Which reference equation should we use for interpreting spirometry values for First Nations Australians? A cross‐sectional study

To evaluate the suitability of the Global Lung Function Initiative (GLI)‐2012 other/mixed and GLI‐2022 global reference equations for evaluating the respiratory capacity of First Nations Australians.


S
pirometry, a widely used lung function test, is recommended when assessing the respiratory system for the diagnosis and monitoring of airway obstruction. 1 Interpreting spirometry findings requires appropriate reference values.Age, height, sex, and ethnic background influence spirometry values, and are therefore taken into account by the Global Lung Function Initiative (GLI)-2012 2 reference equations, the most widely used and recommended in Australian 3 and overseas guidelines. 4quations for four ethnic groups are defined (Caucasian, North East Asian, South East Asian, African American); a fifth equation, for "other/mixed", is used for people who are of mixed ethnic background or do not fit one of the other four categories. 2 The other/mixed equation is recommended when testing Aboriginal and Torres Strait Islander (First Nations) Australians. 3To overcome ethnic bias inherent to these reference equations, a new GLI reference equation (GLI-2022 global) was developed using a race-neutral approach. 5ven the high respiratory disease burden for First Nations Australians, 6,7 and the reliance on spirometry for diagnosing and monitoring chronic respiratory disease, it is important that reference values reflect the respiratory characteristics of healthy First Nations people.][10][11][12][13] Using reference spirometry equations based on these findings risks interpreting abnormal lung function as normal for First Nations Australians.
In an earlier study, we found that spirometry values for 930 healthy children and young adults, predominantly from rural and remote Queensland, were 7-8% lower than predicted by the GLI-2012 Caucasian equation, and that the GLI-2012 other/mixed reference equation provided a better overall fit. 14

Main outcome measures:
Goodness of fit to spirometry data for each GLI reference equation, based on mean Zscore and its standard deviation, and proportions of participants with respiratory parameter values within 1.64 Zscores of the mean value.
Results: Acceptable and repeatable forced expiratory volume in the first second (FEV 1 ) values were available for 2700 First Nations participants in the three trials; 1467 were classified as healthy and included in our analysis (1062 children, 405 adults).Their median age was 12 years (interquartile range, 9-19 years; range, 3-91 years), 768 (52%) were female, and 1013 were tested in rural or remote areas (69%).Acceptable and repeatable forced vital capacity (FVC) values were available for 1294 of the healthy participants (88%).The GLI-2012 other/mixed and GLI-2022 global equations provided good fits to the spirometry data; the race-neutral GLI-2022 global equation better accounted for the influence of ageing on FEV 1 and FVC, and of height on FVC.Using the GLI-2012 other/mixed reference equation and after adjusting for age, sex, and height, mean FEV 1 (estimated difference, -0.34; 95% confidence interval [CI], -0.46 to -0.22) and FVC Zscores (estimated difference, -0.45; 95% CI, -0.59 to -0.32) were lower for rural or remote than for urban participants, but their mean FEV 1 /FVC Zscore was higher (estimated difference, 0.14; 95% CI, 0.03-0.25).

Conclusion:
The normal spirometry values of healthy First Nations Australians may be substantially higher than previously reported.Until more spirometry data are available for people in urban areas, the race-neutral GLI-2022 global or the GLI-2012 other/mixed reference equations can be used when assessing the respiratory function of First Nations Australians.
The known: Spirometry, critical for diagnosing lung conditions, relies on reference equations that reflect normal values for the relevant population.No validated equations are available for First Nations Australians.
The new: Analysis of spirometry data for 1467 healthy First Nations children and adults indicated that the Global Lung Function Initiative (GLI)-2012 other/mixed and the race-neutral GLI-2022 global reference equations can be used to assess lung function in First Nations people.Mean spirometry values were poorer in rural and remote than in urban areas.
The implications: Until more data from urban areas are available, the race-neutral GLI-2022 global and GLI-2012 other/mixed reference equations are appropriate for assessing lung function in First Nations Australians.

