Probabilistic Temporal Prediction of Continuous Disease Trajectories and Treatment Effects Using Neural SDEs

Personalized medicine based on medical images, including predicting future individualized clinical disease progression and treatment response, would have an enormous impact on healthcare and drug development, particularly for diseases (e.g. multiple sclerosis (MS)) with long term, complex, heterogeneous evolutions and no cure. In this work, we present the first stochastic causal temporal framework to model the continuous temporal evolution of disease progression via Neural Stochastic Differential Equations (NSDE). The proposed causal inference model takes as input the patient's high dimensional images (MRI) and tabular data, and predicts both factual and counterfactual progression trajectories on different treatments in latent space. The NSDE permits the estimation of high-confidence personalized trajectories and treatment effects. Extensive experiments were performed on a large, multi-centre, proprietary dataset of patient 3D MRI and clinical data acquired during several randomized clinical trials for MS treatments. Our results present the first successful uncertainty-based causal Deep Learning (DL) model to: (a) accurately predict future patient MS disability evolution (e.g. EDSS) and treatment effects leveraging baseline MRI, and (b) permit the discovery of subgroups of patients for which the model has high confidence in their response to treatment even in clinical trials which did not reach their clinical endpoints.

DeCoDEx: Confounder Detector Guidance for Improved Diffusion-based Counterfactual Explanations

Deep learning classifiers are prone to latching onto dominant confounders present in a dataset rather than on the causal markers associated with the target class, leading to poor generalization and biased predictions. Although explainability via counterfactual image generation has been successful at exposing the problem, bias mitigation strategies that permit accurate explainability in the presence of dominant and diverse artifacts remain unsolved. In this work, we propose the DeCoDEx framework and show how an external, pre-trained binary artifact detector can be leveraged during inference to guide a diffusion-based counterfactual image generator towards accurate explainability. Experiments on the CheXpert dataset, using both synthetic artifacts and real visual artifacts (support devices), show that the proposed method successfully synthesizes the counterfactual images that change the causal pathology markers associated with Pleural Effusion while preserving or ignoring the visual artifacts. Augmentation of ERM and Group-DRO classifiers with the DeCoDEx generated images substantially improves the results across underrepresented groups that are out of distribution for each class. The code is made publicly available at https://github.com/NimaFathi/DeCoDEx.

HyperFusion: A Hypernetwork Approach to Multimodal Integration of Tabular and Medical Imaging Data for Predictive Modeling

The integration of diverse clinical modalities such as medical imaging and the tabular data obtained by the patients' Electronic Health Records (EHRs) is a crucial aspect of modern healthcare. The integrative analysis of multiple sources can provide a comprehensive understanding of a patient's condition and can enhance diagnoses and treatment decisions. Deep Neural Networks (DNNs) consistently showcase outstanding performance in a wide range of multimodal tasks in the medical domain. However, the complex endeavor of effectively merging medical imaging with clinical, demographic and genetic information represented as numerical tabular data remains a highly active and ongoing research pursuit. We present a novel framework based on hypernetworks to fuse clinical imaging and tabular data by conditioning the image processing on the EHR's values and measurements. This approach aims to leverage the complementary information present in these modalities to enhance the accuracy of various medical applications. We demonstrate the strength and the generality of our method on two different brain Magnetic Resonance Imaging (MRI) analysis tasks, namely, brain age prediction conditioned by subject's sex, and multiclass Alzheimer's Disease (AD) classification conditioned by tabular data. We show that our framework outperforms both single-modality models and state-of-the-art MRI-tabular data fusion methods. The code, enclosed to this manuscript will be made publicly available.

Improving Robustness and Reliability in Medical Image Classification with Latent-Guided Diffusion and Nested-Ensembles

While deep learning models have achieved remarkable success across a range of medical image analysis tasks, deployment of these models in real clinical contexts requires that they be robust to variability in the acquired images. While many methods apply predefined transformations to augment the training data to enhance test-time robustness, these transformations may not ensure the model's robustness to the diverse variability seen in patient images. In this paper, we introduce a novel three-stage approach based on transformers coupled with conditional diffusion models, with the goal of improving model robustness to the kinds of imaging variability commonly encountered in practice without the need for pre-determined data augmentation strategies. To this end, multiple image encoders first learn hierarchical feature representations to build discriminative latent spaces. Next, a reverse diffusion process, guided by the latent code, acts on an informative prior and proposes prediction candidates in a generative manner. Finally, several prediction candidates are aggregated in a bi-level aggregation protocol to produce the final output. Through extensive experiments on medical imaging benchmark datasets, we show that our method improves upon state-of-the-art methods in terms of robustness and confidence calibration. Additionally, we introduce a strategy to quantify the prediction uncertainty at the instance level, increasing their trustworthiness to clinicians using them in clinical practice.

Debiasing Counterfactuals In the Presence of Spurious Correlations

Deep learning models can perform well in complex medical imaging classification tasks, even when basing their conclusions on spurious correlations (i.e. confounders), should they be prevalent in the training dataset, rather than on the causal image markers of interest. This would thereby limit their ability to generalize across the population. Explainability based on counterfactual image generation can be used to expose the confounders but does not provide a strategy to mitigate the bias. In this work, we introduce the first end-to-end training framework that integrates both (i) popular debiasing classifiers (e.g. distributionally robust optimization (DRO)) to avoid latching onto the spurious correlations and (ii) counterfactual image generation to unveil generalizable imaging markers of relevance to the task. Additionally, we propose a novel metric, Spurious Correlation Latching Score (SCLS), to quantify the extent of the classifier reliance on the spurious correlation as exposed by the counterfactual images. Through comprehensive experiments on two public datasets (with the simulated and real visual artifacts), we demonstrate that the debiasing method: (i) learns generalizable markers across the population, and (ii) successfully ignores spurious correlations and focuses on the underlying disease pathology.

