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Movies of human induced pluripotent stem cell (hiPSC)-derived engineered cardiac tissue (microbundles) contain abundant information about structural and functional maturity. However, extracting these data in a reproducible and high-throughput manner remains a major challenge. Furthermore, it is not straightforward to make direct quantitative comparisons across the multiple in vitro experimental platforms employed to fabricate these tissues. Here, we present "MicroBundlePillarTrack," an open-source optical flow-based package developed in Python to track the deflection of pillars in cardiac microbundles grown on experimental platforms with two different pillar designs ("Type 1" and "Type 2" design). Our software is able to automatically segment the pillars, track their displacements, and output time-dependent metrics for contractility analysis, including beating amplitude and rate, contractile force, and tissue stress. Because this software is fully automated, it will allow for both faster and more reproducible analyses of larger datasets and it will enable more reliable cross-platform comparisons as compared to existing approaches that require manual steps and are tailored to a specific experimental platform. To complement this open-source software, we share a dataset of 1,540 brightfield example movies on which we have tested our software. Through sharing this data and software, our goal is to directly enable quantitative comparisons across labs, and facilitate future collective progress via the biomedical engineering open-source data and software ecosystem.

The processes of gene expression are inherently stochastic, even for essential genes required for growth. How does the cell maximize fitness in light of noise? To answer this question, we build a mathematical model to explore the trade-off between metabolic load and growth robustness. The model predicts novel principles of central dogma regulation: Optimal protein expression levels for many genes are in vast overabundance. Essential genes are transcribed above a lower limit of one message per cell cycle. Gene expression is achieved by load balancing between transcription and translation. We present evidence that each of these novel regulatory principles is observed. These results reveal that robustness and metabolic load determine the global regulatory principles that govern gene expression processes, and these principles have broad implications for cellular function.

In chest X-ray (CXR) image analysis, rule-based systems are usually employed to extract labels from reports for dataset releases. However, there is still room for improvement in label quality. These labelers typically output only presence labels, sometimes with binary uncertainty indicators, which limits their usefulness. Supervised deep learning models have also been developed for report labeling but lack adaptability, similar to rule-based systems. In this work, we present MAPLEZ (Medical report Annotations with Privacy-preserving Large language model using Expeditious Zero shot answers), a novel approach leveraging a locally executable Large Language Model (LLM) to extract and enhance findings labels on CXR reports. MAPLEZ extracts not only binary labels indicating the presence or absence of a finding but also the location, severity, and radiologists' uncertainty about the finding. Over eight abnormalities from five test sets, we show that our method can extract these annotations with an increase of 3.6 percentage points (pp) in macro F1 score for categorical presence annotations and more than 20 pp increase in F1 score for the location annotations over competing labelers. Additionally, using the combination of improved annotations and multi-type annotations in classification supervision, we demonstrate substantial advancements in model quality, with an increase of 1.1 pp in AUROC over models trained with annotations from the best alternative approach. We share code and annotations.

Deep learning based approaches are now widely used across biophysics to help automate a variety of tasks including image segmentation, feature selection, and deconvolution. However, the presence of multiple competing deep learning architectures, each with its own unique advantages and disadvantages, makes it challenging to select an architecture best suited for a specific application. As such, we present a comprehensive comparison of common models. Here, we focus on the task of segmentation assuming the typically small training dataset sizes available from biophysics experiments and compare the following four commonly used architectures: convolutional neural networks, U-Nets, vision transformers, and vision state space models. In doing so, we establish criteria for determining optimal conditions under which each model excels, thereby offering practical guidelines for researchers and practitioners in the field.

Stochastic diffusion is the noisy and uncertain process through which dynamics like epidemics, or agents like animal species, disperse over a larger area. Understanding these processes is becoming increasingly important as we attempt to better prepare for potential pandemics and as species ranges shift in response to climate change. Unfortunately, modeling of stochastic diffusion is mostly done through inaccurate deterministic tools that fail to capture the random nature of dispersal or else through expensive computational simulations. In particular, standard tools fail to fully capture the heterogeneity of the area over which this diffusion occurs. Rural areas with low population density require different epidemic models than urban areas; likewise, the edges of a species range require us to explicitly track low integer numbers of individuals rather than vague averages. In this work, we introduce a series of new tools called "mean-FLAME" models that track stochastic dispersion using approximate master equations that explicitly follow the probability distribution of an area of interest over all of its possible states, up to states that are active enough to be approximated using a mean-field model. In one limit, this approach is locally exact if we explicitly track enough states, and in the other limit collapses back to traditional deterministic models if we track no state explicitly. Applying this approach, we show how deterministic tools fail to capture the uncertainty around the speed of nonlinear dynamical processes. This is especially true for marginal areas that are close to unsuitable for diffusion, like the edge of a species range or epidemics in small populations. Capturing the uncertainty in such areas is key to producing accurate forecasts and guiding potential interventions.

