In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

Electronic health records (EHR) are rich heterogeneous collections of patient health information, whose broad adoption provides clinicians and researchers unprecedented opportunities for health informatics, disease-risk prediction, actionable clinical recommendations, and precision medicine. However, EHRs present several modeling challenges, including highly sparse data matrices, noisy irregular clinical notes, arbitrary biases in billing code assignment, diagnosis-driven lab tests, and heterogeneous data types. To address these challenges, we present MixEHR, a multi-view Bayesian topic model. We demonstrate MixEHR on MIMIC-III, Mayo Clinic Bipolar Disorder, and Quebec Congenital Heart Disease EHR datasets. Qualitatively, MixEHR disease topics reveal meaningful combinations of clinical features across heterogeneous data types. Quantitatively, we observe superior prediction accuracy of diagnostic codes and lab test imputations compared to the state-of-art methods. We leverage the inferred patient topic mixtures to classify target diseases and predict mortality of patients in critical conditions. In all comparison, MixEHR confers competitive performance and reveals meaningful disease-related topics.

Objective A major bottleneck hindering utilization of electronic health record data for translational research is the lack of precise phenotype labels. Chart review as well as rule-based and supervised phenotyping approaches require laborious expert input, hampering applicability to studies that require many phenotypes to be defined and labeled de novo. Though International Classification of Diseases codes are often used as surrogates for true labels in this setting, these sometimes suffer from poor specificity. We propose a fully automated topic modeling algorithm to simultaneously annotate multiple phenotypes. Materials and Methods Surrogate-guided ensemble latent Dirichlet allocation (sureLDA) is a label-free multidimensional phenotyping method. It first uses the PheNorm algorithm to initialize probabilities based on 2 surrogate features for each target phenotype, and then leverages these probabilities to constrain the LDA topic model to generate phenotype-specific topics. Finally, it combines phenotype-feature counts with surrogates via clustering ensemble to yield final phenotype probabilities. Results sureLDA achieves reliably high accuracy and precision across a range of simulated and real-world phenotypes. Its performance is robust to phenotype prevalence and relative informativeness of surogate vs nonsurrogate features. It also exhibits powerful feature selection properties. Discussion sureLDA combines attractive properties of PheNorm and LDA to achieve high accuracy and precision robust to diverse phenotype characteristics. It offers particular improvement for phenotypes insufficiently captured by a few surrogate features. Moreover, sureLDA’s feature selection ability enables it to handle high feature dimensions and produce interpretable computational phenotypes. Conclusions sureLDA is well suited toward large-scale electronic health record phenotyping for highly multiphenotype applications such as phenome-wide association studies .

Objective No relapse risk prediction tool is currently available to guide treatment selection for multiple sclerosis (MS). Leveraging electronic health record (EHR) data readily available at the point of care, we developed a clinical tool for predicting MS relapse risk. Methods Using data from a clinic‐based research registry and linked EHR system between 2006 and 2016, we developed models predicting relapse events from the registry in a training set (n = 1435) and tested the model performance in an independent validation set of MS patients (n = 186). This iterative process identified prior 1‐year relapse history as a key predictor of future relapse but ascertaining relapse history through the labor‐intensive chart review is impractical. We pursued two‐stage algorithm development: (1) L1‐regularized logistic regression (LASSO) to phenotype past 1‐year relapse status from contemporaneous EHR data, (2) LASSO to predict future 1‐year relapse risk using imputed prior 1‐year relapse status and other algorithm‐selected features. Results The final model, comprising age, disease duration, and imputed prior 1‐year relapse history, achieved a predictive AUC and F score of 0.707 and 0.307, respectively. The performance was significantly better than the baseline model (age, sex, race/ethnicity, and disease duration) and noninferior to a model containing actual prior 1‐year relapse history. The predicted risk probability declined with disease duration and age. Conclusion Our novel machine‐learning algorithm predicts 1‐year MS relapse with accuracy comparable to other clinical prediction tools and has applicability at the point of care. This EHR‐based two‐stage approach of outcome prediction may have application to neurological disease beyond MS.

Objective Identifying pseudogout in large data sets is difficult due to its episodic nature and a lack of billing codes specific to this acute subtype of calcium pyrophosphate (CPP) deposition disease. The objective of this study was to evaluate a novel machine learning approach for classifying pseudogout using electronic health record (EHR) data. Methods We created an EHR data mart of patients with ≥1 relevant billing code or ≥2 natural language processing (NLP) mentions of pseudogout or chondrocalcinosis, 1991–2017. We selected 900 subjects for gold standard chart review for definite pseudogout (synovitis + synovial fluid CPP crystals), probable pseudogout (synovitis + chondrocalcinosis), or not pseudogout. We applied a topic modeling approach to identify definite/probable pseudogout. A combined algorithm included topic modeling plus manually reviewed CPP crystal results. We compared algorithm performance and cohorts identified by billing codes, the presence of CPP crystals, topic modeling, and a combined algorithm. Results Among 900 subjects, 123 (13.7%) had pseudogout by chart review (68 definite, 55 probable). Billing codes had a sensitivity of 65% and a positive predictive value (PPV) of 22% for pseudogout. The presence of CPP crystals had a sensitivity of 29% and a PPV of 92%. Without using CPP crystal results, topic modeling had a sensitivity of 29% and a PPV of 79%. The combined algorithm yielded a sensitivity of 42% and a PPV of 81%. The combined algorithm identified 50% more patients than the presence of CPP crystals; the latter captured a portion of definite pseudogout and missed probable pseudogout. Conclusion For pseudogout, an episodic disease with no specific billing code, combining NLP, machine learning methods, and synovial fluid laboratory results yielded an algorithm that significantly boosted the PPV compared to billing codes.