title: A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis genetic modifier studies.
abstract: 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.
authors.affiliation: Child Health Evaluative Sciences Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Taylor
authors.forename: Clayton W
authors.initials: CW
authors.lastname: Commander
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Collaco
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
authors.forename: Weili
authors.initials: W
authors.lastname: Li
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Webel
authors.forename: Rhonda G
authors.initials: RG
authors.lastname: Pace
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Stonebraker
authors.forename: Kathleen
authors.initials: K
authors.lastname: Naughton
authors.forename: Ruslan
authors.initials: R
authors.lastname: Dorfman
authors.forename: Andrew
authors.initials: A
authors.lastname: Sandford
authors.forename: Scott M
authors.initials: SM
authors.lastname: Blackman
authors.forename: Yves
authors.initials: Y
authors.lastname: Berthiaume
authors.forename: Peter
authors.initials: P
authors.lastname: Paré
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.forename: Julian
authors.initials: J
authors.lastname: Zielenski
authors.forename: Peter
authors.initials: P
authors.lastname: Durie
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Mary
authors.initials: M
authors.lastname: Corey
mesh_terms: D000293:Adolescent; D002648:Child; D002908:Chronic Disease; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000235:genetics* / Q000401:mortality*; D005260:Female; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D010641:Phenotype; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D016019:Survival Analysis