Research
reside in rural or remote areas. 15Socio-economic factors influence lung function, 16,17 and comparisons of urban and rural and remote First Nations Australians have not been reported.
Underestimating normal spirometry values for First Nations Australians increases the risks of underdiagnosis and disease misclassification, and robust data from healthy First Nations people are needed to develop appropriate spirometry reference equations for this population.For our study, we combined previously collected data for First Nations children 14 with newly collected data for children and adults in urban and rural or remote locations across Australia.Our objectives were to determine whether the GLI-2012 other/mixed or GLI-2022 global reference equations are appropriate for assessing First Nations people at different ages, and whether spirometry values for rural or remote people differ from those of urban First Nations people.

Methods
We undertook a cross-sectional study of spirometry values for opportunistically recruited First Nations Australian children and adults from three prospective studies: • the Indigenous Respiratory Reference Values (IRRV) study 14 included First Nations children and young adults aged 3-25 years, recruited predominantly in childcare centres and schools in nine Queensland and Northern Territory communities during 18 March 2015 -24 November 2017; • the Healthy Indigenous Lung Function Testing in Adults (HILTA) study included First Nations adults (18 years or older) from six Queensland and Northern Territory, communities recruited during 14 August 2019 -15 December 2022, as well as adults who visited Indigenous respiratory outreach care clinics (a specialist respiratory outreach service in rural and remote Queensland) for free respiratory health checks; and • the Western Australian Many Healthy Lungs (MHL) study included First Nations children and adults (aged five years or older) from Perth, Broome, and the Kimberley recruited during 10 October 2018 -7 November 2021.

Participant recruitment and classification as healthy or not healthy
In each of the three studies, a testing stall or booth was set up in each community or at each testing event; all community members could ask questions and undergo testing.For IRRV recruitment in schools, information and consent forms were distributed to parents and carers, and signed consent forms returned prior to the testing days.Local radio stations and community networks promoted participation in the IRRV and HILTA studies; community networks and social media promoted the MHL study.
Participants were assigned to the "healthy" group if they met all inclusion criteria (Box 1), and otherwise to the "not healthy" group.They were classified as urban (Brisbane, Darwin, Perth, Caboolture, Townsville) or rural or remote residents (Dalby, Cherbourg, Bamaga, Woorabinda, Thursday Island, Broome, and four Aboriginal communities in the Kimberley) according to the testing location.Body mass index (BMI) criteria were applied to participants aged 30 years or older because obesity affects lung function; 18 as many participants were recruited at sporting events featuring young athletes with greater muscle mass, BMI criteria were not applied to people under 30 years of age.
Spirometry data were included in our analysis if they satisfied 2019 American Thoracic Society (ATS) and European Respiratory Society (ERS) criteria for acceptability and repeatability. 4,19

Statistical analysis
We summarise demographic characteristics as medians with interquartile ranges (IQRs).Z-scores (number of standard deviations [SDs] of values from the mean) and percentagepredicted spirometry test values were generated with the GLI-2012 Caucasian and other/mixed reference equations 2 and the GLI-2022 global reference equation 6 (Supporting Information, part 1), using a custom calculator.Mean Z-scores (with SDs) for male and female participants in each of three ethnic categories (Aboriginal, Torres Strait Islander, Aboriginal and Torres Strait Islander) were calculated.Mean Z-scores of zero (maximum of ±0.5), an SD of one, and about 90% of results falling within 1.64 SDs of the mean was deemed to indicate a good fit to the sample data. 14The GLI conversion software (GLI2012_DataConversion, version 1.3.4,build 4 20 ) was used to calculate L (skewness), S (variation), and M coefficients (predicted mean respiratory function value for a given combination of age and height, within the GLI-2012 bounds) for the healthy and not healthy groups.
We undertook multivariable ordinary least-squares linear regression analyses including age, sex, and height as explanatory variables to assess whether these factors were sufficiently taken into account by each reference equation (model A).In model B, remoteness (urban or rural/remote) was also included as a variable.Data were analysed in Stata 17; P < 0.05 (2-tailed) was deemed statistically significant.

Ethics approval and First Nations community approval
The

Research
values for the not healthy participants we excluded were 18-20% lower than predicted by the GLI-2012 Caucasian equation, a difference similar to previously reported putatively normative findings. 12,13Finally, we found that spirometry values for rural or remote First Nations people were lower than for urban participants, and that the difference increased with age.
As Z-scores generated with the GLI-2012 other/mixed and GLI-2022 global reference equations take into account the influence of age, sex, and height on spirometry values, we examined these associations in our sample of healthy First Nations Australians.We found that the age-related decline in FEV 1 and FVC values is overestimated in this population when using the GLI-2012 other/mixed equation; the influence of height on FEV 1 and FVC values was also overestimated by the GLI-2012 other/mixed equation, but not the race-neutral GLI-2022 global reference equation.We have previously reported that the body proportions of First Nations children are different to those of children who participated in the Third National Health and Nutrition Examination Survey; for example, sitting height comprises a smaller proportion of standing height. 213][24] Even if reference data are representative of healthy people, ethnic correction entails several other problems, including inadequate consideration of differences in socio-economic standing when surveying ethnic populations, which may normalise atypical results in disadvantaged groups.

Limitations
We did not analyse the impact of socio-economic determinants of respiratory function.The spirometry data we analysed were collected in urban and rural or remote communities in three states and territories, but the generalisability of our findings is limited by the unknown broader representativeness of our sample.

Conclusion
The development of the race-neutral GLI-2022 global reference equation is an important step toward reducing the influence of simplistic concepts of race and ethnicity. 5

4
Spirometry value distributions for healthy First Nations participants, by age* FEV 1 = forced expiratory volume in the first second; FVC = forced vital capacity.* Locally weighted smoothed curves; FEV 1 values are reported for 1467 healthy participants (768 female, 699 male participants), FVC and FEV 1 /FVC values for 1294 healthy participants (683 female, 611 male participants).◆ 5 Z-scores generated from spirometry value distributions for healthy First Nations participants, by age and GLI reference equation* FEV 1 = forced expiratory volume in the first second; FVC = forced vital capacity.* Locally weighted smoothed curves; FEV 1 values are reported for 1467 healthy participants (768 female, 699 male participants), FVC and FEV 1 /FVC values for 1294 healthy participants (683 female, 611 male participants).◆ While most Australians (including First Nations people) live in metropolitan areas, larger proportions of First Nations people than of other Australians

criteria for the healthy group in the three spirometery studies contributing data to our analysis Category Criteria
Acceptable and repeatable forced expiratory volume in the first second (FEV 1 ) values were available for 2700 First Nations participants in the three trials; 1062 of 1359 children under 18 years of age (78%) and 405 of 1341 adults (30%) with such values were classified as healthy (Box 2).Compared with the healthy group, the median age of participants classified as not healthy was higher (40 [IQR,19-55]v 12 [IQR, 9-19] years), and larger proportions were female participants (63% v 52%) or Aboriginal people (ie, no Torres Strait Islander background; 72% v 54%) (Box 3).Acceptable and repeatable forced vital capacity (FVC) values were available for 1294 of the 1467 healthy participants (88%) and 1185 of the 1233 participants classified as not healthy (96%).In almost all the cases in which FVC values were not acceptable or repeatable, participants did not meet the volume plateau criterion (≤ 0.025 L volume change in the final second of expiration 4 ).
human research ethics committees of Education Queensland (15/192648), Children's Health Queensland (HREC/14/ QRCH/111), Far North Queensland (Cairns and Hinterland Hospital and Health Service) (HREC/14/QCH/96-929), Darling Downs Health (HREC/15/QTDD/27), and the Menzies School of Health Research (HREC-2017-2833) approved the IRRV and HILTA studies.The Western Australian Aboriginal Health Ethics Committee (HREC707) and the Curtin University human research ethics committee (HR89/2016) approved the MHL study.Community Elders and First Nations leaders at all locations were consulted and approved the studies prior to commencement.1 Inclusion 1 , FVC, and FEV 1 /FVC values for healthy participants differed sex (Box 4).The distribution by age of Z-scores generated from these values indicated that the goodness of fit of each reference equation declined with age for both FEV 1 and FVC, but improved for FEV 1 /FVC (Box 5).Lung function Z-score density plots for the healthy and not healthy groups were better centred on zero for the GLI-2022 global equation than the GLI-2012 other/mixed equation (Supporting Information, figure2).for acceptability and repeatability.We found that the GLI-2012 Caucasian equation overestimated FEV 1 and FVC values by about 9% in healthy First Nations participants.The spirometry

