Self-supervised pre-training paradigm has gained increasing prominence for learning transferable representations in medical imaging, yet existing methods for ultrasound (US) images operate at the image or frame level, overlooking the anatomical context for clinical-aligned representation learning. In this work, we propose an anatomy-anchored ultrasound self-supervision framework ANAUS that shifts representation learning from generic visual regions to clinically meaningful anatomical structures. Utilizing a learnable latent prompt engine alongside a one-time domain adaptation on existing public image-mask pairs, we empower the LP-SAM module to achieve annotation-free anatomy delineation at scale. Building upon this anatomical grounding, we propose a dual-policy self-supervised learning paradigm consisting of inter-view semantics-aware anatomy-separating alignment and contextual core-region prediction to enhance representation learning. Specifically, the former enforces feature invariance within identical anatomical regions while promoting discriminability across distinct structures; the latter compels the model to reconstruct corrupted regions, thereby capturing fine-grained structu
With the increasing interest in deploying Artificial Intelligence in medicine, we previously introduced HAIM (Holistic AI in Medicine), a framework that fuses multimodal data to solve downstream clinical tasks. However, HAIM uses data in a task-agnostic manner and lacks explainability. To address these limitations, we introduce xHAIM (Explainable HAIM), a novel framework leveraging Generative AI to enhance both prediction and explainability through four structured steps: (1) automatically identifying task-relevant patient data across modalities, (2) generating comprehensive patient summaries, (3) using these summaries for improved predictive modeling, and (4) providing clinical explanations by linking predictions to patient-specific medical knowledge. Evaluated on the HAIM-MIMIC-MM dataset, xHAIM improves average AUC from 79.9% to 90.3% across chest pathology and operative tasks. Importantly, xHAIM transforms AI from a black-box predictor into an explainable decision support system, enabling clinicians to interactively trace predictions back to relevant patient data, bridging AI advancements with clinical utility.
Medicine, including fields in healthcare and life sciences, has seen a flurry of quantum-related activities and experiments in the last few years (although biology and quantum theory have arguably been entangled ever since Schrödinger's cat). The initial focus was on biochemical and computational biology problems; recently, however, clinical and medical quantum solutions have drawn increasing interest. The rapid emergence of quantum computing in health and medicine necessitates a mapping of the landscape. In this review, clinical and medical proof-of-concept quantum computing applications are outlined and put into perspective. These consist of over 40 experimental and theoretical studies. The use case areas span genomics, clinical research and discovery, diagnostics, and treatments and interventions. Quantum machine learning (QML) in particular has rapidly evolved and shown to be competitive with classical benchmarks in recent medical research. Near-term QML algorithms have been trained with diverse clinical and real-world data sets. This includes studies in generating new molecular entities as drug candidates, diagnosing based on medical image classification, predicting patient pe
Understanding the biological mechanisms of disease is crucial for medicine, and in particular, for drug discovery. AI-powered analysis of genome-scale biological data holds great potential in this regard. The increasing availability of single-cell RNA sequencing data has enabled the development of large foundation models for disease biology. However, existing foundation models only modestly improve over task-specific models in downstream applications. Here, we explored two avenues for improving single-cell foundation models. First, we scaled the pre-training data to a diverse collection of 116 million cells, which is larger than those used by previous models. Second, we leveraged the availability of large-scale biological annotations as a form of supervision during pre-training. We trained the \model family of models comprising six transformer-based state-of-the-art single-cell foundation models with 70 million, 160 million, and 400 million parameters. We vetted our models on several downstream evaluation tasks, including identifying the underlying disease state of held-out donors not seen during training, distinguishing between diseased and healthy cells for disease conditions and
Understanding the mechanisms of interactions within cells, tissues, and organisms is crucial to driving developments across biology and medicine. Mathematical modeling is an essential tool for simulating biological systems and revealing biochemical regulatory mechanisms. Building on experiments, mechanistic models are widely used to describe small-scale intracellular networks and uncover biochemical mechanisms in healthy and diseased states. The rapid development of high-throughput sequencing techniques and computational tools has recently enabled models that span multiple scales, often integrating signaling, gene regulatory, and metabolic networks. These multiscale models enable comprehensive investigations of cellular networks and thus reveal previously unknown disease mechanisms and pharmacological interventions. Here, we review systems biology models from classical mechanistic models to larger, multiscale models that integrate multiple layers of cellular networks. We introduce several examples of models of hypertrophic cardiomyopathy, exercise, and cancer cell proliferation. Additionally, we discuss methods that increase the certainty and accuracy of model predictions. Integrat
Quantum computing holds significant potential for applications in biology and medicine, spanning from the simulation of biomolecules to machine learning approaches for subtyping cancers on the basis of clinical features. This potential is encapsulated by the concept of a quantum advantage, which is typically contingent on a reduction in the consumption of a computational resource, such as time, space, or data. Here, we distill the concept of a quantum advantage into a simple framework that we hope will aid researchers in biology and medicine pursuing the development of quantum applications. We then apply this framework to a wide variety of computational problems relevant to these domains in an effort to i) assess the potential of quantum advantages in specific application areas and ii) identify gaps that may be addressed with novel quantum approaches. Bearing in mind the rapid pace of change in the fields of quantum computing and classical algorithms, we aim to provide an extensive survey of applications in biology and medicine that may lead to practical quantum advantages.
Systems biology relies on mathematical models that often involve complex and intractable likelihood functions, posing challenges for efficient inference and model selection. Generative models, such as normalizing flows, have shown remarkable ability in approximating complex distributions in various domains. However, their application in systems biology for approximating intractable likelihood functions remains unexplored. Here, we elucidate a framework for leveraging normalizing flows to approximate complex likelihood functions inherent to systems biology models. By using normalizing flows in the Simulation-based inference setting, we demonstrate a method that not only approximates a likelihood function but also allows for model inference in the model selection setting. We showcase the effectiveness of this approach on real-world systems biology problems, providing practical guidance for implementation and highlighting its advantages over traditional computational methods.
Ultrasound-based bone surface segmentation is crucial in computer-assisted orthopedic surgery. However, ultrasound images have limitations, including a low signal-to-noise ratio, and acoustic shadowing, which make interpretation difficult. Existing deep learning models for bone segmentation rely primarily on costly manual labeling by experts, limiting dataset size and model generalizability. Additionally, the complexity of ultrasound physics and acoustic shadow makes the images difficult for humans to interpret, leading to incomplete labels in anechoic regions and limiting model performance. To advance ultrasound bone segmentation and establish effective model benchmarks, larger and higher-quality datasets are needed. We propose a methodology for collecting ex-vivo ultrasound datasets with automatically generated bone labels, including anechoic regions. The proposed labels are derived by accurately superimposing tracked bone CT models onto the tracked ultrasound images. These initial labels are refined to account for ultrasound physics. A clinical evaluation is conducted by an expert physician specialized on orthopedic sonography to assess the quality of the generated bone labels.
In its broadest definition, systems biology is the application of a `systems' way of thinking about and doing cell biology. By implication, this also invites us to consider a systems approach in the context of medicine and the treatment of disease. In particular, the idea that systems biology can form the basis of a personalised, predictive medicine will require that much closer attention is paid to the analytic properties of the feedback loops which will be set up by a personalised approach to healthcare. To emphasize the role that feedback theory will play in understanding personalised medicine, we use the term feedback medicine to describe the issues outlined.In these notes we consider feedback and control systems concepts applied to two important themes in medical systems biology - personalised medicine and combinatorial intervention. In particular, we formulate a feedback control interpretation for the administration of medicine, and relate them to various forms of medical treatment.
Efficient intravascular access in trauma and critical care significantly impacts patient outcomes. However, the availability of skilled medical personnel in austere environments is often limited. Autonomous robotic ultrasound systems can aid in needle insertion for medication delivery and support non-experts in such tasks. Despite advances in autonomous needle insertion, inaccuracies in vessel segmentation predictions pose risks. Understanding the uncertainty of predictive models in ultrasound imaging is crucial for assessing their reliability. We introduce MSU-Net, a novel multistage approach for training an ensemble of U-Nets to yield accurate ultrasound image segmentation maps. We demonstrate substantial improvements, 18.1% over a single Monte Carlo U-Net, enhancing uncertainty evaluations, model transparency, and trustworthiness. By highlighting areas of model certainty, MSU-Net can guide safe needle insertions, empowering non-experts to accomplish such tasks.
Ultrasound Localization Microscopy (ULM) relies on the injection of microbubbles (MBs) to obtain highly resolved density maps of blood circulation in vivo, with a resolution that can reach 10 μm ~ λ/10 in the rodent brain. Static mean velocity maps can be extracted but are intrinsically biased by potential significant changes in the number of MBs detected during the cardiac cycle. Dynamic ULM (DULM) is a technique developed for non-invasive pulsatility measurements in the brain of rodents, leading to temporally resolved velocity and density cine-loops. It was previously based on external triggers such as the electrocardiogram (ECG), limiting its use to datasets acquired specifically for DULM applications while also increasing the required acquisition time. This study presents a new motion matching method using tissue Doppler that eliminates the need for ECG-gating in DULM experiments. DULM can now be performed on any ULM datasets, recovering pertinent temporal information, and improving the robustness of the mean velocity estimates.
In a recent paper, Wilmes et al. demonstrated a qualitative integration of omics data streams to gain a mechanistic understanding of cyclosporine A toxicity. One of their major conclusions was that cyclosporine A strongly activates the nuclear factor (erythroid-derived 2)-like 2 pathway (Nrf2) in renal proximal tubular epithelial cells exposed in vitro. We pursue here the analysis of those data with a quantitative integration of omics data with a differential equation model of the Nrf2 pathway. That was done in two steps: (i) Modeling the in vitro pharmacokinetics of cyclosporine A (exchange between cells, culture medium and vial walls) with a minimal distribution model. (ii) Modeling the time course of omics markers in response to cyclosporine A exposure at the cell level with a coupled PK-systems biology model. Posterior statistical distributions of the parameter values were obtained by Markov chain Monte Carlo sampling. Data were well simulated, and the known in vitro toxic effect EC50 was well matched by model predictions. The integration of in vitro pharmacokinetics and systems biology modeling gives us a quantitative insight into mechanisms of cyclosporine A oxidative-stress
Confounding information in the form of text or markings embedded in medical images can severely affect the training of diagnostic deep learning algorithms. However, data collected for clinical purposes often have such markings embedded in them. In dermatology, known examples include drawings or rulers that are overrepresented in images of malignant lesions. In this paper, we encounter text and calipers placed on the images found in national databases containing fetal screening ultrasound scans, which correlate with standard planes to be predicted. In order to utilize the vast amounts of data available in these databases, we develop and validate a series of methods for minimizing the confounding effects of embedded text and calipers on deep learning algorithms designed for ultrasound, using standard plane classification as a test case.
The International Society of Ultrasound advocates Intrapartum Ultrasound (US) Imaging in Obstetrics and Gynecology (ISUOG) to monitor labour progression through changes in fetal head position. Two reliable ultrasound-derived parameters that are used to predict outcomes of instrumental vaginal delivery are the angle of progression (AoP) and head-symphysis distance (HSD). In this work, as part of the Intrapartum Ultrasounds Grand Challenge (IUGC) 2024, we propose an automated fetal biometry measurement pipeline to reduce intra- and inter-observer variability and improve measurement reliability. Our pipeline consists of three key tasks: (i) classification of standard planes (SP) from US videos, (ii) segmentation of fetal head and pubic symphysis from the detected SPs, and (iii) computation of the AoP and HSD from the segmented regions. We perform sparse sampling to mitigate class imbalances and reduce spurious correlations in task (i), and utilize ensemble-based deep learning methods for task (i) and (ii) to enhance generalizability under different US acquisition settings. Finally, to promote robustness in task iii) with respect to the structural fidelity of measurements, we retain th
A number of models in mathematical epidemiology have been developed to account for control measures such as vaccination or quarantine. However, COVID-19 has brought unprecedented social distancing measures, with a challenge on how to include these in a manner that can explain the data but avoid overfitting in parameter inference. We here develop a simple time-dependent model, where social distancing effects are introduced analogous to coarse-grained models of gene expression control in systems biology. We apply our approach to understand drastic differences in COVID-19 infection and fatality counts, observed between Hubei (Wuhan) and other Mainland China provinces. We find that these unintuitive data may be explained through an interplay of differences in transmissibility, effective protection, and detection efficiencies between Hubei and other provinces. More generally, our results demonstrate that regional differences may drastically shape infection outbursts. The obtained results demonstrate the applicability of our developed method to extract key infection parameters directly from publically available data so that it can be globally applied to outbreaks of COVID-19 in a number
