Identifying Treatments That Halt Progression of Pulmonary Disease in Cystic Fibrosis

Davis, Pamela B.; Byard, Pamela J.; Konstan, Michael W.

doi:10.1203/00006450-199702000-00001

Cited by 86 publications

(63 citation statements)

References 18 publications

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“…The similarity of these longitudinal prediction models may be explained by relative homogeneity in patterns of disease progression in CF. Indeed, different samples of the CF population have reported similar annual rates of decline in FEV 1 %pred, with mean values ranging from Ϫ1.5 to Ϫ3.6 (7,14,(43)(44)(45)(46). The results presented here indicate that AvgFEV 1 CF% or EstFEV 1 %@20yrs corrected for pancreatic status can be used to test genes that are candidate modifiers of CF lung disease.…”

Section: Table 3 Intrapair Correlations For Cross-sectional and Longmentioning

confidence: 85%

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Heritability of Lung Disease Severity in Cystic Fibrosis

Vanscoy

Blackman²,

Collaco³

et al. 2007

Am J Respir Crit Care Med

176

168

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Rationale: Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the diseasecausing gene, indicating that other factors determine severity of lung disease. Objectives: To quantify the contribution of modifier genes to variation in CF lung disease severity. Methods: Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV 1 within the last year was used for cross-sectional analysis. FEV 1 measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins ‫ف(‬ 100% gene sharing) with that of dizygous (DZ) twins/siblings ‫ف(‬ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects. Measurements and Main Results

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Section: Table 3 Intrapair Correlations For Cross-sectional and Longmentioning

confidence: 85%

“…Traditionally, pulmonary function testing (PFT) has been used to determine severity of and monitor progression in CF lung disease (13,14). The FEV 1 is the PFT measurement that is most predictive of survival in CF (15,16).…”

mentioning

confidence: 99%

Heritability of Lung Disease Severity in Cystic Fibrosis

Vanscoy

Blackman²,

Collaco³

et al. 2007

Am J Respir Crit Care Med

176

168

View full text Add to dashboard Cite

show abstract

“…As indicated by the ROC areas in Table 2, LS estimates of slopes or levels of FEV 1 (% pred) do not discriminate between groups as well as the mixed model estimates do. It is well known that LS slopes can be highly variable and imprecise for patients with few data points over a short time period (17)(18)(19)(20). When restricted to subjects with 5 yr of data, the discriminating ability of LS estimates improved, but mixed model estimates still outperformed the LS estimates ( Table 2).…”

Section: Ability Of Measures Of Disease Severity To Discriminate Betwmentioning

confidence: 90%

“…Mixed model estimates of slope and intercept (at birth; i.e., age, 0 yr) of the regression of FEV 1 (% pred) versus age were used to estimate the level of FEV 1 at the age of enrollment for each patient and at other fixed ages (e.g., 15,10,15,20, and 25 yr). In Figure 2, the estimated FEV 1 (% pred) values at enrollment (obtained from an analysis of all FEV 1 values) are plotted against age of enrollment for the 820 patients.…”

Section: Screening For Outliers and Characterization Of Severity Groupsmentioning

confidence: 99%

Classifying Severity of Cystic Fibrosis Lung Disease Using Longitudinal Pulmonary Function Data

Schluchter

Konstan

Drumm

et al. 2006

Am J Respir Crit Care Med

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Rationale:The study of genetic modifiers in cystic fibrosis (CF) lung disease requires rigorous phenotyping. One type of genetic association study design compares polymorphisms in patients at extremes of phenotype, requiring accurate classification of pulmonary disease at varying ages. Objective: To evaluate approaches to quantify severity of pulmonary disease and their ability to discriminate between patients with CF at the extremes of phenotype. Methods: ⌬F508 homozygotes (n ϭ 828) were initially classified as "severe" (approximate lowest quartile of FEV 1 (% pred) for age, 8-25 yr) or "mild" disease (highest quartile of FEV 1 for age, у 15 yr). FEV 1 measurements from the 5 yr before enrollment (total ϭ 18,501 measurements; average 23 per subject) were analyzed with mixed models, and patient-specific estimates of FEV 1 (% pred) at ages 5, 10, 15, 20, and 25 yr and slope of FEV 1 versus age were examined for their ability to discriminate between groups using receiver operating characteristics (ROC) curve areas. Results: Logistic regression of severity group on mixed model (empirical Bayes) estimates of intercept and slope of FEV 1 (% pred) versus age discriminated better than did classification using Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Because most patients with CF develop progressive pulmonary disease, measures of pulmonary involvement, in particular FEV 1 , have been used as markers of disease severity and to predict survival (1-3). However, considerable heterogeneity exists in prognosis and severity, even among patients of the same genotype, suggesting that genetic modifiers may play a role (4). The study of gene modifiers in monogenic disorders requires rigorous phenotyping, and inadequate characterization of the phenotype is a well-recognized limitation of case-control genetic association studies (5-8). In CF, pulmonary phenotyping is complex because the progression of lung disease is likely multifactorial and is multiphasic or nonlinear for some patients (9, 10).One specific type of case-control genetic association study design compares patients at the extremes of phenotype (i.e., those with severe versus mild disease) because it provides additional power to detect gene modifiers (11). In such studies, it is particularly important to be able to accurately identify patients at the extremes of phenotype. In this article, we investigate approaches to classifying severity of disease when longitudinal lung function measures are available and compare them using data from the Gene Modifier Study (GMS), a large, multicenter study of genetic modifiers of CF lung disease (12). The goal of the GMS is to examine the association of genetic polymorphisms with pulmonary phenotype in ⌬F508 homozygotes by comparing patients with "severe" versus "mild" pulmonary disease. METHODS Design and Enrollment Criteria in the GMSPatients were initially enrolled into "severe" or "mild' groups based on current age an...

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“…However, these end points are not suitable for early phase II trials, because large patient numbers (4500) and long follow-up (412 months) would be required. 62 It is therefore crucial to identify clinical surrogate end points (such as bacterial burden, inflammatory markers and imaging) that can be assessed in smaller patient cohorts with shorter follow-up. It is unlikely that one-time administration of a short acting GTA will change these clinical surrogate end points, but will more likely require repeat administration and it is therefore important to design future gene therapy trials with these surrogate end points in mind.…”

Section: Assaysmentioning

confidence: 99%