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A coloring of the vertex set of a graph using the colors red and blue is a closed neighborhood balanced coloring if for each vertex there are an equal number of red and blue vertices in its closed neighborhood. A graph with such a coloring is called a CNBC graph. Freyberg and Marr studied the related class of NBC graphs where closed neighborhood is replaced by open neighborhood. We prove results about CNBC graphs and NBC graphs. We show that the class of CNBC graphs is not hereditary, that the sizes of the color classes can be arbitrarily different, and that if the sizes of the color classes are equal, then a graph is a CNBC graph if and only if its complement is an NBC graph. When the sizes of the color classes are equal, we show that the join of two CNBC graphs is a CNBC graph, and the lexicographic product of a CNBC graph with any graph is a CNBC graph. We prove that the Cartesian product of any CNBC graph and any NBC graph is a CNBC graph, and characterize when a hypercube is an NBC graph or a CNBC graph, but show that the product of two CNBC graphs need not be an NBC graph. We show that the strong product of a CNBC graph with any graph is a CNBC graph. We construct infinite families of circulants that are CNBC graphs, and give characterizations of CNBC trees, generalized Petersen graphs, cubic circulants and quintic circulants when $n\equiv 2 \pmod 4$., Comment: 22 pages, 11 figures, 4 tables

Histopathology, the microscopic study of diseased tissue, is increasingly digitized, enabling improved visualization and streamlined workflows. An important task in histopathology is the segmentation of cells and glands, essential for determining shape and frequencies that can serve as indicators of disease. Deep learning tools are widely used in histopathology. However, variability in tissue appearance and cell morphology presents challenges for achieving reliable segmentation, often requiring manual correction to improve accuracy. This work introduces CellPilot, a framework that bridges the gap between automatic and interactive segmentation by providing initial automatic segmentation as well as guided interactive refinement. Our model was trained on over 675,000 masks of nine diverse cell and gland segmentation datasets, spanning 16 organs. CellPilot demonstrates superior performance compared to other interactive tools on three held-out histopathological datasets while enabling automatic segmentation. We make the model and a graphical user interface designed to assist practitioners in creating large-scale annotated datasets available as open-source, fostering the development of more robust and generalized diagnostic models.

Background: The integration of multi-stain histopathology images through deep learning poses a significant challenge in digital histopathology. Current multi-modal approaches struggle with data heterogeneity and missing data. This study aims to overcome these limitations by developing a novel transformer model for multi-stain integration that can handle missing data during training as well as inference. Methods: We propose UNICORN (UNiversal modality Integration Network for CORonary classificatioN) a multi-modal transformer capable of processing multi-stain histopathology for atherosclerosis severity class prediction. The architecture comprises a two-stage, end-to-end trainable model with specialized modules utilizing transformer self-attention blocks. The initial stage employs domain-specific expert modules to extract features from each modality. In the subsequent stage, an aggregation expert module integrates these features by learning the interactions between the different data modalities. Results: Evaluation was performed using a multi-class dataset of atherosclerotic lesions from the Munich Cardiovascular Studies Biobank (MISSION), using over 4,000 paired multi-stain whole slide images (WSIs) from 170 deceased individuals on 7 prespecified segments of the coronary tree, each stained according to four histopathological protocols. UNICORN achieved a classification accuracy of 0.67, outperforming other state-of-the-art models. The model effectively identifies relevant tissue phenotypes across stainings and implicitly models disease progression. Conclusion: Our proposed multi-modal transformer model addresses key challenges in medical data analysis, including data heterogeneity and missing modalities. Explainability and the model's effectiveness in predicting atherosclerosis progression underscores its potential for broader applications in medical research.

Biomedical imaging and RNA sequencing with single-cell resolution improves our understanding of white blood cell diseases like leukemia. By combining morphological and transcriptomic data, we can gain insights into cellular functions and trajectoriess involved in blood cell differentiation. However, existing methodologies struggle with integrating morphological and transcriptomic data, leaving a significant research gap in comprehensively understanding the dynamics of cell differentiation. Here, we introduce an unsupervised method that explores and reconstructs these two modalities and uncovers the relationship between different subtypes of white blood cells from human peripheral blood smears in terms of morphology and their corresponding transcriptome. Our method is based on a beta-variational autoencoder ({\ss}-VAE) with a customized loss function, incorporating a R-CNN architecture to distinguish single-cell from background and to minimize any interference from artifacts. This implementation of {\ss}-VAE shows good reconstruction capability along with continuous latent embeddings, while maintaining clear differentiation between single-cell classes. Our novel approach is especially helpful to uncover the correlation of two latent features in complex biological processes such as formation of granules in the cell (granulopoiesis) with gene expression patterns. It thus provides a unique tool to improve the understanding of white blood cell maturation for biomedicine and diagnostics., Comment: Accepted for publication at MICCAI 2024 workshop on AI for Imaging Genomics Learning (AIIG)

Historical linguists have long written a kind of incompletely formalized ''program'' that converts reconstructed words in an ancestor language into words in one of its attested descendants that consist of a series of ordered string rewrite functions (called sound laws). They do this by observing pairs of words in the reconstructed language (protoforms) and the descendent language (reflexes) and constructing a program that transforms protoforms into reflexes. However, writing these programs is error-prone and time-consuming. Prior work has successfully scaffolded this process computationally, but fewer researchers have tackled Sound Law Induction (SLI), which we approach in this paper by casting it as Programming by Examples. We propose a language-agnostic solution that utilizes the programming ability of Large Language Models (LLMs) by generating Python sound law programs from sound change examples. We evaluate the effectiveness of our approach for various LLMs, propose effective methods to generate additional language-agnostic synthetic data to fine-tune LLMs for SLI, and compare our method with existing automated SLI methods showing that while LLMs lag behind them they can complement some of their weaknesses.

Diagnosis of hematological malignancies depends on accurate identification of white blood cells in peripheral blood smears. Deep learning techniques are emerging as a viable solution to scale and optimize this process by automatic cell classification. However, these techniques face several challenges such as limited generalizability, sensitivity to domain shifts, and lack of explainability. Here, we introduce a novel approach for white blood cell classification based on neural cellular automata (NCA). We test our approach on three datasets of white blood cell images and show that we achieve competitive performance compared to conventional methods. Our NCA-based method is significantly smaller in terms of parameters and exhibits robustness to domain shifts. Furthermore, the architecture is inherently explainable, providing insights into the decision process for each classification, which helps to understand and validate model predictions. Our results demonstrate that NCA can be used for image classification, and that they address key challenges of conventional methods, indicating a high potential for applicability in clinical practice., Comment: Accepted for publication at the 27th International Conference on Medical Image Computing and Computer Assisted Intervention - MICCAI 2024

In hematology, computational models offer significant potential to improve diagnostic accuracy, streamline workflows, and reduce the tedious work of analyzing single cells in peripheral blood or bone marrow smears. However, clinical adoption of computational models has been hampered by the lack of generalization due to large batch effects, small dataset sizes, and poor performance in transfer learning from natural images. To address these challenges, we introduce DinoBloom, the first foundation model for single cell images in hematology, utilizing a tailored DINOv2 pipeline. Our model is built upon an extensive collection of 13 diverse, publicly available datasets of peripheral blood and bone marrow smears, the most substantial open-source cohort in hematology so far, comprising over 380,000 white blood cell images. To assess its generalization capability, we evaluate it on an external dataset with a challenging domain shift. We show that our model outperforms existing medical and non-medical vision models in (i) linear probing and k-nearest neighbor evaluations for cell-type classification on blood and bone marrow smears and (ii) weakly supervised multiple instance learning for acute myeloid leukemia subtyping by a large margin. A family of four DinoBloom models (small, base, large, and giant) can be adapted for a wide range of downstream applications, be a strong baseline for classification problems, and facilitate the assessment of batch effects in new datasets. All models are available at github.com/marrlab/DinoBloom.

