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ResearchIn-Press PreviewImmunologyPulmonology Open Access | 10.1172/jci.insight.202442

Aberrant mucin expression and keratinization distinguishing severe from mild asthma revealed by interpretable machine learning

Sagar L. Kale,1 Augusta M. Vincent,2 Mark A. Ross,3 Isha Mehta,2 Michael J. Calderon,3 Richard P. Ramonell,1 Himanshu Setya,4 Jessica C. McCreary-Partyka,1 Huijuan Yuan,1 Stephanie A. Christenson,5 Prescott G. Woodruff,5 Mario Castro,6 Kaharu Sumino,7 Nizar N. Jarjour,8 Loren C. Denlinger,8 Benjamin Gaston,9 Eugene R. Bleecker,10 Deborah A. Meyers,10 Wendy C. Moore,11 Elliot Israel,12 Bruce D. Levy,12 David Mauger,13 Serpil Erzurum,14 Anthony Newbrough,1 Taylor J. Nee,1 Prabir Ray,1 Claudette M. St. Croix,3 Sally E. Wenzel,1 Jishnu Das,15 Anuradha Ray,1 and Marc C. Gauthier1

1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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1Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Departme, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

3Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America

4University of Pittsburgh School of Medicine, Pittsburgh, United States of America

5Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medi, UCSF, San Francisco, United States of America

6Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, United States of America

7Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, United States of America

8Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, United States of America

9Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, United States of America

10Division of Genetics, Genomics and Precision Medicine, Department of Medici, University of Arizona, Tucson, United States of America

11Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, United States of America

12Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Division of Statistics and Bioinformatics, Department of Public Health Scie, Pennsylvania State University, University Park, United States of America

14Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, United States of America

15Center for Systems Immunology, University of Pittsburgh, Pittsburgh, United States of America

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Published July 30, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.202442.
Copyright © 2026, Kale et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 30, 2026 - Version history
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Abstract

Type 2 (T2) immune cells dominate the airways of mild-moderate asthma (MMA) patients with a more complex Type 1 (T1)-T2 mixed immune response evident in treatment-refractory severe asthma (SA). We hypothesized that comparing the transcriptomes of the airway epithelium of SA and MMA patients would reveal molecular signatures associated with more severe disease in the context of a complex immune response. Using our novel interpretable machine learning tool, SLIDE, meaningful latent factors (context-specific gene co-expression networks) were revealed that distinguished SA from MMA. Unexpectedly, an aberrant high expression of normally host-protective, membrane-tethered and IFN-inducible mucins, MUC1 and MUC4, was identified in SA. Gene networks in the significant latent factors discriminating SA from MMA corresponded to enrichment of a keratinization program in SA airways. Keratinization was marked by increased expression of the stress keratin KRT16, signifying squamous metaplasia suggesting adaptive reprogramming of the airway epithelium in response to chronic stress. These mucins and KRT16 were inversely associated with lung function in two separate asthma cohorts. Imaging of endobronchial biopsies revealed significantly higher KRT16 protein expression in SA compared to MMA that strongly correlated with MUC1 protein expression. Our study identifies dysregulated host-protective and maladaptive repair responses in SA distinguishing from MMA.

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