Yingnan He

Yu Leng, Yingnan He, Colin Magdamo et al.

Identifying cognitive impairment within electronic health records (EHRs) is crucial not only for timely diagnoses but also for facilitating research. Information about cognitive impairment often exists within unstructured clinician notes in EHRs, but manual chart reviews are both time-consuming and error-prone. To address this issue, our study evaluates an automated approach using zero-shot GPT-4o to determine stage of cognitive impairment in two different tasks. First, we evaluated the ability of GPT-4o to determine the global Clinical Dementia Rating (CDR) on specialist notes from 769 patients who visited the memory clinic at Massachusetts General Hospital (MGH), and achieved a weighted kappa score of 0.83. Second, we assessed GPT-4o's ability to differentiate between normal cognition, mild cognitive impairment (MCI), and dementia on all notes in a 3-year window from 860 Medicare patients. GPT-4o attained a weighted kappa score of 0.91 in comparison to specialist chart reviews and 0.96 on cases that the clinical adjudicators rated with high confidence. Our findings demonstrate GPT-4o's potential as a scalable chart review tool for creating research datasets and assisting diagnosis in clinical settings in the future.

Ayush Noori, Joaquín Polonuer, Katharina Meyer et al.

Neurological diseases are the leading global cause of disability, yet most lack disease-modifying treatments. We present PROTON, a heterogeneous graph transformer that generates testable hypotheses across molecular, organoid, and clinical systems. To evaluate PROTON, we apply it to Parkinson's disease (PD), bipolar disorder (BD), and Alzheimer's disease (AD). In PD, PROTON linked genetic risk loci to genes essential for dopaminergic neuron survival and predicted pesticides toxic to patient-derived neurons, including the insecticide endosulfan, which ranked within the top 1.29% of predictions. In silico screens performed by PROTON reproduced six genome-wide $α$-synuclein experiments, including a split-ubiquitin yeast two-hybrid system (normalized enrichment score [NES] = 2.30, FDR-adjusted $p < 1 \times 10^{-4}$), an ascorbate peroxidase proximity labeling assay (NES = 2.16, FDR $< 1 \times 10^{-4}$), and a high-depth targeted exome sequencing study in 496 synucleinopathy patients (NES = 2.13, FDR $< 1 \times 10^{-4}$). In BD, PROTON predicted calcitriol as a candidate drug that reversed proteomic alterations observed in cortical organoids derived from BD patients. In AD, we evaluated PROTON predictions in health records from $n = 610,524$ patients at Mass General Brigham, confirming that five PROTON-predicted drugs were associated with reduced seven-year dementia risk (minimum hazard ratio = 0.63, 95% CI: 0.53-0.75, $p < 1 \times 10^{-7}$). PROTON generated neurological hypotheses that were evaluated across molecular, organoid, and clinical systems, defining a path for AI-driven discovery in neurological disease.

Anya Chauhan, Ayush Noori, Zhaozhi Li et al.

Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder characterized by extracellular A\b{eta} plaques, neurofibrillary tau tangles, glial activation, and neuronal degeneration, involving multiple cell types and pathways. Current models often overlook the cellular context of these pathways. To address this, we developed a multiscale graph neural network (GNN) model, ALZ PINNACLE, using brain omics data from donors spanning the entire aging to AD spectrum. ALZ PINNACLE is based on the PINNACLE GNN framework, which learns context-aware protein, cell type, and tissue representations within a unified latent space. ALZ PINNACLE was trained on 14,951 proteins, 206,850 protein interactions, 7 cell types, and 48 cell subtypes or states. After pretraining, we investigated the learned embedding of APOE, the largest genetic risk factor for AD, across different cell types. Notably, APOE embeddings showed high similarity in microglial, neuronal, and CD8 cells, suggesting a similar role of APOE in these cell types. Fine tuning the model on AD risk genes revealed cell type contexts predictive of the role of APOE in AD. Our results suggest that ALZ PINNACLE may provide a valuable framework for uncovering novel insights into AD neurobiology.

Matthew West, Colin Magdamo, Lily Cheng et al.

Alzheimer's disease is a progressive, debilitating neurodegenerative disease that affects 50 million people globally. Despite this substantial health burden, available treatments for the disease are limited and its fundamental causes remain poorly understood. Previous work has suggested the existence of clinically-meaningful sub-types, which it is suggested may correspond to distinct etiologies, disease courses, and ultimately appropriate treatments. Here, we use unsupervised learning techniques on electronic health records (EHRs) from a cohort of memory disorder patients to characterise heterogeneity in this disease population. Pre-trained embeddings for medical codes as well as transformer-derived Clinical BERT embeddings of free text are used to encode patient EHRs. We identify the existence of sub-populations on the basis of comorbidities and shared textual features, and discuss their clinical significance.