Objective: Magnetomotive ultrasound (MMUS) using magnetic nanoparticle contrast agents has shown promise for thrombosis imaging and quantitative elastometry via magnetomotive resonant acoustic spectroscopy (MRAS). Young's modulus measurements of smaller, stiffer thrombi require an MRAS system capable of generating forces at higher temporal frequencies. Solenoids with fewer turns, and thus less inductance, could improve high frequency performance, but the reduced force may compromise results. In this work, a computational model capable of predicting improved MRAS magnet configurations optimized for elastometry is presented and validated.

Approach: Finite element analysis (FEA) was used to model the force and inductance of MRAS systems. The simulations incorporated both solenoid electromagnets and permanent magnets in three-dimensional steady-state, frequency domain, and time domain studies.

Main results: The model successfully predicted a configuration in which permanent magnets could be used to increase the force supplied by an existing MRAS system. Accordingly, the displacement measured in a magnetically labeled validation phantom increased by a factor of 2.2 ± 0.3 when the force was predicted to increase by a factor of 2.2 ± 0.2. The model additionally identified a new solenoid configuration consisting of four smaller coils capable of providing sufficient force at higher driving frequencies.

Significance: These results indicate two methods by which MRAS systems could be designed to deliver higher frequency magnetic forces without the need for experimental trial and error. Either the number of turns within each solenoid could be reduced while permanent magnets are added at precise locations, or a larger number of smaller solenoids could be used. These findings overcome a key challenge toward the goal of thrombosis elastometry via MMUS.

When predicting physical phenomena through simulation, quantification of the total uncertainty due to multiple sources is as crucial as making sure the underlying numerical model is accurate. Possible sources include irreducible aleatoric uncertainty due to noise in the data, epistemic uncertainty induced by insufficient data or inadequate parameterization, and model-form uncertainty related to the use of misspecified model equations. In addition, recently proposed approaches provide flexible ways to combine information from data with full or partial satisfaction of equations that typically encode physical principles. Physics-based regularization interacts in nontrivial ways with aleatoric, epistemic and model-form uncertainty and their combination, and a better understanding of this interaction is needed to improve the predictive performance of physics-informed digital twins that operate under real conditions. To better understand this interaction, with a specific focus on biological and physiological models, this study investigates the decomposition of total uncertainty in the estimation of states and parameters of a differential system simulated with MC X-TFC, a new physics-informed approach for uncertainty quantification based on random projections and Monte-Carlo sampling. After an introductory comparison between approaches for physics-informed estimation, MC X-TFC is applied to a six-compartment stiff ODE system, the CVSim-6 model, developed in the context of human physiology. The system is first analyzed by progressively removing data while estimating an increasing number of parameters, and subsequently by investigating total uncertainty under model-form misspecification of non-linear resistance in the pulmonary compartment. In particular, we focus on the interaction between the formulation of the discrepancy term and quantification of model-form uncertainty, and show how additional physics can help in the estimation process. The method demonstrates robustness and efficiency in estimating unknown states and parameters, even with limited, sparse, and noisy data. It also offers great flexibility in integrating data with physics for improved estimation, even in cases of model misspecification.

Purpose: This study quantifies the variation in dose-volume histogram (DVH) and normal tissue complication probability (NTCP) metrics for head-and-neck (HN) cancer patients when alternative organ-at-risk (OAR) delineations are used for treatment planning and for treatment plan evaluation. We particularly focus on the effects of daily patient positioning/setup variations (SV) in relation to treatment technique and delineation variability.

Materials and methods: We generated two-arc VMAT, 5-beam IMRT, and 9-beam IMRT treatment plans for a cohort of 209 HN patients. These plans incorporated five different OAR delineation sets, including manual and four automated algorithms. Each treatment plan was assessed under various simulated per-fraction patient setup uncertainties, evaluating the potential clinical impacts through DVH and NTCP metrics.

