Application of the European Respiratory Society/American Thoracic Society Spirometry Standards and Race-Neutral Equations in the COPDGene Study

Abstract

Rationale: For spirometry interpretation, the European Respiratory Society (ERS) and American Thoracic Society (ATS) recommend using z-scores, and the ATS has recommended using Global Lung Initiative (GLI) "Global" race-neutral reference equations. However, these recommendations have been variably implemented, and the impact has not been widely assessed in clinical or research settings. Objectives: To evaluate the ERS/ATS classification of airflow obstruction severity. Methods: In COPDGene (Genetic Epidemiology of COPD Study) (N = 10,108), airflow obstruction has been defined by an FEV₁/FVC ratio <0.70, with spirometric severity graded from class 1 to class 4 based on race-specific percent predicted (pp) FEV₁ cutoff points as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We compared the GOLD approach, using National Health and Nutrition Examination Survey III race-specific equations, versus the application of GLI Global equations using the ERS/ATS definition of airflow obstruction as an FEV₁/FVC ratio below the lower limit of normal and z-score-based FEV₁ cutoff points of -1.645, -2.5, and -4 ("zGLI Global"). We tested the four-tier severity scheme for association with chronic obstructive pulmonary disease outcomes. Measurements and Main Results: The lowest agreement between ERS/ATS with zGLI Global and the GOLD classification was observed in individuals with milder disease (56.9% and 42.5% in GOLD stages 1 and 2, respectively), and race was a major determinant of redistribution. After adjustment for relevant covariates, zGLI Global distinguished all-cause mortality risk between normal spirometry and the first grade of chronic obstructive pulmonary disease (hazard ratio, 1.23; 95% confidence interval, 1.04-1.44; P = 0.014) and showed a linear increase in exacerbation rates with increasing disease severity in comparison with GOLD. Conclusions: The zGLI Global severity classification outperformed the GOLD criteria in the discrimination of survival, exacerbations, and imaging characteristics.

Keywords: COPD; ethnicity; pulmonary function tests; survival analysis.

Figure 1.

Distribution of COPDGene (Genetic Epidemiology of COPD Study) subjects by zGLI Global Classification. COPD = chronic obstructive pulmonary disease; GLI = Global Lung Function Initiative; PRISm = preserved-ratio impaired spirometry; zGLI = z-score–based Global Lung Function Initiative classification.

Figure 2.

Bangdiwala agreement plot (A) and Sankey diagram (B) between Global Initiative for Chronic Obstructive Lung Disease (GOLD)–National Health and Nutrition Examination Survey (NHANES) and z-score–based Global Lung Function Initiative (zGLI) Global severity classes. (A) The agreement plot is a k × k square, where k is the total sample size (N = 10,108). The labels on the top and right axes correspond to the GOLD and GLI Global severity classes, respectively. Within each larger rectangle (maximum possible agreement), each black, gray, and white rectangle indicates progressively lower agreement, as displayed in the agreement legend. In the case of perfect agreement, all the rectangles would be black squares with a 45° diagonal line touching the corners of each square. The weighted Bangdiwala (“B”) statistic assesses agreement between multiple classes, adjusting for the frequency of each severity class. (B) The Sankey diagram visually describes the redistribution of participants from GOLD–NHANES to zGLI Global classification. The major redistributions occurred from GOLD stage 2 to less severe borderline (n = 413, 21.4%) and to more severe moderate (n = 396, 20.6%) categories, from GOLD stage 1 chronic obstructive pulmonary disease to pre–COPD (n = 315, 40.0%), and from GOLD stage 4 to the less severe moderate category (n = 147, 24.3%). See Table E2 for the numbers of patients and percentages for each class. PR = preserved-ratio impaired spirometry.

Figure 3.

Racial distribution of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 (A) and GOLD stage 1 (B) subjects reclassified by z-score–based Global Lung Function Initiative (zGLI) Global. (A) GOLD stage 2 subjects were re-grouped as “GOLD2-down” (n = 553, 31.3%) when classified as zGLI Global pre–chronic obstructive pulmonary disease (COPD) (n = 140, 7.9%) or borderline (n = 413, 23.4%), “GOLD2-stable” (n = 818, 46.3%) when classified as zGLI Global mild, and “GOLD2-up” (n = 396, 22.4%) when classified as zGLI Global moderate. (B) GOLD stage 1 subjects were regrouped as “GOLD1-pre” (n = 315, 40.2%) when classified as zGLI Global pre-COPD and as “GOLD1-COPD” (n = 468, 59.8%) when classified as zGLI Global borderline (n = 448, 57.2%) or mild (n = 20, 2.6%).

Figure 4.

Racial distribution of (A) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 subjects by z-score–based Global Lung Function Initiative (zGLI) Race-Specific (step 1) and (B) subjects with zGLI Race-Specific mild obstruction by zGLI Global (step 2). (A) In step 1, GOLD stage 2 subjects were regrouped as “GOLD2-down” (n = 369, 21.6%) when classified as zGLI Race-Specific pre-COPD (n = 135, 7.9%) or borderline (n = 234, 13.7%), “GOLD2-stable” (n = 796, 46.5%) when classified as zGLI Race-Specific mild, and “GOLD2-up” (n = 547, 31.9%) when classified as zGLI Race-Specific moderate. (B) In step 2, subjects with zGLI Race-Specific mild obstruction were regrouped as “zGLI Race-Specific mild-down” (n = 218, 27.4%) when classified as zGLI Global borderline, “zGLI Race-Specific mild-stable” when classified as zGLI Global mild (n = 474, 59.5%), and as “zGLI Race-Specific mild-up” when classified as zGLI Global moderate (n = 104, 13.1%).

Figure 5.

Exacerbation rates by severity class. Incidence rate ratios are displayed on the y-axis and are adjusted for age, sex, race, height, smoking status, and history of exacerbations in the 1 year before enrollment. “GOLD-NHANES” is NHANES III race-specific, and cutoff points are based on percent predicted. “zGLI Race-Specific” and “zGLI Global” each apply a z-score approach for severity classification. BL = borderline; GLI = Global Lung Function Initiative; GOLD = Global Initiative for Chronic Obstructive Lung Disease; NHANES = National Health and Nutrition Examination Survey; P1 = baseline visit; P2 = 5-year follow-up visit; zGLI = z-score–based Global Lung Function Initiative classification.