Data-driven discovery of probable Alzheimer's disease and related dementia subphenotypes using electronic health records

Jie Xu, Fei Wang, Zhenxing Xu, Prakash Adekkanattu, Pascal Brandt, Guoqian Jiang, Richard C. Kiefer, Yuan Luo, Chengsheng Mao, Jennifer A. Pacheco, Luke V. Rasmussen, Yiye Zhang, Richard Isaacson, Jyotishman Pathak

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Introduction: We sought to assess longitudinal electronic health records (EHRs) using machine learning (ML) methods to computationally derive probable Alzheimer's Disease (AD) and related dementia subphenotypes. Methods: A retrospective analysis of EHR data from a cohort of 7587 patients seen at a large, multi-specialty urban academic medical center in New York was conducted. Subphenotypes were derived using hierarchical clustering from 792 probable AD patients (cases) who had received at least one diagnosis of AD using their clinical data. The other 6795 patients, labeled as controls, were matched on age and gender with the cases and randomly selected in the ratio of 9:1. Prediction models with multiple ML algorithms were trained on this cohort using 5-fold cross-validation. XGBoost was used to rank the variable importance. Results: Four subphenotypes were computationally derived. Subphenotype A (n = 273; 28.2%) had more patients with cardiovascular diseases; subphenotype B (n = 221; 27.9%) had more patients with mental health illnesses, such as depression and anxiety; patients in subphenotype C (n = 183; 23.1%) were overall older (mean (SD) age, 79.5 (5.4) years) and had the most comorbidities including diabetes, cardiovascular diseases, and mental health disorders; and subphenotype D (n = 115; 14.5%) included patients who took anti-dementia drugs and had sensory problems, such as deafness and hearing impairment. The 0-year prediction model for AD risk achieved an area under the receiver operating curve (AUC) of 0.764 (SD: 0.02); the 6-month model, 0.751 (SD: 0.02); the 1-year model, 0.752 (SD: 0.02); the 2-year model, 0.749 (SD: 0.03); and the 3-year model, 0.735 (SD: 0.03), respectively. Based on variable importance, the top-ranked comorbidities included depression, stroke/transient ischemic attack, hypertension, anxiety, mobility impairments, and atrial fibrillation. The top-ranked medications included anti-dementia drugs, antipsychotics, antiepileptics, and antidepressants. Conclusions: Four subphenotypes were computationally derived that correlated with cardiovascular diseases and mental health illnesses. ML algorithms based on patient demographics, diagnosis, and treatment demonstrated promising results in predicting the risk of developing AD at different time points across an individual's lifespan.

Original languageEnglish (US)
Article numbere10246
JournalLearning Health Systems
Issue number4
StatePublished - Oct 1 2020


  • Alzheimer's disease
  • electronic health records
  • subphenotypes

ASJC Scopus subject areas

  • Health Informatics
  • Public Health, Environmental and Occupational Health
  • Health Information Management


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