Britt Clynick1,2,3,4, Tamera J Corte1,5,6,4, Helen E Jo1,5,6, Iain Stewart7, Ian N Glaspole8,9, Christopher Grainge10,11, Toby M Maher12, Vidya Navaratnam7,13, Richard Hubbard7, Peter M A Hopkins14,15, Paul N Reynolds16,17, Sally Chapman17, Christopher Zappala14, Gregory J Keir14, Wendy A Cooper5,6,18, Annabelle M Mahar6, Samantha Ellis8,9, Nicole S Goh19,20, Emma De Jong2,3, Lilian Cha2,3, Dino B A Tan2,3, Lucy Leigh10,21, Christopher Oldmeadow10,21, E Haydn Walters1,9,22,23,24, R Gisli Jenkins7, Yuben Moodley25,2,3,26. 1. Centre of Research Excellence in Pulmonary Fibrosis, Camperdown, Australia. 2. Institute for Respiratory Health Inc., Nedlands, Australia. 3. University of Western Australia, Crawley, Australia. 4. These two authors are joint first authors. 5. The University of Sydney Central Clinical School, Camperdown, Australia. 6. Royal Prince Alfred Hospital, Camperdown, Australia. 7. NIHR Biomedical Research Centre, Respiratory Theme, University of Nottingham, Nottingham, UK. 8. Monash University, Clayton, Australia. 9. Alfred Hospital, Melbourne, Australia. 10. University of Newcastle, Callaghan, Australia. 11. John Hunter Hospital, New Lambton Heights, Australia. 12. University of Southern California, Los Angeles, CA, USA. 13. Nottingham University Hospitals, Nottingham, UK. 14. University of Queensland, St Lucia, Australia. 15. Prince Charles Hospital, Chermside, Australia. 16. University of Adelaide, Adelaide, Australia. 17. Royal Adelaide Hospital, Adelaide, Australia. 18. Western Sydney University, Sydney, Australia. 19. Austin Hospital, Heidelberg, Australia. 20. Institute of Breathing and Sleep, Heidelberg, Australia. 21. Hunter Medical Research Institute, Newcastle, Australia. 22. University of Tasmania, Hobart, Australia. 23. University of Melbourne, Parkville, Australia. 24. Royal Hobart Hospital, Hobart, Australia. 25. Centre of Research Excellence in Pulmonary Fibrosis, Camperdown, Australia yuben.moodley@uwa.edu.au. 26. Fiona Stanley Hospital, Murdoch, Australia.
Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE). METHODS: In the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations. RESULTS: 189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts. CONCLUSION: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE). METHODS: In the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations. RESULTS: 189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts. CONCLUSION: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients.