Philip H. Quanjer

Multi-ethnic reference values for spirometry for the 3-95-yr age range: The global lung function 2012 equations

The aim of the Task Force was to derive continuous prediction equations and their lower limits of normal for spirometric indices, which are applicable globally. Over 160,000 data points from 72 centres in 33 countries were shared with the European Respiratory Society Global Lung Function Initiative. Eliminating data that could not be used (mostly missing ethnic group, some outliers) left 97,759 records of healthy nonsmokers (55.3% females) aged 2.5–95 yrs. Lung function data were collated and prediction equations derived using the LMS method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of a distribution family. After discarding 23,572 records, mostly because they could not be combined with other ethnic or geographic groups, reference equations were derived for healthy individuals aged 3–95 yrs for Caucasians (n=57,395), African–Americans (n=3,545), and North (n=4,992) and South East Asians (n=8,255). Forced expiratory value in 1 s (FEV1) and forced vital capacity (FVC) between ethnic groups differed proportionally from that in Caucasians, such that FEV1/FVC remained virtually independent of ethnic group. For individuals not represented by these four groups, or of mixed ethnic origins, a composite equation taken as the average of the above equations is provided to facilitate interpretation until a more appropriate solution is developed. Spirometric prediction equations for the 3–95-age range are now available that include appropriate age-dependent lower limits of normal. They can be applied globally to different ethnic groups. Additional data from the Indian subcontinent and Arabic, Polynesian and Latin American countries, as well as Africa will further improve these equations in the future.

Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction.

Aim: The prevalence of airway obstruction varies widely with the definition used. Objectives: To study differences in the prevalence of airway obstruction when applying four international guidelines to three population samples using four regression equations. Methods: We collected predicted values for forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) and its lower limit of normal (LLN) from the literature. FEV1/FVC from 40 646 adults (including 13 136 asymptomatic never smokers) aged 17–90+years were available from American, English and Dutch population based surveys. The prevalence of airway obstruction was determined by the LLN for FEV1/FVC, and by using the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society/European Respiratory Society (ATS/ERS) or British Thoracic Society (BTS) guidelines, initially in the healthy subgroup and then in the entire population. Results: The LLN for FEV1/FVC varied between prediction equations (57 available for men and 55 for women), and demonstrated marked negative age dependency. Median age at which the LLN fell below 0.70 in healthy subjects was 42 and 48 years in men and women, respectively. When applying the reference equations (Health Survey for England 1995–1996, National Health and Nutrition Examination Survey (NHANES) III, European Community for Coal and Steel (ECCS)/ERS and a Dutch population study) to the selected population samples, the prevalence of airway obstruction in healthy never smokers aged over 60 years varied for each guideline: 17–45% of men and 7–26% of women for GOLD; 0–18% of men and 0–16% of women for ATS/ERS; and 0–9% of men and 0–11% of women for BTS. GOLD guidelines caused false positive rates of up to 60% when applied to entire populations. Conclusions: Airway obstruction should be defined by FEV1/FVC and FEV1 being below the LLN using appropriate reference equations.

Diagnostic spirometry in primary care: Proposed standards for general practice compliant with American Thoracic Society and European Respiratory Society recommendations: a General Practice Airways Group (GPIAG)1 document, in association with the Association for Respiratory Technology & Physiology (ARTP)2 and Education for Health3 1 www.gpiag.org 2 www.artp.org 3 www.educationforhealth.org.uk.

Primary care spirometry services can be provided by trained primary care staff, peripatetic specialist services, or through referral to hospital-based or laboratory spirometry. The first of these options is the focus of this Standards Document. It aims to provide detailed information for clinicians, managers and healthcare commissioners on the key areas of quality required for diagnostic spirometry in primary care--including training requirements and quality assurance. These proposals and recommendations are designed to raise the standard of spirometry and respiratory diagnosis in primary care and to provide the impetus for debate, improvement and maintenance of quality for diagnostic (rather than screening) spirometry performed in primary care. This document should therefore challenge current performance and should constitute an aspirational guide for delivery of this service.

Interpreting lung function data using 80% predicted and fixed thresholds misclassifies more than 20% of patients.

BACKGROUND Differences in COPD classification have been shown in population data sets when using fifth percentiles as the lower limit of normal (LLN) vs the current GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines of FEV(1)/FVC < 0.70 for detecting airway obstruction and an FEV(1) of 80% predicted for detecting and classifying the severity of COPD (GOLD/PP). Many lung function laboratories use 80% predicted to determine whether results are abnormal. Misclassification of the full range of lung diseases in large patient groups when using GOLD/PP criteria instead of the LLN has not been explored previously. METHODS We determined the discrepancy rates in pulmonary function test interpretation between the GOLD/PP and LLN methods on prebronchodilator lung function results from a large number of adult patients from the United Kingdom, New Zealand, and the United States. RESULTS In 11,413 patients, the GOLD/PP method misclassified 24%. Ten percent of patients who had normal lung function were falsely classified with a disease category, and 7% of patients were falsely attributed with emphysema. The GOLD/PP method gave false-positive classifications for airflow obstruction and restrictive defects to significantly more men (P < .01) and older patients (P < .0001) and also missed airflow obstruction and restrictive defects in younger patients (P < .0001). CONCLUSIONS Using lung function tests on their own with 80% predicted and fixed cut points to determine whether a test is abnormal could misdiagnose > 20% of patients referred for pulmonary function tests. The GOLD/PP method introduces clinically important biases in assessing disease status that could affect allocation to treatment groups. This misclassification is avoided by using the LLN based on the fifth-percentile values.

