Development of predictive models for airflow obstruction in alpha-1-antitrypsin deficiency

Abstract

Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).

Figure 1.

Relation between forced expiratory volume in 1 second (FEV₁) and pack-years of cigarette smoking in 231 smokers with the protease inhibitor ZZ genotype, AAT Genetic Modifier Study, 2002–2005. The figure shows a scatterplot with a smoothing curve demonstrating the trend in FEV₁ percent predicted with increasing pack-years of tobacco exposure, with a linear trend from 0 pack-years to 19.9 pack-years. Nonsmoking subjects with the protease inhibitor ZZ genotype were not included. AAT, α₁-antitrypsin.

Figure 2.

Receiver operating characteristic curve for the predictive model for severe chronic obstructive pulmonary disease, AAT Genetic Modifier Study, 2002–2005. The curve was derived from model performance in the validation sample. Area under the receiver operator characteristic curve = 0.88. AAT, α₁-antitrypsin.

Figure 3.

Calibration of the predictive model for severe chronic obstructive pulmonary disease (COPD), AAT Genetic Modifier Study, 2002–2005. Subjects with the protease inhibitor ZZ genotype are grouped along the x-axis by quartile of predicted likelihood of having a forced expiratory volume in 1 second less than 50% predicted. The mean prediction for each quartile is represented by the dark bars, and the observed percentage of persons with severe COPD in each quartile is represented by the hashed bars. The model predictions conform closely to the observed outcomes. AAT, α₁-antitrypsin.