Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set

Pierre-Marie Wardyn; Virginie de Broucker; Cécile Chenivesse; Annie Sobaszek; Richard Van Bulck; Thierry Perez; Jean-Louis Edmé; Sébastien Hulo

doi:10.1371/journal.pone.0245434

. 2021 Jan 14;16(1):e0245434. doi: 10.1371/journal.pone.0245434

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set

Pierre-Marie Wardyn ^1,^#, Virginie de Broucker ^1,^2,^#, Cécile Chenivesse ^3,^4,^5,^‡, Annie Sobaszek ^2,^6,^‡, Richard Van Bulck ^1,^‡, Thierry Perez ^1,^4,^‡, Jean-Louis Edmé ^1,^2,^#, Sébastien Hulo ^1,^2,^*,^#

Editor: Davor Plavec⁷

PMCID: PMC7808798 PMID: 33445178

Abstract

Background

The single-breath diffusing capacity of the lung for carbon monoxide (D_LCO) interpretation needs the comparison of measured values to reference values. In 2017, the Global Lung Function Initiative published new reference values (GLI-2017) for D_LCO, alveolar volume (V_A) and transfer coefficient of the lung for carbon monoxide (K_CO). We aimed to assess the applicability of GLI-2017 reference values for D_LCO on a large population by comparing them to the European Community of Steel and Coal equations of 1993 (ECSC-93) widely used.

Methods

In this retrospective study, spirometric indices, total lung capacity, D_LCO, V_A and K_CO were measured in adults classified in 5 groups (controls, asthma, chronic bronchitis, cystic fibrosis, and interstitial lung diseases (ILD)). Statistical analysis comparing the 2 equations sets were stratified by sex.

Results

4180 tests were included. GLI-2017 z-scores of the 3 D_LCO indices of the controls (n = 150) are nearer to 0 (expected value in a normal population) than ECSC-93 z-scores. All groups combined, in both genders, D_LCO GLI-2017 z-scores and %predicted are significantly higher than ECSC z-scores and %predicted. In the ILD group, differences between the 2 equation sets depend on the D_LCO impairment severity: GLI-2017 z-scores are higher than ECSC z-scores in patients with no or “mild” decrease in D_LCO, but are lower in “moderate” or “severe” decrease.

Conclusion

GLI-2017 reference values for D_LCO are more suitable to our population and influence the diagnostic criteria and severity definition of several lung diseases.

Introduction

The single-breath diffusing capacity of the lung for carbon monoxide (D_LCO) is a simple non-invasive way to evaluate the alveolar-capillary gas exchanges [1]. D_LCO is a key element in the diagnosis and follow-up of diseases in which lung gas transfer is altered by an alveolar-capillary membrane damage, as seen in interstitial lung diseases.

D_LCO measured values need to be compared to reference values calculated with equations based on age, sex and height. Nowadays, in Europe, the European Community of Steel and Coal (ECSC) reference values for D_LCO parameters, published in 1983 [2] (ECSC-83) and updated in 1993 [3,4] (ECSC-93), are the most commonly used. They are linear regression equations based on regression equations collation published before 1983. They are suitable for European women and men from 25 to 70 years old. Between 18 and 25 years old, predicted values are based on an age fixed at 25 years old. Before 18 years old, several equations sets can be applied including those of Polgar and Promadhat published in 1971 [5]. Besides the discontinuity problem between adults and children, the methods employed to produce those equations are far from current standards.

In 2017, the Global Lung Function Initiative (GLI) published new reference values for D_LCO, alveolar volume (V_A) and transfer coefficient of the lung for carbon monoxide (K_CO) for Caucasians aged from 5 to 85 years old (GLI-2017) [6]. Data derived from measured values in 9170 subjects from 14 countries excluding France due to French ethical laws.

Before using a set of equations on daily basis, the most appropriate should be chosen after comparison to the different available options [7,8]. To date, two articles have been published with this aim for GLI-2017 D_LCO equations. The first on 145 patients with idiopathic pulmonary fibrosis evaluating the impact of GLI-2017 on clinical trial eligibility for those patients [9], and the second evaluating the effect of GLI-2017 on the normal/abnormal classification of D_LCO results [10]. Even if they both concluded that the GLI-2017 should be adopted in laboratories, the need for a study including controls and multiple categories of patients with several degrees of decrease in D_LCO still remains.

In our study, we aimed to assess the applicability of the GLI-2017 reference values for D_LCO in adults by comparing them to the ECSC-93 equations currently used.

Materials and methods

Study population

We selected data of a control group and patients with symptoms compatible with one of four diseases (asthma, chronic bronchitis, cystic fibrosis, and interstitial lung diseases (ILD)) from pulmonary function tests (PFT) performed on daily basis between November 15^th 2012 and May 30^th 2016 in the PFT laboratory of the university hospital of Lille, France. PFTs providing all the following indices were selected: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), FEV₁ to FVC ratio (FEV₁/FVC), total lung capacity (TLC), D_LCO, V_A and K_CO. Only measurements performed before bronchodilation were included.

Exclusion criteria were: patients under 18 years old; patients classified in more than one group; missing data or outliers for sex, weight or height; any PFT other than spirometry with D_LCO measurement; D_LCO<1mmol.min^-1.kPa^-1 (minimal value for the D_LCO predicted value calculation [6,11]).

For each test, patient’s characteristics (sex, age, height, weight), PFTs indices values and patient’s medical history were recorded in the laboratory database. For the tests’ inclusion, data from the PFT performed between November 15^th 2012 and May 30^th 2016, and including the indices mentioned above, were extracted to a Microsoft Excel^® spreadsheet by the laboratory engineer. Then tests meeting exclusion criteria were excluded using the statistical software SAS^® (version 9.4; Statistical Analysis System).

This study was performed in accordance with the Declaration of Helsinki. This human study was approved by the Research Ethics Board of the University Hospital of Lille (Comité de Protection des Personnes Nord Ouest IV)—approval: HP20/02. All adult participants provided written informed consent for the use of their data in the research field. Included patients were addressed to our department for routine functional evaluation.

PFT measurements and results reports

Spirometry and lung volumes measured by body plethysmography and/or helium dilution were performed on a JAEGER^® MasterScreen Body device (CareFusion, Hoechberg, Germany). Helium dilution was used for lung volumes measurements when body plethysmography was not feasible. D_LCO, V_A and K_CO measurements were performed on a JAEGER^® MasterScreen PFT device (CareFusion, Hoechberg, Germany). Only test results meeting criteria for acceptability and reproducibility of the 2005 American Thoracic Society/European Respiratory Society recommendations (ATS/ERS-2005) [12–14] were included. In addition to the daily calibrations and verifications recommended by the manufacturer, the laboratory engineer (healthy and non-smoker) carried out a CO uptake measurement (biological calibration) every week. A D_LCO variability above 10% led to a device verification.

ECSC-93 were applied to all concerned indices (FVC, FEV₁, FEV₁/FVC and TLC) [2], the 2012 GLI equations for spirometry (GLI-2012) to FVC, FEV₁ and FEV₁/FVC ratio [15] and ECSC-93 to D_LCO [2]. The 1993 ECSC update recommend to calculate the K_CO predicted value as the predicted D_LCO to predicted TLC ratio [4], so the predicted V_A used in this study is the predicted TLC for the K_CO calculation according to ECSC. GLI-2017 were applied to D_LCO, V_A and K_CO [11].

Spirometric and TLC values were expressed as z-scores, D_LCO and V_A results as z-scores and %predicted, K_CO adjustment on the ECSC-1993 predicted value as %predicted only (the standard deviations required for z-scores is not available).