Poor generalization performance caused by distribution shifts in unseen domains often hinders the trustworthy deployment of deep neural networks. Many domain generalization techniques address this problem by adding a domain invariant regularization loss terms during training. However, there is a lack of modular software that allows users to combine the advantages of different methods with minimal effort for reproducibility. DomainLab is a modular Python package for training user specified neural networks with composable regularization loss terms. Its decoupled design allows the separation of neural networks from regularization loss construction. Hierarchical combinations of neural networks, different domain generalization methods, and associated hyperparameters, can all be specified together with other experimental setup in a single configuration file. Hierarchical combinations of neural networks, different domain generalization methods, and associated hyperparameters, can all be specified together with other experimental setup in a single configuration file. In addition, DomainLab offers powerful benchmarking functionality to evaluate the generalization performance of neural networks in out-of-distribution data. The package supports running the specified benchmark on an HPC cluster or on a standalone machine. The package is well tested with over 95 percent coverage and well documented. From the user perspective, it is closed to modification but open to extension. The package is under the MIT license, and its source code, tutorial and documentation can be found at https://github.com/marrlab/DomainLab.

We address the online combinatorial choice of weight multipliers for multi-objective optimization of many loss terms parameterized by neural works via a probabilistic graphical model (PGM) for the joint model parameter and multiplier evolution process, with a hypervolume based likelihood promoting multi-objective descent. The corresponding parameter and multiplier estimation as a sequential decision process is then cast into an optimal control problem, where the multi-objective descent goal is dispatched hierarchically into a series of constraint optimization sub-problems. The subproblem constraint automatically adapts itself according to Pareto dominance and serves as the setpoint for the low level multiplier controller to schedule loss landscapes via output feedback of each loss term. Our method is multiplier-free and operates at the timescale of epochs, thus saves tremendous computational resources compared to full training cycle multiplier tuning. It also circumvents the excessive memory requirements and heavy computational burden of existing multi-objective deep learning methods. We applied it to domain invariant variational auto-encoding with 6 loss terms on the PACS domain generalization task, and observed robust performance across a range of controller hyperparameters, as well as different multiplier initial conditions, outperforming other multiplier scheduling methods. We offered modular implementation of our method, admitting extension to custom definition of many loss terms.

Automated disease diagnosis using medical image analysis relies on deep learning, often requiring large labeled datasets for supervised model training. Diseases like Acute Myeloid Leukemia (AML) pose challenges due to scarce and costly annotations on a single-cell level. Multiple Instance Learning (MIL) addresses weakly labeled scenarios but necessitates powerful encoders typically trained with labeled data. In this study, we explore Self-Supervised Learning (SSL) as a pre-training approach for MIL-based AML subtype classification from blood smears, removing the need for labeled data during encoder training. We investigate the three state-of-the-art SSL methods SimCLR, SwAV, and DINO, and compare their performance against supervised pre-training. Our findings show that SSL-pretrained encoders achieve comparable performance, showcasing the potential of SSL in MIL. This breakthrough offers a cost-effective and data-efficient solution, propelling the field of AI-based disease diagnosis.

To handle the large scale of whole slide images in computational pathology, most approaches first tessellate the images into smaller patches, extract features from these patches, and finally aggregate the feature vectors with weakly-supervised learning. The performance of this workflow strongly depends on the quality of the extracted features. Recently, foundation models in computer vision showed that leveraging huge amounts of data through supervised or self-supervised learning improves feature quality and generalizability for a variety of tasks. In this study, we benchmark the most popular vision foundation models as feature extractors for histopathology data. We evaluate the models in two settings: slide-level classification and patch-level classification. We show that foundation models are a strong baseline. Our experiments demonstrate that by finetuning a foundation model on a single GPU for only two hours or three days depending on the dataset, we can match or outperform state-of-the-art feature extractors for computational pathology. These findings imply that even with little resources one can finetune a feature extractor tailored towards a specific downstream task and dataset. This is a considerable shift from the current state, where only few institutions with large amounts of resources and datasets are able to train a feature extractor. We publish all code used for training and evaluation as well as the finetuned models.

