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Original research
Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study
  1. Pratik Sinha1,
  2. Kevin L Delucchi2,
  3. Yue Chen3,
  4. Hanjing Zhuo4,
  5. Jason Abbott4,
  6. Chunxue Wang5,
  7. Nancy Wickersham5,
  8. J Brennan McNeil5,
  9. Alejandra Jauregui3,
  10. Serena Ke3,
  11. Kathryn Vessel3,
  12. Antonio Gomez3,6,
  13. Carolyn M Hendrickson6,
  14. Kirsten N Kangelaris3,7,
  15. Aartik Sarma8,
  16. Aleksandra Leligdowicz9,
  17. Kathleen D Liu4,
  18. Michael A Matthay10,
  19. Lorraine B Ware11,12,
  20. Carolyn S Calfee4,8,10
  1. 1Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri, USA
  2. 2Department of Psychiatry, University of California San Francisco, San Francisco, California, USA
  3. 3Department of Medicine, University of California San Francisco, San Francisco, California, USA
  4. 4Department of Anesthesiology, University of California San Francisco, San Francisco, California, USA
  5. 5Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  6. 6Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California, USA
  7. 7University of California San Francisco, San Francisco, California, USA
  8. 8Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, California, USA
  9. 9Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  10. 10Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA
  11. 11Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  12. 12Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  1. Correspondence to Dr Pratik Sinha; p.sinha{at}wustl.edu

Abstract

Rationale Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA.

Methods LCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard.

Results A 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described ‘hyperinflammatory’ subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92–0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower.

Conclusion Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

  • ARDS
  • cytokine biology
  • critical care

Data availability statement

Data are available upon reasonable request. Requests for data sharing will be reviewed on an individual basis by PS, LBW and CSC.

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Data availability statement

Data are available upon reasonable request. Requests for data sharing will be reviewed on an individual basis by PS, LBW and CSC.

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Footnotes

  • Twitter @AartikSarma

  • Author Contributions: PS, CSC, LBW and MAM were responsible for study conception and design. PS, KLD, YC, HZ, CW, NW, JBM, LBW and CSC were responsible for the data cleaning and analysis. All authors were responsible for data collection and/or clinical adjudication. PS, CSC and LBW developed the first draft of the manuscript. All authors reviewed and edited the final version of the manuscript.

  • Funding National Heart, Lung, and Blood Institute: HL131621, HL133390, HL103836 (LBW), HL135849 (LBW), HL140026 (CSC), National Institute of General Medical Sciences: GM008440-21 (PS).

  • Competing interests PS declares no competing interests. CSC has received grant funding from the NIH, US Food and Drug Administration, Roche-Genentech, Quantum Leap Healthcare Collaborative, and Bayer Pharmaceuticals and has served as a consultant to Vasomune, Quark, and Gen1e Life Sciences.

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

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