Personalized Predictions of Glioblastoma Infiltration: Mathematical Models, Physics-Informed Neural Networks and Multimodal Scans

Predicting the infiltration of Glioblastoma (GBM) from medical MRI scans is crucial for understanding tumor growth dynamics and designing personalized radiotherapy treatment plans.Mathematical models of GBM growth can complement the data in the prediction of spatial distributions of tumor cells. However, this requires estimating patient-specific parameters of the model from clinical data, which is a challenging inverse problem due to limited temporal data and the limited time between imaging and diagnosis. This work proposes a method that uses Physics-Informed Neural Networks (PINNs) to estimate patient-specific parameters of a reaction-diffusion PDE model of GBM growth from a single 3D structural MRI snapshot. PINNs embed both the data and the PDE into a loss function, thus integrating theory and data. Key innovations include the identification and estimation of characteristic non-dimensional parameters, a pre-training step that utilizes the non-dimensional parameters and a fine-tuning step to determine the patient specific parameters. Additionally, the diffuse domain method is employed to handle the complex brain geometry within the PINN framework. Our method is validated both on synthetic and patient datasets, and shows promise for real-time parametric inference in the clinical setting for personalized GBM treatment.

(Predictable) Performance Bias in Unsupervised Anomaly Detection

Background: With the ever-increasing amount of medical imaging data, the demand for algorithms to assist clinicians has amplified. Unsupervised anomaly detection (UAD) models promise to aid in the crucial first step of disease detection. While previous studies have thoroughly explored fairness in supervised models in healthcare, for UAD, this has so far been unexplored. Methods: In this study, we evaluated how dataset composition regarding subgroups manifests in disparate performance of UAD models along multiple protected variables on three large-scale publicly available chest X-ray datasets. Our experiments were validated using two state-of-the-art UAD models for medical images. Finally, we introduced a novel subgroup-AUROC (sAUROC) metric, which aids in quantifying fairness in machine learning. Findings: Our experiments revealed empirical "fairness laws" (similar to "scaling laws" for Transformers) for training-dataset composition: Linear relationships between anomaly detection performance within a subpopulation and its representation in the training data. Our study further revealed performance disparities, even in the case of balanced training data, and compound effects that exacerbate the drop in performance for subjects associated with multiple adversely affected groups. Interpretation: Our study quantified the disparate performance of UAD models against certain demographic subgroups. Importantly, we showed that this unfairness cannot be mitigated by balanced representation alone. Instead, the representation of some subgroups seems harder to learn by UAD models than that of others. The empirical fairness laws discovered in our study make disparate performance in UAD models easier to estimate and aid in determining the most desirable dataset composition.

Self-pruning Graph Neural Network for Predicting Inflammatory Disease Activity in Multiple Sclerosis from Brain MR Images

Multiple Sclerosis (MS) is a severe neurological disease characterized by inflammatory lesions in the central nervous system. Hence, predicting inflammatory disease activity is crucial for disease assessment and treatment. However, MS lesions can occur throughout the brain and vary in shape, size and total count among patients. The high variance in lesion load and locations makes it challenging for machine learning methods to learn a globally effective representation of whole-brain MRI scans to assess and predict disease. Technically it is non-trivial to incorporate essential biomarkers such as lesion load or spatial proximity. Our work represents the first attempt to utilize graph neural networks (GNN) to aggregate these biomarkers for a novel global representation. We propose a two-stage MS inflammatory disease activity prediction approach. First, a 3D segmentation network detects lesions, and a self-supervised algorithm extracts their image features. Second, the detected lesions are used to build a patient graph. The lesions act as nodes in the graph and are initialized with image features extracted in the first stage. Finally, the lesions are connected based on their spatial proximity and the inflammatory disease activity prediction is formulated as a graph classification task. Furthermore, we propose a self-pruning strategy to auto-select the most critical lesions for prediction. Our proposed method outperforms the existing baseline by a large margin (AUCs of 0.67 vs. 0.61 and 0.66 vs. 0.60 for one-year and two-year inflammatory disease activity, respectively). Finally, our proposed method enjoys inherent explainability by assigning an importance score to each lesion for the overall prediction. Code is available at https://github.com/chinmay5/ms_ida.git