Results: The study demonstrates that increasing setup variability generally reduces differences in DVH metrics between alternative delineations. However, in contrast, differences in NTCP metrics tend to increase with higher setup variability. This pattern is observed consistently across different treatment plans and delineator combinations, illustrating the intricate relationship between SV and delineation accuracy. Additionally, the need for delineation accuracy in treatment planning is shown to be case-specific and dependent on factors beyond geometric variations.

Conclusions: The findings highlight the necessity for comprehensive quality assurance programs in radiotherapy, incorporating both dosimetric impact analysis and geometric variation assessment to ensure optimal delineation quality. The study emphasizes the complex dynamics of treatment planning in radiotherapy, advocating for personalized, case-specific strategies in clinical practice to enhance patient care quality and efficacy in the face of varying SV and delineation accuracies.

Purpose: Estimation of multi-compartment intravoxel 'flow' in fD in ml/100g/min with multi-b-value diffusion weighted imaging and a multi-Gaussian model in the kidneys.

Theory and methods: A multi-Gaussian model of intravoxel flow using water transport time to quantify $fD$ (ml/100g/min) is presented and simulated. Multi-compartment anisotropic DWI signal is simulated with Rician noise and SNR=50 and analyzed with a rigid bi-exponential, a rigid tri-exponential and diffusion spectrum imaging model of intravoxel incoherent motion (spectral diffusion) to study extraction of multi-compartment flow. The regularization parameter for spectral diffusion is varied to study the impact on the resulting spectrum and computation speed. The application is demonstrated in a two-center study of 54 kidney allografts with 9 b-value advanced DWI that were split by function (CKD-EPI 2021 eGFR<45ml/min/1.73m²) and fibrosis (Banff 2017 interstitial fibrosis and tubular atrophy score 0-6) to demonstrate multi-compartment flow of various kidney pathologies.

Results: Simulation of anisotropic multi-compartment flow from spectral diffusion demonstrated strong correlation to truth for both three-compartment anisotropic diffusion ( $y=1.08x+0.1,R^2=0.71$ ) and two-compartment anisotropic diffusion ( $y=0.91+0.6,R^2=0.74$ ), outperforming rigid models in cases of variable compartment number. Use of a fixed regularization parameter set to $\lambda =0.1$ increased computation up to 208-fold and agreed with voxel-wise cross-validated regularization (concordance correlation coefficient=0.99). Spectral diffusion of renal allografts showed decreasing trend of tubular and vascular flow with higher levels of fibrosis, and significant increase in tissue parenchyma flow (f-stat=3.86, p=0.02). Tubular $fD$ was significantly decreased in allografts with impaired function (eGFR<45ml/min/1.73m²)(Mann-Whitney U t-stat=-2.14, p=0.04).

Conclusions: Quantitative multi-compartment intravoxel 'flow' can be estimated in ml/100g/min with $fD$ from multi-Gaussian diffusion with water transport time, even with moderate anisotropy such as in kidneys. The use of spectral diffusion with a multi-Gaussian model and a fixed regularization parameter is particularly promising in organs such as the kidney with variable numbers of physiologic compartments.

The burgeoning field of brain health research increasingly leverages artificial intelligence (AI) to interpret and analyze neurological data. This study introduces a novel approach towards the creation of medical foundation models by integrating a large-scale multi-modal magnetic resonance imaging (MRI) dataset derived from 41,400 participants in its own. Our method involves a novel two-stage pretraining approach using vision transformers. The first stage is dedicated to encoding anatomical structures in generally healthy brains, identifying key features such as shapes and sizes of different brain regions. The second stage concentrates on spatial information, encompassing aspects like location and the relative positioning of brain structures. We rigorously evaluate our model, BrainFounder, using the Brain Tumor Segmentation (BraTS) challenge and Anatomical Tracings of Lesions After Stroke v2.0 (ATLAS v2.0) datasets. BrainFounder demonstrates a significant performance gain, surpassing the achievements of the previous winning solutions using fully supervised learning. Our findings underscore the impact of scaling up both the complexity of the model and the volume of unlabeled training data derived from generally healthy brains, which enhances the accuracy and predictive capabilities of the model in complex neuroimaging tasks with MRI. The implications of this research provide transformative insights and practical applications in healthcare and make substantial steps towards the creation of foundation models for Medical AI. Our pretrained models and training code can be found at https://github.com/lab-smile/GatorBrain.