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We hypothesized that clustering analysis of vital signs measured within six hours of hospital admission would reveal distinct patient phenotypes with unique pathophysiological signatures and clinical outcomes. We created a longitudinal electronic health record dataset for 75,762 adult patient admissions to a tertiary care center in 2014\u20132016 lasting six hours or longer. Physiotypes were derived via unsupervised machine learning in a training cohort of 41,502 patients applying consensus <jats:italic>k<\/jats:italic>-means clustering to six vital signs measured within six hours of admission. Reproducibility and correlation with clinical biomarkers and outcomes were assessed in validation cohort of 17,415 patients and testing cohort of 16,845 patients. Training, validation, and testing cohorts had similar age (54\u201355 years) and sex (55% female), distributions. There were four distinct clusters. Physiotype A had physiologic signals consistent with early vasoplegia, hypothermia, and low-grade inflammation and favorable short-and long-term clinical outcomes despite early, severe illness. Physiotype B exhibited early tachycardia, tachypnea, and hypoxemia followed by the highest incidence of prolonged respiratory insufficiency, sepsis, acute kidney injury, and short- and long-term mortality. Physiotype C had minimal early physiological derangement and favorable clinical outcomes. Physiotype D had the greatest prevalence of chronic cardiovascular and kidney disease, presented with severely elevated blood pressure, and had good short-term outcomes but suffered increased 3-year mortality. Comparing sequential organ failure assessment (SOFA) scores across physiotypes demonstrated that clustering did not simply recapitulate previously established acuity assessments. In a heterogeneous cohort of hospitalized patients, unsupervised machine learning techniques applied to routine, early vital sign data identified physiotypes with unique disease categories and distinct clinical outcomes. This approach has the potential to augment understanding of pathophysiology by distilling thousands of disease states into a few physiological signatures.<\/jats:p>","DOI":"10.1371\/journal.pdig.0000110","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T17:47:50Z","timestamp":1665683270000},"page":"e0000110","update-policy":"https:\/\/doi.org\/10.1371\/journal.pdig.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Physiologic signatures within six hours of hospitalization identify acute illness phenotypes"],"prefix":"10.1371","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-2408","authenticated-orcid":true,"given":"Yuanfang","family":"Ren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5354-443X","authenticated-orcid":true,"given":"Tyler 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