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Microscopy and imaging are essential to understanding and exploring biology. Modern staining and imaging techniques generate large amounts of data resulting in the need for automated analysis approaches. Many earlier approaches relied on handcrafted feature extractors, while today's deep-learning-based methods open up new ways to analyze data automatically.

Deep learning has become popular in bioimage processing as it can extract high-level features describing image content (Paper III). The work in this thesis explores various aspects and limitations of machine learning and deep learning with applications in biology. Learning-based methods have generalization issues on out-of-distribution data points, and methods such as uncertainty estimation (Paper II) and visual quality control (Paper V) can provide ways to mitigate those issues. Furthermore, deep learning methods often require large amounts of data during training. Here the focus is on optimizing deep learning methods to meet current computational capabilities and handle the increasing volume and size of data (Paper I). Model uncertainty and data augmentation techniques are also explored (Papers II and III).

This thesis is split into chapters describing the main components of cell biology, microscopy imaging, and the mathematical and machine-learning theories to give readers an introduction to biomedical image processing. The main contributions of this thesis are deep-learning methods for reconstructing patch-based segmentation (Paper I) and pixel regression of traction force images (Paper II), followed by methods for aligning images from different sensors in a common coordinate system (named multimodal image registration) using representation learning (Paper III) and Bayesian optimization (Paper IV). Finally, the thesis introduces TissUUmaps 3, a tool for visualizing multiplexed spatial transcriptomics data (Paper V). These contributions provide methods and tools detailing how to apply mathematical frameworks and machine-learning theory to biology, giving us concrete tools to improve our understanding of complex biological processes.