2 Selection of participants for inclusion in our analysis, and their categorisation as healthy or not healthy
BMI = body mass index; FEV 1 = forced expiratory volume in the first second; FVC = forced vital capacity.* Among the 1212 HILTA participants initially included in our study were 56 of 570 people who had undergone respiratory health checks at outreach clinics.◆

3 Demographic characteristics and spirometry values (by GLI reference equation) for the 1467 healthy and 1233 not healthy First Nations participants*
Mean lung function values were lower for rural and remote than urban participants, indicating that social and environmental factors affect lung function; however, remoteness classification in our study was based on the location of testing and not of the participant's residence.
funded by the Queensland Health Aboriginal and Torres Strait Islander Health Branch and a Prince Charles Hospital Foundation (TPCHF) New Investigator grant (NI2017-34).The Healthy Indigenous Lung Testing in Adults study was funded by a TPCHF Innovation Grant (INN2018-24), Queensland Health Statewide Clinical Network project funding, the Northern Australia Tropical Disease Collaborative Research Programme (HOT NORTH Round 6), and a Thoracic Society of Australia and New Zealand Rob Pierce Grant-in-Aid for Indigenous Lung Health.Western Australian data collection was supported by a National Health and Medical Research Council (NHMRC) project grant (APP1104562), Curtin University, and sponsorship by Coles.Andrew Collaro is supported by an NHMRC Postgraduate Scholarship (APP2003334).Julie Marchant is supported by a Lung Foundation of Australia and NHMRC Centre for Research Excellence (AusBREATHE, GNT 1170958) fellowships.Anne Chang is supported by an NHMRC Senior Practitioner Fellowship (APP1154302) and several NHMRC grants, and has received fees (paid to her institution) for membership of an independent data monitoring committee evaluating an unlicensed vaccine (GSK) and a COVID-19 vaccine (Moderna) not related to this article.
population.The GLI-2012 other/mixed and GLI-2022 global reference equations each provided good fits to the spirometry data, but the GLI-2022 global equations better accounted for the influence of ageing on FEV 1 and FVC values, and of height on FVC.While the GLI-2012 other/mixed equation is acceptable for assessing First Nations Australians, we recommend the race-neutral GLI-2022 global reference equation, given the general shift from ethnicity-based corrections in other fields of medicine.Investigation of the influence of social factors on spirometry values are important next steps, as are the further collection of data from First Nations people in urban areas and evaluation of the performance of these reference equations in respiratory screening and diagnosis.We acknowledge the invaluable assistance of many health professionals and community members: in Queensland we thank Vera Assan (First Nations health practitioner, Cairns and Hinterland Hospital and Health Service), Allan Takken and Brian Peacock (Indigenous project officers, Indigenous Respiratory Outreach Care program; Metro North Hospital and Health Service), Leanne Rodwell and Loren Grant (Children's Health Queensland), Simon Smith, Malcolm McDonald, and Suzy Munns (James Cook University), Unngoorra Harbour, and Holly Marchant; in the Northern Territory we thank Lesley Versteegh (Aboriginal research nurse, Menzies School of Health Research) and Gabrielle McCallum (Menzies School of Health