Purpose Clinical image pairs provide the most realistic test data for image registration evaluation. However, the optimal registration is unknown. Using combinatorial rigid registration optimization (CORRO) we demonstrate a method to estimate the optimal alignment for rigid‐registration of clinical image pairs. Methods Expert selected landmark pairs were selected for each CT/CBCT image pair for six cases representing head and neck, thoracic, and pelvic anatomic regions. Combination subsets of a k number of landmark pairs (k‐combination set) were generated without repeat to form a large set of k‐combination sets (k‐set) for k?=?4,8,12. The rigid transformation between the image pairs was calculated for each k‐combination set. The mean and standard deviation of these transformations were used to derive final registration for each k‐set. Results The standard deviation of registration output decreased as the k‐size increased for all cases. The joint entropy evaluated for each k‐set of each case was smaller than those from two commercially available registration programs indicating a stronger correlation between the image pair after CORRO was used. A joint histogram plot of all three algorithms showed high correlation between them. As further proof of the efficacy of CORRO the joint entropy of each member of 30?000?k‐combination sets in k?=?4 were calculated for one of the thoracic cases. The minimum joint entropy was found to exist at the estimated mean of registration indicating CORRO converges to the optimal rigid‐registration results. Conclusions We have developed a methodology called CORRO that allows us to estimate optimal alignment for rigid‐registration of clinical image pairs using a large set landmark point. The results for the rigid‐body registration have been shown to be comparable to results from commercially available algorithms for all six cases. CORRO can serve as an excellent tool that can be used to test and validate rigid registration algorithms.
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