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Stability of ARDS subphenotypes over time in two randomised controlled trials
  1. Kevin Delucchi1,
  2. Katie R Famous2,
  3. Lorraine B Ware3,
  4. Polly E Parsons4,
  5. B Taylor Thompson5,
  6. Carolyn S Calfee6
  7. for the ARDS Network
  1. 1 Department of Psychiatry, University of California, San Francisco, California, USA
  2. 2 Critical Care Medicine, Kaiser Permanente Oakland Medical Center, Oakland, California, USA
  3. 3 Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
  4. 4 Department of Medicine, University of Vermont School of Medicine, Burlington, Vermont, USA
  5. 5 Department of Medicine, Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6 Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, California, USA
  1. Correspondence to Dr Carolyn S Calfee, Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, CA 94143-0111, USA; Carolyn.Calfee{at}


Rationale Two distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over time.

Objective To determine the stability of ARDS subphenotypes over time.

Methods Secondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only) and the ALVEOLI trial of low versus high positive end-expiratory pressure (n=549). Latent class analysis (LCA) and latent transition analysis (LTA) were applied to data from day 0 and day 3, independent of clinical outcomes.

Measurements and main results In ALVEOLI, LCA indicated strong evidence of two ARDS latent classes at days 0 and 3; in ARMA, evidence of two classes was stronger at day 0 than at day 3. The clinical and biological features of these two classes were similar to those in our prior work and were largely stable over time, though class 2 demonstrated evidence of progressive organ failures by day 3, compared with class 1. In both LCA and LTA models, the majority of patients (>94%) stayed in the same class from day 0 to day 3. Clinical outcomes were statistically significantly worse in class 2 than class 1 and were more strongly associated with day 3 class assignment.

Conclusions ARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials.

  • acute respiratory distress syndrome
  • acute lung injury
  • subphenotypes
  • endotypes
  • precision medicine
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  • Contributors KD, KRF and CSC drafted the manuscript. KD and KRF performed the statistical analyses. LBW and PEP contributed biomarker measurements. CSC supervised the study design, data interpretation and manuscript preparation. All authors contributed significantly to study design and/or interpretation. All authors made significant intellectual contributions to the final manuscript and approve its submission.

  • Funding NIH grants T32 HL7185-39 and F32 HL129680-01 (KRF); HL103836 and HL112656 (LBW); HL131621 and HL133390 (CSC, KD). NIH/NHLBI ARDS Network contracts: N01-HR 46054-46064.

  • Competing interests CSC has ongoing grant funding from Bayer, prior grant funding from GlaxoSmithKline and consulting for GlaxoSmithKline, Bayer and Boehringer Ingelheim. Other authors have no competing interests to declare.

  • Ethics approval Ethics approval obtained for original studies at each participating institution.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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