Groups creation

Selected PFTs came from 4 groups of patients with symptoms compatible with one of the following diseases: asthma, chronic bronchitis, cystic fibrosis, and ILD. The chronic bronchitis group included patients with symptoms compatible with chronic bronchitis (with a FEV₁/FVC ratio ≥ 0.7) or with chronic obstructive pulmonary disease (COPD) (with a FEV₁/FVC ratio < 0.7 according to the GOLD 2021 report [16]). ILD category covers more than 150 entities such as sarcoidosis, idiopathic pulmonary fibrosis or pneumoconiosis [17]. The disease was initially filled out by the prescribing physician and recorded in the laboratory database at the time of the PFT validation. In order to ensure data quality, diagnoses were checked from patient files in random samples of each groups (see S1 Appendix and S1 Table in S1 Appendix). Selected PFTs could have been performed at any stage of the concerned disease, from initial evaluation to advanced stage. The control group consisted of subjects complaining of dyspnea without parenchymal lung abnormalities and subjects from a health monitoring checking their work ability. Employees with professional exposures were excluded. Subject selection for this control group was performed independently from the PFT results.

Statistical analysis

Data analysis was performed using the statistical software SAS^® (version 9.4; Statistical Analysis System) and R (version 3.6.1; R Foundation, www.r-project.org). Five types of ventilatory disorders were created from spirometric and TLC values: “obstruction” (FEV₁/FVC below lower limit of normal (LLN) (z-score <-1.645), TLC ≥LLN), “restriction” (TLC <LLN, FEV₁/FVC ≥LLN), “mixed” (coexistence of obstruction and restriction) [18], Preserved Ratio Impaired Spirometry (PRISm) (FEV₁/FVC and TLC ≥LLN, FEV₁ <LLN) [19], “normal” (FVC, FEV₁, FEV₁/FVC and TLC ≥LLN) and “other” (not elsewhere classified).

D_LCO parameters below LLN were considered altered. The ATS/ERS-2005 degrees of D_LCO impairment were used: “Mild” (D_LCO>60%predicted and <LLN), “Moderate” (D_LCO>40% and ≤60%predicted), “Severe” (D_LCO≤40%predicted) [18].

Data analysis were stratified by sex and reported by subject groups. Continuous quantitative variables were expressed as medians, 1^st and 3^rd quartiles; qualitative variables as absolute values and frequencies (percentages).

Non-parametric Wilcoxon and Kruskall-Wallis tests were used for data without normal distribution to compare quantitative variables between groups, Chi-squared tests to compare qualitative variables, Wilcoxon signed-rank tests to compare PFT values between equation sets. Differences in D_LCO and V_A alteration prevalence rates according to each equation sets were tested using McNemar’s Chi-squared test.

Linear or multilinear regressions were used to study the relationship between the differences of the 2 D_LCO z-scores, calculated with each equation sets, and age, sex, and decrease severity.

Statistical significance was set at p < 0.05 for all tests.

Results

From the 15^th November 2012 to the 30 May 2016, 9699 tests with spirometry and D_LCO measurements were performed. 4180 tests were included (representing 2898 subjects) with 2181 tests in men and 1999 in women (Fig 1).

Fig 1 — D_LCO: Diffusing capacity of the lung for carbon monoxide. §: Minimal value for the D_LCO predicted value calculation [6,11].

Table 1 shows the main characteristics of our population. Ventilatory defect types are significantly different between groups (Table 1). In the control group, “normal” ventilatory profiles proportions are close to the 95% expected in a normal population.

Table 1. Characteristics of the population by sex.

Variables	Overall	Controls	Asthma	Chronic bronchitis	Cystic fibrosis	ILD	Statistics between groups p-value
Variables	n = 4180	n = 150	n = 527	n = 732	n = 145	n = 2626	Statistics between groups p-value
Male
Subjects, n	2181	77	197	534	70	1303
Age, years	59 (47; 68)	40 (27; 51)	46 (34; 56)	59 (51; 66)	28 (24; 37)	62 (52; 70)	< 0.0001
Weight, kg	80 (70; 90)	81 (72; 91)	78 (69; 90)	75 (66; 90)	64 (57; 77)	81 (72; 91)	< 0.0001
Height, cm	173 (169; 178)	178 (174; 184)	176 (171; 180)	172 (168; 178)	171 (168; 176)	173 (168; 178)	< 0.0001
BMI, kg.m^-2	26.3 (23.2; 29.8)	25.9 (23.1; 28.1)	25.1 (22.5; 28.4)	25.3 (22.0; 29.4)	21.7 (19.9; 24.9)	27.2 (24.1; 30.4)	< 0.0001
Ventilatory defect type	2167	73	189	532	69	1300	< 0.0001
Normal	658 (30.4%)	73 (94.8%)	83 (43.9%)	80 (15.0%)	22 (31.9%)	400 (30.8%)
Restriction	793 (36.6%)	2 (2.6%)	18 (9.5%)	36 (6.8%)	6 (8.7%)	731 (56.2%)
Obstruction	361 (16.7%)	2 (2.6%)	55 (29.1%)	234 (44.0%)	12 (17.4%)	58 (4.5%)
Mixed	322 (14.9%)	0	26 (13.8%)	168 (31.6%)	29 (42%)	99 (7.6%)
PRISm	31 (1.4%)	0	7 (3.7%)	14 (2.6%)	0	10 (0.8%)
Other	2 (0.1%)	0	0	0	0	2 (0.1%)
Missing data‡	14	0	8	2	1	3
Female
Subjects, n	1999	73	330	198	75	1323
Age, years	53 (41; 65)	43 (29; 54)	48 (34; 57)	55 (48; 65)	31 (22; 42)	56 (43; 66)	< 0.0001
Weight, kg	67 (57; 80)	63 (56; 78)	67 (58; 79)	62 (53; 76)	53 (50; 60)	68 (58; 82)	< 0.0001
Height, cm	162 (157; 167)	163 (160; 167)	162 (157; 168)	161 (157; 166)	164 (160; 167)	161 (156; 166)	0.00022
BMI, kg.m^-2	25.5 (21.8; 30.8)	23.7 (21.3; 28.9)	25.3 (21.3; 29.7)	23.4 (20.7; 28.4)	20.2 (18.7; 21.8)	26.4 (22.5; 31.5)	< 0.0001
Ventilatory defect type	1963	70	301	194	75	1323	< 0.0001
Normal	1104 (56.2%)	66 (94.3%)	173 (57.5%)	32 (16.5%)	25 (33.3%)	808 (61.1%)
Restriction	393 (20.2%)	0	15 (5%)	6 (3.1%)	6 (8%)	366 (27.7%)
Obstruction	294 (15.0%)	2 (2.9%)	76 (25.2%)	110 (56.7%)	20 (26.7%)	86 (6.5%)
Mixed	118 (6.0%)	0	27 (9%)	40 (20.6%)	21 (28%)	30 (2.3%)
PRISm	51 (2.6%)	1 (1.4%)	9 (3.0%)	6 (3.1%)	3 (4%)	32 (2.4%)
Other	3 (0.1%)	2 (1.4%)	1 (0.3%)	0	0	1 (0.1%)
Missing data‡	36	3	29	4	0	0

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Ventilatory defect types according to the 2005 recommendations for lung function test interpretation from the American Thoracic Society (ATS) and the European Respiratory Society (ERS): Obstruction: z-score of FEV₁/FVC ratio < -1.645 and TLC z-score ≥ -1.645; restriction: TLC z-score < -1.645 and z-score of FEV₁/FVC ratio ≥ -1.645; mixed (coexistence of obstruction and restriction); [18] PRISm (Preserved Ratio Impaired Spirometry): z-score of FEV₁/FVC ratio ≥ -1.645, TLC z-score ≥ -1.645 and FEV₁ z-score < -1.645; [19] normal: z-score of FVC, FEV₁, FEV₁/FVC ratio and TLC ≥ -1.645; other: Not elsewhere classified. ILD: Interstitial lung disease; BMI: Body mass index; FEV₁: Forced expiratory volume in 1 s; FVC: Forced vital capacity; TLC: Total lung capacity. Data are presented as n, median (Q1; Q3) and n (%). Kruskall-Wallis tests were used to compare qualitative variables between disease groups, Chi-squared tests to compare qualitative variables between disease groups.