Bias in Unsupervised Anomaly Detection in Brain MRI

Unsupervised anomaly detection methods offer a promising and flexible alternative to supervised approaches, holding the potential to revolutionize medical scan analysis and enhance diagnostic performance. In the current landscape, it is commonly assumed that differences between a test case and the training distribution are attributed solely to pathological conditions, implying that any disparity indicates an anomaly. However, the presence of other potential sources of distributional shift, including scanner, age, sex, or race, is frequently overlooked. These shifts can significantly impact the accuracy of the anomaly detection task. Prominent instances of such failures have sparked concerns regarding the bias, credibility, and fairness of anomaly detection. This work presents a novel analysis of biases in unsupervised anomaly detection. By examining potential non-pathological distributional shifts between the training and testing distributions, we shed light on the extent of these biases and their influence on anomaly detection results. Moreover, this study examines the algorithmic limitations that arise due to biases, providing valuable insights into the challenges encountered by anomaly detection algorithms in accurately learning and capturing the entire range of variability present in the normative distribution. Through this analysis, we aim to enhance the understanding of these biases and pave the way for future improvements in the field. Here, we specifically investigate Alzheimer's disease detection from brain MR imaging as a case study, revealing significant biases related to sex, race, and scanner variations that substantially impact the results. These findings align with the broader goal of improving the reliability, fairness, and effectiveness of anomaly detection in medical imaging.

Denoising diffusion-based MR to CT image translation enables whole spine vertebral segmentation in 2D and 3D without manual annotations

Background: Automated segmentation of spinal MR images plays a vital role both scientifically and clinically. However, accurately delineating posterior spine structures presents challenges. Methods: This retrospective study, approved by the ethical committee, involved translating T1w and T2w MR image series into CT images in a total of n=263 pairs of CT/MR series. Landmark-based registration was performed to align image pairs. We compared 2D paired (Pix2Pix, denoising diffusion implicit models (DDIM) image mode, DDIM noise mode) and unpaired (contrastive unpaired translation, SynDiff) image-to-image translation using "peak signal to noise ratio" (PSNR) as quality measure. A publicly available segmentation network segmented the synthesized CT datasets, and Dice scores were evaluated on in-house test sets and the "MRSpineSeg Challenge" volumes. The 2D findings were extended to 3D Pix2Pix and DDIM. Results: 2D paired methods and SynDiff exhibited similar translation performance and Dice scores on paired data. DDIM image mode achieved the highest image quality. SynDiff, Pix2Pix, and DDIM image mode demonstrated similar Dice scores (0.77). For craniocaudal axis rotations, at least two landmarks per vertebra were required for registration. The 3D translation outperformed the 2D approach, resulting in improved Dice scores (0.80) and anatomically accurate segmentations in a higher resolution than the original MR image. Conclusion: Two landmarks per vertebra registration enabled paired image-to-image translation from MR to CT and outperformed all unpaired approaches. The 3D techniques provided anatomically correct segmentations, avoiding underprediction of small structures like the spinous process.

Metrics to Quantify Global Consistency in Synthetic Medical Images

Image synthesis is increasingly being adopted in medical image processing, for example for data augmentation or inter-modality image translation. In these critical applications, the generated images must fulfill a high standard of biological correctness. A particular requirement for these images is global consistency, i.e an image being overall coherent and structured so that all parts of the image fit together in a realistic and meaningful way. Yet, established image quality metrics do not explicitly quantify this property of synthetic images. In this work, we introduce two metrics that can measure the global consistency of synthetic images on a per-image basis. To measure the global consistency, we presume that a realistic image exhibits consistent properties, e.g., a person's body fat in a whole-body MRI, throughout the depicted object or scene. Hence, we quantify global consistency by predicting and comparing explicit attributes of images on patches using supervised trained neural networks. Next, we adapt this strategy to an unlabeled setting by measuring the similarity of implicit image features predicted by a self-supervised trained network. Our results demonstrate that predicting explicit attributes of synthetic images on patches can distinguish globally consistent from inconsistent images. Implicit representations of images are less sensitive to assess global consistency but are still serviceable when labeled data is unavailable. Compared to established metrics, such as the FID, our method can explicitly measure global consistency on a per-image basis, enabling a dedicated analysis of the biological plausibility of single synthetic images.

Framing image registration as a landmark detection problem for better representation of clinical relevance

Nowadays, registration methods are typically evaluated based on sub-resolution tracking error differences. In an effort to reinfuse this evaluation process with clinical relevance, we propose to reframe image registration as a landmark detection problem. Ideally, landmark-specific detection thresholds are derived from an inter-rater analysis. To approximate this costly process, we propose to compute hit rate curves based on the distribution of errors of a sub-sample inter-rater analysis. Therefore, we suggest deriving thresholds from the error distribution using the formula: median + delta * median absolute deviation. The method promises differentiation of previously indistinguishable registration algorithms and further enables assessing the clinical significance in algorithm development.

