Disclosed is a method of iteratively optimizing two (or more) interrelated sets of probes for the multi-step analysis of sets of designated sequences, each such sequence requiring, for conversion, at least one conversion probe (“primer”), and each converted sequence requiring, for detection, at least one capture probe. The iterative method disclosed herein for the concurrent optimization of primer and probe selection invokes fast logical string matching functions to perform a complete cross-correlation of probe sequences and target sequences. The score function assigns to each probe-target alignment a “degree of matching” score on the basis of position-weighted Hamming distance functions introduced herein. Pairs of probes in the final selection may differ in several positions, while other pairs of probes may differ in only a single position. Not all such positions are of equal importance, and a score function is introduced, reflecting the position of the mismatch within the probe sequence.