Putting lung function reference equations into context

Discussion

The selection of appropriate reference sets is critical to interpretation of results. Incorrect selection of reference equations may impact diagnosis and incorrectly inform clinical management options.

The multiethnic GLI spirometry reference set illustrates differences in lung function based on ethnicity, with Caucasian and North East Asian populations having higher FEV₁ and FVC predicted values than South East Asian and African American populations in the study [2]. Figure 1 illustrates the differences. Of note, in the examples shown in figure 1, the North East Asian LLN sits higher than the Caucasian LLN, despite the Caucasian predicted value being higher than the North East Asian predicted value. While this suggests less variation in the North East Asian population used to create the reference equations, it also suggests that using Caucasian reference equations in a North East Asian population may result in underestimation of abnormal findings. Using Caucasian reference values for a person of South East Asian background may result in an abnormal finding simply because the LLN using the Caucasian reference equations is higher than the South East Asian LLN (table 2). Similarly, a person of Caucasian descent may appear to have lung function in the normal range if compared against the South East Asian LLN but be abnormal if compared to the Caucasian LLN.

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Figure 1

a) Predicted (pred) FVC and FVC LLN for a 172-cm-tall adult male versus age using the multiethnic GLI equations. b) Pred FVC and FVC LLN for a 163-cm-tall adult female. For both, the “other/mixed” pred FVC and FVC LLN represent the pooled data of the four ethnic groups and sit approximately in the middle of the range of plotted data. Note also that the North East (NE) Asian FVC LLN sits above the Caucasian FVC LLN despite the NE Asian predicted FVC sitting below the Caucasian pred FVC. SE: South East.

In the case presented, the subject has been assigned “other/mixed” for ethnic ancestry as he does not identify with the four defined GLI ethnic groupings or is of mixed ancestry. The GLI “other/mixed” equations represent the combination of the entire data set and hence sit somewhere in the middle of the range (figure 1). Cautionary statements regarding reference equations must be used when “other/mixed” group is selected, as it is unclear whether the reference values are truly representative of the subject's ethnicity and they may be assigned normal or abnormal patterns based on a generalised normal range.

While the GLI spirometry reference set, which has been endorsed for use by many respiratory societies around the world, provides equations for multiple ethnic groups, similar multiethnic reference equations are not available for T_LCO or SLV parameters. Whether similar differences in gas exchange and SLV parameters across racial groups exist is still to be determined. However, it is probable that similar findings of racial differences for SLVs exist based on the common parameter of vital capacity (VC). In a normal, healthy cohort without any history of respiratory disease, we expect FVC and VC to be similar. Spirometry data submitted with lung volume data used to create the GLI SLV reference set overall showed small, insignificant deviations from the GLI predicted FVC (mean±sd z-score 0.31±1.00) [3]. Furthermore, equations for VC [3] and FVC [2] were similar [3]. The differences between VC and FVC amplify, however, when using spirometry reference equations other than Caucasian to calculate FVC. Figure 2 shows that the difference between predicted FVC and predicted VC is larger when predicted FVC is calculated using reference equations appropriate to ancestry in a male cohort (n=365) referred to an Australian lung function laboratory for clinical testing (unpublished data). By assigning the “other/mixed” spirometry reference set to the case presented, the predicted FVC and LLN become 3.60 L and 2.72 L respectively, while the predicted VC and LLN are 4.25 L and 3.38 L respectively: a 0.65 L and 0.66 L difference respectively. It is probable that the difference seen between predicted VC and FVC in this case is likely to be reflected in other subdivisions of SLVs too. SLV reference data for ancestry other than Caucasian are sparse and it is unclear how to account for possible differences when using Caucasian reference equations to interpret results of patients with ancestry other than Caucasian. It is incumbent upon reporters of lung function to understand the limitations of the reference sets being used; the use of cautionary statements in reports is strongly recommended where the ancestry of the patient differs from the reference sets used (e.g. reference values used may not be representative of the patient's ethnicity and should be used with caution).

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Figure 2

Male predicted FVC [2] minus predicted VC [3] plotted against age. “Non-Caucasian” includes North East Asian, South East Asian, African American or other/mixed ancestry. The difference in predicted FVC and VC is substantially larger in those of non-Caucasian ancestry.

In the case presented, the patient has IPF and the medical team are assessing his eligibility to access antifibrotics. Quite apart from the differences in eligibility between jurisdictions around the world, the patient's ability to access the medication may depend on the reference set chosen. Two recent papers have reviewed eligibility for access to antifibrotics based on reference set chosen. Ward et al. [5] looked at the proportion of English and Scottish patients with IPF who were eligible for antifibrotics dependent on reference sets chosen. Eligibility in England and Scotland at the time of the study was FVC ≤80% of predicted. The eligibility criteria did not state which reference values should be used. Approximately 34 out of 98 patients (total n=528) who were ineligible for treatment using the European Community for Steel and Coal reference set [6] to calculate FVC % predicted became eligible when using the Third National Health and Nutrition Examination Survery spirometry reference set [7], and 25 became eligible using the GLI 2012 reference set [2] instead. The second study from Australia, where antifibrotic lung function eligibility criteria is FVC ≥50% predicted and T_LCO ≥30% predicted, found variation in eligibility ranged from 74% to 86% dependent on the reference sets chosen [8]. Table 3 shows the variation in FVC % predicted and T_LCO % predicted in a selection of commonly used reference sets using the presented case's gender, age and height. Using the GLI spirometry “other/mixed” and T_LCO reference equations, the patient (just) meets the lung function eligibility criteria for government-subsidised treatment.