Discussion
The present study evaluated the impact of different reference equation on interpretation of spirometry in a multi-ethnic cohort in a large Canadian city. It revealed that application of the all-Caucasian Canadian reference equations led to the over-interpretation of abnormal (<LLN) FVC and FEV1 compared with GLI-Race and GLI-Other equations in all ethnic groups. The magnitude of the discordance was especially large in Black, Mixed/other and SE Asian population. The discordance was statistically significant even after adjusting for the key factors used for derivation of the reference values, that is, sex, age and height, when the Canadian reference equations were compared with GLI-Race reference equations. Although we observed discordance between ethnic groups when comparing the Canadian and the GLI-Other reference equations, these were not statistically significant; only male sex was found to be a significant factor in the discordance of FVC while age and weight were significant factors in the discordance of FEV1. Unsurprisingly, FEV1/FVC was highly consistent between the two equations.
Although some studies have shown disagreement,21 GLI-Race reference equations generally fit for multiple race/ethnicities.6–12 The current study revealed that the Canadian reference equations, compared with GLI-Race, led to higher rates of abnormal FVC and FEV1, especially in non-Caucasian groups. Moreover, the LLN values of FVC and FEV1 did not show perfect agreement even in the Caucasian group when comparing the Canadian and GLI-Race reference equations. For the Caucasian group, predicted LLN values of FVC and FEV1 according to the Canadian reference equations were higher than those derived from reference equations developed from data of Canadian Caucasian adults22 and the third National Health and Nutrition Examination Survey (NHANES) Ⅲ reference equations for Caucasian (non-Hispanic White) ethnic group14 (online supplemental table S12). Thus, there is also the possibility of over-interpretation of abnormal lung function (<LLN) in Caucasian patients when the Canadian reference equations are applied. An Italian group compared the reference equations which were developed from several existing reference equations and concluded the necessity of applying reference equations derived from normal subjects who are as similar as possible to the study population being evaluated and using similar conditions of measurements.23 These results emphasised the importance of using appropriate reference predictions that are most representative of the population in question.
The significance of considering race/ethnicity in lung function prediction equations is not limited to genetic/racial differences. Race and ethnicity are constructed by a complex combination of social, cultural and genetic factors.24 It has been suggested that other factors, such as socioeconomic status and education, are associated with lung function.25 26 For example, Asian-Indians born in USA have higher pulmonary function compared with immigrant Asian Indians, suggesting the effect of differing environmental conditions.27 In other words, in multi-ethnic cities such as the one where this study was conducted or other large cosmopolitan cities around the world, the race/ethnicity categories may be ambiguous in many participants. A recent report of 567 Asian subjects living in the USA found that the GLI-Other reference equations adequately fitted spirometry data compared with the NHANES III and GLI-Race equations.28 Comparison of the percent predicted lung function based on GLI-Other versus the GLI-Race equations in 3972 Black participants who participated in the NHANES III study showed that FEV1 and FVC z-scores based on GLI-Other had more agreement between White and Black populations rather than GLI-Race equations.29 Although the GLI-Race references led to lower FEV1 and FVC in Black compared with the White populations, modelling of mortality risk was similar when GLI-Other was applied for lung function interpretation.29 These studies have led some scholars to suggest that consideration of race/ethnicity may be counterproductive in the interpretation of PFT.30 There is considerable debate as to whether race-specific equations or universal reference equations is superior.31 Our data revealed the extent to which discrepancies occurs in each reference set according to race/ethnic groups by comparing the Canadian reference equations to both GLI-Race and GLI-Other of the GLI. Our findings suggest that the choice of reference equations should be carefully evaluated in different ethnic groups and considered when interpreting PFT.
In the current study, there was a difference in the interpretation of FEV1 and FVC, but no discrepancy in interpretation of airway obstruction (FEV1/FVC<LLN) between the reference equations. While some have argued that incorporation of FEV1/FVC ratio in interpretations of PFTs may minimise the impact of race/ethnicity,30 recent reports of clinical outcomes in preserved ratio impaired spirometry (PRISm), defined as FEV1<80% predicted and FEV1/FVC≥70%, suggest that the use of inappropriate reference equations could have clinical consequence. In two large population studies in the USA where the NHANES III reference equation was applied31 and in a Belgian study where the GLI-Race equations were used, participants with PRISm have increased respiratory symptoms, mortality and faster FEV1 decline.32 33 Although some patients with PRISm transitioned to normal spirometry over time,32 34 early identification of this group is important. The prevalence of PRISm decreases when post-bronchodilator data are assessed.35 While our study evaluated pre-bronchodilator spirometry data, discrepancies in the interpretations of spirometry between the GLI and Canadian equations of restrictive patterns and PRISm would still be found.
There are several limitations to this study. First, GLI-2012 equations do not incorporate all race/ethnicities. For example, Black reference equations in GLI-2012 were generated by the data only from African Americans, and classification of non-African American Black individuals is inconsistent.36 37 By classifying all Black participants in the GLI-2012 Black ethnic group, we are undoubtedly not accounting for the diversity of the people from the African continent and other locations, such as the Caribbean, the geographic origin of the many of the Black population in Toronto. For other races/ethnicities not covered by GLI-2012, reference equations for geographically and ethnically proximate groups were applied according to GLI-2012.20 Second, race/ethnicity was self-reported, which may not be accurate enough for the clinical purposes as described in original GLI-2012 paper,5 as inter-racial families are common in the greater Toronto area. Third, the number of participants included in some ethnicity groups was not large although the ethnic mix is reflective of the population in the region. While our PFT Laboratory assesses 250 patients weekly, race/ethnicity data collection is not routine clinical practice. Only data from REB-approved studies where this information was collected were included in this paper. While we assessed mathematical considerations such as the difference in LLN values and the clinical concordance rate, larger-scale studies are required to validate our findings. Fourth, this study compared the Canadian and two GLI-2012 equations for interpretation of spirometry, rather than clinical outcomes or mortality risk. As the Canadian reference equations only considered the age range of 20–80 years,16 we excluded 13 patients outside of this age range. As the GLI allowed for the modelling of complex nonlinear relationships over a wide age range, this omission will not have significant impact.
It should also be noted that the purpose of the current study is not to evaluate clinical outcomes associated with the labelling of the pulmonary function pattern but rather, to evaluate the discrepancies in the prevalence of pulmonary function abnormalities when different reference equations are applied to the same test data. The observed discrepancies in the interpretation of spirometry based on the choice of reference equations provide the rationale for ongoing discussion as the physiological pattern of PFT are key early factors that determine the clinical pathway of patients with respect to subsequent investigations, treatment and other therapeutic management. Thus, the use of lung function prediction equations should be carefully considered in each medical centre to ensure best practices in providing medical care to multiethnic populations.