Detecting Rare Diseases in Electronic Health Records Using Machine Learning and Knowledge Engineering: Case Study of Acute Hepatic Porphyria
Authors: Cohen Aaron , Chamberlin Steven , Deloughery Thomas , Nguyen Michelle , Bedrick Steven , Meninger Stephen , Ko John J. , Amin Jigar , Wei Alex , Hersh William 
Published: April 2020

AbstractBackgroundWith the growing adoption of the electronic health record (EHR) worldwide over the last decade, new opportunities exist for leveraging EHR data for detection of rare diseases. Rare diseases are often not diagnosed or delayed in diagnosis by clinicians who encounter them infrequently. One such rare disease that may be amenable to EHR-based detection is acute hepatic porphyria (AHP). AHP consists of a family of rare, metabolic diseases characterized by potentially life-threatening acute attacks and, for some patients, chronic debilitating symptoms that negatively impact daily functioning and quality of life. The goal of this study was to apply machine learning and knowledge engineering to a large extract of EHR data to determine whether they could be effective in identifying patients not previously tested for AHP who should receive a proper diagnostic workup for AHP.Methods and FindingsWe used an extract of the complete EHR data of 200,000 patients from an academic medical center for up to 10 years longitudinally and enriched it with records from an additional 5,571 patients from the center containing any mention of porphyria in notes, laboratory tests, diagnosis codes, and other parts of the record. After manually reviewing all patients with the ICD-10-CM code E80.21 (Acute intermittent [hepatic] porphyria), we identified 30 patients who were positive cases for our machine learning models, with the rest of the patients used as negative cases. We parsed the record into features, which were scored by frequency of appearance and labeled by the EHR source document. We then carried out a univariate feature analysis, manually choosing features not directly tied to provider attributes or suspicion of the patient having AHP. We next trained on the full dataset, with the best cross-validation performance coming from support vector machine (SVM) algorithm using a radial basis function (RBF) kernel. The trained model was applied back to the full data set and patients were ranked by margin distance. The top 100 ranked negative cases were manually reviewed for symptom complexes similar to AHP, finding four patients where AHP diagnostic testing was likely indicated and 18 patients where AHP diagnostic testing was possibly indicated. From the top 100 ranked cases of patients with mention of porphyria in their record, we identified four patients for whom AHP diagnostic testing was possibly indicated and had not been previously performed. Based solely on the reported prevalence of AHP, we would have expected only 0.002 cases out of the 200 patients manually reviewed.ConclusionsThe application of machine learning and knowledge engineering to EHR data may facilitate the diagnosis of rare diseases such as AHP. The only manual modifications to this work were the removal of disease-specific or medical center specific features that might undermine our ability to find new cases. Further work will recommend clinical investigation to identified patients’ clinicians, evaluate more patients, assess additional feature selection and machine learning algorithms, and apply this methodology to other rare diseases.