‡Missing data only concern TLC.

GLI-2012 produce significantly lower median z-scores for FEV₁ (p < 0.0001 in both genders), FVC (p < 0.0001 in both genders) and FEV₁/FVC (p < 0.0001 in both genders) than ECSC, all groups combined, in both genders (Table 2). In control subjects, ECSC FEV₁ and FVC median z-scores are more distant from the zero expected value than GLI-2012 values.

Table 2. Z-scores of FVC, FEV₁, FEV₁/FVC and TLC according to ECSC-93 and GLI-2012 (except for TLC) by sex.

Variables		Overall	Controls	Asthma	Chronic bronchitis	Cystic fibrosis	ILD
Variables		n = 4180	n = 150	n = 527	n = 732	n = 145	n = 2626
Male
Tests, n		2181	77	197	534	70	1303
FVC	ECSC-93	-0.759 (-1.77; 0.19)	0.88 (0.08; 1.35)	-0.13 (-1.29; 0.64)	-0.94 (-1.97; 0.09)	-0.67 (-2.18; 0.09)	-0.87 (-1.80; 0.05)
	GLI-2012	-1.18 (-2.21; -0.26)	0.23 (-0.46; 0.65)	-0.58 (-1.61; 0.08)	-1.33 (-2.34; -0.40)	-1.15 (-2.62; -0.36)	-1.25 (-2.24; -0.39)
FEV₁	ECSC-93	-1.29 (-2.47; -0.33)	0.59 (-0.36; 1.17)	-1.31 (-2.47; -0.17)	-2.52 (-3.60; -1.41)	-2.19 (-4.22; -0.76)	-1.00 (-1.88; -0.21)
	GLI-2012	-1.65 (-2.73; -0.68)	0.16 (-0.77; 0.68)	-1.63 (-2.69; -0.54)	-2.79 (-3.73; -1.82)	-2.54 (-4.36; -0.89)	-1.37 (-2.24; -0.54)
FEV₁/FVC	ECSC-93	-0.685 (-2.09; 0.40)	0.002 (-0.48; 0.43)	-1.34 (-2.56; -0.32)	-2.75 (-4.42; -1.67)	-2.37 (-3.65; -0.74)	0.05 (-0.84; 0.83)
	GLI-2012	-0.910 (-2.19; 0.21)	-0.23 (-0.67; 0.38)	-1.58 (-2.56; -0.48)	-2.68 (-3.89; -1.83)	-2.55 (-3.51; -1.07)	-0.13 (-1.00; 0.58)
TLC	ECSC-93	-1.70 (-3.06; -0.50)	-0.10 (-0.53; 0.63)	-0.77 (-1.56; 0.25)	-1.14 (-2.21; -0.14)	-1.65 (-2.60; -0.58)	-2.34 (-3.48; -1.16)
	Missing data	14 (0.6%)	0	8 (4.1%)	2 (0.4%)	1 (1.4%)	3 (0.2%)
Female
Tests, n		1999	73	330	198	75	1323
FVC	ECSC-93	-0.03 (-0.97; 0.83)	0.91 (0.01; 1.69)	0.13 (-0.75; 1.02)	-0.46 (-1.21; 0.41)	-0.99 (-2.33; 0.29)	-0.01 (-0.94; 0.80)
	GLI-2012	-0.85 (-1.81; -0.09)	-0.04 (-0.64; 0.77)	-0.70 (-1.60; 0.21)	-1.28 (-2.07; -0.51)	-1.48 (-2.55; -0.48)	-0.86 (-1.81; -0.12)
FEV₁	ECSC-93	-0.62 (-1.73; 0.23)	0.31 (-0.29; 1.08)	-0.65 (-1.81; 0.23)	-1.96 (-3.54; -1.11)	-1.92 (-4.10; -0.54)	-0.47 (-1.43; 0.30)
	GLI-2012	-1.15 (-2.24; -0.28)	-0.042 (-0.74; 0.71)	-1.18 (-2.44; -0.26)	-2.70 (-3.76; -1.77)	-1.94 (-4.21; -0.88)	-1.03 (-1.98; -0.23)
FEV₁/FVC	ECSC-93	-0.29 (-1.33; 0.55)	0.04 (-0.60; 0.60)	-0.72 (-1.99; 0.02)	-2.52 (-4.90; -1.71)	-2.00 (-3.16; -0.52)	0.03 (-0.68; 0.77)
	GLI-2012	-0.52 (-1.43; 0.26)	-0.17 (-0.82; 0.33)	-0.97 (-1.98; -0.24)	-2.32 (-3.64; -1.75)	-1.98 (-2.81; -0.75)	-0.18 (-0.88; 0.50)
TLC	ECSC-93	-0.72 (-1.68; 0.17)	0.44 (-0.25; 0.99)	-0.23 (-1.09; 0.50)	-0.72 (-1.55; 0.21)	-1.30 (-2.40; -0.20)	-0.85 (-1.90; 0.01)
	Missing data	36 (1.8%)	3 (4.1%)	29 (8.8%)	4 (2.0%)	0	0

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ILD: Interstitial lung disease; FVC: Forced vital capacity; FEV₁: Forced expiratory volume in 1 s; TLC: Total lung capacity; ECSC-93: European Community for Steel and Coal 1993 reference values; [2,4] GLI-2012: Global Lung function Initiative 2012 reference values [15]. Data are presented as n, median z-score (Q1; Q3) and n (%).

For both equation sets, D_LCO, V_A and K_CO z-score and %predicted are statistically linked to subject groups (p < 0.0001 in both genders; Kruskall-Wallis tests). Median z-scores in the control group are close to the zero expected with GLI-2017 in both genders (Table 3). In this group, standard deviations are also slightly closer to zero using GLI-2017 (0.819 in women, 0.928 in men) than using ECSC (0.866 in women, 0.968 in men). Furthermore, in this group, z-score differences between the 2 equations sets are linearly correlated to age (p < 0.0001) and height (p = 0.0004 in women, p = 0.0392 in men) in both genders, with a stronger trend in women. In the asthma and cystic fibrosis groups, GLI-2017 produce significantly higher D_LCO z-scores than ECSC in both genders (Asthma group: p < 0.0001 in both genders. Cystic fibrosis group: p < 0.0001 in both genders). In the chronic bronchitis and ILD groups, the same trends are seen only in women, with a significant difference between D_LCO z-scores in the ILD group only (p < 0.0001 in the ILD group; p = 0.27 in the chronic bronchitis group). In men with chronic bronchitis or ILD, which are the groups with the lowest D_LCO values, GLI-2017 generate significantly lower D_LCO z-scores than ECSC (p < 0.0001 in the chronic bronchitis group; p < 0.0001 in the ILD group).

Table 3. Measured values, z-scores and %predicted for D_LCO, V_A and K_CO according to ECSC-93 and GLI-2017 by sex.

