title: Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation.
abstract: BACKGROUND
  Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.
  
  
  RESULTS
  Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.
  
  
  CONCLUSIONS
  Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Department of Internal Medicine, Gachon University Gil Hospital, Incheon, South Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kyung
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, California, United States of America.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Rogers
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lee
authors.initials: L
authors.lastname: Gazourian
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sojung
authors.initials: S
authors.lastname: Youn
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Massaro
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Carolina
authors.initials: C
authors.lastname: Quintana
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Osorio
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Lawler
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Finnian R
authors.initials: FR
authors.lastname: Mc Causland
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Sushrut S
authors.initials: SS
authors.lastname: Waikar
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Waxman
authors.affiliation: Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Baron
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Hunninghake
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America ; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood*; D004272:DNA, Mitochondrial / Q000097:blood*; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units / Q000706:statistics & numerical data*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial