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Clinical impact of the lower limit of normal of FEV1/FVC on detecting chronic obstructive pulmonary disease: A follow-up study based on cross-sectional data

  • Sha Liu
    Affiliations
    The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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  • Yumin Zhou
    Affiliations
    The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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  • Shiliang Liu
    Affiliations
    The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China

    Department of Epidemiology and Community Medicine Faculty of Medicine University of Ottawa, Ottawa, Ontario, Canada
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  • Weifeng Zou
    Affiliations
    Guangzhou Chest Hospital, Guangzhou, Guangdong, China
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  • Xiaochen Li
    Affiliations
    The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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  • Chenglong Li
    Affiliations
    The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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  • Zhishan Deng
    Affiliations
    The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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  • Jinzhen Zheng
    Affiliations
    The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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  • Bing Li
    Affiliations
    College of Life Science, Guangzhou Medical University, Guangzhou, Guangdong, China
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  • Pixin Ran
    Correspondence
    Corresponding author.
    Affiliations
    The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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Open ArchivePublished:April 18, 2018DOI:https://doi.org/10.1016/j.rmed.2018.04.011

      Highlights

      • A Follow-up Study Based on Cross-sectional Data.
      • Poor lung function, rapid declining FEV1 and reduced exercise capacity were found in participants under-diagnosed.
      • The elderly overdiagnosed participants showed similar characteristics with normal contrast participants.
      • More attention should be paid on participants under-diagnosed.

      Abstract

      Background

      Criteria of obstruction that establish a diagnosis of COPD have been debated in recent years. We carried out a follow-up study to assess the impact of the new LLN reference equation for Chinese on detecting COPD compared with the traditional 0.7fixed criteria.

      Methods

      We examined the prevalence and characteristics of airflow limitation for a non-child population using post-bronchodilator airflow with both age-dependent predicted lower limit of the normal value and fixed-ratio spirometric criterion. Questionnaires and spirometry were completed for all eligible subjects during the baseline examination. Participants with inconsistent diagnosis according to the two criteria, normal participants (controls) and COPD patients in stages I or II, were invited to take a cardiopulmonary exercise testing (CPET) examination and follow up for 2–4 years.

      Results

      A total of 5448 (mean age 50.51 ± 13.2 yr) study subjects with acceptable spirometry and complete questionnaire data were included in our final analyses. COPD detection based on LLN was consistent with the GOLD 0.7 fixed-ratio in general, as 51 subjects (0.9%) were underdiagnosed, and 61 subjects (1.1%) were overdiagnosed when using LLN as the reference diagnostic criterion. The underdiagnosed subjects were younger, had more symptoms, more exposure to biofuels and worse FEV1 than the normal group; they also demonstrated a damaged cardiopulmonary reserve capacity and significant FEV1 decline. Except for being older, the overdiagnosed subjects differed little from the normal group.

      Conclusions

      Individual-dependent LLN appears to better reveal impacts on detecting airflow limitation. Participants underdiagnosed by GOLD criterion should be paid more attention.

      Clinical Trial Registration

      ChiCTR-ECS-13004110

      Keywords

      Abbreviations List:

      COPD (Chronic Obstructive Pulmonary Disease), LLN (Lower Limit of Normal), GOLD (Global initiative for chronic obstructive pulmonary disease), GIRD/SKLRD (Guangzhou Institute of Respiratory Diseases/ The State Key Laboratory of Respiratory Diseases), CPET (Cardiopulmonary exercise test), VE/VCO2 (Ventilatory equivalent for carbon dioxide), VD/VT-peak (Dead space to tidal volume ratio at peak exercise), VE/VO2 (Ventilatory equivalent for oxygen), AT (Anaerobic threshold), VO2max%pred (Maximal oxygen uptake percentage predicted value)

      1. Introcution

      Criteria that establish a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) have been debated in recent years [
      • Swanney M.P.
      • Ruppel G.
      • Enright P.L.
      • Pedersen O.F.
      • Crapo R.O.
      • Miller M.R.
      • Jensen R.L.
      • Falaschetti E.
      • Schouten J.P.
      • Hankinson J.L.
      • et al.
      Using the lower limit of normal for the fev1/fvc ratio reduces the misclassification of airway obstruction.
      ]. Numerous studies have demonstrated that regular changes in FEV1/FVC are seen with aging, and therefore the fixed ratio of 70% may be inappropriate [
      • Culver B.H.
      How should the lower limit of the normal range be defined?.
      ,
      • Stanojevic S.
      • Wade A.
      • Stocks J.
      • Hankinson J.
      • Coates A.L.
      • Pan H.
      • Rosenthal M.
      • Corey M.
      • Lebecque P.
      • Cole T.J.
      Reference ranges for spirometry across all ages: a new approach.
      ]. Hardie and colleagues found among people aged more than 70 years, approximately 35% of the healthy, elderly never-smokers had an FEV1/FVC% of <70%. This percentage increased with age [
      • Hardie J.A.
      • Buist A.S.
      • Vollmer W.M.
      • Ellingsen I.
      • Bakke P.S.
      • Morkve O.
      Risk of over-diagnosis of copd in asymptomatic elderly never-smokers.
      ]. Cerveri's study found that in those aged less than 50, normal LLN of general pulmonary function of FEV1/FVC value was close to but greater than 70% [
      • Cerveri I.
      • Corsico A.G.
      • Accordini S.
      • Niniano R.
      • Ansaldo E.
      • Anto J.M.
      • Kunzli N.
      • Janson C.
      • Sunyer J.
      • Jarvis D.
      • et al.
      Underestimation of airflow obstruction among young adults using fev1/fvc <70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes.
      ]. In white people aged 40–80 years, an FEV1/FVC less than LMS-LLN5 indicates persons with an increased risk of death and prevalence of respiratory symptoms [
      • Vaz F.C.
      • Concato J.
      • McAvay G.
      • Van Ness P.H.
      • Rochester C.L.
      • Yaggi H.K.
      • Gill T.M.
      The ratio of fev1 to fvc as a basis for establishing chronic obstructive pulmonary disease.
      ]. Thus the threshold of Lower Limit of Normal (LLN) was gradually been recommended to establish a diagnosis of COPD [
      • Swanney M.P.
      • Ruppel G.
      • Enright P.L.
      • Pedersen O.F.
      • Crapo R.O.
      • Miller M.R.
      • Jensen R.L.
      • Falaschetti E.
      • Schouten J.P.
      • Hankinson J.L.
      • et al.
      Using the lower limit of normal for the fev1/fvc ratio reduces the misclassification of airway obstruction.
      ,
      • Vaz F.C.
      • Concato J.
      • McAvay G.
      • Van Ness P.H.
      • Rochester C.L.
      • Yaggi H.K.
      • Gill T.M.
      The ratio of fev1 to fvc as a basis for establishing chronic obstructive pulmonary disease.
      ,
      • Enright P.
      • Brusasco V.
      Counterpoint: should we abandon fev(1)/fvc < 0.70 to detect airway obstruction? Yes.
      ]. Previous studies have shown that the use of the LLN FEV1/FVC ratio reduces age-related increases in COPD prevalence that are observed in healthy population according to the fixed ratio criterion (FEV1/FVC <0.7) as recommended by GOLD [
      • Vollmer W.M.
      • Gislason T.
      • Burney P.
      • Enright P.L.
      • Gulsvik A.
      • Kocabas A.
      • Buist A.S.
      Comparison of spirometry criteria for the diagnosis of copd: results from the bold study.
      ,
      • Luoto J.A.
      • Elmstahl S.
      • Wollmer P.
      • Pihlsgard M.
      Incidence of airflow limitation in subjects 65-100 years of age.
      ,
      • Guder G.
      • Brenner S.
      • Angermann C.E.
      • Ertl G.
      • Held M.
      • Sachs A.P.
      • Lammers J.W.
      • Zanen P.
      • Hoes A.W.
      • Stork S.
      • et al.
      Gold or lower limit of normal definition? A comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study.
      ]. It seems challengeable to promote reference equations globally although the European Respiratory Society Global Lung Function Initiative(GLI) have created continuous prediction equations and lower limits of normal for spirometric values with adjustment of fixed ethnic conversion factors [
      • Quanjer P.H.
      • Stanojevic S.
      • Cole T.J.
      • Baur X.
      • Hall G.L.
      • Culver B.H.
      • Enright P.L.
      • Hankinson J.L.
      • Ip M.S.
      • Zheng J.
      • et al.
      Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.
      ,
      • Jian W.
      • Gao Y.
      • Hao C.
      • Wang N.
      • Ai T.
      • Liu C.
      • Xu Y.
      • Kang J.
      • Yang L.
      • Shen H.
      • et al.
      Reference values for spirometry in Chinese aged 4-80 years.
      ]. However, a recent study of the establishment of a new LLN reference values based on a nation-wide sample of Chinese population yields the possibility of a correct diagnosis in Chinese [
      • Jian W.
      • Gao Y.
      • Hao C.
      • Wang N.
      • Ai T.
      • Liu C.
      • Xu Y.
      • Kang J.
      • Yang L.
      • Shen H.
      • et al.
      Reference values for spirometry in Chinese aged 4-80 years.
      ]. More importantly, few studies have reported the characteristics and evolution of the participants with inconsistent diagnosis of these two methods based on longitudinal follow-up, although several other studies described the prevalence based on cross-sectional design [
      • Guillien A.
      • Puyraveau M.
      • Soumagne T.
      • Guillot S.
      • Rannou F.
      • Marquette D.
      • Berger P.
      • Jouneau S.
      • Monnet E.
      • Mauny F.
      • et al.
      Prevalence and risk factors for copd in farmers: a cross-sectional controlled study.
      ,
      • Jordan R.E.
      • Miller M.R.
      • Lam K.B.
      • Cheng K.K.
      • Marsh J.
      • Adab P.
      Sex, susceptibility to smoking and chronic obstructive pulmonary disease: the effect of different diagnostic criteria. Analysis of the health survey for england.
      ]. Therefore, we carried out a follow-up study to assess the impact of the new LLN reference equation for Chinese on detecting COPD [
      • Jian W.
      • Gao Y.
      • Hao C.
      • Wang N.
      • Ai T.
      • Liu C.
      • Xu Y.
      • Kang J.
      • Yang L.
      • Shen H.
      • et al.
      Reference values for spirometry in Chinese aged 4-80 years.
      ] as compared with the traditional 0.7fixed criteria, and to reveal the lung function decline and cardiopulmonary reserve capacity of the participants diagnosed inconsistently.

      2. Methods

      2.1 Design and subjects

      In this study, we used data collected from participants in part of the National Science-Technology Support Plan Program for the 12th five-year plan which was a population-based, cross-sectional, multicentric and randomized survey of COPD conducted in China (2012–2015) [
      • Liu S.
      • Zhou Y.
      • Liu S.
      • Chen X.
      • Zou W.
      • Zhao D.
      • Li X.
      • Pu J.
      • Huang L.
      • Chen J.
      • et al.
      Association between exposure to ambient particulate matter and chronic obstructive pulmonary disease: results from a cross-sectional study in China.
      ]. A total of 5448 (mean age 50.51 ± 13.2 yr.) study subjects with complete questionnaires and acceptable spirometry data (spirometry results with grades A, B, or C) from the data base were considered as eligible subjects included in our baseline assessment. Spirometry was performed as COPD diagnosis criterion by post-bronchodilator (salbutamol sulfate aerosol, 400 μg 20 min later) with two criteria: GOLD fixed-ratio FEV1/FVC% < 70% and FEV1/FVC% < LLN.
      We used FEV1/FVC at cohort inception of the National Science-Technology Support Plan Program for the 12th five-year plan and the presence or absence of COPD according to both the age-dependent predicted LLN and GOLD 0.7 fixed-ratio to define four groups: met both criteria for COPD (COPD group); diagnosed by LLN but not by GOLD fixed-ratio (underdiagnosis group, LLN was used as reference criteria); diagnosed by GOLD fixed-ratio but not according to LLN (overdiagnosis group); and not diagnosed by either of the two diagnostic criteria (normal group). Subjects from the ‘normal group’ served as normal controls for the overdiagnosis and underdiagnosis groups and were labeled “normal control group1” and “normal control group2 in cardiopulmonary exercise test (CPET)”, respectively.
      In an attempt to assess whether subjects who were inconsistently diagnosed at baseline were clinically different from those who were consistently diagnosed as normal or having COPD, we conducted CPET examinations and follow up. During the follow up, participants in the underdiagnosis and overdiagnosis groups and COPD patients in stages I or II (FEV1 reference equations: European Coal and Steel Community 1993 (ECSC-1993)) underwent spirometry semi-annually, while subjects with normal lung function underwent spirometry annually. All spirometric data were measured using the same spirometers and by the same professional operators. The Ethics Committee of Scientific research project review of the first affiliated hospital of Guangzhou Medical University approved this research, No. 2013-37.
      Out of the 5448 recruited study subjects, 261 performed CPET correctly and effectively, and 1880 participants completed a follow-up of at least 2 years. See Fig. 1 for an overview of the study.
      Fig. 1
      Fig. 1Study overview of equation assessment. LLN: lower limt of normal; GOLD: The Global Initiative of Chronic Obstructive Lung Disease; PFT: pulmonary function test; CPET:cardiopulmonary exercise testing.

      2.2 Questionnaire

      Questionnaire interview was performed using a standardized questionnaire revised from the international BOLD (Burden of Obstructive Lung Diseases) study, including general information, possible risk factors of COPD such as family history of respiratory diseases, smoking status, occupational exposure, biomass fuel exposure and related medical history [
      • Liu S.
      • Zhou Y.
      • Liu S.
      • Chen X.
      • Zou W.
      • Zhao D.
      • Li X.
      • Pu J.
      • Huang L.
      • Chen J.
      • et al.
      Association between exposure to ambient particulate matter and chronic obstructive pulmonary disease: results from a cross-sectional study in China.
      ].

      2.3 Spirometry

      Spirometric data were collected using a portable spirometer (Carefusion™ MasterScreen Pneumo, Germany) interfaced for pulmonary function data acquisition and quality control software (Sentrysuite Version 2.3) and calibrated daily. All spirometric measurements were performed according to the European Respiratory Society/American Thoracic Society standards (ERS/ATS 2005) [
      • Miller M.R.
      • Hankinson J.
      • Brusasco V.
      • Burgos F.
      • Casaburi R.
      • Coates A.
      • Crapo R.
      • Enright P.
      • van der Grinten C.P.
      • Gustafsson P.
      • et al.
      Standardisation of spirometry.
      ].

      2.4 Cardiopulmonary exercise test (CPET)

      CPET was undertaken through a physician-supervised calibrated cycle ergometer (Quark PFT Ergo Bp900, COSMED co., Italy) in 2014 using the following protocol: 2 min of rest, 2 min of unloaded cycling at 60 rpm, stepwise increases in work load of 5–30 W/min until symptom-limited or terminated by the physician due to chest pain or ECG abnormalities with a total of approximately 8–12 min, then 10 min of recovery and 3 min of rest. The following exclusions were applied: presence of asthma, other medical conditions that could contribute to dyspnea or exercise limitations, contraindications to exercise testing or use of daytime oxygen. Measurements of ventilatory efficiency such as maximal oxygen uptake(VO2max), ventilatory equivalent for CO2 (VE/VCO2) ratio and ventilatory equivalent for O2 (VE/VO2) ratio at anaerobic threshold and dead space to tidal volume ratio (VD/VT) at peak exercise were obtained. Anaerobic threshold was detected using the V-slope method using computerized regression analysis of the slopes of the CO2 output (VCO2) vs O2 uptake (VO2) plot.

      2.5 Statistical analysis

      We first used McNemar method to assess the consistency in diagnosis results between the two criteria among the 5448 participants. Then, we examined the differences in categorical variables of the participants using chi-square tests. Differences in the continuous variables were examined using one-way ANOVA. Characteristics differences between overdiagnosis and underdiagnosis group were assessed with the comparison of normal and COPD groups. Logistic regression was performed to analyze the adjusted distribution of difference in each pair at baseline examination. Spirometric data at baseline and after follow-up of each subgroup (underdiagnosed, overdiagnosed, normal and COPD) were analyzed using the analysis of covariance (ANCOVA) with sex and subgroups as fixed variables, age, height, weight and smoking pack*years as covariates. Analysis of FEV1 decline were also adjusted with baseline FEV1 measured values. Spirometric data for those who were followed up for more than 2 years were included in the analysis, and parameters like FEV1, FEV1%pred and FEV1 decline/year were estimated. A statistically significant P value (p < 0.05) signified a difference between each pair of two comparison groups. Participants with CPET data for analysis in normal control group1 and overdiagnosis group were matched by age, sex, smoking state, and comorbidities. So did the matching in group of normal control group2 and underdiagnosis. All normal control subjects were randomly recruited from the normal population at the baseline examination based on the match variables. Presence of COPD symptoms is defined as any of the following symptoms persisting for more than 3 months over at least 2 years: dyspnea, cough, sputum production, wheezing, and chest tightness. Comorbidities refer to subjects suffering from one or more of the following diseases: high blood pressure, diabetes, or coronary heart disease. All analyses were performed using IBM SPSS 19.0.

      3. Results

      3.1 COPD diagnosis at baseline

      COPD detection was 10.11% (551/5448) based on the GOLD 0.7 fixed-ratio, and 10.07% (549/5448) for LLN in our baseline survey population. There was no difference between these two diagnostic criteria, since 51 participants were underdiagnosed and 61 were overdiagnosed, and 488 were diagnosed by both as having COPD (McNemar method P = 0.922 Table 1).
      Table 1COPD Diagnosis based on Criteria of LLN and GOLD Fixed Ratio
      Statistical methods: McNemar method, P = 0.922.
      .
      FrequencyGOLD
      +Total
      LLN+48851539
      6148484909
      Total54948995448
      a Statistical methods: McNemar method, P = 0.922.

      3.2 Clinical characteristics of each group at baseline examination

      The clinical characteristics of the subgroups were given in Table 2. Subjects in the underdiagnosis group showed significantly younger when compared with the COPD group (52.7 ± 5.4 vs. 62.2 ± 8.6 yrs, P < 0.001), but the overdiagnosis showed older when compared with the COPD group (66.6 ± 6.2 vs. 62.2 ± 8.6 yrs, P < 0.001). Meanwhile, more symptoms and a higher rate of biofuel exposure history were found in the underdiagnosed group than in the normal group (37.3% vs. 18.4%, P = 0.009 for positive symptom frequency; 54.9% vs. 35.3%, P = 0.025 for biofuel exposure). Smoking and high smoking capacity were more prevalent for the overdiagnosis group than for the normal group (70.5% vs. 26.2%, P = 0.029; 33.0 ± 31.4 pack*year vs. 9.0 ± 19.0 pack*year, P < 0.001). Both the overdiagnosis and groups showed low rates of exposures to other associated risk factors(Table 2).
      Table 2Characteristics Distribution of the Participants in Each Group at Baseline Examination according to the Two Criteria.
      CharacteristicOver-diagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      Under-diagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      Normal group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      COPD group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      P value
      Analyses of differences in baseline characteristics are conducted using logistic regression in each pair. All models were adjusted with age, sex, smoking, childhood cough, biofuel or occupational exposure, family history, symptom, comorbidity and BMI.
      Overdiagnosis VS. normal groupUnderdiagnosis VS. normal groupOverdiagnosis VS. COPDUnderdiagnosis VS. COPD
      N61514848488
      Male Sex - N (%)
      51(83.6)25(49.0)1965(40.5)380(77.9)0.0070.3100.2890.963
      Age – yr.(SD)
      66.6(6.2)52.7(5.4)49.1(13.0)62.2(8.6)<0.0010.111<0.001<0.001
      Smoking – N (%)
      43(70.5)16(31.4)1268(26.2)333(68.2)0.0290.4370.9250.005
      Smoking – pack*yr.(SD)
      33.0(31.4)14.4(27.9)9.0(19.0)33.6(33.4)0.0410.6000.9970.189
      BMI - kg/m2(SD)
      21.8(3.1)23.0(2.8)22.9(3.5)21.6(3.4)0.0770.8860.5070.193
      Childhood cough – N (%)
      2(3.3)2(3.9)123(2.5)36(7.3)0.9520.8760.4250.173
      Occupational exposure – N (%)
      35(57.4)28(54.9)2071(42.7)301(61.7)0.3030.9180.8380.857
      Family history – N (%)
      5(8.2)7(13.7)326(6.7)57(11.7)0.5470.0940.6230.267
      Biofuel exposure – N (%)
      27(44.3)28(54.9)1713(35.3)246(50.4)0.9720.0250.7120.221
      Symptom – N (%)
      21(34.4)19(37.3)890(18.4)250(51.2)0.2390.0090.0090.797
      Comorbidity – N (%)
      10(16.4)6(11.8)546(11.3)72(14.8)0.2580.6740.9100.318
      a Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      b Analyses of differences in baseline characteristics are conducted using logistic regression in each pair. All models were adjusted with age, sex, smoking, childhood cough, biofuel or occupational exposure, family history, symptom, comorbidity and BMI.
      Subjects in the underdiagnosis and overdiagnosis groups both showed better values of baseline absolute FEV1 and FEV1%pred than the COPD group, because most of them had FEV1%pred ≥80% (93.4% vs. 53.5%, and 86.3% vs. 53.3%, Table 3). But significantly lower FEV1 and FEV1%pred were seen among participants in the underdiagnosed group when compared with the normal group after adjusting for sex, age, smoking pack*year, height and weight (2.5 ± 0.6L vs. 2.6 ± 0.7L p = 0.012 for FEV1 and 99.3 ± 20% vs. 102.4 ± 14% p = 0.013 for FEV1%pred-LLN; 97.3 ± 15% vs. 100.3 ± 14% p = 0.048 for FEV1%pred(ECSC93)). However, the corresponding comparison between the overdiagnosed group and the normal group indicated no substantial differences (2.3 ± 0.6L vs. 2.6 ± 0.7L, p = 0.117 for FEV1, and102.9 ± 19% vs. 102.4 ± 16%, p = 0.052 for FEV1%pred-LLN; 102.9 ± 19% vs. 102.4 ± 16%, p = 0.079 for FEV1%pred –ECSC1993).
      Table 3Lung Function of the Participants in Each Group at Baseline Examination according to the Two Criteria among 5448 Participants.
      CharacteristicOverdiagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      Under-diagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      Normal group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      COPD group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      P value
      Lung function parameters (FEV1, FEV1%pred-ECSC93, and FEV1%pred-LLN) were analyzed using the analysis of covariance (ANCOVA) with sex and subgroups as fixed variables, age, smoking pack*year, height and weight as covariates.
      Overdiagnosis VS. normal groupUnderdiagnosis VS. normal groupOverdiagnosis VS. COPDUnderdiagn-osis VS. COPD
      N61514848488
      FEV1 - L(SD)
      2.3(0.6)2.5(0.6)2.6(0.7)1.9(0.7)0.1170.012<0.001<0.001
      FEV1/pred-LLN - % (SD)
      The two FEV1%pred values represented the using of two FEV1 prediction reference equations of LLN(12) and ECSC-93 respectively.
      102.9(19)99.3(20)102.4(16)80.2(24)0.0520.013<0.001<0.001
      FEV1/pred-ECSC1993 - % (SD)
      The two FEV1%pred values represented the using of two FEV1 prediction reference equations of LLN(12) and ECSC-93 respectively.
      94.5(15)97.3(15)100.3(14)73.9(22.3)0.0790.048<0.001<0.001
      FEV1/FVC - %(SD)
      69.0(0.8)71.4(2.5)83.8(6.1)58.1(10.4)
      FEV1%pred stage-N (%)
      The FEV1%pred values were calculated using FEV1 prediction reference equations of LLN(12).
      <0.0010.009
      ≥80%57(93.4)44(86.3)264(53.5)
      ≥50% and <80%4(6.6)7(13.7)156(40.0)
      a Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; participants who were never diagnosed by either of the two criteria were considered the normal group; participants who met the two criteria for COPD were referred to as the COPD group.
      b Lung function parameters (FEV1, FEV1%pred-ECSC93, and FEV1%pred-LLN) were analyzed using the analysis of covariance (ANCOVA) with sex and subgroups as fixed variables, age, smoking pack*year, height and weight as covariates.
      c The two FEV1%pred values represented the using of two FEV1 prediction reference equations of LLN(12) and ECSC-93 respectively.
      d The FEV1%pred values were calculated using FEV1 prediction reference equations of LLN(12).
      Results for the participants who underwent CPET at the baseline examination are shown in Table 4. The subgroups appeared to be comparable for age, sex, smoking history and comorbidities. The underdiagnosis group showed considerably lower VO2max%pred (77.4% vs. 85.4%, p < 0.001), higher dead space to tidal volume ratio (VD/VT) at peak exercise (0.17 vs. 0.16, p = 0.024), and higher VE/VCO2 at anaerobic threshold (32.81 vs.29.76 at AT, p = 0.012) compared with the normal control group2 (Table 4). However, these CPET variables were not differential between the participants in the overdiagnosis group and normal control group1 (82.5% vs. 83.1% p = 0.840 for VO2max%pred, 0.18 vs. 0.17 p = 0.130 for VD/VT-peak, 28.5 vs. 28.3 p = 0.863 for VE/VO2-AT, and 31.9 vs.31.5 p = 0.958 for VE/VCO2-AT).
      Table 4Characteristics Distribution of CPET at Baseline Examination in All Groups.
      CharacteristicOverdiagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; the group that met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      Normal control group1
      Subjects in the normal control group1 and 2 were recruited from the normal group with age, sex, smoking state and comorbidities compared with the overdiagnosis or underdiagnosis groups.
      Underdiagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; the group that met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      Normal control group2
      Subjects in the normal control group1 and 2 were recruited from the normal group with age, sex, smoking state and comorbidities compared with the overdiagnosis or underdiagnosis groups.
      COPD group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; the group that met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      P-value
      Categorical variables were analyzed using chi-square tests, continuous variables were analyzed using one-way ANOVA.
      Overdiagnosis VS. normal control 1Underdiagnosis VS. normal control 2Overdiagnosis VS. COPDUnderdiagnosis VS. COPD
      N
      23 participants who were overdiagnosed and 20 who were underdiagnosed were excluded from CPET for reasons of comorbidities or refusal.
      38373134103
      Male Sex - N35/3834/3720/3125/3494/1030.6500.3020.5880.001
      Smoking - N30/3833/3716/3116/3484/1030.1860.4530.4480.001
      BMI- kg/m222.2(2.8)21.8(3.1)23.6(3.7)23.1(3.3)22.2(3.3)0.6590.6170.9360.008
      FEV1/FVC-%69.1(0.6)77.0(4.9)71.2(1.0)82.2(5.7)61.1(6.9)<0.001<0.001<0.001<0.001
      VO2max%pred - %(SD)
      82.51(10.6)83.11(8.5)78.35(12.6)85.4(8.0)76.7(12.0)0.840<0.0010.0050.31
      VD/VT-PEAK - (SD)
      0.18(0.03)0.17(0.03)0.17(0.04)0.16(0.03)0.21(0.03)0.1300.024<0.001<0.001
      VE/O2-AT28.48(3.3)28.27(3.6)28.23(3.6)26.77(3.0)31.90(5.1)0.8630.173<0.001<0.001
      VE/CO2-AT31.86(4.1)31.54(3.4)32.81(3.7)29.76(3.0)36.15(5.8)0.9580.0120.0010.001
      a Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; the group that met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      b Subjects in the normal control group1 and 2 were recruited from the normal group with age, sex, smoking state and comorbidities compared with the overdiagnosis or underdiagnosis groups.
      c 23 participants who were overdiagnosed and 20 who were underdiagnosed were excluded from CPET for reasons of comorbidities or refusal.
      d Categorical variables were analyzed using chi-square tests, continuous variables were analyzed using one-way ANOVA.

      3.3 FEV1 decline after follow-up of 2–4 years

      Characteristics of participants who were followed up for more than 2 years and had lung function measurement above C level were showed in Table 5. 11 overdiagnosed participants and 5 underdiagnosed participants were excluded for FEV1 decline analysis due to loss to follow up. Decline in FEV1 after follow-up of 2–4 years appeared to be significantly greater for the underdiagnosed group and COPD group than for the normal group (a decline of 45.1 ml per year in the underdiagnosis group vs 26.4 ml per year in the normal group, P = 0.011; a decline of 46.9 ml per year in the COPD group vs 26.4 ml per year in the normal group, P < 0.001; a decline of 45.1 ml per year in the underdiagnosis group vs 46.9 ml per year in the COPD group, P = 0.179) (Fig. 2). P values were shown with adjustment of sex, age, height, weight, smoking pack*year and baseline FEV1. A corresponding comparison of the declines in FEV1 showed no significant difference between the overdiagnosis group and the normal group (20.7 ml per year vs 26.4 ml per year, P = 0.898), but a significantly lower decline as compared with the COPD group (20.7 ml per year vs 46.9 ml per year, P = 0.013).
      Table 5Characteristics Distribution of Participants after follow up in All Groups.
      CharacteristicOverdiagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; those who met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      Underdiagnosis group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; those who met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      Normal group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; those who met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      COPD group
      Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; those who met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      N
      11 overdiagnosed participants and 5 underdiagnosed participants were excluded for FEV1 decline analysis due to loss to follow up.
      50461544240
      Age - yr.(SD)67.65(5.7)51.2(8.6)54.1(10.6)62.2(8.5)
      Male Sex - N4024621184
      Smoking - N3216409161
      Childhood cough - N223614
      Occupational exposure - N2628618123
      Family history - N5215228
      Baseline FEV1- L(SD)2.4(0.7)2.5(0.6)2.5(0.6)1.9(0.7)
      Baseline FEV1/FVC - %(SD)69.1(0.7)71.3(2.0)82.4(5.8)57.0(13.8)
      Follow up - yr.(SD)2.3(0.9)2.2(0.8)2.0(0.4)2.2(0.9)
      a Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; those who met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included.
      b 11 overdiagnosed participants and 5 underdiagnosed participants were excluded for FEV1 decline analysis due to loss to follow up.
      Fig. 2
      Fig. 2Lung Function Decline after Follow-up of 24 Years. Values are shown as mean ± 95% C.I. Overdiagnosis group was defined as COPD diagnosed by GOLD fixed criterion but not by LLN; underdiagnosis group was COPD diagnosed by LLN but not by GOLD fixed criterion; those who met the two criteria for COPD were referred to as the COPD group, and only stages I and II were included. 11 overdiagnosed participants and 5 underdiagnosed participants were excluded for FEV1 decline analysis due to loss to follow up. 1544 normal participants and 240 COPD patients, who were followed up or more than 2 years, were included in the analysis. The characteristics distribution of the four subgroups were showed in Table3. FEV1 decline were analyzed using ANCOVA with sex and subgroups as fixed variables, age, height, weight, smoking pack*year and baseline FEV1 as covariates. The mean decline in FEV1 was 20.1 ml per year in overdiagnosis group, 45.1 ml per year in underdiagnosis group, 26.4 ml per year in normal group, and 46.9 ml per year in COPD group. The decline in FEV1 in underdiagnosis group and COPD group were considered to be rapid.

      4. Discussion

      Our study has shown that there are significant differences between the two sets of diagnostic criteria when considering the interests of the individual subjects, since some participants could be wrongly diagnosed, as seen in this study with 51 participants underdiagnosed by the GOLD fixed-ratio, and 61 subjects were overdiagnosed.
      The baseline characteristics data showed low rates of COPD symptoms and other related risk factors for the overdiagnosis group. Consistently, VAZ Fragoso's study also reported a higher frequency of respiratory impairment when used GOLD approach for classification in asymptomatic older adults [
      • Vaz F.C.
      • Gill T.M.
      • McAvay G.
      • Quanjer P.H.
      • Van Ness P.H.
      • Concato J.
      Respiratory impairment in older persons: when less means more.
      ]. As for the underdiagnosis group, participants with symptoms account for a considerable portion. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 report advocated that COPD should be considered in any patient with symptom and then spirometry is required to make the diagnosis in the clinical context. The report indicated a higher prevalence in subjects with respiratory symptoms. Meanwhile, we also found a higher percentage of biofuel exposure history in this group. Emerging evidence has suggested that exposure to biofuel is important for development of COPD, especially in developing countries[
      • Salvi S.S.
      • Barnes P.J.
      Chronic obstructive pulmonary disease in non-smokers.
      ,
      • Liu S.
      • Zhou Y.
      • Wang X.
      • Wang D.
      • Lu J.
      • Zheng J.
      • Zhong N.
      • Ran P.
      Biomass fuels are the probable risk factor for chronic obstructive pulmonary disease in rural south China.
      ]. Less noted is that approximately 3 billion people, half of the worldwide population, are exposed to smoke from biofuels, compared with 1.01 billion people who smoke tobacco, suggesting that exposure to biomass smoke be the most important risk factor for COPD globally[
      • Salvi S.S.
      • Barnes P.J.
      Chronic obstructive pulmonary disease in non-smokers.
      ]. Even so, the relationship between biofuels exposure and COPD is still an open topic. Importantly, more attention should be paid to those people with a history of biofuel exposure.
      The cardiopulmonary exercise test (CPET) shows a valid evaluation of cardiopulmonary function capability and a recognition of existing limitations for COPD patients [
      • Ganju A.A.
      • Fuladi A.B.
      • Tayade B.O.
      • Ganju N.A.
      Cardiopulmonary exercise testing in evaluation of patients of chronic obstructive pulmonary disease.
      ,
      • Borghi-Silva A.
      • Mendes R.G.
      • Trimer R.
      • Oliveira C.R.
      • Fregonezi G.A.
      • Resqueti V.R.
      • Arena R.
      • Sampaio-Jorge L.M.
      Potential effect of 6 vs 12-weeks of physical training on cardiac autonomic function and exercise capacity in chronic obstructive pulmonary disease.
      ,
      • Ewert R.
      • Glaser S.
      • Winkler J.
      • Schrader H.
      • Trumper B.G.
      • Haase P.U.
      • Obst A.
      • Hoheisel G.
      Cardiopulmonary exercise testing (cpet) in severe copd–a multicentre comparison of two test protocols.
      ,
      • Ross R.M.
      • Murthy J.N.
      • Wollak I.D.
      • Jackson A.S.
      The six minute walk test accurately estimates mean peak oxygen uptake.
      ]. Our data have shown the poor maximal exercise capacity in underdiagnosis group with distinctively lower VO2max%pred and higher VE/VCO2-AT and VD/VT-peak than the normal control group. The presence of a high VE/VCO2 or reduced ventilatory efficiency, has consistently been reported in several exercise studies of mild chronic obstructive pulmonary disease than healthy controls [
      • Ofir D.
      • Laveneziana P.
      • Webb K.A.
      • Lam Y.M.
      • O'Donnell D.E.
      Mechanisms of dyspnea during cycle exercise in symptomatic patients with gold stage i chronic obstructive pulmonary disease.
      ,
      • Guenette J.A.
      • Jensen D.
      • Webb K.A.
      • Ofir D.
      • Raghavan N.
      • O'Donnell D.E.
      Sex differences in exertional dyspnea in patients with mild copd: physiological mechanisms.
      ,
      • Elbehairy A.F.
      • Raghavan N.
      • Cheng S.
      • Yang L.
      • Webb K.A.
      • Neder J.A.
      • Guenette J.A.
      • Mahmoud M.I.
      • O'Donnell D.E.
      Physiologic characterization of the chronic bronchitis phenotype in gold grade ib copd.
      ]. The value of VD/VT were well correlated with the VE/VCO2 ratio during submaximal exercise (r = 0.780, P = 0.001) in both mild COPD and healthy controls[
      • Elbehairy A.F.
      • Ciavaglia C.E.
      • Webb K.A.
      • Guenette J.A.
      • Jensen D.
      • Mourad S.M.
      • Neder J.A.
      • O'Donnell D.E.
      Pulmonary gas exchange abnormalities in mild chronic obstructive pulmonary disease. Implications for dyspnea and exercise intolerance.
      ] The elevated VD/VT also indicated a reduced ventilatory efficiency. The investigators further proved that compensatory increases in minute ventilation during exercise could maintain alveolar ventilation and arterial blood gas homeostasis at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD(27). This evidence supports the observation of impaired exercise capacity in participants underdiagnosed.
      However, we have observed no significant difference in these CPET parameters between the overdiagnosis group and the normal control group1. These two groups showed good VO2max%pred. Most doctors may think that dyspnea or a chronic cough for an adult smoker may be useful indications for initiating treatment of COPD. The shortness of breath is often due to a ‘comorbidity’ such as obesity, cardiovascular deconditioning, or congestive heart failure [
      • Enright P.
      Patients are hurt by a false diagnosis of chronic obstructive pulmonary disease.
      ], leading to overuse of expensive COPD bronchodilator inhalers since studies have shown that bronchodilator are effective in early treatment of chronic obstructive pulmonary disease [
