

Journal of the New Zealand Medical Association, 27October2006, Vol 119 No 1244 

Complete reference ranges for pulmonary function
tests from a single New Zealand population
Suzanne Marsh, Sarah Aldington, Mathew Williams, Mark
Weatherall, Philippa Shirtcliffe, Amanda McNaughton, Alison Pritchard,
Richard Beasley
Reference ranges for pulmonary function tests are a
prerequisite for the accurate interpretation of
results.1 They are also important in a wide
range of respiratory disorders in which guidelines concerning diagnosis,
assessment of severity and management rely on lung function measurements
expressed in relation to reference values.2,3
The combined American Thoracic Society (ATS) and European Respiratory Society
(ERS) guidelines encourage regular review of reference equations suggesting 10
years as an appropriate equation lifespan.4
Reference equations should be derived from study populations
closely anthropomorphically and ethnically matched to the populations in whom
they are used.4 This implies it would be
beneficial to use reference equations derived from the same study population for
all parameters. However, few authors have supplied such
data,5–8 and although numerous equations
have been produced for spirometry, fewer are available for static lung volumes
and gas transfer.4 The most recently derived
reference equations from a New Zealand population were produced over 25 years
ago.9
The widely used equations of the European Community for
Steel and Coal (ECSC), first published in
198310 and adopted by the ERS in
1993,11,12 provide a single source of reference
ranges for many commonly measured respiratory parameters. These equations have
frequently been used in studies of respiratory
function13,14 including the European Community
Respiratory Health Survey (ECRHS) in which New Zealand played a significant
part.15 However, although these equations are
presented as a single source, they are composite equations derived from many
separate studies conducted in different
populations.10
Although validated at the time of their original
publication,11 more recent data suggests that
at least some of these equations, particularly for spirometry, are now out of
date in European populations.16,17 In addition,
ECSC reference ranges are not available for newer parameters such as the forced
expiratory volume in 6 seconds (FEV6), which may
become increasingly used as a substitute for FVC in the detection of airflow
obstruction.18,19
To address these issues, we obtained a complete set of
pulmonary function tests from a single population of nonsmoking New Zealand
adults of European origin, free from respiratory disease and symptoms. Reference
equations were derived, using linear regression techniques, for all commonly
measured respiratory function parameters. Pulmonary function measurements were
compared to those predicted by both the ECSC/ERS
equations10–12 and more recently
published equations for static lung
volumes.8
MethodsStudy
participants—Study participants, forming part of the
Wellington Respiratory Survey (WRS), were recruited using a postal questionnaire
sent to 3500 individuals, aged 25 to 75 years, randomly selected from the
electoral register. Subjects returning completed surveys were invited to
undertake a more detailed, intervieweradministered, questionnaire followed by
pulmonary function tests.
To increase the number of normal participants, healthy
subjects were also recruited from a concurrent study investigating the pulmonary
effects of marijuana smoking. This represented a convenience sample of adults
aged between 18 and 70 years, recruited through newspaper and radio
advertisements and informal contacts.
Normal subjects from both studies were defined using
ATS guidelines,20 and for this study, were
required to selfidentify as “New Zealand European”, and be never
smokers with no diagnosis of respiratory disease, no recent respiratory
symptoms, and no use of inhaled medication (Table 1).
Both studies were approved by Wellington Ethics
Committee, and written informed consent was obtained from each subject.
Pulmonary function
testing—Pulmonary function tests undertaken as part of the WRS
have been described in detail.21 In brief,
tests were carried out by one of three trained operators (SA, SM, MVW) at one
site using two Jaegar Master Screen Body volume constant plethysmography units
with pneumotachograph and diffusion unit (Masterlab 4.5 and 4.6 ErichJaegar,
Wurzberg, Germany). Prior to testing, equipment was calibrated daily in
accordance with ERS and ATS
guidelines.22–24
Subjects were not tested within 3 weeks of an upper or
lower respiratory tract infection (cough, sputum production, sore throat, or
nasal congestion). Subjects were weighed (wearing indoor clothing without shoes)
to the nearest kg and height was measured, without shoes, using a vertical
backboard, to the nearest 0.5 cm. Subjects greater than 125 kg were excluded due
to simultaneous involvement in a study involving CT scanning in which a weight
limit was determined by the limits of scanner equipment.
