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Purpose: Multiplex staining allows molecular co-localization analysis of same cell or tissue sections and maximizes the amount of data acquired from individual samples. We developed a non-linear registration framework for automated alignment of whole mount multiplexed histology images of prostate cancer. To achieve a precise automatic fit of bleached and restained high resolution tissue samples, a patch-based approach is proposed to improve annotation speed and analysis. Methods: The three-step co-registration process begins with a coarse low-resolution registration of the IHC stained image to the fixed H&E-stained image. The initial registration is then refined separately for each high-resolution patch using a smaller search window. Finally, registered patches are stitched back together using speeded up robust features (SURF). We apply the method to five multiplex whole mount prostate histology slides. To determine its effectiveness, we compare the automatic registration to the initial coarse registration and a manual control point based-method varying the number of control points. Results: For the control point-based approach, 25, 50, and 100 manually placed set landmarks resulted in a decrease of - 76.20%, -75.9% and -75.48% of the root mean squared error (RMSE), respectively. Compared to the initial registration an improvement of -76.29% of RMSE can be seen, illustrating the potential benefits of a patch-based automatic approach. Conclusion: The proposed method achieved excellent registration of the IHC to the input image. The automated method for registration of multiplexed histology images achieves high accuracy in shorter time and with greater reproducibility than conventional registration approaches and semi-automatic control points without the need for time consuming and subjective manual control-point setting. The accuracy of the fit especially improves in complex areas close to tissue tears and folds.
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