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We present INSPIRE, a top-performing general-purpose method for deformable image registration. INSPIRE brings distance measures which combine intensity and spatial information into an elastic B-splines-based transformation model and incorporates an inverse inconsistency penalization supporting symmetric registration performance. We introduce several theoretical and algorithmic solutions which provide high computational efficiency and thereby applicability of the proposed framework in a wide range of real scenarios. We show that INSPIRE delivers highly accurate, as well as stable and robust registration results. We evaluate the method on a 2D dataset created from retinal images, characterized by presence of networks of thin structures. Here INSPIRE exhibits excellent performance, substantially outperforming the widely used reference methods. We also evaluate INSPIRE on the Fundus Image Registration Dataset (FIRE), which consists of 134 pairs of separately acquired retinal images. INSPIRE exhibits excellent performance on the FIRE dataset, substantially outperforming several domain-specific methods. We also evaluate the method on four benchmark datasets of 3D magnetic resonance images of brains, for a total of 2088 pairwise registrations. A comparison with 17 other state-of-the-art methods reveals that INSPIRE provides the best overall performance. Code is available at github.com/MIDA-group/inspire.

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Despite current advancement in the field of biomedical image processing, propelled by the deep learning revolution, multimodal image registration, due to its several challenges, is still often performed manually by specialists. The recent success of image-to-image (I2I) translation in computer vision applications and its growing use in biomedical areas provide a tempting possibility of transforming the multimodal registration problem into a, potentially easier, monomodal one. We conduct an empirical study of the applicability of modern I2I translation methods for the task of rigid registration of multimodal biomedical and medical 2D and 3D images. We compare the performance of four Generative Adversarial Network (GAN)-based I2I translation methods and one contrastive representation learning method, subsequently combined with two representative monomodal registration methods, to judge the effectiveness of modality translation for multimodal image registration. We evaluate these method combinations on four publicly available multimodal (2D and 3D) datasets and compare with the performance of registration achieved by several well-known approaches acting directly on multimodal image data. Our results suggest that, although I2I translation may be helpful when the modalities to register are clearly correlated, registration of modalities which express distinctly different properties of the sample are not well handled by the I2I translation approach. The evaluated representation learning method, which aims to find abstract image-like representations of the information shared between the modalities, manages better, and so does the Mutual Information maximisation approach, acting directly on the original multimodal images. We share our complete experimental setup as open-source (https://github.com/MIDA-group/MultiRegEval), including method implementations, evaluation code, and all datasets, for further reproducing and benchmarking.

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Multiplexed and spatially resolved single-cell analyses that intend to study tissue heterogeneity and cell organization invariably face as a first step the challenge of cell classification. Accuracy and reproducibility are important for the downstream process of counting cells, quantifying cell-cell interactions, and extracting information on disease-specific localized cell niches. Novel staining techniques make it possible to visualize and quantify large numbers of cell-specific molecular markers in parallel. However, due to variations in sample handling and artifacts from staining and scanning, cells of the same type may present different marker profiles both within and across samples. We address multiplexed immunofluorescence data from tissue microarrays of low-grade gliomas and present a methodology using two different machine learning architectures and features insensitive to illumination to perform cell classification. The fully automated cell classification provides a measure of confidence for the decision and requires a comparably small annotated data set for training, which can be created using freely available tools. Using the proposed method, we reached an accuracy of 83.1% on cell classification without the need for standardization of samples. Using our confidence measure, cells with low-confidence classifications could be excluded, pushing the classification accuracy to 94.5%. Next, we used the cell classification results to search for cell niches with an unsupervised learning approach based on graph neural networks. We show that the approach can re-detect specialized tissue niches in previously published data, and that our proposed cell classification leads to niche definitions that may be relevant for sub-groups of glioma, if applied to larger data sets.

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Intensity-based image registration approaches rely on similarity measures to guide the search for geometric correspondences with high affinity between images. The properties of the used measure are vital for the robustness and accuracy of the registration. In this study a symmetric, intensity interpolationfree, affine registration framework based on a combination of intensity and spatial information is proposed. The excellent performance of the framework is demonstrated on a combination of synthetic tests, recovering known transformations in the presence of noise, and real applications in biomedical and medical image registration, for both 2D and 3D images. The method exhibits greater robustness and higher accuracy than similarity measures in common use, when inserted into a standard gradientbased registration framework available as part of the open source Insight Segmentation and Registration Toolkit (ITK). The method is also empirically shown to have a low computational cost, making it practical for real applications. Source code is available.