Airway resistance, static lung volumes, and slow
spirometric measurements were made prior to forced manoeuvres and gas transfer
measurements followed these. A nose clip was worn for all tests.
Airway resistance was measured during relaxed breathing
at a rate of approximately 0.5 Hz. Following attainment of a stable baseline,
thoracic gas volume representing functional residual capacity (FRC) was
calculated using plethysmography. The subject was then instructed to breath out
comfortably, maximally inspire, and expire slowly to measure slow vital capacity
(SVC).
Expiratory reserve volume (ERV) was measured from FRC
to the point of maximum expiration. Inspiratory capacity (IC) was calculated
from SVC – ERV and residual volume (RV) was calculated from FRC–ERV.
The total lung capacity (TLC) was calculated as SVC (measured) + RV.
FRC and airway resistance measurements were used to
calculate specific airway resistance (sRaw) and conductance (sGaw).
Spirometry measurements were carried out in accordance
with ATS criteria.22 The largest
FEV1 and FVC from a minimum of three acceptable
manoeuvres were used with all other flow volume parameters taken from the
manoeuvre with the largest combination of FEV1
and FVC.
FEV6 and
FEV1/FEV6
measurements were obtained by analysis of stored data.
Gas transfer was measured in accordance with ATS
criteria,24 and a minimum of three measurements
of diffusion capacity (DLCO) were made with
5minute intervals. The average DLCO of tests
meeting recommended reproducibility criteria were
reported.24
Alveolar volume (VA) was simultaneously measured, using
helium as a tracer gas, and used to calculate carbon monoxide diffusing capacity
per unit of alveolar volume (DLCO/VA).
A blood sample was taken to adjust results for
haemoglobin concentration using the formula recommended by the
ATS.24 Results for pulmonary function tests
except those measuring gas transfer were corrected to BTPS units.
Table 1. Selection criteria for the normal
population
†CB: Chronic bronchitis, E: Emphysema, A: Asthma,
COPD: Chronic Obstructive Pulmonary Disease, B: Bronchiectasis; *Production of
sputum on most days for as much as three months each year; ¶Cough on most
days for as much as three months each year; # Did not selfidentify as New
Zealand European.
Statistical analysis—Reference
equations were developed by linear regression. Sex was included as an
explanatory variable in each model and for each lung function a further group of
candidate explanatory variables was explored; height,
height2, age,
age2, weight, and body mass index
(BMI)—plus interaction terms between sex and age and sex and height. The
best regression equation for each parameter was developed with regard to the
amount of variability explained, the number of explanatory variables, and
consistency between parameters measuring similar physiological aspects of lung
function.
Rsquared and Mallow’s Cp were used to examine
different predictor equations. Mallow’s Cp adjusts Rsquared by a penalty
term that takes account of the number of predictors in an
equation.25 Normality assumptions were tested
by examination of the distribution of residuals from the regression equations,
by histograms, QQplots, and formal tests of normality of the
residuals.25
Agreement between the newly developed equations and the
ECSC/ERS [known henceforth as European]
equations10–12 was by plots of the
difference between the actual value of a particular lung function minus its
predicted value using each equation (difference plots).
If height or age were important predictors of bias
(actual value minus predicted value) then the estimates of it were calculated at
the mean age or height. Bias between measured and predicted values was also
examined for the static lung volume equations produced by Roca et
al.8
SAS (version 8.2) software was used for all statistical
analyses.
ResultsInitial recruitment from the WRS study resulted in 2319
responses from 3500 screening questionnaires. Of these subjects, 758 completed
the detailed questionnaire and pulmonary function tests. The secondary
recruitment resulted in 267 subjects completing the detailed questionnaire and
pulmonary function testing thus giving a total population group of 1025
subjects.
Exclusion of subjects with previous smoking; diagnosis of a
respiratory disorder; symptoms suggestive of COPD, asthma, or bronchiectasis;
recent inhaler use; and those who did not selfidentify as New Zealand European
resulted in 212 subjects in the reference population (Table 1).
