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Background  Opioid misuse screening in hospitals is resource-intensive and rarely done. Many hospitalized patients are never offered opioid treatment. An automated approach leveraging routinely captured electronic health record (EHR) data may be easier for hospitals to institute. We previously derived and internally validated an opioid classifier in a separate hospital setting. The aim is to externally validate our previously published and open-source machine-learning classifier at a different hospital for identifying cases of opioid misuse.    Methods  An observational cohort of 56,227 adult hospitalizations was examined between October 2017 and December 2019 during a hospital-wide substance use screening program with manual screening. Manually completed Drug Abuse Screening Test served as the reference standard to validate a convolutional neural network (CNN) classifier with coded word embedding features from the clinical notes of the EHR. The opioid classifier utilized all notes in the EHR and sensitivity analysis was also performed on the first 24 h of notes. Calibration was performed to account for the lower prevalence than in the original cohort.    Results  Manual screening for substance misuse was completed in 67.8% (n = 56,227) with 1.1% (n = 628) identified with opioid misuse. The data for external validation included 2,482,900 notes with 67,969 unique clinical concept features. The opioid classifier had an AUC of 0.99 (95% CI 0.99–0.99) across the encounter and 0.98 (95% CI 0.98–0.99) using only the first 24 h of notes. In the calibrated classifier, the sensitivity and positive predictive value were 0.81 (95% CI 0.77–0.84) and 0.72 (95% CI 0.68–0.75). For the first 24 h, they were 0.75 (95% CI 0.71–0.78) and 0.61 (95% CI 0.57–0.64).    Conclusions  Our opioid misuse classifier had good discrimination during external validation. Our model may provide a comprehensive and automated approach to opioid misuse identification that augments current workflows and overcomes manual screening barriers.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13722-021-00229-7.

External validation of an opioid misuse machine learning classifier in hospitalized adult patients