Scott D Sagel1, Brandie D Wagner2, Assem Ziady3, Tom Kelley4, John P Clancy3, Monica Narvaez-Rivas5, Joseph Pilewski6, Elizabeth Joseloff7, Wei Sha8, Leila Zelnick9, Kenneth D R Setchell5, Sonya L Heltshe10, Marianne S Muhlebach11. 1. Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address: scott.sagel@childrenscolorado.org. 2. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA. 3. Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 4. Division of Pulmonology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH. 5. Department of Pathology, Children's Hospital of Cincinnati, Cincinnati, OH, USA. 6. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 7. Cystic Fibrosis Foundation, Bethesda, MD, USA. 8. Bioinformatics Services Division, Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, 150 Research Campus Dr., Kannapolis, NC, USA. 9. Division of Nephrology, University of Washington School of Medicine, Seattle, WA, USA. 10. Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, School of Medicine, Seattle, WA, USA. 11. Division of Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract
BACKGROUND: Circulating biomarkers reflective of lung disease activity and severity have the potential to improve patient care and accelerate drug development in CF. The objective of this study was to leverage banked specimens to test the hypothesis that blood-based biomarkers discriminate CF children segregated by lung disease severity. METHODS: Banked serum samples were selected from children who were categorized into two extremes of phenotype associated with lung function ('mild' or 'severe') based on CF-specific data and were matched on age, gender, CFTR genotype, and P. aeruginosa infection status. Targeted inflammatory proteins, lipids, and discovery metabolite profiles were measured in these serum samples. RESULTS: The severe cohort, characterized by a lower CF-specific FEV1 percentile, had significantly higher circulating concentrations of high sensitivity C-reactive protein, serum amyloid A, granulocyte colony stimulating factor, and calprotectin compared to the mild cohort. The mild cohort tended to have higher serum linoleic acid concentrations. The metabolite arabitol was lower in the severe cohort while other CF relevant metabolic pathways showed non-significant differences after adjusting for multiple comparisons. A sensitivity analysis to correct for biased estimates that may result from selecting subjects using an extremes of phenotype approach confirmed the protein biomarker findings. CONCLUSIONS: Circulating inflammatory proteins differ in CF children segregated by lung function. These findings serve to demonstrate the value of maintaining centralized, high quality patient derived samples for future research, with linkage to clinical information to answer testable hypotheses in biomarker development.
BACKGROUND: Circulating biomarkers reflective of lung disease activity and severity have the potential to improve patient care and accelerate drug development in CF. The objective of this study was to leverage banked specimens to test the hypothesis that blood-based biomarkers discriminate CF children segregated by lung diseaseseverity. METHODS: Banked serum samples were selected from children who were categorized into two extremes of phenotype associated with lung function ('mild' or 'severe') based on CF-specific data and were matched on age, gender, CFTR genotype, and P. aeruginosa infection status. Targeted inflammatory proteins, lipids, and discovery metabolite profiles were measured in these serum samples. RESULTS: The severe cohort, characterized by a lower CF-specific FEV1 percentile, had significantly higher circulating concentrations of high sensitivity C-reactive protein, serum amyloid A, granulocyte colony stimulating factor, and calprotectin compared to the mild cohort. The mild cohort tended to have higher serum linoleic acid concentrations. The metabolite arabitol was lower in the severe cohort while other CF relevant metabolic pathways showed non-significant differences after adjusting for multiple comparisons. A sensitivity analysis to correct for biased estimates that may result from selecting subjects using an extremes of phenotype approach confirmed the protein biomarker findings. CONCLUSIONS: Circulating inflammatory proteins differ in CF children segregated by lung function. These findings serve to demonstrate the value of maintaining centralized, high quality patient derived samples for future research, with linkage to clinical information to answer testable hypotheses in biomarker development.
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