Kyle J. Lafata

Lucas Kreiss, Shaowei Jiang, Xiang Li et al. · pku

Until recently, conventional biochemical staining had the undisputed status as well-established benchmark for most biomedical problems related to clinical diagnostics, fundamental research and biotechnology. Despite this role as gold-standard, staining protocols face several challenges, such as a need for extensive, manual processing of samples, substantial time delays, altered tissue homeostasis, limited choice of contrast agents for a given sample, 2D imaging instead of 3D tomography and many more. Label-free optical technologies, on the other hand, do not rely on exogenous and artificial markers, by exploiting intrinsic optical contrast mechanisms, where the specificity is typically less obvious to the human observer. Over the past few years, digital staining has emerged as a promising concept to use modern deep learning for the translation from optical contrast to established biochemical contrast of actual stainings. In this review article, we provide an in-depth analysis of the current state-of-the-art in this field, suggest methods of good practice, identify pitfalls and challenges and postulate promising advances towards potential future implementations and applications.

Zhenyu Yang, Zongsheng Hu, Hangjie Ji et al.

Purpose: To develop a neural ordinary differential equation (ODE) model for visualizing deep neural network (DNN) behavior during multi-parametric MRI (mp-MRI) based glioma segmentation as a method to enhance deep learning explainability. Methods: By hypothesizing that deep feature extraction can be modeled as a spatiotemporally continuous process, we designed a novel deep learning model, neural ODE, in which deep feature extraction was governed by an ODE without explicit expression. The dynamics of 1) MR images after interactions with DNN and 2) segmentation formation can be visualized after solving ODE. An accumulative contribution curve (ACC) was designed to quantitatively evaluate the utilization of each MRI by DNN towards the final segmentation results. The proposed neural ODE model was demonstrated using 369 glioma patients with a 4-modality mp-MRI protocol: T1, contrast-enhanced T1 (T1-Ce), T2, and FLAIR. Three neural ODE models were trained to segment enhancing tumor (ET), tumor core (TC), and whole tumor (WT). The key MR modalities with significant utilization by DNN were identified based on ACC analysis. Segmentation results by DNN using only the key MR modalities were compared to the ones using all 4 MR modalities. Results: All neural ODE models successfully illustrated image dynamics as expected. ACC analysis identified T1-Ce as the only key modality in ET and TC segmentations, while both FLAIR and T2 were key modalities in WT segmentation. Compared to the U-Net results using all 4 MR modalities, Dice coefficient of ET (0.784->0.775), TC (0.760->0.758), and WT (0.841->0.837) using the key modalities only had minimal differences without significance. Conclusion: The neural ODE model offers a new tool for optimizing the deep learning model inputs with enhanced explainability. The presented methodology can be generalized to other medical image-related deep learning applications.

Zhenyu Yang, Kyle Lafata, Eugene Vaios et al.

The projection of planar MRI data onto a spherical surface is equivalent to a nonlinear image transformation that retains global anatomical information. By incorporating this image transformation process in our proposed spherical projection-based U-Net (SPU-Net) segmentation model design, multiple independent segmentation predictions can be obtained from a single MRI. The final segmentation is the average of all available results, and the variation can be visualized as a pixel-wise uncertainty map. An uncertainty score was introduced to evaluate and compare the performance of uncertainty measurements. The proposed SPU-Net model was implemented on the basis of 369 glioma patients with MP-MRI scans (T1, T1-Ce, T2, and FLAIR). Three SPU-Net models were trained to segment enhancing tumor (ET), tumor core (TC), and whole tumor (WT), respectively. The SPU-Net model was compared with (1) the classic U-Net model with test-time augmentation (TTA) and (2) linear scaling-based U-Net (LSU-Net) segmentation models in terms of both segmentation accuracy (Dice coefficient, sensitivity, specificity, and accuracy) and segmentation uncertainty (uncertainty map and uncertainty score). The developed SPU-Net model successfully achieved low uncertainty for correct segmentation predictions (e.g., tumor interior or healthy tissue interior) and high uncertainty for incorrect results (e.g., tumor boundaries). This model could allow the identification of missed tumor targets or segmentation errors in U-Net. Quantitatively, the SPU-Net model achieved the highest uncertainty scores for three segmentation targets (ET/TC/WT): 0.826/0.848/0.936, compared to 0.784/0.643/0.872 using the U-Net with TTA and 0.743/0.702/0.876 with the LSU-Net (scaling factor = 2). The SPU-Net also achieved statistically significantly higher Dice coefficients, underscoring the improved segmentation accuracy.

Yuqi Wang, Aarzu Gupta, David Carpenter et al.

TodevelopanovelUncertaintyQuantification (UQ) framework to estimate the uncertainty of patient survival models in the absence of ground truth, we developed and evaluated our approach based on a dataset of 1383 patients treated with stereotactic radiosurgery (SRS) for brain metastases between January 2015 and December 2020. Our motivating hypothesis is that a time-to-event prediction of a test patient on inference is more certain given a higher feature-space-similarity to patients in the training set. Therefore, the uncertainty for a particular patient-of-interest is represented by the concordance index between a patient similarity rank and a prediction similarity rank. Model uncertainty was defined as the increased percentage of the max uncertainty-constrained-AUC compared to the model AUC. We evaluated our method on multiple clinically-relevant endpoints, including time to intracranial progression (ICP), progression-free survival (PFS) after SRS, overall survival (OS), and time to ICP and/or death (ICPD), on a variety of both statistical and non-statistical models, including CoxPH, conditional survival forest (CSF), and neural multi-task linear regression (NMTLR). Our results show that all models had the lowest uncertainty on ICP (2.21%) and the highest uncertainty (17.28%) on ICPD. OS models demonstrated high variation in uncertainty performance, where NMTLR had the lowest uncertainty(1.96%)and CSF had the highest uncertainty (14.29%). In conclusion, our method can estimate the uncertainty of individual patient survival modeling results. As expected, our data empirically demonstrate that as model uncertainty measured via our technique increases, the similarity between a feature-space and its predicted outcome decreases.

Fakrul Islam Tushar, Lavsen Dahal, Cindy McCabe et al.

AI models for lung cancer screening are limited by data scarcity, impacting generalizability and clinical applicability. Generative models address this issue but are constrained by training data variability. We introduce SYN-LUNGS, a framework for generating high-quality 3D CT images with detailed annotations. SYN-LUNGS integrates XCAT3 phantoms for digital twin generation, X-Lesions for nodule simulation (varying size, location, and appearance), and DukeSim for CT image formation with vendor and parameter variability. The dataset includes 3,072 nodule images from 1,044 simulated CT scans, with 512 lesions and 174 digital twins. Models trained on clinical + simulated data outperform clinical only models, achieving 10% improvement in detection, 2-9% in segmentation and classification, and enhanced synthesis. By incorporating anatomy-informed simulations, SYN-LUNGS provides a scalable approach for AI model development, particularly in rare disease representation and improving model reliability.

Michael E. Garcia-Alcoser, Mobina GhojoghNejad, Fakrul Islam Tushar et al.

Purpose: This study aims to evaluate the effectiveness of large language models (LLMs) in automating disease annotation of CT radiology reports. We compare a rule-based algorithm (RBA), RadBERT, and three lightweight open-weight LLMs for multi-disease labeling of chest, abdomen, and pelvis (CAP) CT reports. Materials and Methods: This retrospective study analyzed 40,833 CT reports from 29,540 patients, with 1,789 CAP reports manually annotated across three organ systems. External validation was conducted using the CT-RATE dataset. Three open-weight LLMs were tested with zero-shot prompting. Performance was evaluated using Cohen's Kappa and micro/macro-averaged F1 scores. Results: In 12,197 Duke CAP reports from 8,854 patients, Llama-3.1 8B and Gemma-3 27B showed the highest agreement ($κ$ median: 0.87). On the manually annotated set, Gemma-3 27B achieved the top macro-F1 (0.82), followed by Llama-3.1 8B (0.79), while the RBA scored lowest (0.64). On the CT-RATE dataset (lungs/pleura only), Llama-3.1 8B performed best (0.91), with Gemma-3 27B close behind (0.89). Performance differences were mainly due to differing labeling practices, especially for lung atelectasis. Conclusion: Lightweight LLMs outperform rule-based methods for CT report annotation and generalize across organ systems with zero-shot prompting. However, binary labels alone cannot capture the full nuance of report language. LLMs can provide a flexible, efficient solution aligned with clinical judgment and user needs.

Yuqi Wang, Jacob A. Macdonald, Katelyn R. Morgan et al.

Spleen volumetry is primarily associated with patients suffering from chronic liver disease and portal hypertension, as they often have spleens with abnormal shapes and sizes. However, manually segmenting the spleen to obtain its volume is a time-consuming process. Deep learning algorithms have proven to be effective in automating spleen segmentation, but a suitable dataset is necessary for training such algorithms. To our knowledge, the few publicly available datasets for spleen segmentation lack confounding features such as ascites and abdominal varices. To address this issue, the Duke Spleen Data Set (DSDS) has been developed, which includes 109 CT and MRI volumes from patients with chronic liver disease and portal hypertension. The dataset includes a diverse range of image types, vendors, planes, and contrasts, as well as varying spleen shapes and sizes due to underlying disease states. The DSDS aims to facilitate the creation of robust spleen segmentation models that can take into account these variations and confounding factors.

Hangjie Ji, Kyle Lafata, Yvonne Mowery et al.

This paper develops a method of biologically guided deep learning for post-radiation FDG-PET image outcome prediction based on pre-radiation images and radiotherapy dose information. Based on the classic reaction-diffusion mechanism, a novel biological model was proposed using a partial differential equation that incorporates spatial radiation dose distribution as a patient-specific treatment information variable. A 7-layer encoder-decoder-based convolutional neural network (CNN) was designed and trained to learn the proposed biological model. As such, the model could generate post-radiation FDG-PET image outcome predictions with possible time-series transition from pre-radiotherapy image states to post-radiotherapy states. The proposed method was developed using 64 oropharyngeal patients with paired FDG-PET studies before and after 20Gy delivery (2Gy/daily fraction) by IMRT. In a two-branch deep learning execution, the proposed CNN learns specific terms in the biological model from paired FDG-PET images and spatial dose distribution as in one branch, and the biological model generates post-20Gy FDG-PET image prediction in the other branch. The proposed method successfully generated post-20Gy FDG-PET image outcome prediction with breakdown illustrations of biological model components. Time-series FDG-PET image predictions were generated to demonstrate the feasibility of disease response rendering. The developed biologically guided deep learning method achieved post-20Gy FDG-PET image outcome predictions in good agreement with ground-truth results. With break-down biological modeling components, the outcome image predictions could be used in adaptive radiotherapy decision-making to optimize personalized plans for the best outcome in the future.