Inter-Rater Uncertainty Quantification in Medical Image Segmentation via Rater-Specific Bayesian Neural Networks

Automated medical image segmentation inherently involves a certain degree of uncertainty. One key factor contributing to this uncertainty is the ambiguity that can arise in determining the boundaries of a target region of interest, primarily due to variations in image appearance. On top of this, even among experts in the field, different opinions can emerge regarding the precise definition of specific anatomical structures. This work specifically addresses the modeling of segmentation uncertainty, known as inter-rater uncertainty. Its primary objective is to explore and analyze the variability in segmentation outcomes that can occur when multiple experts in medical imaging interpret and annotate the same images. We introduce a novel Bayesian neural network-based architecture to estimate inter-rater uncertainty in medical image segmentation. Our approach has three key advancements. Firstly, we introduce a one-encoder-multi-decoder architecture specifically tailored for uncertainty estimation, enabling us to capture the rater-specific representation of each expert involved. Secondly, we propose Bayesian modeling for the new architecture, allowing efficient capture of the inter-rater distribution, particularly in scenarios with limited annotations. Lastly, we enhance the rater-specific representation by integrating an attention module into each decoder. This module facilitates focused and refined segmentation results for each rater. We conduct extensive evaluations using synthetic and real-world datasets to validate our technical innovations rigorously. Our method surpasses existing baseline methods in five out of seven diverse tasks on the publicly available \emph{QUBIQ} dataset, considering two evaluation metrics encompassing different uncertainty aspects. Our codes, models, and the new dataset are available through our GitHub repository: https://github.com/HaoWang420/bOEMD-net .

The Brain Tumor Segmentation (BraTS-METS) Challenge 2023: Brain Metastasis Segmentation on Pre-treatment MRI

Clinical monitoring of metastatic disease to the brain can be a laborious and time-consuming process, especially in cases involving multiple metastases when the assessment is performed manually. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) guideline, which utilizes the unidimensional longest diameter, is commonly used in clinical and research settings to evaluate response to therapy in patients with brain metastases. However, accurate volumetric assessment of the lesion and surrounding peri-lesional edema holds significant importance in clinical decision-making and can greatly enhance outcome prediction. The unique challenge in performing segmentations of brain metastases lies in their common occurrence as small lesions. Detection and segmentation of lesions that are smaller than 10 mm in size has not demonstrated high accuracy in prior publications. The brain metastases challenge sets itself apart from previously conducted MICCAI challenges on glioma segmentation due to the significant variability in lesion size. Unlike gliomas, which tend to be larger on presentation scans, brain metastases exhibit a wide range of sizes and tend to include small lesions. We hope that the BraTS-METS dataset and challenge will advance the field of automated brain metastasis detection and segmentation.

The Brain Tumor Segmentation (BraTS) Challenge 2023: Glioma Segmentation in Sub-Saharan Africa Patient Population (BraTS-Africa)

Gliomas are the most common type of primary brain tumors. Although gliomas are relatively rare, they are among the deadliest types of cancer, with a survival rate of less than 2 years after diagnosis. Gliomas are challenging to diagnose, hard to treat and inherently resistant to conventional therapy. Years of extensive research to improve diagnosis and treatment of gliomas have decreased mortality rates across the Global North, while chances of survival among individuals in low- and middle-income countries (LMICs) remain unchanged and are significantly worse in Sub-Saharan Africa (SSA) populations. Long-term survival with glioma is associated with the identification of appropriate pathological features on brain MRI and confirmation by histopathology. Since 2012, the Brain Tumor Segmentation (BraTS) Challenge have evaluated state-of-the-art machine learning methods to detect, characterize, and classify gliomas. However, it is unclear if the state-of-the-art methods can be widely implemented in SSA given the extensive use of lower-quality MRI technology, which produces poor image contrast and resolution and more importantly, the propensity for late presentation of disease at advanced stages as well as the unique characteristics of gliomas in SSA (i.e., suspected higher rates of gliomatosis cerebri). Thus, the BraTS-Africa Challenge provides a unique opportunity to include brain MRI glioma cases from SSA in global efforts through the BraTS Challenge to develop and evaluate computer-aided-diagnostic (CAD) methods for the detection and characterization of glioma in resource-limited settings, where the potential for CAD tools to transform healthcare are more likely.