for variability and consistency across countries and within the pooled sample from all countries. This study, which drew participants from countries in North America, Europe, Africa, and Asia, provided the opportunity for a systematic evaluation of the reference range of airway response after bronchodilator in healthy general populations in different regions of the world. METHODS Subject design and participants The target population included women and men aged 40 years and older in random population samples from 14 countries in North America, Europe, Africa and Asia. A detailed description of the study design and rationale, and initial results of the BOLD study have been published elsewhere.21 22 Population-based sampling plans were used to recruit participants who were then invited to complete interviewer-administered standardised questionnaires on respiratory health and symptoms, smoking history, quality of life, use of healthcare services, cardiovascular comorbidities and other respiratory diseases. Pre-bronchodilator and post-bronchodilator spirometry testing was done for all eligible participants. Spirometric testing and quality assurance review Lung function was obtained at all BOLD sites with the use of a portable spirometer (EasyOne, ndd Medical Technologies, Andover, Massachusetts, USA) to collect data on FEV1 and FVC with forced expiratory time standardised at >6 s or a plateau in the last second of expiration. With the rare exception in which spirometry was contraindicated,21 22 all sites attempted to collect pre- and post-bronchodilator measurements from all participants. Lung function was measured before and 15 min after administering two doses of 100 mg of salbutamol (albu- terol) via a spacer. All spirograms were reviewed by the BOLD Pulmonary Function Reading Center and assigned a quality score based on acceptability and repeatability criteria from the ATS.23 Data for FEV1 and FVC were deemed usable and included in this analysis if they fully met ATS acceptability criteria and were repeatable to within 200 ml. Deﬁnition of COPD As in all BOLD publications, we used the Global Initiative for Chronic Obstructive Lung Disease (GOLD) post-bronchodilator lung function criteria for deﬁning and staging COPD,21 24 and the prediction equations for Caucasian derived from the third US National Health and Nutrition Examination Survey25 to compute percentage predicted FEV1 and FVC. COPD is deﬁned as GOLD stage 2 and greater for subgroups computation. Statistical analysis Indices of BDR We generated six measures of BDR, three each for FEV1 and FVC, using indices recommended by the ATS12 and the ERS10: Absolute change from baseline values (DFEV1 and DFVC);10 12 percentage change relative to initial value (%DFEV1i and % DFVCi)10 12; and percentage change relative to predicted value (%DFEV1p and %DFVCp).8 9 13 18 Establishment of the upper normal limit of BDR The ‘normal’ range of BDR was determined from its distribution among healthy never-smoking participants, deﬁned as never smokers who did not report current asthma, chronic bronchitis, doctor diagnosis of emphysema, COPD or tuberculosis. The upper limit of normality of the BDR was deﬁned as the observed Thorax 2012;67:718e726. doi:10.1136/thoraxjnl-2011-201445 Respiratory epidemiology upper 95th percentile18 calculated separately for each site. These estimates and their associated 95% CIs were then used to generate forest plots and accompanying weighted estimates of the 95th percentiles that are pooled across sites along with tests for heterogeneity across sites. Individual sites are weighted according to the precision of the estimate at that site and these weights are reﬂected in the forest plots. We used simple unweighted statistics to summarise various statistics in tabular form for the cohort overall and for subgroups. All analyses were done using Stata V.10.0 (Stata Corp), and the forest plot analyses used the metan procedure. RESULTS Of a total of 10 712 subjects, 10 360 (97%) had either acceptable pre-bronchodilator and post-bronchodilator FEV1 data (n¼10 217) or acceptable pre-bronchodilator and post-broncho- dilator FVC data (n¼9546) and are included in this analysis. Table 1 shows their demographical and baseline characteristics by site. The mean ages and SDs ranged from 52.3 (10.3) years in the Philippines to 60.1 (12.8) years in Norway. Patterns of current cigarette smoking varied widely across sites: the lowest smoking rate was 14% in Canada; the highest smoking rate was 46% in South Africa. The intensity of tobacco exposure for smokers expressed as mean (SD) pack-years ranged from 17.0 (17.4) in South Africa to 38.6 (28.9) in Kentucky, USA. All indices of BDR in FEV1 and FVC displayed normal or near- normal distribution for the whole study population. Table 2 shows the simple unweighted estimates of the mean change and SD of BDR. For the healthy subgroup, these averages were several fold smaller than the mean values for the subgroup with COPD. Table 3 shows the simple unweighted estimates of the upper 95th percentiles (and associated 95% CIs) for the whole study population and for selected subgroups. BDR, when expressed as an absolute change, was larger in men than in women. However the opposite pattern was seen when BDR was expressed as a percentage change. In addition, per cent change when expressed relative to initial value was always greater (sometimes markedly so) when expressed relative to initial rather than predicted value. Finally, the 95th percentiles were consistently larger for individuals with COPD (regardless of comorbid asthma status) than for healthy lifetime never smokers. Figures 1e6 show the forest plots of the upper 95th percentile for the six measures of BDR for the subset of healthy never smokers. More precise estimates received greater weight, as shown in the ﬁgures, when calculating the pooled estimates, and hence the pooled estimates here differ somewhat from the unweighted estimates of 95th percentiles for all subjects shown in table 3, although they are qualitatively similar. In healthy lifetime non-smokers, the pooled weighted estimate of the threshold for absolute change (DFEV1) is 284 ml, with signiﬁ- cant cross-site heterogeneity in estimates, that is 54% of overall variation in estimate comes from site to site variability (ﬁgure 1). The pooled weighted estimate for %DFEV1p (ﬁgure 3) is smaller than for %DFEV1i (ﬁgure 2), with no cross-site heterogeneity in both cases. In contrast, the estimates for the FVC-based thresholds (ﬁgures 4e6) all demonstrated marked cross-site heterogeneity, ranging from 66% to 80%. Using the weighted thresholds from ﬁgures 1e6, we then calculated the simple, unweighted proportion of individuals who exceeded these thresholds for various subgroups (table 4). The proportion of people without airway obstruction who exceeded the threshold was consistently lower than that for people with airway obstruction for both the FEV1-based and FVC-based 719