Predicting Early Functional Decline from Longitudinal Laboratory and Vital Sign Trajectories: A Large-Scale Study Using the All of Us Research Program

Wearable and mobile sensing technologies enable continuous monitoring of human behavior and health in real-world settings. However, predictive modeling in longitudinal multimodal data remains challenging, particularly when targeting complex or clinically derived outcomes. In this work, we present a longitudinal multimodal study of 66 older adults conducted in real-world conditions and combining wearable sensing, behavioral monitoring, and clinical assessments. This setting provides a rare opportunity to study an underrepresented population in long-term, into-the-wild conditions. Building on this dataset, we investigate how the alignment between sensed signals and target variables affects predictive performance across health-related tasks. We design a unified evaluation framework spanning tasks with increasing levels of observability, including Activity Levels prediction, Sleep Duration estimation, and Sleep Apnea Severity classification. Our results reveal a clear gradient of predictability: highly observable behavioral targets achieve robust performance (macro-F1 65%), while more abstract outcomes remain challenging despite consistent improvements over baseline models. Moreover, through explainability analysis, we show that historical features consistently emerge as the most informative predictors, highlighting the central role of longitudinal information.

Amyotrophic lateral sclerosis (ALS) is a progressive and heterogeneous neurodegenerative disease in which predicting clinically meaningful milestones, such as assistive device use, remains challenging. We developed a time-to-event, digital-twin-inspired framework that integrates longitudinal ALS Functional Rating Scale-Revised (ALSFRS-R) trajectories with survival modeling to support individualized prediction of functional decline and assistive device utilization. We constructed a harmonized longitudinal dataset by integrating diagnosis records, ALSFRS-R assessments, activities of daily living, and demographic information, followed by preprocessing to ensure data quality, temporal alignment, and cohort consistency. Correlation-based clustering identified coherent functional domains spanning bulbar, upper limb, axial, lower limb, and respiratory systems. Generalized additive mixed models characterized nonlinear, domain-specific functional decline across all domains. In addition, a temporal machine learning model was developed to predict longitudinal functional decline and capture stage-dependent disease progression. Cox proportional hazards modeling further identified lower limb function, particularly walking and stair climbing, as the strongest predictors of earlier wheelchair access. Building on these results, we implemented a digital twin-inspired temporal machine learning-based time-to-event (TTE) model that generates individualized survival curves and dynamically predicts wheelchair-free survival. This framework provides a scalable, interpretable, and clinically actionable approach for linking ALS progression with personalized decision support, with applications in proactive care planning, clinical trial stratification, and precision medicine.

Gait is increasingly recognized as a vital sign, yet current approaches treat it as a symptom of specific pathologies rather than a systemic biomarker. We developed a gait foundation model for 3D skeletal motion from 3,414 deeply phenotyped adults, recorded via a depth camera during five motor tasks. Learned embeddings outperformed engineered features, predicting age (Pearson r = 0.69), BMI (r = 0.90), and visceral adipose tissue area (r = 0.82). Embeddings significantly predicted 1,980 of 3,210 phenotypic targets; after adjustment for age, BMI, VAT, and height, gait provided independent gains in all 18 body systems in males and 17 of 18 in females, and improved prediction of clinical diagnoses and medication use. Anatomical ablation revealed that legs dominated metabolic and frailty predictions while torso encoded sleep and lifestyle phenotypes. These findings establish gait as an independent multi-system biosignal, motivating translation to consumer-grade video and its integration as a scalable, passive vital sign.