The final normal cohort consisted of 180 subjects from the
WRS study and 32 from the secondary recruitment. Subject characteristics are
shown in Table 2.
Table 2. Subject characteristics
Table 3 shows the lung function reference equations derived
from the WRS data. Different intercept terms were created for males and females
except for the equations for FEV1/FVC,
FEV1/FEV6, FRC,
and DLCO/VA in which no significant sex effect
was noted. The values for sRaw and sGaw are presented as single expected values
for males and females since sex was the only important predictor in this model.
The Rsquared (R2) values
represent the percentage of explained variance in each measurement accounted for
by the equation.
Table 3. Wellington Respiratory Survey (WRS)
prediction equations for lung function
Prediction equations take the form:
Abbreviations:
FEVn: Forced expiratory volume in n seconds (L);
FVC: Forced vital capacity (L); PEF: Peak expiratory flow (L
min1); MMEF: Maximal mid expiratory flow (L
min1); FEFn: Forced expiratory flow rate when
n% of FVC expired (L min1). sGaw: Airway
conductance
(s1·kPa1);
sRaw: Airway resistance (kPa·s); SVC: Slow vital capacity (L); IC:
Inspiratory capacity (L); FRC: Functional residual capacity (L); TLC: Total lung
capacity (L); RV: Residual volume (L); ERV: Expiratory reserve volume (L);
DLCO: Gas transfer (mmol/min/kPa); VA: Alveolar
volume (L).
Most lung function parameters met normality assumptions and
did not require transformation. A natural logarithmic transformation appeared to
give a better statistical model for PEF (which did not meet normality
assumptions) suggesting that the relationship between age, sex, and height was
multiplicative for this variable.
Results for maximal mid expiratory flow (MMEF or
FEF2575), sRaw, and sGaw did not meet normality
assumptions as well as other lung function measurements but were not improved
with logarithmic or other transformations.
The majority of the equations use sex, height, and age as
explanatory variables. Residual plots did not suggest that the addition of
squared or higher power terms to model curvature improved the fit of any of the
equations.
In univariate analyses of the individual variables, weight
accounted for a moderate amount of explained variance (data not shown) but was
probably acting as a substitute for body size, since, in the multivariate
analysis, addition of weight added little to the predictive value of the
equations. The only exception to this was for
FEV1/FEV6 where
weight had a weak effect in the multivariate analysis. Adding BMI was of
marginal statistical significance and did not substantially improve the model
fit for any equation. The addition of sex by age or height interaction terms was
not helpful in developing better prediction equations.
A standard method of calculating normal limits for measured
parameters in individual subjects is to add or subtract 1.645 × the root
mean square error (RMSE) of the equation from the predicted
value17,20,26 and these values are given in the
final columns of Table 3.
Comparisons of the WRS equations with the European
equations10–12 for
FEV1, TLC, RV, and DLCO
are shown as difference plots in Figure 1. Table 4
shows a summary of mean bias (measured minus predicted values) by sex.
Predicted values for spirometry using the European
equations10,11 were significantly lower than
measured values particularly for FEV1 (mean bias,
male 0.48 L; female 0.36 L) and FVC (mean bias male and female 0.77 L). In many
of the spirometry variables, the difference was greater than 12% of the mean
lung measurements of the cohort (Table 4). For
FEV1, bias was
weakly dependent on age decreasing by 0.05 L per decade.
For lung volumes large differences were seen between
measured and predicted values using the European
equations10,11 (Figure 1, Table 4). The
greatest consistent difference, of around 15% of the mean predicted measurement,
was seen in TLC with a mean bias (measured minus predicted value) of 1.14 L for
males, 0.89 L for females. Bias was height dependent, being greater in taller
subjects (increase in bias (L) per 10 cm increase in height: SVC 0.084, TLC
0.22, FRC 0.23, RV 0.12). The bias for RV was also weakly dependent on age
(increased bias of 0.05 L per decade). Measured lung volumes were also compared
to those predicted by the equations of Roca et
al8 derived using measurements obtained with a
plethysmographic technique (Table 5). The bias in these predicted values was
significantly less than that seen with the European
equations.10,11
Table 4. Comparison between measured values of
WRS study and predicted values using the equations of the ECSC/ERS
The columns show the estimated bias (measured minus
predicted value) for each parameter when the equations of the ECSC are compared
to measured values obtained in the WRS study. Results are shown as mean
difference in measured units and as a percentage of the mean measurement for all
male and female subjects in the cohort. A positive figure means that the
measured value was greater than the predicted value (underprediction) and a
negative value that the measured value was less than the predicted value
(overprediction).
