Quantitative Electroencephalogram Trends Predict Recovery in Hypoxic-Ischemic Encephalopathy,                    Objectives: Electroencephalogram features predict neurologic recovery following cardiac arrest. Recent work has shown that prognostic implications of some key electroencephalogram features change over time. We explore whether time dependence exists for an expanded selection of quantitative electroencephalogram features and whether accounting for this time dependence enables better prognostic predictions. Design: Retrospective. Setting: ICUs at four academic medical centers in the United States. Patients: Comatose patients with acute hypoxic-ischemic encephalopathy. Interventions: None. Measurements and Main Results: We analyzed 12,397 hours of electroencephalogram from 438 subjects. From the electroencephalogram, we extracted 52 features that quantify signal complexity, category, and connectivity. We modeled associations between dichotomized neurologic outcome (good vs poor) and quantitative electroencephalogram features in 12-hour intervals using sequential logistic regression with Elastic Net regularization. We compared a predictive model using time-varying features to a model using time-invariant features and to models based on two prior published approaches. Models were evaluated for their ability to predict binary outcomes using area under the receiver operator curve, model calibration (how closely the predicted probability of good outcomes matches the observed proportion of good outcomes), and sensitivity at several common specificity thresholds of interest. A model using time-dependent features outperformed (area under the receiver operator curve, 0.83 ± 0.08) one trained with time-invariant features (0.79 ± 0.07; p < 0.05) and a random forest approach (0.74 ± 0.13; p < 0.05). The time-sensitive model was also the best-calibrated. Conclusions: The statistical association between quantitative electroencephalogram features and neurologic outcome changed over time, and accounting for these changes improved prognostication performance. Drs. Ghassemi and Amorim contributed equally as co-first authors of this work. The Critical Care Electroencephalogram Monitoring Research Consortium Board consists of: Chair: Brandon M. Westover, MD, PhD; Vice-Chair: Emily Gilmore, MD; Secretary: Aaron Struck, MD; Member-at-Large: Nicholas Gaspard, MD, PhD; Immediate Past Chair: Jong Woo Lee, MD, PhD; and Past Chair: Nicholas S. Abend, MD, MSCE. Drs. Ghassemi, Amorim, Lee, Cash, Brown, Mark, and Westover contributed to conception and design of the study. Drs. Ghassemi, Amorim, and Westover contributed to analysis of data. Drs. Ghassemi, Amorim, and Westover contributed to preparing the figures. Drs. Ghassemi and Amorim, Mr. Al Hanai, Drs. Lee, Herman, Sivaraju, and Gaspard, Mr. Biswal, Mr. Moura Junior, and Dr. Westover contributed to data acquisition. Drs. Ghassemi and Amorim, Mr. Al Hanai, Drs. Lee, Herman, Sivaraju, and Gaspard, Mr. Biswal, Mr. Moura Junior, and Drs. Cash, Brown, Mark, and Westover contributed to drafting the text. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from National Institutes of Health (NIH) 1R01NS102190, 1R01NS102574, and 1R01NS107291 (to Dr. Westover); R01GM104987 (to Dr. Mark); T32HL007901, T90DA22759, and T32EB001680 (to Dr. Ghassemi); National Institute of Neurological Disorders and Stroke 1K23NS090900 (to Dr. Westover); Salerno foundation (M.G.M.); Neurocritical Care Society research training fellowship and American Heart Association postdoctoral fellowship (to Dr. Amorim); and Andrew David Heitman Neuroendovascular Research Fund and the Rappaport Foundation (to Dr. Westover). Preliminary findings of this study were presented at the 14th Annual Neurocritical Care Society Meeting, National Harbor, MD, September 15–18, 2016. Dr. Amorim’s institution received funding from the National Institutes of Health (NIH), Neurocritical Care Society, and American Heart Association. Drs. Amorim, Mark, and Westover received support for article research from the NIH. Dr. Lee received funding from SleepMed/DigiTrace, Advance Medical, and United Diagnostics. Drs. Lee’s and Mark’s institutions received funding from the NIH. Dr. Herman’s institution received funding from UCB Pharma, Sage Therapeutics, Neurospace, Epilepsy Therapy Development Project, Acorda Therapeutics, Pfizer, and Philips. Dr. Hirsch’s institution received funding from Upsher-Smith and Monteris. He received funding from Adamas; consultation fees for advising from Aquestive, Ceribell, Eisai, and Medtronic; honoraria for speaking from Neuropace; and royalties for authoring chapters for UpToDate-Neurology and from Wiley for coauthoring a book on electroencephalograms in critical care. Dr. Scirica’s institution received funding from Merck, Eisai, and Novartis, and he received consulting fees from AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, Covance, Eisai, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, NovoNordisk, Sanofi, and equity in Health [at] Scale. Dr. Brown’s institution received funding from Massachusetts General Hospital and Massachusetts Institute of Technology. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mwestover@mgh.harvard.edu; edilbertoamorim@gmail.com. Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.