Object-oriented languages often use virtual machines (VMs) that provide mechanisms such as just-in-time (JIT) compilation and garbage collection (GC). These VM components are typically implemented in a separate layer, isolating them from the application. While this approach brings the software engineering benefits of clear separation and decoupling, it introduces barriers for both understanding VM behavior and evolving the VM implementation. For example, the GC and JIT compiler are typically fixed at VM build time, limiting arbitrary adaptation at run time. Furthermore, because of this separation, the implementation of the VM cannot typically be inspected and debugged in the same way as application code, enshrining a distinction in easy-to-work-with application and hard-to-work-with VM code. These characteristics pose a barrier for application developers to understand the engine on top of which their own code runs, and fosters a knowledge gap that prevents application developers to change the VM. We propose Live Metacircular Runtimes (LMRs) to overcome this problem. LMRs are language runtime systems that seamlessly integrate the VM into the application in live programming environments. Unlike classic metacircular approaches, we propose to completely remove the separation between application and VM. By systematically applying object-oriented design to VM components, we can build live runtime systems that are small and flexible enough, where VM engineers can benefit of live programming features such as short feedback loops, and application developers with fewer VM expertise can benefit of the stronger causal connections between their programs and the VM implementation. To evaluate our proposal, we implemented Bee/LMR, a live VM for a Smalltalk-derivative environment in 22057 lines of code. We analyze case studies on tuning the garbage collector, avoiding recompilations by the just-in-time compiler, and adding support to optimize code with vector instructions to demonstrate the trade-offs of extending exploratory programming to VM development in the context of an industrial application used in production. Based on the case studies, we illustrate how our approach facilitates the daily development work of a small team of application developers. Our approach enables VM developers to gain access to live programming tools traditionally reserved for application developers, while application developers can interact with the VM and modify it using the high-level tools they use every day. Both application and VM developers can seamlessly inspect, debug, understand, and modify the different parts of the VM with shorter feedback loops and higher-level tools.

Light-sheet fluorescence microscopy (LSFM), a planar illumination technique that enables high-resolution imaging of samples, experiences defocused image quality caused by light scattering when photons propagate through thick tissues. To circumvent this issue, dualview imaging is helpful. It allows various sections of the specimen to be scanned ideally by viewing the sample from opposing orientations. Recent image fusion approaches can then be applied to determine in-focus pixels by comparing image qualities of two views locally and thus yield spatially inconsistent focus measures due to their limited field-of-view. Here, we propose BigFUSE, a global context-aware image fuser that stabilizes image fusion in LSFM by considering the global impact of photon propagation in the specimen while determining focus-defocus based on local image qualities. Inspired by the image formation prior in dual-view LSFM, image fusion is considered as estimating a focus-defocus boundary using Bayes Theorem, where (i) the effect of light scattering onto focus measures is included within Likelihood; and (ii) the spatial consistency regarding focus-defocus is imposed in Prior. The expectation-maximum algorithm is then adopted to estimate the focus-defocus boundary. Competitive experimental results show that BigFUSE is the first dual-view LSFM fuser that is able to exclude structured artifacts when fusing information, highlighting its abilities of automatic image fusion., Comment: paper in MICCAI 2023

Accurate classification of white blood cells in peripheral blood is essential for diagnosing hematological diseases. Due to constantly evolving clinical settings, data sources, and disease classifications, it is necessary to update machine learning classification models regularly for practical real-world use. Such models significantly benefit from sequentially learning from incoming data streams without forgetting previously acquired knowledge. However, models can suffer from catastrophic forgetting, causing a drop in performance on previous tasks when fine-tuned on new data. Here, we propose a rehearsal-based continual learning approach for class incremental and domain incremental scenarios in white blood cell classification. To choose representative samples from previous tasks, we employ exemplar set selection based on the model's predictions. This involves selecting the most confident samples and the most challenging samples identified through uncertainty estimation of the model. We thoroughly evaluated our proposed approach on three white blood cell classification datasets that differ in color, resolution, and class composition, including scenarios where new domains or new classes are introduced to the model with every task. We also test a long class incremental experiment with both new domains and new classes. Our results demonstrate that our approach outperforms established baselines in continual learning, including existing iCaRL and EWC methods for classifying white blood cells in cross-domain environments., Comment: Accepted for publication at workshop on Domain Adaptation and Representation Transfer (DART) in International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2023)