Abbreviations:
*The 1983 10
and 1993 11 publications of the formulae for
DLCO/VA (also known as
KCO) are different giving different values for
the mean bias depending on which equation is used.
Table 5: Comparison between measured values of
WRS study and predicted values using the equations of Roca et
al8
See Tables 3 and 4 for abbreviations and explanation of
terminology
Measured results for gas transfer variables show close
agreement with those predicted by European
equations,10,12 with the only exception being
the results for DLCO/VA using the 1983 ECSC
formulae.10
The difference plots (Figure 1) show that the variability
and spread of the differences between actual and predicted values are similar
for both the European equations10–12 and
those of the WRS. This suggests that the precision of the equations, reflecting
the variability of the sample with respect to predicted values, was similar
whichever equation was used.
DiscussionThis study provides reference equations for all commonly
used measurements of static and dynamic lung function and new reference values
for specific resistance and conductance from a single adult New Zealand
population of European origin. In addition, we have produced reference equations
for FEV6 and
FEV1/FEV6. To the
best of our knowledge, this is the first time that reference equations have been
derived for this complete set of respiratory function measurements on the same
well characterised Caucasian reference population.
Methodological issues—A number of
methodological issues relevant to the reporting of these results were
identified. Whilst this sample size of 212 subjects was adequate for validation
of preexisting equations,4 it is smaller than
that used to derive reference equations in several recently published
studies.8,26,27 However other published
reference equations dealing with a wide range of testing modalities were
obtained using a similar sample size.5
Subjects who did not selfidentify as “New Zealand
European” were excluded since a low response rate resulted in this group
representing less than 7% of those completing testing despite approximately 20%
of the local population being nonEuropean in
origin.28 The priority will now be to develop
comparable reference equations for Maori and Pacific Island people.
The age range of the participants in this study also has
implications for the clinical use of the reference equations, being restricted
to adult subjects aged 25–75 years. Our equations incorporated sex and
standard variables such as age and height. We found that use of polynomial
expressions did not improve the fit of our equations.
Although other studies have produced equations incorporating
such terms,17,29,30 we have taken a pragmatic
approach under the simple assumptions of linear relationships, when they exist,
in an attempt not to ‘over fit’ the data. This should make our
equations more likely to be appropriate in other populations similar to our own.
Sex is a major determinant of lung
function,20 although it is not typically
included as an explanatory variable in reference equations. We decided a
priori to include this variable since inclusion of a factor accounting for
such significant variation in pulmonary function should improve the explained
variance of resultant equations.
In addition, analysis of data separately by sex implicitly
states that males and females have a different estimate of variation.
Incorporating sex as a variable also results in smaller standard errors, since
the sample size is that for both groups combined. Despite postulating that the
inclusion of sex might require age/sex or height/sex interaction terms to be
included, the addition of these added little to the fit of any individual
model.
A further methodological issue relates to the technique used
for measuring static lung volumes. Whilst the most recent ERS/ATS guidelines on
measurement of lung volumes by body
plethysmography31 recommend a
‘panting’ technique, this method was not available using our
equipment at the start of the study (Masterlab 4.5 ErichJaegar, Wurzberg,
Germany). However in a comparison of the two techniques, Roca et
al8 found no significant difference in results
for FRC obtained using either panting or tidal breathing methods.
Spirometry and static lung volumes—In
keeping with a previous study incorporating sex into a single
equation,32 our equations for
FEV1 and FVC had high values for
R2 with 80% of population variability being
explained by the equation. This compares favourably with typical
R2 values for spirometric data of the order of
16–85%.17,26,29 Lower values for
R2 are often seen for static lung
volumes33—but using our equations,
similarly high values of explained variance were seen for TLC and SVC.
