This paper introduces an innovative Electronic Health Record (EHR) foundation model that integrates Polygenic Risk Scores (PRS) as a foundational data modality, moving beyond traditional EHR-only approaches to build more holistic health profiles. Leveraging the extensive and diverse data from the All of Us (AoU) Research Program, this multimodal framework aims to learn complex relationships between clinical data and genetic predispositions. The methodology extends advancements in generative AI to the EHR foundation model space, enhancing predictive capabilities and interpretability. Evaluation on AoU data demonstrates the model's predictive value for the onset of various conditions, particularly Type 2 Diabetes (T2D), and illustrates the interplay between PRS and EHR data. The work also explores transfer learning for custom classification tasks, showcasing the architecture's versatility and efficiency. This approach is pivotal for unlocking new insights into disease prediction, proactive health management, risk stratification, and personalized treatment strategies, laying the groundwork for more personalized, equitable, and actionable real-world evidence generation in healthcare.

Predicting an individual's aging trajectory is a central challenge in preventative medicine and bioinformatics. While machine learning models can predict chronological age from biomarkers, they often fail to capture the dynamic, longitudinal nature of the aging process. In this work, we developed and validated a machine learning pipeline to predict age using a longitudinal cohort with data from two distinct time periods (2019-2020 and 2021-2022). We demonstrate that a model using only static, cross-sectional biomarkers has limited predictive power when generalizing to future time points. However, by engineering novel features that explicitly capture the rate of change (slope) of key biomarkers over time, we significantly improved model performance. Our final LightGBM model, trained on the initial wave of data, successfully predicted age in the subsequent wave with high accuracy ($R^2 = 0.515$ for males, $R^2 = 0.498$ for females), significantly outperforming both traditional linear models and other tree-based ensembles. SHAP analysis of our successful model revealed that the engineered slope features were among the most important predictors, highlighting that an individual's health trajectory, not just their static health snapshot, is a key determinant of biological age. Our framework paves the way for clinical tools that dynamically track patient health trajectories, enabling early intervention and personalized prevention strategies for age-related diseases.

Health registers contain rich information about individuals' health histories. Here our interest lies in understanding how individuals' health trajectories evolve in a nationwide longitudinal dataset with coded features, such as clinical codes, procedures, and drug purchases. We introduce a straightforward approach for training a Transformer-based deep learning model in a way that lets us analyze how individuals' trajectories change over time. This is achieved by modifying the training objective and by applying a causal attention mask. We focus here on a general task of predicting the onset of a range of common diseases in a given future forecast interval. However, instead of providing a single prediction about diagnoses that could occur in this forecast interval, our approach enable the model to provide continuous predictions at every time point up until, and conditioned on, the time of the forecast period. We find that this model performs comparably to other models, including a bi-directional transformer model, in terms of basic prediction performance while at the same time offering promising trajectory modeling properties. We explore a couple of ways to use this model for analyzing health trajectories and aiding in early detection of events that forecast possible later disease onsets. We hypothesize that this method may be helpful in continuous monitoring of peoples' health trajectories and enabling interventions in ongoing health trajectories, as well as being useful in retrospective analyses.

Clinical data informs the personalization of health care with a potential for more effective disease management. In practice, this is achieved by subgrouping, whereby clusters with similar patient characteristics are identified and then receive customized treatment plans with the goal of targeting subgroup-specific disease dynamics. In this paper, we propose a novel mixture hidden Markov model for subgrouping patient trajectories from chronic diseases. Our model is probabilistic and carefully designed to capture different trajectory phases of chronic diseases (i.e., "severe", "moderate", and "mild") through tailored latent states. We demonstrate our subgrouping framework based on a longitudinal study across 847 patients with non-specific low back pain. Here, our subgrouping framework identifies 8 subgroups. Further, we show that our subgrouping framework outperforms common baselines in terms of cluster validity indices. Finally, we discuss the applicability of the model to other chronic and long-lasting diseases.

Cardiovascular diseases are the most common cause of death in the world. More than a third of deaths in Finland are caused by cardiovascular diseases. The current objective is to create an assessment, based on health data, of each person's risk of illness before they consult a doctor. Andrea Ganna, Group Leader from Institute for Molecular Medicine Finland FIMM at the University of Helsinki and instructor from Harvard Medical School, wants to establish a nationwide, personalised risk assessment as foundation for planning public health interventions. The assessment is based on the health, demographic and genetic information of the citizens.