New technologies have enabled the investigation of biology and human health at an unprecedented scale and in multiple dimensions. These dimensions include a myriad of properties describing genome, epigenome, transcriptome, microbiome, phenotype, and lifestyle. No single data type, however, can capture the complexity of all the factors relevant to understanding a phenomenon such as a disease. Integrative methods that combine data from multiple technologies have thus emerged as critical statistical and computational approaches. The key challenge in developing such approaches is the identification of effective models to provide a comprehensive and relevant systems view. An ideal method can answer a biological or medical question, identifying important features and predicting outcomes, by harnessing heterogeneous data across several dimensions of biological variation. In this Review, we describe the principles of data integration and discuss current methods and available implementations. We provide examples of successful data integration in biology and medicine. Finally, we discuss current challenges in biomedical integrative methods and our perspective on the future development of the
The success of precision medicine requires computational models that can effectively process and interpret diverse physiological signals across heterogeneous patient populations. While foundation models have demonstrated remarkable transfer capabilities across various domains, their effectiveness in handling individual-specific physiological signals - crucial for precision medicine - remains largely unexplored. This work introduces a systematic pipeline for rapidly and efficiently evaluating foundation models' transfer capabilities in medical contexts. Our pipeline employs a three-stage approach. First, it leverages physiological simulation software to generate diverse, clinically relevant scenarios, particularly focusing on data-scarce medical conditions. This simulation-based approach enables both targeted capability assessment and subsequent model fine-tuning. Second, the pipeline projects these simulated signals through the foundation model to obtain embeddings, which are then evaluated using linear methods. This evaluation quantifies the model's ability to capture three critical aspects: physiological feature independence, temporal dynamics preservation, and medical scenario d
The last decade has seen an explosion in models that describe phenomena in systems medicine. Such models are especially useful for studying signaling pathways, such as the Wnt pathway. In this chapter we use the Wnt pathway to showcase current mathematical and statistical techniques that enable modelers to gain insight into (models of) gene regulation, and generate testable predictions. We introduce a range of modeling frameworks, but focus on ordinary differential equation (ODE) models since they remain the most widely used approach in systems biology and medicine and continue to offer great potential. We present methods for the analysis of a single model, comprising applications of standard dynamical systems approaches such as nondimensionalization, steady state, asymptotic and sensitivity analysis, and more recent statistical and algebraic approaches to compare models with data. We present parameter estimation and model comparison techniques, focusing on Bayesian analysis and coplanarity via algebraic geometry. Our intention is that this (non exhaustive) review may serve as a useful starting point for the analysis of models in systems medicine.
Dynamical systems modeling, particularly via systems of ordinary differential equations, has been used to effectively capture the temporal behavior of different biochemical components in signal transduction networks. Despite the recent advances in experimental measurements, including sensor development and '-omics' studies that have helped populate protein-protein interaction networks in great detail, modeling in systems biology lacks systematic methods to estimate kinetic parameters and quantify associated uncertainties. This is because of multiple reasons, including sparse and noisy experimental measurements, lack of detailed molecular mechanisms underlying the reactions, and missing biochemical interactions. Additionally, the inherent nonlinearities with respect to the states and parameters associated with the system of differential equations further compound the challenges of parameter estimation. In this study, we propose a comprehensive framework for Bayesian parameter estimation and complete quantification of the effects of uncertainties in the data and models. We apply these methods to a series of signaling models of increasing mathematical complexity. Systematic analysis o
Medical ultrasound imaging relies heavily on high-quality signal processing to provide reliable and interpretable image reconstructions. Conventionally, reconstruction algorithms where derived from physical principles. These algorithms rely on assumptions and approximations of the underlying measurement model, limiting image quality in settings were these assumptions break down. Conversely, more sophisticated solutions based on statistical modelling, careful parameter tuning, or through increased model complexity, can be sensitive to different environments. Recently, deep learning based methods, which are optimized in a data-driven fashion, have gained popularity. These model-agnostic techniques often rely on generic model structures, and require vast training data to converge to a robust solution. A relatively new paradigm combines the power of the two: leveraging data-driven deep learning, as well as exploiting domain knowledge. These model-based solutions yield high robustness, and require less parameters and training data than conventional neural networks. In this work we provide an overview of these techniques from recent literature, and discuss a wide variety of ultrasound ap