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Background: As the most commonly occurring form of mental illness worldwide, depression poses significant health and economic burdens to both the individual and community. Different types of depression pose different levels of risk. Individuals who suffer from mild forms of depression may recover without any assistance or be effectively managed by primary care or family practitioners. However, other forms of depression are far more severe and require advanced care by certified mental health providers. However, identifying cases of depression that require advanced care may be challenging to primary care providers and health care team members whose skill sets run broad rather than deep., Objective: This study aimed to leverage a comprehensive range of patient-level diagnostic, behavioral, and demographic data, as well as past visit history data from a statewide health information exchange to build decision models capable of predicting the need of advanced care for depression across patients presenting at Eskenazi Health, the public safety net health system for Marion County, Indianapolis, Indiana., Methods: Patient-level diagnostic, behavioral, demographic, and past visit history data extracted from structured datasets were merged with outcome variables extracted from unstructured free-text datasets and were used to train random forest decision models that predicted the need of advanced care for depression across (1) the overall patient population and (2) various subsets of patients at higher risk for depression-related adverse events; patients with a past diagnosis of depression; patients with a Charlson comorbidity index of ≥1; patients with a Charlson comorbidity index of ≥2; and all unique patients identified across the 3 above-mentioned high-risk groups., Results: The overall patient population consisted of 84,317 adult (aged ≥18 years) patients. A total of 6992 (8.29%) of these patients were in need of advanced care for depression. Decision models for high-risk patient groups yielded area under the curve (AUC) scores between 86.31% and 94.43%. The decision model for the overall patient population yielded a comparatively lower AUC score of 78.87%. The variance of optimal sensitivity and specificity for all decision models, as identified using Youden J Index, is as follows: sensitivity=68.79% to 83.91% and specificity=76.03% to 92.18%., Conclusions: This study demonstrates the ability to automate screening for patients in need of advanced care for depression across (1) an overall patient population or (2) various high-risk patient groups using structured datasets covering acute and chronic conditions, patient demographics, behaviors, and past visit history. Furthermore, these results show considerable potential to enable preventative care and can be easily integrated into existing clinical workflows to improve access to wraparound health care services., (©Suranga N Kasthurirathne, Paul G Biondich, Shaun J Grannis, Saptarshi Purkayastha, Joshua R Vest, Josette F Jones. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 22.07.2019.)