A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis Genetic modifier studies

Chelsea Taylor, Clayton W. Commander, Joseph M. Collaco, Lisa J. Strug, Weili Li, Fred A. Wright, Aaron D. Webel, Rhonda G. Pace, Jaclyn R. Stonebraker, Kathleen Naughton, Ruslan Dorfman, Andrew Sandford, Scott M. Blackman, Yves Berthiaume, Peter Paré, Mitchell L. Drumm, Julian Zielenski, Peter Durie, Garry R. Cutting, Michael R. KnowlesMary Corey

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Genetic studies of lung disease in cystic fibrosis (CF) are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2,061 patients representing the Canadian CF population, 1,137 extreme phenotype patients in the UNC/Case Western study, and 1,323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality-adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power, and avoiding possible distortions. This approach will facilitate large-scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF.

Original languageEnglish (US)
Pages (from-to)857-869
Number of pages13
JournalPediatric pulmonology
Issue number9
StatePublished - Sep 2011


  • age effects
  • forced expiratory volume
  • severity of illness index

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine


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