Probabilistic learning to perform pre-onset individualised prediction of disease severity: application to Veno Occlusive Disease
Authors: Dalia Chakrabarty, Kane Warrior, Chuqiao Zhang, Akash Bhojgaria, Joydeep Chakrabartty
Abstract
We advance a new probabilistic supervised learning approach that permits reliable, automated, and early individualised prediction of the severity with which a disease will develop in a prospective patient. The prediction capacity is illustrated via the pre-transplant prediction of the score of severity of Veno Occlusive Disease (or VOD) in the digital twin (DT) of the considered prospective patient, where this score parametrises the severity with which VOD will develop in this patient, after they undergo their Bone Marrow Transplant. The learning of the relationship between the pre-transplant variables, and a severity score variable is undertaken by modelling this relationship as a (random) function that is treated as a sample function of an adequately-chosen stochastic process. The parameters of this underlying process are learnt using a training dataset that is generated using the real-time evolution of retrospective patients in a cohort, with this training dataset subsequently augmented in size by a probabilistic inverse learning of the score of prospective patients. The augmented training set, then permits the learning of the function that capacitates - at the pre-transplant stage - automated prediction of the score of the severity of VOD that characterises the DT of a physical patient in their unique pre-transplant state. This score is subsequently fed back to the real prospective patient as the severity with which VOD will develop in them, after this patient undergoes their transplant. Such a score then permits the treating Haematologist-Oncologists to decide on the treatment regimen, which in this illustration reduces to deciding on treating the patient with Defibrotide. An AI facility is developed to undertake such automated prediction, with the physician inputting the data on the pre-transplant state that characterises the DT of the prospective patient under consideration.
We convert black-box clinical prediction models for tabular data into standalone nomograms that can be audited term by term. PRiSM (Partial Responses in Structured Models) takes the shape of each effect and interaction from the source model, not merely which variables mattered, and lets the outcome select and weight them. We tested this in 50,356 heart transplant recipients, with validation in a later era than training. Nomograms from all 5 source models - a public clinical risk score, logistic regression, neural networks, random forests and extreme gradient boosting - met a prespecified noninferiority criterion for discrimination before any further simplification, and generally preserved calibration and clinical net benefit. Those from the 3 machine-learning models showed no detectable difference in discrimination from de novo generalized additive and explainable boosting models, exceeded neural additive models, and carried fewer terms than the explainable boosting model. PRiSM is released as an open-source Python package.
Henry Pigot, Paulo J. G. Lisboa, Sandra Ortega-Martorell +3
Precision medicine in ophthalmology requires accurate longitudinal predictions, but the fragmented nature of multimodal clinical data remains a barrier to forecasting. We introduce OphthaDT, an LLM-based digital twin for ophthalmology that serializes longitudinal patient histories from 3,220 patients across four Phase III clinical trials into structured narratives to forecast best corrected visual acuity (BCVA). In benchmarks spanning up to 100 weeks, OphthaDT demonstrated the lowest prediction error in neovascular age-related macular degeneration (nAMD), achieving an average mean absolute error (MAE) reduction of 6.0% compared to all baselines. In diabetic macular edema (DME), OphthaDT demonstrated competitive performance against all baselines while outperforming Random Forest and XGBoost by an average MAE reduction of 2.6% and 6.9%, respectively. Results reveal that OphthaDT's predictive advantage scales with trajectory complexity: whereas linear models remain effective for the more stable treatment responses of DME, OphthaDT's capacity is better suited for capturing the high longitudinal variability of nAMD. Finally, OphthaDT handles irregular sampling without imputation, positioning LLM-based clinical trajectory modeling as a methodology that could reduce patient burden and accelerate drug development.
Pietro Belligoli, Nikita Makarov, Sayedali Shetab Boushehri +3
Early prediction of severe clinical deterioration and remaining length of stay can enable timely intervention and better resource allocation in high-acuity settings such as the ICU. This has driven the development of machine learning models that leverage continuous streams of vital signs and other physiological signals for real-time risk prediction. Despite their promise, existing methods have important limitations. Contrastive pretraining treats all patients as equally strong negatives, failing to capture clinically meaningful similarity between patients with related diagnoses. Meanwhile, downstream fine-tuning typically ignores complementary modalities such as clinical notes, which provide rich contextual information unavailable in physiological signals alone. To address these challenges, we propose OC-Distill, a two-stage framework that leverages multimodal supervision during training while requiring only vital signs at inference. In the first stage, we introduce an ontology-aware contrastive objective that exploits the ICD hierarchy to quantify patient similarity and learn clinically grounded representations. In the second stage, we fine-tune the pretrained encoder via cross-modal knowledge distillation, transferring complementary information from clinical notes into the model. Across multiple ICU prediction tasks on MIMIC, OC-Distill demonstrates improved label efficiency and achieves state-of-the-art performance among methods that use only vital signs at inference.