Variables		Overall	Controls	Asthma	Chronic bronchitis	Cystic fibrosis	ILD
Variables		n = 4180	n = 150	n = 527	n = 732	n = 145	n = 2626
Male
Subjects, n		2181	77	197	534	70	1303
D_LCO, mmol.min^-1.kPa^-1		5.64 (3.80; 8.13)	10.08 (8.84; 11.42)	9.01 (7.63; 10.05)	5.20 (3.74; 6.70)	9.01 (7.78; 10.46)	5.08 (3.42; 7.06)
Z-score	ECSC-93	-2.50 (-3.61; -1.41)	-0.95 (-1.48; 0.10)	-1.12 (-1.99; -0.16)	-2.67 (-3.80; -1.62)	-1.42 (-2.31; -0.55)	-2.76 (-3.83; -1.73)
	GLI-2017	-2.45 (-4.05; -1.00)	-0.45 (-1.02; 0.43)	-0.64 (-1.50; 0.27)	-2.82 (-4.23; -1.48)	-0.67 (-1.68; 0.13)	-2.86 (-4.40; -1.52)
	ECSC vs GLI	p = 0.02	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
% pred.	ECSC-93	61.7 (43.9; 80.2)	88.5 (80.6; 101.4)	85.3 (73.4; 97.5)	57.2 (41.7; 74.0)	83.3 (71.5; 92.9)	56.7 (40.1; 73.2)
	GLI-2017	64.7 (46.1; 85.1)	93.9 (85.1; 107.2)	90.9 (78.6; 104.6)	60.0 (44.5; 78.4)	91.0 (78.4; 101.8)	59.5 (41.9; 77.4)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
V_A, L		5.16 (4.17; 6.12)	6.65 (6.12; 7.51)	6.24 (5.37; 6.70)	5.48 (4.64; 6.15)	5.06 (4.51; 5.94)	4.75 (3.81; 5.73)
Z-score	ECSC-93	-2.21 (-3.56; -1.05)	-0.40 (-1.03; .18)	-1.21 (-1.87; -0.24)	-1.68 (-2.77; -0.74)	-2.16 (-2.97; -1.01)	-2.86 (-3.96; -1.64)
	GLI-2017	-1.26 (-2.60; -0.18)	0.25 (-0.41; 0.63)	-0.24 (-1.05; 0.51)	-0.79 (-1.77; 0.12)	-1.26 (-2.25; -0.16)	-1.91 (-3.00; -0.71)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
% pred.	ECSC-93	76.8 (62.7; 89.2)	93.9 (89.1; 99.5)	87.8 (81.1; 97.6)	82.2 (71.2; 92.0)	76.9 (69.0; 87.8)	69.9 (58.3; 83.5)
	GLI-2017	85.1 (69.6; 97.8)	103.0 (95.4; 107.0)	97.1 (88.4; 106.0)	90.5 (79.5; 101.4)	86.3 (76.0; 98.3)	77.5 (65.2; 91.4)
	ECSC vs GLI	p < 0.0001	p = 0.00039	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
K_CO, mmol.min^-1.kPa^-1.L^-1		1.12 (0.87; 1.40)	1.45 (1.29; 1.61)	1.43 (1.28; 1.65)	0.97 (0.72; 1.25)	1.70 (1.59; 1.91)	1.08 (0.86; 1.34)
Z-score	GLI-2017	-1.49 (-2.78; -0.44)	-0.50 (-1.03; -0.08)	-0.44 (-1.03; 0.38)	-2.23 (-3.63; -1.09)	0.15 (-0.48; 1.00)	-1.60 (-2.77; -0.59)
% pred.	ECSC-93	82.4 (64.3; 97.4)	94.3 (87.4; 100.3)	97.1 (87.3; 107.5)	71.5 (52.7; 88.2)	102.4 (94.0; 115.0)	80.9 (64.4; 96.1)
	GLI-2017	78.0 (60.7; 93.6)	93.1 (85.2; 99.0)	94.0 (85.2; 105.4)	67.6 (49.7; 84.0)	101.9 (93.8; 113.8)	75.6 (60.7; 91.2)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
Female
Subjects, n		1999	73	330	198	75	1323
D_LCO, mmol.min^-1.kPa^-1		5.44 (3.97; 6.67)	6.99 (6.57; 7.81)	6.45 (5.46; 7.41)	4.54 (2.89; 5.91)	6.40 (5.49; 7.53)	5.06 (3.60; 6.31)
Z-score	ECSC-93	-2.11 (-3.04; -1.27)	-1.27 (-1.74; -0.57)	-1.59 (-2.28; -0.87)	-2.56 (-3.64; -1.65)	-2.07 (-2.88; -1.08)	-2.27 (-3.17; -1.40)
	GLI-2017	-1.46 (-3.11; -0.41)	-0.13 (-0.72; 0.42)	-0.67 (-1.48; 0.13)	-2.19 (-5.12; -1.03)	-0.96 (-1.68; 0.12)	-1.78 (-3.60; -0.66)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p = 0.27	p < 0.0001	p < 0.0001
% pred.	ECSC-93	69.0 (54.1; 81.2)	82.7 (76.9; 92.1)	77.3 (68.1; 87.0)	61.5 (40.6; 73.4)	72.7 (62.8; 85.7)	65.9 (50.4; 78.5)
	GLI-2017	79.3 (61.0; 93.6)	97.8 (88.8; 107.1)	89.6 (78.7; 102.1)	69.6 (46.0; 84.4)	86.2 (77.4; 101.8)	74.8 (56.3; 89.8)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
V_A, L		4.12 (3.44; 4.73)	4.85 (4.50; 5.37)	4.51 (3.87; 5.02)	4.06 (3.51; 4.69)	4.13 (3.30; 4.65)	4.01 (3.28; 4.58)
Z-score	ECSC-93	-1.21 (-2.20; -0.30)	0.17 (-0.54; 0.86)	-0.67 (-1.44; 0.06)	-1.36 (-2.36; -0.23)	-1.65 (-2.51; -0.78)	-1.40 (-2.38; -0.50)
	GLI-2017	-1.04 (-2.18; -0.11)	0.09 (-0.58; 0.63)	-0.49 (-1.33; 0.23)	-1.15 (-2.33; -0.07)	-1.61 (-2.76; -0.64)	-1.23 (-2.42; -0.29)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p = 0.0031	p = 0.66	p = 0.00037
% pred.	ECSC-93	85.1 (72.6; 96.1)	98.7 (91.3; 106.1)	91.8 (81.7; 100.8)	82.5 (71.8; 96.1)	80.7 (69.3; 90.7)	82.8 (70.5; 93.7)
	GLI-2017	87.5 (75.2; 98.7)	101.1 (93.1; 108.1)	93.6 (84.8; 102.8)	85.7 (73.2; 99.1)	81.5 (71.2; 92.5)	85.0 (72.8; 96.4)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
K_CO, mmol.min^-1.kPa^-1.L^-1		1.32 (1.09; 1.52)	1.43 (1.31; 1.60)	1.45 (1.27; 1.63)	1.11 (0.78; 1.42)	1.62 (1.38; 1.88)	1.28 (1.06; 1.47)
Z-score	GLI-2017	-0.72 (-1.78; 0.18)	-0.16 (-0.90; 0.47)	-0.25 (-0.97; 0.60)	-1.57 (-3.77; -0.16)	0.28 (-0.64; 1.22)	-0.88 (-1.96; 0.01)
% pred.	ECSC-93	80.9 (68.6; 92.6)	85.0 (77.1; 94.7)	85.6 (77.2; 96.4)	70.0 (48.1; 87.6)	90.7 (78.5; 104.0)	79.4 (67.5; 90.9)
	GLI-2017	89.8 (75.5; 102.6)	97.7 (87.3; 107.0)	96.5 (86.6; 109.0)	78.4 (52.9; 97.7)	104.0 (91.0; 119.3)	87.4 (73.5; 100.2)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001

Open in a new tab

ILD: Interstitial lung disease; D_LCO: Diffusing capacity of the lung for carbon monoxide; ECSC-93: European Community for Steel and Coal 1993 reference values; [2,4] GLI-2017: Global Lung function Initiative 2017 reference values; [6] % pred.: %predicted; V_A: Alveolar volume; K_CO: Transfer coefficient of the lung for carbon monoxide. Data are presented as n and median (Q1; Q3). Wilcoxon signed-rank tests were used. All D_LCO, V_A and K_CO values expressed as %pred. or z-scores were significantly different between groups of subjects using ECSC and GLI equations sets (p < 0.0001; Kruskall-Wallis tests).