Mitigating Calibration Bias Without Fixed Attribute Grouping for Improved Fairness in Medical Imaging Analysis

Trustworthy deployment of deep learning medical imaging models into real-world clinical practice requires that they be calibrated. However, models that are well calibrated overall can still be poorly calibrated for a sub-population, potentially resulting in a clinician unwittingly making poor decisions for this group based on the recommendations of the model. Although methods have been shown to successfully mitigate biases across subgroups in terms of model accuracy, this work focuses on the open problem of mitigating calibration biases in the context of medical image analysis. Our method does not require subgroup attributes during training, permitting the flexibility to mitigate biases for different choices of sensitive attributes without re-training. To this end, we propose a novel two-stage method: Cluster-Focal to first identify poorly calibrated samples, cluster them into groups, and then introduce group-wise focal loss to improve calibration bias. We evaluate our method on skin lesion classification with the public HAM10000 dataset, and on predicting future lesional activity for multiple sclerosis (MS) patients. In addition to considering traditional sensitive attributes (e.g. age, sex) with demographic subgroups, we also consider biases among groups with different image-derived attributes, such as lesion load, which are required in medical image analysis. Our results demonstrate that our method effectively controls calibration error in the worst-performing subgroups while preserving prediction performance, and outperforming recent baselines.

Improving Image-Based Precision Medicine with Uncertainty-Aware Causal Models

Image-based precision medicine aims to personalize treatment decisions based on an individual's unique imaging features so as to improve their clinical outcome. Machine learning frameworks that integrate uncertainty estimation as part of their treatment recommendations would be safer and more reliable. However, little work has been done in adapting uncertainty estimation techniques and validation metrics for precision medicine. In this paper, we use Bayesian deep learning for estimating the posterior distribution over factual and counterfactual outcomes on several treatments. This allows for estimating the uncertainty for each treatment option and for the individual treatment effects (ITE) between any two treatments. We train and evaluate this model to predict future new and enlarging T2 lesion counts on a large, multi-center dataset of MR brain images of patients with multiple sclerosis, exposed to several treatments during randomized controlled trials. We evaluate the correlation of the uncertainty estimate with the factual error, and, given the lack of ground truth counterfactual outcomes, demonstrate how uncertainty for the ITE prediction relates to bounds on the ITE error. Lastly, we demonstrate how knowledge of uncertainty could modify clinical decision-making to improve individual patient and clinical trial outcomes.

Evaluating the Fairness of Deep Learning Uncertainty Estimates in Medical Image Analysis

Although deep learning (DL) models have shown great success in many medical image analysis tasks, deployment of the resulting models into real clinical contexts requires: (1) that they exhibit robustness and fairness across different sub-populations, and (2) that the confidence in DL model predictions be accurately expressed in the form of uncertainties. Unfortunately, recent studies have indeed shown significant biases in DL models across demographic subgroups (e.g., race, sex, age) in the context of medical image analysis, indicating a lack of fairness in the models. Although several methods have been proposed in the ML literature to mitigate a lack of fairness in DL models, they focus entirely on the absolute performance between groups without considering their effect on uncertainty estimation. In this work, we present the first exploration of the effect of popular fairness models on overcoming biases across subgroups in medical image analysis in terms of bottom-line performance, and their effects on uncertainty quantification. We perform extensive experiments on three different clinically relevant tasks: (i) skin lesion classification, (ii) brain tumour segmentation, and (iii) Alzheimer's disease clinical score regression. Our results indicate that popular ML methods, such as data-balancing and distributionally robust optimization, succeed in mitigating fairness issues in terms of the model performances for some of the tasks. However, this can come at the cost of poor uncertainty estimates associated with the model predictions. This tradeoff must be mitigated if fairness models are to be adopted in medical image analysis.

Understanding metric-related pitfalls in image analysis validation

Validation metrics are key for the reliable tracking of scientific progress and for bridging the current chasm between artificial intelligence (AI) research and its translation into practice. However, increasing evidence shows that particularly in image analysis, metrics are often chosen inadequately in relation to the underlying research problem. This could be attributed to a lack of accessibility of metric-related knowledge: While taking into account the individual strengths, weaknesses, and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers. Based on a multi-stage Delphi process conducted by a multidisciplinary expert consortium as well as extensive community feedback, the present work provides the first reliable and comprehensive common point of access to information on pitfalls related to validation metrics in image analysis. Focusing on biomedical image analysis but with the potential of transfer to other fields, the addressed pitfalls generalize across application domains and are categorized according to a newly created, domain-agnostic taxonomy. To facilitate comprehension, illustrations and specific examples accompany each pitfall. As a structured body of information accessible to researchers of all levels of expertise, this work enhances global comprehension of a key topic in image analysis validation.

Clinically Plausible Pathology-Anatomy Disentanglement in Patient Brain MRI with Structured Variational Priors

We propose a hierarchically structured variational inference model for accurately disentangling observable evidence of disease (e.g. brain lesions or atrophy) from subject-specific anatomy in brain MRIs. With flexible, partially autoregressive priors, our model (1) addresses the subtle and fine-grained dependencies that typically exist between anatomical and pathological generating factors of an MRI to ensure the clinical validity of generated samples; (2) preserves and disentangles finer pathological details pertaining to a patient's disease state. Additionally, we experiment with an alternative training configuration where we provide supervision to a subset of latent units. It is shown that (1) a partially supervised latent space achieves a higher degree of disentanglement between evidence of disease and subject-specific anatomy; (2) when the prior is formulated with an autoregressive structure, knowledge from the supervision can propagate to the unsupervised latent units, resulting in more informative latent representations capable of modelling anatomy-pathology interdependencies.