Clinical decision making heavily relies on predicting the disease progression trajectory by seeking to understand patient's health status which is characterised by multimodal medical data. AI holds great potential for learning useful representations from multimodal medical data to predict disease progression and aid clinical decision making. However, development of predictive AI models is constrained by missing modalities and incomplete tabular data frequently occurring in medical datasets. In addition, disease labels alone may only provide limited supervisory signals for learning representations from high-dimensional multimodal data. Here, we present MMAP, a novel Multimodal Missing-aware Alignment Pretraining method for learning image-tabular representations from incomplete data. An image encoder is pretrained with efficient sigmoid contrastive learning combined with generative reconstruction. A tabular encoder is built upon a tabular foundation model. A missing token generator enables the two encoders to take incomplete data as input, enabling the model to be robust against missing modalities, either with missing images or missing tabular data. We evaluate the clinical usefulness of the learnt multimodal representations on two challenging longitudinal clinical tasks for Alzheimer's disease: predicting disease stage conversion and predicting amyloid status. The proposed method outperforms strong multimodal and unimodal baselines.
Missing modalities are prevalent in real-world Alzheimer's disease (AD) assessment and pose a significant challenge to multimodal learning, particularly when the distribution of observed modality subsets differs between training and deployment. Such missingness pattern mismatch induces a conditional representation shift across modality subsets. Existing approaches that rely on implicit imputation or modality synthesis often fail to explicitly model modality availability and uncertainty, leading to overconfident dependence on synthesized features, reduced robustness, and miscalibrated uncertainty estimates. To address these limitations, we propose PRA-PoE, an incomplete multimodal learning framework that is equipped with Prototype-anchored Representation Alignment (PRA) and an Uncertainty-aware Product of Experts (UA-PoE) fusion mechanism. First, PRA uses learnable global prototypes and availability-conditioned tokens to encode modality availability, distinguish observed from missing modalities, re-synthesize features for missing modalities, and adaptively refine observed representations to align latent spaces across modality subsets, with the goal of reducing representation shift under varying missingness patterns. Second, UA-PoE models each modality as a Gaussian expert and performs closed-form Product of Experts fusion, where experts with higher uncertainty are automatically down-weighted via lower precision, improving uncertainty reliability. We evaluate PRA-PoE under a clinically realistic protocol by training with naturally missing data and testing on all non-empty modality combinations. PRA-PoE consistently outperforms the state-of-the-art across datasets, achieving a 5.4% relative improvement in average accuracy on ADNI and a 10.9% relative gain in average F1 on OASIS-3 over the strongest baseline across all non-empty modality subsets.
An active challenge in developing multimodal machine learning (ML) models for healthcare is handling missing modalities during training and deployment. As clinical datasets are inherently temporal and sparse in terms of modality presence, capturing the underlying predictive signal via diagnostic multimodal ML models while retaining model explainability remains an ongoing challenge. In this work, we address this by re-framing clinical diagnosis as an autoregressive sequence modeling task, utilizing causal decoders from large language models (LLMs) to model a patient's multimodal trajectory. We first introduce a missingness-aware contrastive pre-training objective that integrates multiple modalities in datasets with missingness in a shared latent space. We then show that autoregressive sequence modeling with transformer-based architectures outperforms baselines on the MIMIC-IV and eICU fine-tuning benchmarks. Finally, we use interpretability techniques to move beyond performance boosts and find that across various patient stays, removing modalities leads to divergent behavior that our contrastive pre-training mitigates. By abstracting clinical diagnosis as sequence modeling and interpreting patient stay trajectories, we develop a framework to profile and handle missing modalities while addressing the canonical desideratum of safe, transparent clinical AI.
Deep learning models in medical imaging typically operate as parametric memory, diagnosing patients by recalling fixed knowledge learned during training. This contrasts sharply with clinical practice, where physicians employ analogical reasoning to diagnose new cases by referencing similar records from past exemplars. While In-Context Learning (ICL) frameworks such as Tabular Prior-Fitted Networks (TabPFN) offer a promising diagnosis-by-reference paradigm, they are designed with tabular-specific inductive priors and rely on non-differentiable preprocessing pipelines, leading to manifold mismatch and gradient fracture when applied to heterogeneous multimodal data. To address these limitations, we propose PromptDx, a novel diagnosis-by-reference framework that leverages a pre-trained TabPFN as an ICL engine while enabling seamless integration with multimodal representations. Our core contribution is a Differentiable Prompt Tuning (DPT) mechanism that aligns a Masked Multimodal Modeling module with the pre-trained ICL engine. By training a lightweight adapter as a differentiable surrogate for the engine's non-differentiable preprocessors, we enable an end-to-end optimization of multimodal prompts within the ICL paradigm. We validate our method on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset using 3D MRI and tabular biomarkers. Experiments demonstrate that our approach outperforms traditional parametric baselines. Notably, our method achieves superior performance using only 1% context samples compared to 30% in standard ICL, demonstrating exceptional manifold condensation ability. We further validate the generalizability of our DPT framework across six tabular datasets with diverse scales. Overall, our method offers a more data-efficient and clinically aligned paradigm for Alzheimer's Disease diagnosis.