R2 values higher than previously reported using
plethysmography 8 were also found for other
static lung volumes.
At the time of their original publication, the reference
equations for the ECSC10 represented a major
effort in standardisation of pulmonary function
testing.16 However, our findings that measured
FEV1 values were on average 0.36 L (female) and
0.48 L (male) higher than those predicted by the ECSC equations, with FVC values
showing an even greater discrepancy, suggest that the spirometry equations from
this source can no longer be considered suitable for contemporary use in New
Zealand.
These results are consistent with previous European and
Australian findings16,17,30 and are not
unexpected since the ECSC equations were compiled from a series of studies
conducted between 1954–1980. The under prediction seen with these
equations is likely to be due to both anthropomorphic population changes as well
as changes in and standardisation of lung function
measurement.17
Whilst the equations of
NHANES26 have recently been shown to be
suitable for use for spirometry in New
Zealand34 these do not extend to cover the
measurement of static lung volumes or gas transfer. Indeed, fewer reference
equations are available for static lung volumes than for
spirometry.4
We found that the European
equations,10,11 which were mostly derived from
studies using gas dilution methods, underpredicted measured values for FRC and
TLC in our cohort.
In contrast, a direct comparison between our equations and
those of Roca et al8 showed much smaller
differences  these equations were also produced using a plethysmographic
technique. As a result, it is likely that the differences between the European
and WRS equations for static lung volumes can be attributed to both measurement
techniques and historical anthropomorphic changes. This means that that the
European equations are probably no longer suitable for predicting static lung
volumes in contemporary New Zealand subjects of European origin, particularly
since in New Zealand such measurements are typically made using
plethysmography.
Newer spirometric
variables—The measurement of
FEV6 has recently been recognised as an important
addition in the spirometric assessment of airflow
obstruction18,19 and, with
FEV1/FEV6,35
offers particular advantages in screening for and assessment of COPD.
Since these are ‘new’ parameters, fewer
reference equations are available for their
prediction.26,29 Our results provide further
reference values applicable across a wide age range.
Gas transfer—Traditionally it has
been recognised that measurement of DLCO between
different laboratories is subject to wide
variation.24 The results for
DLCO from our cohort show good agreement with the
predicted values derived using the European equations of the
ECSC/ERS.10,12 The explained variance of 71%
for our new equation for DLCO was significantly
higher than that reported in other
studies36–38 possibly due to the
incorporation of sex into the prediction equation.
SummaryWe have presented a complete set of reference equations for
a comprehensive range of lung function measurements suitable for use in an adult
New Zealand population of European origin.
The development of comparable reference equations for Maori
and Pacific Island people is a priority.
Author information: Suzanne Marsh, Medical
Research Fellow, Medical Research Institute of New Zealand (MRINZ); Sarah
Aldington, Medical Research Fellow, MRINZ; Mathew Williams, Respiratory
Scientist, MRINZ; Mark Weatherall, Medical Consultant and Biostatistician,
Wellington School of Medicine and Health Sciences; Philippa Shirtcliffe; COPD
Programme Director, MRINZ; Amanda McNaughton, Senior Research Fellow, MRINZ;
Alison Pritchard; IT Manager, MRINZ; Richard Beasley, Director, MRINZ;
Wellington
Acknowledgements: This study was supported
by a research grant from GlaxoSmithKline. We thank Joan Soriano and Harvey
Coxson for their helpful comments in the design of the WRS study and
interpretation of the results; P Sherwood Burge for his comments on the
manuscript; Denise Fabian for her help with the Wellington Respiratory Health
Survey and in producing the manuscript; and Avrille Holt, Patricia Heuser, and
Eleanore Chambers for their help in conducting the questionnaires.
Correspondence: Richard Beasley, Medical
Research Institute of New Zealand, PO Box 10055, Wellington. Fax: (04) 472 9224;
email: Richard.Beasley@mrinz.ac.nz
References:
This article was corrected on 18 May 2007 to
reflect the Erratum at http://www.nzma.org.nz/journal/1201254/2551


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