Background
Reference values for spirometry are necessary for identifying subjects with abnormal lung function. The European Coal and Steel Community (ECSC) reference values [
1] have until recently been recommended for European countries by the European Respiratory Society (ERS). In Sweden, two domestic reference values have been widely used [
2-
4]. In 2012, The Global Lung Function Initiative (GLI), an ERS task force, presented new multi-ethnic reference values for spirometry [
5] for several different ethnicities within the three to 95 years age-span. These GLI reference values are currently endorsed by several respiratory societies [
5,
6]. For Caucasians, the GLI reference values are based on data from asymptomatic lifelong non-smokers from 30 different centres comprising 57,395 subjects with European ancestry from several European countries including Sweden, along with Israel, Australia, USA, Canada, Brazil, Chile, Mexico, Uruguay, Venezuela, Algeria and Tunisia. They have been evaluated and found to be applicable for the Australasian population aged 4–80 years [
7] as well as for British children [
8], but do not reflect data for Tunisian adults very well [
9]. Further evaluations of applicability from other parts of the world are required in order to verify the appropriateness in these areas. Hitherto, there are no publications evaluating the applicability of the GLI reference values for Caucasian adult residents in any of the European countries.
The definition of airway obstruction is based on the ratio between forced expiratory volume in one second (FEV
1) and the vital capacity (VC) measured by slow (SVC) and/or forced (FVC) manoeuvres. According to the Global Initiative on Obstructive Lung Disease (GOLD) a post-bronchodilator ratio < 0.7 is defined as not fully reversible airway obstruction [
10]. The ERS and American Thoracic Society (ATS) recommend the use of Lower Limit of Normal (LLN) defined as the lower fifth percentile of the distribution for healthy non-smokers to define an abnormally low ratio [
11-
13]. The LLN definition is dependent on the set of reference values in use. Consequently, when implementing the LLN criteria in a population of healthy non-smoking subjects, a prevalence of obstruction of 5% indicates perfect applicability of the reference values in use.
It is of great importance that the population from which the reference values are derived is representative for the population under study. The age distribution and other anthropometric, ethnic, environmental and socio-economic factors should be equivalent since such factors can affect lung function. Additionally, the methodology for performing spirometric measurements in terms of protocol and equipment etc. must be stringent [
11,
14].
The aim of the present study was to evaluate if the GLI reference values, although endorsed by several respiratory societies including the ERS and ATS, are applicable for an adult Caucasian population resident in Sweden.
Discussion
Compared to the ECSC reference values, the GLI reference values are superior, but not perfect, for Swedish adults. The original intention of GLI was that the same reference values should be possible to use in most parts of the world, covering different ethnicities and ages to avoid age-related junction points between different sets of reference values. The data which the GLI equations are based on were collected from 1978 to 2008, which may question whether or not the oldest data still are valid. However, earlier studies by Quanjer et al. found no evidence of impact of secular trends in FEV
1, FVC or FEV
1/FVC in Caucasians during the last 30 years. They also found that reference equations derived from collated datasets, such as the GLI, are applicable across different centres using different equipment, which is another strong argument for using GLI [
24].
The GLI reference values represent the average of all available data they are based on and may thus not be representative for every specific subpopulation included. Since there are substantial differences in e.g. occupational exposures and environmental pollution which may affect lung function between countries and regions populated by Caucasians, differences in lung function can be expected. Data from Swedish centres are included in the reference data from which the GLI reference values are derived, but comprise only 123 subjects. Since there are substantial differences in anthropometric, environmental and socio-economic factors between e.g. Scandinavia and southern Europe, an evaluation of the fit for Swedish subjects is required.
Swanney et al. [
25] argues that adopting the GLI reference values in clinical practice worldwide is essential and urgent, in order to reduce the confusion regarding which reference values to rely on. In essence, Swanney et al. argues that the use of GLI worldwide is preferable to local specific reference values obtained with different techniques, especially since the GLI reference values have been evaluated and considered applicable for both Caucasian adults and children [
7,
8]. Similar matters have also been argued previously by Stanojevic et al. [
14]. However, despite the fact that the GLI reference values may be applicable for Caucasian populations in several countries, the present findings demonstrate that there are differences between countries that have to be considered.
