Byline: Aaron M. Yengo-Kahn, Department of Neurological Surgery (Drs Yengo-Kahn, Bonfield, and Zuckerman), Vanderbilt Sport Concussion Center (Drs Yengo-Kahn, Bonfield, Gifford, Zuckerman, and Dennis and Ms Hibshman), Division of Epidemiology, Department of Medicine (Mr Torstenson), Vanderbilt Epidemiology Center, Institute for Medicine and Public Health (Mr Torstenson), Vanderbilt Genetics Institute (Mr Torstenson and Drs Davis and Dennis), Department of Neurology (Dr Gifford), and Division of Genetic Medicine, Department of Medicine (Drs Davis and Dennis), Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt University School of Medicine, Nashville, Tennessee (Ms Hibshman); British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada (Ms Belikau and Dr Dennis); and Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada (Dr Dennis).; Natalie Hibshman; Christopher M. Bonfield; Eric S. Torstenson; Katherine A. Gifford; Daniil Belikau; Lea K. Davis; Scott L. Zuckerman; Jessica K. Dennis Abstract OBJECTIVE: To identify risk factors and generate hypotheses for pediatric persistent postconcussion symptoms (PPCS). SETTING: A regional healthcare system in the Southeastern United States. PARTICIPANTS: An electronic health record-based algorithm was developed and validated to identify PPCS cases and controls from an institutional database of more than 2.8 million patients. PPCS cases (n = 274) were patients aged 5 to 18 years with PPCS-related diagnostic codes or with PPCS key words identified by natural language processing of clinical notes. Age, sex, and year of index event-matched controls (n = 1096) were patients with mild traumatic brain injury codes only. Patients with moderate or severe traumatic brain injury were excluded. All patients used our healthcare system at least 3 times 180 days before their injury. DESIGN: Case-control study. MAIN MEASURES: The outcome was algorithmic classification of PPCS. Exposures were all preinjury medical diagnoses assigned at least 180 days before the injury. RESULTS: Cases and controls both had a mean of more than 9 years of healthcare system use preinjury. Of 221 preinjury medical diagnoses, headache disorder was associated with PPCS after accounting for multiple testing (odds ratio [OR] = 2.9; 95% confidence interval [CI]: 1.6-5.0; P = 2.1e-4). Six diagnoses were associated with PPCS at a suggestive threshold for statistical significance (false discovery rate P CONCLUSIONS: These results support the strong association of preinjury headache disorders with PPCS. An association of PPCS with prior gastritis/duodenitis, sinusitis, and pharyngitis/nasopharyngitis suggests a role for chronic inflammation in PPCS pathophysiology and risk, although results could equally be attributable to a higher likelihood of somatization among PPCS cases. Identified risk factors should be investigated further and potentially considered during the management of pediatric mild traumatic brain injury cases.