For %predicted D_LCO, GLI-2017 results are significantly higher than ECSC values (p < 0.0001 in men and women). In the control group, D_LCO impairment prevalence rates are nearer to the expected 5% using GLI-2017 (6.5% in men, 1.4% in women) compared to ECSC (19.5% in men, 31.5% in women) (Table 4). In the other groups, D_LCO impairment prevalence rates are significantly lower using GLI-2017 than using ECSC with larger differences in women (in women: p < 0.0001 in the chronic bronchitis group, p < 0.0001 in the cystic fibrosis group, p < 0.0001 in the ILD group; in men: p < 0.0001 in the chronic bronchitis group, p = 0.0026 in the cystic fibrosis group, p < 0.0001 in the ILD group). In the asthma group, for example, the proportion of D_LCO measurements categorized as normal with GLI-2017 is significantly higher than using ECSC, especially in women (p < 0.0001 in both genders).

Table 4. Number of tests and prevalence rates for D_LCO, V_A and K_CO impairment according to ECSC-93 and GLI-2017, by sex.

Variables		Overall	Controls	Asthma	Chronic bronchitis	Cystic Fibrosis	ILD
Variables		n = 4180	n = 150	n = 527	n = 732	n = 145	n = 2626
Male
Subjects, n		2181	77	197	534	70	1303
Abnormalities in D_LCO^‡	ECSC-93	1 507 (69.1%)	15 (19.5%)	67 (34%)	397 (74.3%)	29 (41.4%)	999 (76.7%)
	GLI-2017	1 400 (64.2%)	5 (6.5%)	46 (23.4%)	376 (70.4%)	18 (25.7%)	955 (73.3%)
	ECSC vs GLI	p < 0.0001	p = 0.0044	p < 0.0001	p < 0.0001	p = 0.0026	p < 0.0001
Abnormalities in V_A^‡	ECSC-93	1 360 (62.4%)	9 (11.7%)	62 (31.5%)	271 (50.7%)	43 (61.4%)	975 (74.8%)
	GLI-2017	924 (42.4%)	0	35 (17.8%)	145 (27.1%)	31 (44.3%)	713 (54.7%)
	ECSC vs GLI	p < 0.0001	p = 0.0077	p < 0.0001	p < 0.0001	p = 0.0015	p < 0.0001
Abnormalities in K_CO^‡	GLI-2017	1013 (46.4%)	7 (9.1%)	29 (14.7%)	334 (62.5%)	2 (2.9%)	641 (49.2%)
Female
Subjects, n		1999	73	330	198	75	1323
Abnormalities in D_LCO^‡	ECSC-93	1 282 (64.1%)	23 (31.5%)	152 (46.1%)	150 (75.8%)	43 (57.3%)	914 (69.1%)
	GLI-2017	912 (45.6%)	1 (1.4%)	69 (20.9%)	123 (62.1%)	19 (25.3%)	700 (52.9%)
	ECSC vs GLI	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001	p < 0.0001
Abnormalities in V_A^‡	ECSC-93	758 (37.9%)	6 (8.2%)	69 (20.9%)	84 (42.4%)	38 (50.7%)	561 (42.4%)
	GLI-2017	702 (35.1%)	3 (4.1%)	65 (19.7%)	75 (37.8%)	37 (49.3%)	522 (39.5%)
	ECSC vs GLI	p < 0.0001	p = 0.25	p = 0.29	p = 0.0077	p = 1	p < 0.0001
Abnormalities in K_CO^‡	GLI-2017	552 (27.6%)	4 (5.5%)	35 (10.6%)	97 (49.0%)	7 (9.3%)	409 (30.9%)

Open in a new tab

‡Abnormalities in indices if the z-score was strictly less than -1.645.

GLI-2017 and ECSC D_LCO z-scores comparison by degree of decrease in D_LCO according to ATS/ERS-2005 in the ILD group is shown in Fig 2. GLI-2017 D_LCO z-scores are -2.03, -3.39, -5.47 in men and -1.55, -3.36, -7.22 in women, in “mild”, “moderate” and “severe” categories respectively. GLI-2017 z-scores are significantly higher than ECSC z-scores in patients with no (p < 0.0001 in both genders) or “mild” decrease in D_LCO (p < 0.0001 in both genders), but are significantly lower in “moderate” (p < 0.0001 in both genders) or “severe” (p < 0.0001 in both genders) decrease in D_LCO. The multivariate analysis confirmed that the z-scores differences (ECSC vs GLI-2017 z-scores) is influenced by the DLCO severity grade (taking age in account). Multiple linear regression analysis showed, in both genders, a highly significant relationship between z-scores differences (ECSC vs GLI-2017) and age (as in the “control” group) (p < 0.0001, in both genders), the decrease in D_LCO severity (p < 0.0001, in both genders) and the interaction between age and severity (p < 0.0001 in both genders).

Discussion

To our knowledge, this study is the first to apply D_LCO measured values to the GLI-2017 reference values on a large population of patients and controls. Results in control group showed that the z-scores of the 3 D_LCO indices are nearer to 0 (expected value in a normal population) according to GLI-2017 than with ECSC-93. Moreover, in this control population, the proportion of tests with altered indices was near the expected 5%. GLI-2017 equations increase the proportion of tests classified as normal for D_LCO compared to ECSC, notably in the control and asthma groups. In the disease groups, we found a significant relationship between the severity degree of decrease in D_LCO and the z-scores differences between GLI-2017 and ECSC. GLI-2017 produce lower D_LCO z-scores for moderate to severe decrease in D_LCO than ECSC, notably in the ILD group. In all groups, differences between the 2 equation sets were more pronounced in women. Finally, K_CO results expressed as %predicted using GLI-2017 were significantly lower than using ECSC in men, but significantly higher in women.

We recruited subjects without a disease diagnosed by a physician. Ventilatory disorder types analysis showed a “normal” type proportion close to the 95% expected in a healthy population. To validate this control group, we applied the approach used to validate GLI-2012 [20,21]: z-scores close to zero, tests with a D_LCO below LLN proportion. In this group, GLI-2017 z-scores of the 3 D_LCO indices are closer to zero (expected value in a normal population) than ECSC-93 z-scores and the proportion of tests with an impaired D_LCO is close to the expected 5%. This finding is important for clinical practice, obviating the need for additional diagnostic evaluations in females with falsely abnormal D_LCO when using ECSC.

Our results are consistent with recent literature. In our study, GLI-2017 produce significantly higher %predicted than ECSC for D_LCO and V_A in both gender (all groups combined) with larger differences in women. These findings were already reported on mathematical modelling by Oostveen et al. [22]. Similarly to our results, Brazzale et al. [10] showed that GLI-2017 tend to increase the proportion of tests classified as normal, with a larger difference in younger women, compared to ECSC-93 and that the level of agreement between GLI and ECSC-93 was lower for females than for males. Unfortunately, there is no information about the pulmonary condition of the included subjects and the analyses were limited to the use of the LLN. Finally, Wapenaar et al. [9] have compared GLI-2017 to ECSC for D_LCO in patient with idiopathic pulmonary fibrosis but their sample was composed of 82% of men and there was no analysis by sex.

In asthma and cystic fibrosis groups, GLI-2017 D_LCO z-scores were significantly higher than ECSC z-scores in both genders. Conversely, in the chronic bronchitis and ILD groups, results are discordant between women and men. D_LCO impairment severity seems to provide some clues. In the ILD group, Fig 2 shows an inversion of the trend for “moderate” or “severe” decrease in D_LCO: in “normal” D_LCO or “mild” decrease in D_LCO, GLI-2017 produce significantly higher z-scores than ECSC, whereas, in “moderate” or “severe” decrease, GLI-2017 produce significantly lower z-scores than ECSC. This observation is even more important in women. Mathematical modelling showed an inversion of the GLI/ECSC z-scores ratio when D_LCO is extremely decreased (see S1 Fig). These findings are consistent with recent literature [9].

One of the main strengths of our study is the size of our population. GLI-2017 were applied to 4180 tests (including 2898 subjects). To our knowledge, this is the first study to compare the GLI-2017 reference values to the ECSC using z-scores which should be favored in the interpretation of PFT results according to the ATS/ERS [1]. We also included control subjects, allowing us to applied the approach used for GLI-2012 [20,21]. To date, studies similar to ours has included patients without information about their pulmonary condition [10] or including only patients with a specific disease (e.g., idiopathic pulmonary fibrosis [9]). We have included PFTs from patients with symptoms compatible with one of four diseases (asthma, chronic bronchitis, cystic fibrosis or ILD). The chosen disease groups seemed to be the most relevant to us according to their definition and the diagnostic entities implied. It is worth noticing that patients with uncertain or associated diagnosis (e.g., a patient with asthma and chronic bronchitis) were excluded. Furthermore, all of the PFTs were performed on the same type of device, by a unique team, implying homogeneity in measurement method.

Our study also shows some weaknesses. We have compared the GLI-2017 reference values only to the ECSC in adults. The ECSC equations are currently one of the most used in European laboratories. Also, focusing on only one equation set and only on adult patients allowed us to detail different types of results (%predicted, z-scores and the 2005-ATS/ERS degrees of D_LCO impairment [18]) and study those results in controls and multiple categories of patients with several degrees of decrease in D_LCO. This retrospective study uses highly suspected diagnoses, established by the referring physician (pulmonologist or internist) prescribing the PFT, and recorded in the laboratory database. However, in order to ensure data quality, diagnoses were checked from patient files in random samples of each groups. Some PFTs from the chronic bronchitis group are classified as normal (16.5% in women and 15% in men). There are 2 main reasons. First, we included tests performed at every stage of the diseases, including patients with mild symptoms of chronic bronchitis without obstruction. Secondly, we used z-score to define obstruction according to the 2005-ATS/ERS recommendations for lung function test interpretation [18] (z-score of FEV₁/FVC ratio < -1.645 and TLC z-score ≥ -1.645). Using the GOLD 2021 definition for COPD (FEV₁/FVC < 0.7) [16] could have led us to classify fewer PFTs as normal in the chronic bronchitis group in our sample due to the fact that a FEV₁/FVC ratio < 0.7 can be associated with a z-score of the FEV₁/FVC ratio > -1.645. On the other hand, some PFTs in the chronic bronchitis group were classified as restrictive without obstruction (3.1% in women and 6.8% in men with chronic bronchitis). This may happen in case of chronic bronchitis evaluation in a patient with a concomitant disease which has not been clinically detected by the prescribing physician. Also, we were unable to collect ethnicity, this data collection being strictly regulated by French law. However, the majority of the laboratory patients are Caucasians. We did not take into account active tobacco consumption and hemoglobinemia (which would only have corrected D_LCO crude value). The aim of this study was not to assess the GLI-2017 diagnostic interest but to compare them to ECSC. Finally, our data come from a single laboratory, but it cover an area of more than 4 million people (approximately 9% of the French population) [23].

In conclusion, we showed that GLI-2017 reference values are more suitable to our sample than ECSC and that the differences between the 2 equation sets depend on the severity of D_LCO impairment in the Interstitial Lung Disease group. Our study shows the impact of a possible future application of these new reference values on the diagnostic criteria for several lung diseases and on the definition of their severity.

Supporting information

S1 Fig. Mathematical modelling of theorical D_LCO as a function of ECSC-93 and GLI-2017 z-scores and height in a 30 years old a) man and b) woman.

D_LCO: Diffusing capacity of the lung for carbon monoxide; ECSC: European Community for Steel and Coal 1993 reference values [2,4]; GLI: Global Lung function Initiative 2017 reference values [6].

(PDF)

Click here for additional data file.^{(370.7KB, pdf)}

S1 Appendix. Quality control of the disease group classification.

Contains: S1 Table. Sample sizes, number of classification errors in the random sample and estimated classification error rate on the population of the study according to the ISO 2859–1 standard [24]. ILD: interstitial lung disease. Data are presented as n or %. §Classification error rate estimated for the overall population of the study in each disease group according to the ISO 2859–1 standard [24].

(PDF)

Click here for additional data file.^{(83.3KB, pdf)}

Acknowledgments

The authors thank all of the staff of the Pulmonary Functional Tests Department for their help in this work.

Data Availability

Please note that we cannot share the de-identified data set for legal reasons on the Research Ethics Board of the University Hospital of Lille demand. The data set includes sensitive medical information about included patients as medical history and PFT results. Sex, age, height and weight are also included in the data set, which can potentially allow the patients’ identification. Data requests may be sent to the Research Ethics Board of the University Hospital of Lille (contact: +33 3.20.44.41.65 / cppnordouestiv@univ-lille2.fr).

Funding Statement

The authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0245434.r001

Decision Letter 0

Davor Plavec

28 Aug 2020

PONE-D-20-24269

Application of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide to a large population

PLOS ONE

Dear Dr. HULO,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I would recommend the change of the title of the manuscript to: „Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set“

Please describe in detail how the used tests were evaluated for inclusion/exclusion into the study.

Add actual p-values to Table 1. You mentioned that “GLI-2012 produce significantly lower median z-scores for FEV1, FVC and FEV1/FVC 180 than ECSC, all groups combined, in both genders (table 2).” but no p-values were cited. Please include actual p-values in the Results. Also for Table 3 include actual p-values and refer them in the text where you state significant differences. Please do the same for Table 4.

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Kind regards,

Davor Plavec, MD, MSc, PhD, Prof.

Academic Editor

PLOS ONE

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Please describe in detail how the used tests were evaluated for inclusion/exclusion into the study.

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PLoS One. 2021 Jan 14;16(1):e0245434. doi: 10.1371/journal.pone.0245434.r002

Author response to Decision Letter 0

10 Oct 2020

EDITOR COMMENTS:

1) I would recommend the change of the title of the manuscript to: „Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set“

The title was changed from “Application of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide to a large population” to „Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set“

2) Please describe in detail how the used tests were evaluated for inclusion/exclusion into the study.

In order to describe in detail how the used tests were evaluated for inclusion/exclusion into the study, the following paragraph was added in “materiel and methods”, in the “study population” part:

“For each test, PFTs indices values and patient’s characteristics (sex, age, height, weight) are recorded in the laboratory database and a test report including patient’s medical history is created using Microsoft Access® which is also recorded in the laboratory database. For the tests’ inclusion, data from the PFT performed between November 15th 2012 and May 30th 2016, and including the indices mentioned above, were extracted to a Microsoft Excel® spreadsheet by the laboratory engineer. Then tests meeting exclusion criteria were excluded using the statistical software SAS® (version 9.4; Statistical Analysis System).”

3) Add actual p-values to Table 1. You mentioned that “GLI-2012 produce significantly lower median z-scores for FEV1, FVC and FEV1/FVC 180 than ECSC, all groups combined, in both genders (table 2).” but no p-values were cited. Please include actual p-values in the Results. Also for Table 3 include actual p-values and refer them in the text where you state significant differences. Please do the same for Table 4.

Actual p-values were added to Table 1, 3 and 4. Actual p-values were added in the Results. We set the limit to p < 0.0001.

Attachment

Submitted filename: Response to Reviewers.docx

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PLoS One. doi: 10.1371/journal.pone.0245434.r003

Decision Letter 1

Davor Plavec

10 Nov 2020

PONE-D-20-24269R1

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set

PLOS ONE

Dear Dr. HULO,

Please do the suggested minor revision by the reviewer or write a detailed rebuttal prior to publication.

Please submit your revised manuscript by Dec 25 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Davor Plavec, MD, MSc, PhD, Prof.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Please do the suggested minor revision by the reviewer or write a detailed rebuttal prior to publication.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: For my point of view there is inconsistency in the definition of the primary disease. Was it "patients with symptoms compatible with one of the diseases" or clinical diagnosis (confirmed or highly suspected diagnoses, established by the referring physician) or "diagnosis were checked from patient files in random samples of each groups"?

That should be better characterised and if the disease was not properly validated the groups should be named accordingly.

The 15% of normal lung function in the COPD group and 7% restriction without obstruction should be explained in the methods and addressed in the discussion.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

PLoS One. 2021 Jan 14;16(1):e0245434. doi: 10.1371/journal.pone.0245434.r004

Author response to Decision Letter 1

25 Nov 2020

EDITOR COMMENTS:

Please do the suggested minor revision by the reviewer or write a detailed rebuttal prior to publication.

Please find below our responses to the suggested minor revision by the reviewer.

REVIEWERS' COMMENTS:

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

In our study, we aimed not to verify the interest of measuring DLCO for specific pulmonary diseases but to assess the applicability of the GLI-2017 reference values for DLCO of adult subjects by comparing the GLI-2017 reference values to the ECSC-93 equations currently used in a large population set. The data in this study support our conclusions: the GLI-2017 reference values are more suitable to our population than the ECSC-93 equations and differences between the 2 equations sets depend on the severity of DLCO impairment in the Interstitial Lung Disease group.

For my point of view there is inconsistency in the definition of the primary disease. Was it "patients with symptoms compatible with one of the diseases" or clinical diagnosis (confirmed or highly suspected diagnoses, established by the referring physician) or "diagnosis were checked from patient files in random samples of each groups"? That should be better characterised and if the disease was not properly validated the groups should be named accordingly.

The diagnoses were confirmed or highly suspected, established by the referring physician (pulmonologist or internist) prescribing the PFT, and to ensure data quality, we checked the diagnoses from patient files in random samples of each groups.

This point was clarified in materials and methods (“In order to ensure data quality, diagnoses were checked from patient files in random samples of each groups”) and discussion (“This retrospective study uses confirmed or highly suspected diagnoses, established by the referring physician (pulmonologist or internist) prescribing the PFT, and recorded in the laboratory database. However, in order to ensure data quality, diagnoses were checked from patient files in random samples of each groups.”).

The 15% of normal lung function in the COPD group and 7% restriction without obstruction should be explained in the methods and addressed in the discussion.

The fact that there are 15% of normal lung function in the COPD group and 7% restriction without obstruction have been explained in materials and methods (“Selected PFTs could have been performed at any stage of the concerned disease, from initial evaluation to advanced stage”) and addressed in the discussion (“We included tests performed at every stage of the diseases, which can be very early, explaining why some PFTs from patients with COPD are classified as normal (16.5% in women and 15% in men). On the other hand, some are classified as restrictive without obstruction (3.1% in women and 6.8% in men with COPD). This can append in case of an early stage COPD evaluation in a patient with a concomitant disease which has not been clinically detected by the prescribing physician.”)

It is also worth noticing that we aimed not to verify the interest of measuring DLCO for specific pulmonary diseases but to assess the applicability of the GLI-2017 reference values for DLCO of adult subjects.

Hoping this revised version of our work will meet with your approval,

Sincerely yours,

Pierre-Marie WARDYN, MD, Virginie de BROUCKER, MD, Cécile CHENIVESSE, MD, PhD, Annie SOBASZEK, MD, PhD, Richard VAN BULCK, Thierry PEREZ, MD, Jean-Louis EDME, PhD, Sébastien HULO, MD, PhD.

Attachment

Submitted filename: Response to Reviewers def.docx

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PLoS One. doi: 10.1371/journal.pone.0245434.r005

Decision Letter 2

Davor Plavec

21 Dec 2020

PONE-D-20-24269R2

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set

PLOS ONE

Dear Dr. HULO,

Please resolve the issue raised by the reviewer.

Please submit your revised manuscript by Feb 04 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Davor Plavec, MD, MSc, PhD, Prof.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Dear Authors,

please resolve the issue raised by the reviewer.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: This is the explanation of my decision and what I believe should be corrected:

Your explanation: “The fact that there are 15% of normal lung function in the COPD group and 7%

restriction without obstruction have been explained in materials and methods

(“Selected PFTs could have been performed at any stage of the concerned disease,

from initial evaluation to advanced stage”) and addressed in the discussion (“We

included tests performed at every stage of the diseases, which can be very early,

explaining why some PFTs from patients with COPD are classified as normal (16.5% in

women and 15% in men). On the other hand, some are classified as restrictive without

obstruction (3.1% in women and 6.8% in men with COPD).”

GOLD 2021: The FEV1/FVC<0,70 is required for the diagnosis of CPOD, normal lung function or restriction without obstruction are ruling out COPD as diagnosis. Your explanation is not in accordance with actual guidelines. It does not matter whether it is important to the whole article, but this group can not be declared as COPD patients.

Study population

We selected data of a control group and patients with symptoms compatible with one of four diseases* (asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and interstitial lung diseases (ILD))

*not with the diagnosed disease!

Groups creation

Selected PFTs came from 4 groups of patients with symptoms compatible* with one of the following diseases: asthma, COPD, cystic fibrosis, and ILD.

*not with the diagnosed disease!

Discussion

We have included PFTs from patients with one defined disease* (asthma, COPD, cystic fibrosis or ILD).

*now we have a defined disease?

This retrospective study uses confirmed or highly suspected diagnoses*, established by the referring physician (pulmonologist or internist) prescribing the PFT.

*Here we have confirmed or highly suspected disease!

We included tests performed at every stage of the diseases, which can be very early, explaining why some PFTs from patients with COPD are classified as normal* (16.5% in women and 15% in men).

*According to actual guidelines, there is no early COPD with normal lung function or please add a reference for that

On the other hand, some are classified as restrictive without obstruction (3.1% in women and 6.8% in men with COPD). This can append* in case of an early-stage COPD** evaluation in a patient with a concomitant disease which has not been clinically detected by the prescribing physician.

*append, maybe happened?

**please correct or reference

Dear colleagues,

I value your work and believe that it is worth of publishing but not with the wrong definition of the COPD. I would suggest you correct the problems I have note with the asterisks. I see two solutions: to rename the COPD group or to exclude the patients without obstruction from the statistical analyze of COPD group.

Best regards

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Attachment

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Click here for additional data file.^{(271KB, docx)}

PLoS One. 2021 Jan 14;16(1):e0245434. doi: 10.1371/journal.pone.0245434.r006

Author response to Decision Letter 2

30 Dec 2020

Dear Editor,

Please find below the responses to each point raised during the reviewing process of our manuscript entitled “Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set” (authors: P.-M. WARDYN, V. de BROUCKER, C. CHENIVESSE, A. SOBASZEK, R. VAN BULCK, T. PEREZ, J.-L. EDME, S. HULO):

EDITOR COMMENTS:

Please resolve the issue raised by the reviewer.

Please find below the solution we proposed in order to resolve the issue raised by the reviewer.

REVIEWERS' COMMENTS:

We would like to thank the reviewer for his interest in our work.