Influence of secular trends and sample size on reference equations for lung function tests

The aim of our study was to determine the contribution of secular trends and sample size to lung function reference equations, and establish the number of local subjects required to validate published reference values. 30 spirometry datasets collected between 1978 and 2009 provided data on healthy, white subjects: 19,291 males and 23,741 females aged 2.5–95 yrs. The best fit for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC as functions of age, height and sex were derived from the entire dataset using GAMLSS. Mean z-scores were calculated for individual datasets to determine inter-centre differences. This was repeated by subdividing one large dataset (3,683 males and 4,759 females) into 36 smaller subsets (comprising 18–227 individuals) to preclude differences due to population/technique. No secular trends were observed and differences between datasets comprising >1,000 subjects were small (maximum difference in FEV1 and FVC from overall mean: 0.30– -0.22 z-scores). Subdividing one large dataset into smaller subsets reproduced the above sample size-related differences and revealed that at least 150 males and 150 females would be necessary to validate reference values to avoid spurious differences due to sampling error. Use of local controls to validate reference equations will rarely be practical due to the numbers required. Reference equations derived from large or collated datasets are recommended.

Age- and height-based prediction bias in spirometry reference equations

Prediction bias in spirometry reference equations can arise from combining equations for different age groups, rounding age or height to integers or using self-reported height. To assess the bias arising from these sources, the fit of 13 prediction equations was tested against the Global Lungs Initiative (GLI) dataset using spirometric data from 55,136 healthy Caucasians (54% female). The effects on predicted values of using whole-year age versus decimal age, and of a 1% bias in height, were quantified. In children, the prediction bias relative to GLI ranged from -22% to +17%. Switching equations at 18 yrs of age led to biases of between -846 (-14%) and +1,309 (+38%) mL. Using age in whole years rather than decimal age introduced biases from -8% to +7%, whereas a 1% overestimation of height introduced bias that ranged from +1% to +40%. Bias was greatest in children and adolescents, and in short elderly subjects. Using a single spirometry equation applicable across all ages and populations reduces prediction bias. Measuring and recording age and height accurately are also essential if bias is to be minimised.

Recommendations for epidemiological studies on COPD

The prevalence of chronic obstructive pulmonary disease (COPD) has been extensively studied, especially in Western Europe and North America. Few of these data are directly comparable because of differences between the surveys regarding composition of study populations, diagnostic criteria of the disease and definitions of the risk factors. Few community studies have examined phenotypes of COPD and included other ways of characterising the disease beyond that of spirometry. The objective of the present Task Force report is to present recommendations for the performance of general population studies in COPD in order to facilitate comparable and valid estimates on COPD prevalence by various risk factors. Diagnostic criteria in epidemiological settings, and standardised methods to examine the disease and its potential risk factors are discussed. The paper also offers practical advice for planning and performing an epidemiological study on COPD. The main message of the paper is that thorough planning is worth half the study. It is crucial to stick to standardised methods and good quality control during sampling. We recommend collecting biological markers, depending on the specific objectives of the study. Finally, studies of COPD in the population at large should assess various phenotypes of the disease.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4–20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry

The aim of this study was to determine the diagnostic and interpretative consequences of adopting the Global Lungs Initiative (GLI) 2012 spirometric prediction equations. We assessed spirometric records from 17 572 subjects (49.5% females), aged 18–85 years, from hospitals in Australia and Poland. We calculated predicted forced expiratory volume in 1 s (FEV1), forced expiratory volume (FVC), FEV1/FVC and lower limits of normal (LLN) using European Community for Steel and Coal (ECSC), National Health and Nutrition Examination Survey (NHANES) III and GLI 2012 equations. Obstruction was defined as FEV1/FVC<LLN and a restrictive pattern as FEV1/FVC>LLN and FVC<LLN. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 and higher was defined as FEV1/FVC <0.70 and FEV1 <80% pred. GLI 2012 equations produce similar predicted values for FEV1 and FVC compared with NHANES, but produce larger values than ECSC. Differences in the LLN lead to an important increase in the prevalence rate of a low FVC compared to ECSC, and a significant decrease compared to NHANES prediction equations. Adopting GLI 2012 equations has small effects on the prevalence rate of airway obstruction. GOLD stages 2–4 lead to >20% underdiagnosis of airway obstruction up to the age of 55 years and to 16–23% overdiagnosis in older subjects. GLI 2012 equations increase the prevalence of a “restrictive spirometric pattern” compared to ECSC but decrease it compared to NHANES. Adopting the Global Lung Initiative 2012 prediction equations will have small effects on spirometric rates of detection http://ow.ly/nrZxe

Changing relationships between stature and lung volumes during puberty

In a follow-up study the relationship between growth in body dimensions and in lung volumes during the adolescent growth spurt was studied in 149 girls and 477 boys, aged 11.5-14.0 years at the start of the study. Total lung capacity (TLC), residual volume, vital capacity (VC) and series dead space were measured twice a year for 6 years. When analyzed cross-sectionally lung volumes can be described by a power function of stature, both for each set of half-yearly measurements and when all data are pooled. The powers were close to 3, increasing at each time of measurement in boys and decreasing in girls. These trends reflect that in each subject the growth spurt does not start at the same age, and that individual growth occurs non-linearly along a steeper line than found in the cross-section. Using simple allometric relationships between stature and lung volumes, volume predictions are too high in the youngest age group, and too low in the oldest adolescents. Including age in the regression equation removes this trend in the cross-sectional data, and for VC and TLC also in the longitudinal data.