The OLIN-studies have conducted research about obstructive lung disease in Northern Sweden since 1985 [
26] and the research staff carrying out the spirometric measurements are highly experienced. The sampling of the reference population was rigorously thorough, as was the data quality and repeatability control. The reference population originates from randomly selected healthy non-smokers of the general population of Norrbotten, the northernmost province of Sweden. Selection bias such as using health personnel [
2], employees within certain industries [
1,
2,
23] or subjects visiting a certain clinic is thus avoided. One of the strengths of this study is that data is contemporary, i.e. collected from 2008 to 2013, and thus possible secular trends in this data set can be ruled out. It has previously been shown that 150 subjects of each sex is a sufficient sample size to make a reliable evaluation of the applicability of reference values for spirometry [
24], and hence this evaluation can be considered convincingly reliable. A possible weakness of this study is that no data of cotinine levels were analysed to confirm non-smoking.
This Swedish study showed a positive offset for observed FEV
1 and FVC compared to the GLI reference values, with mean Z-scores for FEV
1 and FVC above the expected for both sexes and across almost all ages. Mean values of FEV
1 and, in particular, FVC as percent of predicted values exceeded 100% to a greater extent among women than among men. In this study, FVC as percent of predicted value exceeded 100% also according to most of the reference values from other areas, i.e. reference values ECSC [
1], Hankinson [
20], Langhammer [
21] and Gulsvik [
22]. The GLI reference values yield similar results as Hankinson’s, with percent of predicted values closer to 100% compared to the previously recommended ECSC reference values, in line with results from previous studies [
6]. Reference values from Sweden [
3,
4] and Finland [
23] yielded mean percent of predicted values closer to 100%. However, recent debate criticise the use of percent predicted due to the sex-, height- and age-related bias embedded in this measure, and advocates the use of Z-scores instead [
6,
27].
The standard deviations for FEV
1 and FVC Z-scores were close to 0.9 for both sexes, implying that the dispersion around the mean was lower in this sample compared to the GLI. Consequently the LLN for these values may be “too low”. Almost 10% of the subjects were outside the 90% limits of normality as defined by GLI (6.4% for FEV
1, 9.8% for FVC), but most of those subjects were located above the 95th percentile. The authors of the study which evaluated the applicability of GLI on an Australasian population argue that Z-score deviations <0.5 (corresponding to <3% deviations) are clinically insignificant [
7]. In this study however, the deviation of 0.42 Z-scores for FVC among women represent a deviation of 6%. The classification into severity grades of airway and lung disease often relies on FEV
1 or FVC as percent of a reference value, and thus the use of GLI may lead to invalid classification of disease severity in Sweden.
The mean predicted FEV1/FVC ratio was higher compared to the mean observed ratio, and more pronounced so among women compared to men. The Z-score SD’s for both sexes were consistently below 0.9 for the ratio, implying a lower variability in this Swedish dataset also for the ratio. Since the spirometric definition of airway obstruction relies on the ratio, the fact that the GLI predicted ratios are higher means that the prevalence of obstruction may be overestimated in Sweden. Additionally, since the dispersion around the ratio is lower in Sweden compared to GLI, use of the GLI LLN criteria may overestimate the prevalence of obstruction even further. LLN will by definition allow for a 1/20 false positive rate, and this study clearly illustrates that among healthy subjects, those identified as obstructive by the LLN criterion in particular are those with high FVC values.
Regardless of criteria for airway obstruction, the prevalence was higher among women than men in the reference population. If the agreement with GLI is perfect, no such sex-difference should exist when applying the LLN criteria of obstruction based on the GLI reference values. In this study, 9.4% of the women were identified as obstructive according to the GLI LLN criterion (fifth percentile), which indicates that this criterion may overestimate the prevalence of airway obstruction in Swedish women.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
HB carried out all data management and statistical analyses, interpreted data, drafted and finalized the manuscript. AL, BL and ER designed and coordinated the study, revised the manuscript and contributed with important input to the discussion and conclusion. AS and KL contributed with important interpretations and input to the manuscript. ER supervised the data collection process and the statistical analyses. All authors read and approved the final manuscript.