This is the explanation of my decision and what I believe should be corrected:

Your explanation: “The fact that there are 15% of normal lung function in the COPD group and 7% restriction without obstruction have been explained in materials and methods (“Selected PFTs could have been performed at any stage of the concerned disease, from initial evaluation to advanced stage”) and addressed in the discussion (“We included tests performed at every stage of the diseases, which can be very early, explaining why some PFTs from patients with COPD are classified as normal (16.5% in women and 15% in men). On the other hand, some are classified as restrictive without obstruction (3.1% in women and 6.8% in men with COPD).”

In order to clarify our definition of our “COPD group” and to be in accordance with the GOLD 2021, we opted for your second proposition mentioned below: we replaced the name of the "COPD" group with the term "chronic bronchitis". We included the following sentence in the methods in the “group creation” part: “The chronic bronchitis group included patients with symptoms compatible with chronic bronchitis (with a FEV1/FVC ratio ≥ 0.7) or with chronic obstructive pulmonary disease (COPD) (with a FEV1/FVC ratio < 0.7 according to the GOLD 2021 report[1])”.

Study population

*not with the diagnosed disease!

We harmonized the text with the formulation “patients with symptoms compatible with […]” and replaced COPD by chronic bronchitis, and so, we modified the sentence as follow: “We selected data of a control group and patients with symptoms compatible with with one of four diseases* (asthma, chronic bronchitis, cystic fibrosis, and interstitial lung diseases (ILD))”.

Groups creation

Selected PFTs came from 4 groups of patients with symptoms compatible* with one of the following diseases: asthma, COPD, cystic fibrosis, and ILD.

*not with the diagnosed disease!

We harmonized the text with the formulation “patients with symptoms compatible with […]” and replaced COPD by chronic bronchitis, and so, we modified the sentence as follow: “Selected PFTs came from 4 groups of patients with symptoms compatible with one of the following diseases: asthma, chronic bronchitis, cystic fibrosis, and ILD.”

Discussion

We have included PFTs from patients with one defined disease* (asthma, COPD, cystic fibrosis or ILD).

*now we have a defined disease?

We modified the formulation by “patients with symptoms compatible with one of four diseases (asthma, chronic bronchitis, cystic fibrosis or ILD)” in order to harmonize the text of the discussion section with the methods section mentioned above.

This retrospective study uses confirmed or highly suspected diagnoses*, established by the referring physician (pulmonologist or internist) prescribing the PFT.

*Here we have confirmed or highly suspected disease!

We modified the formulation by “This retrospective study uses highly suspected diagnoses […]”.

We included tests performed at every stage of the diseases, which can be very early, explaining why some PFTs from patients with COPD are classified as normal* (16.5% in women and 15% in men).

*There is no early COPD with normal lung function or add a reference

The sentence was modified by “Some PFTs from the chronic bronchitis group are classified as normal (16.5% in women and 15% in men). There are 2 main reasons. First, we included tests performed at every stage of the diseases, including patients with mild symptoms of chronic bronchitis without obstruction. Secondly, we used z-score to define obstruction according to the 2005-ATS/ERS recommendations for lung function test interpretation[2] (z-score of FEV1/FVC ratio < -1.645 and TLC z-score ≥ -1.645). Using the GOLD 2021 definition for COPD (FEV1/FVC < 0.7)[1] could have led us to classify fewer PFTs as normal in the chronic bronchitis group in our sample due to the fact that a FEV1/FVC ratio < 0.7 can be associated with a z-score of the FEV1/FVC ratio > -1.645”.

*append, maybe happened?

This typing error was corrected.

**please correct or reference

The sentence was changed to “On the other hand, some PFTs in the chronic bronchitis group were classified as restrictive without obstruction (3.1% in women and 6.8% in men with chronic bronchitis). This may happen in case of chronic bronchitis evaluation in a patient with a concomitant disease which has not been clinically detected by the prescribing physician”.

As mentioned above, we renamed the COPD group as the chronic bronchitis group.

Hoping this revised version of our work will meet with your approval,

Sincerely yours,

Pierre-Marie WARDYN, MD, Virginie de BROUCKER, MD, Cécile CHENIVESSE, MD, PhD, Annie SOBASZEK, MD, PhD, Richard VAN BULCK, Thierry PEREZ, MD, Jean-Louis EDME, PhD, Sébastien HULO, MD, PhD.

REFERENCES

1. Global initiative for chronic obstructive lung disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2021 report). 2020. Available: https://goldcopd.org/2021-gold-reports/

2. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. European Respiratory Journal. 2005;26: 948–968. doi:10.1183/09031936.05.00035205

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PLoS One. doi: 10.1371/journal.pone.0245434.r007

Decision Letter 3

Davor Plavec

4 Jan 2021

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set

PONE-D-20-24269R3

Dear Dr. HULO,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Davor Plavec, MD, MSc, PhD, Prof.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

After the last revision the reviewer suggested accepting your manuscript.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

PLoS One. doi: 10.1371/journal.pone.0245434.r008

Acceptance letter

Davor Plavec

5 Jan 2021

PONE-D-20-24269R3

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set

Dear Dr. HULO:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Davor Plavec

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Mathematical modelling of theorical D_LCO as a function of ECSC-93 and GLI-2017 z-scores and height in a 30 years old a) man and b) woman.

D_LCO: Diffusing capacity of the lung for carbon monoxide; ECSC: European Community for Steel and Coal 1993 reference values [2,4]; GLI: Global Lung function Initiative 2017 reference values [6].

(PDF)

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S1 Appendix. Quality control of the disease group classification.

(PDF)

Click here for additional data file.^{(83.3KB, pdf)}

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Data Availability Statement

[pone.0245434.ref001] 1.Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017;49: 1600016 10.1183/13993003.00016-2016 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Assessing the applicability of the new Global Lung Function Initiative reference values for the diffusing capacity of the lung for carbon monoxide in a large population set

Pierre-Marie Wardyn

Virginie de Broucker

Cécile Chenivesse

Annie Sobaszek

Richard Van Bulck

Thierry Perez

Jean-Louis Edmé

Sébastien Hulo

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials and methods

Study population

PFT measurements and results reports

Groups creation

Statistical analysis

Results

Fig 1. Study flow-chart.

Table 1. Characteristics of the population by sex.

Table 2. Z-scores of FVC, FEV1, FEV1/FVC and TLC according to ECSC-93 and GLI-2012 (except for TLC) by sex.

Table 3. Measured values, z-scores and %predicted for DLCO, VA and KCO according to ECSC-93 and GLI-2017 by sex.

Table 4. Number of tests and prevalence rates for DLCO, VA and KCO impairment according to ECSC-93 and GLI-2017, by sex.

Fig 2. Box-plots of DLCO ECSC-93 and GLI-2017 z-scores by degree of decrease in DLCO according to ATS/ERS-2005 in (A) men and (B) women with ILD.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Davor Plavec

Roles

Author response to Decision Letter 0

Decision Letter 1

Davor Plavec

Roles

Author response to Decision Letter 1

Decision Letter 2

Davor Plavec

Roles

Author response to Decision Letter 2

Decision Letter 3

Davor Plavec

Roles

Acceptance letter

Davor Plavec

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table 2. Z-scores of FVC, FEV₁, FEV₁/FVC and TLC according to ECSC-93 and GLI-2012 (except for TLC) by sex.

Table 3. Measured values, z-scores and %predicted for D_LCO, V_A and K_CO according to ECSC-93 and GLI-2017 by sex.

Table 4. Number of tests and prevalence rates for D_LCO, V_A and K_CO impairment according to ECSC-93 and GLI-2017, by sex.

Fig 2. Box-plots of D_LCO ECSC-93 and GLI-2017 z-scores by degree of decrease in D_LCO according to ATS/ERS-2005 in (A) men and (B) women with ILD.