Accurate classification of Acute Myeloid Leukemia (AML) subtypes is crucial for clinical decision-making and patient care. In this study, we investigate the potential presence of age and sex bias in AML subtype classification using Multiple Instance Learning (MIL) architectures. To that end, we train multiple MIL models using different levels of sex imbalance in the training set and excluding certain age groups. To assess the sex bias, we evaluate the performance of the models on male and female test sets. For age bias, models are tested against underrepresented age groups in the training data. We find a significant effect of sex and age bias on the performance of the model for AML subtype classification. Specifically, we observe that females are more likely to be affected by sex imbalance dataset and certain age groups, such as patients with 72 to 86 years of age with the RUNX1::RUNX1T1 genetic subtype, are significantly affected by an age bias present in the training data. Ensuring inclusivity in the training data is thus essential for generating reliable and equitable outcomes in AML genetic subtype classification, ultimately benefiting diverse patient populations., Comment: Accepted for publication at workshop on Fairness of AI in Medical Imaging in International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2023)

In biomedical data analysis, Multiple Instance Learning (MIL) models have emerged as a powerful tool to classify patients' microscopy samples. However, the data-intensive requirement of these models poses a significant challenge in scenarios with scarce data availability, e.g., in rare diseases. We introduce a topological regularization term to MIL to mitigate this challenge. It provides a shape-preserving inductive bias that compels the encoder to maintain the essential geometrical-topological structure of input bags during projection into latent space. This enhances the performance and generalization of the MIL classifier regardless of the aggregation function, particularly for scarce training data. The effectiveness of our method is confirmed through experiments across a range of datasets, showing an average enhancement of 2.8% for MIL benchmarks, 15.3% for synthetic MIL datasets, and 5.5% for real-world biomedical datasets over the current state-of-the-art.

Galaxy number counts in the $K$-, $H$-, $I$-, $R$-, $B$- and $U$-bands from the Durham Extragalactic Astronomy and Cosmology catalogue could be well-fitted over their whole range using luminosity function (LF) parameters derived from the SDSS at the bright region and required only modest luminosity evolution with the steepening of the LF slope ($\alpha$), except for a sudden steep increase in the $B$-band and a less steep increase in the $U$-band at faint magnitudes that required a starburst evolutionary model to account for the excess faint number counts. A cosmological model treating Hubble expansion as an Einstein curvature required less correction at faint magnitudes than a standard $\Lambda$CDM model, without requiring dark matter or dark energy. Data from DR17 of the SDSS in the $g$, $i$, $r$, $u$ and $z$ bands over two areas of the sky centred on the North Galactic Cap (NGC) and above the South Galactic Cap (SGC), with areas of 5954 and 859 sq. deg., respectively, and a combined count of 622,121 galaxies, were used to construct bright galaxy number counts and galaxy redshift/density plots within the limits of redshift $\leq0.4$ and mag $\leq20$. Their comparative densities confirmed an extensive void in the Southern sky with a deficit of 26\% out to a redshift $z$$\leq$0.15. Although not included in the number count data set because of its incompleteness at fainter magnitudes, extending the SDSS redshift-number count survey to fainter and more distant galaxies with redshift $\leq1.20$ showed a secondary peak in the number counts with many QSOs, bright X-ray and radio sources, and evolving irregular galaxies with rapid star formation rates. This sub-population at redshifts of 0.45--0.65 may account for the excess counts observed in the $B$-band., Comment: 20 pages, 15 figures