises a data set of exemplar spectral measurements from a representative sampling of a subject population; initially, classifying said exemplar measurements into previously defined classes based on a priori a priori information pertaining to a corresponding subject; further classifying said exemplar measurements into previously defined classes based on at least one instrumental measurement at a tissue measurement site; extracting at least one feature from said exemplar measurements for still further classification, wherein a decision rule makes class assignments; and calculating at least one localized calibration model based on said classified measurements and an associated set of reference values.