      • Zhou Y.
      • Zhong N.S.
      • Li X.
      • Chen S.
      • Zheng J.
      • Zhao D.
      • Yao W.
      • Zhi R.
      • Wei L.
      • He B.
      • et al.
      Tiotropium in early-stage chronic obstructive pulmonary disease.
      ]. The high frequency of smoking in overdiagnosis group possibly imply a high tolerance for cigarettes, for which the intervention of smoking cessation may be highly effective in reducing symptoms, morbidity and mortality.
      It is important to acknowledge that the lung function evolution within these groups could be better measured in a longitudinal study design. Our analysis of lung function decline demonstrated that the underdiagnosed subjects were consistent with the COPD patients who both followed a trajectory of rapid declining FEV1. A study has shown that there is a wide range of individual trajectories, those both low maximally attained lung function in early adulthood and a subsequent rapid decline may contribute to COPD [
      • Postma D.S.
      • Bush A.
      • van den Berge M.
      Risk factors and early origins of chronic obstructive pulmonary disease.
      ]. Instead, persons with a higher initial FEV1 at cohort inception but with the absence of COPD at the final study visit would tend to have a lower observed decline in FEV1 than persons with the presence of COPD [
      • Lange P.
      • Celli B.
      • Agusti A.
      • Boje J.G.
      • Divo M.
      • Faner R.
      • Guerra S.
      • Marott J.L.
      • Martinez F.D.
      • Martinez-Camblor P.
      • et al.
      Lung-function trajectories leading to chronic obstructive pulmonary disease.
      ]. On the other hand, a recent study found that the majority of older persons who had FEV1/VC < 70% showed a normal FEV1 but no increased mortality [
      • Vaz F.C.
      • Concato J.
      • McAvay G.
      • Van Ness P.H.
      • Rochester C.L.
      • Yaggi H.K.
      • Gill T.M.
      Chronic obstructive pulmonary disease in older persons: a comparison of two spirometric definitions.
      ]. In addition, a higher percentage of participants with FEV1%pred lower than 80% in underdiagnosed group further indicates the poor lung function in this group.
      The results in overdiagnosis group suggested that age may be an independent factor for the decline of FEV1/FVC ratio in a geriatric population. Less than 0.7 does not necessarily indicate a diagnosis of COPD but a normal human condition. However, the results of underdiagnosis group turned out to be negative, as they showed more symptoms, impaired ventilation and faster lung function decline, and most importantly, they were younger. Conditions may get worse as age advances. Therefore, it is of great importance to start intervention in the underdiagnosis participants as early as possible, to improve symptoms and slow down lung function decline. Although a fixed ratio is simple and practical to use in clinical practice to diagnose COPD, accurate diagnosis is the most important for personal interest and medical development. Therefore, when other clinical examinations and clinical symptoms are significantly inconsistent with the diagnosis of fixed ratio, confirmation of diagnosis with LLN standard should be recommended.
      There are some strengths and potential limitations in our study. Main strengths of this study include the application of the new equation in a large and independent population and a relatively comprehensive evaluation of distribution differences among the four subgroups. The uptake of CPET examination and longitudinal observation of lung function evolution further demonstrated the differences in diagnosis.
      The major limitations of our study are that selection bias might have been introduced because of relatively small sample size leading to insufficient participants in overdiagnosis and underdiagnosis groups and short follow-up period to estimate declines in FEV1. In this study population, only 51 participants were underdiagnosed and 61 were overdiagnosed by the GOLD fixed-ratio, which resulted in a small number of participants for long term follow-up, and for subgroup comparison. Targeted collection of data for study participants who are inconsistently diagnosed with LLN and the GOLD 0.7 fixed-ratio and longer-term follow-up are both essential to better evaluate the two diagnostic criteria. Furthermore, research task remains challenging although some supports have been achieved. A simpler, more adaptable global formula is still the direction of our future efforts.
      In conclusion, our study has demonstrated that participants in the underdiagnosis group may have a reduced lung function, rapid declining FEV1 and reduced exercise capacity, however, the elderly overdiagnosed participants do not show such impaired respiratory function or exercise limitations. It is suggested that the individual-dependent LLN appears to perform better at detecting airflow limitations and reduces the risk of underdiagnosis for young adults and overdiagnosis for the elderly. A confirming diagnosis with LLN standard should be recommended when significantly inconsistencies appear in other clinical examinations and/or clinical symptoms and the diagnosis of fixed ratio.

      Ethics approval and consent to participate

      We declare that this study has passed the ethics committee, The Ethics Committee of Scientific research project review of the first affiliated hospital of Guangzhou Medical University approved this research, No. 2013-37. All subjects have signed informed consent before research beginning.

      Ethnic statement

      We declare that this study has passed the ethics committee, The Ethics Committee of Scientific research project review of the first affiliated hospital of Guangzhou Medical University approved this research, No. 2013-37. All subjects have signed informed consent before research beginning. In our informed consent, there contains a statement like this: we need to use the subjects' data, but only for the use of scientific research, the data may be published in the related journal, we will never reveal their privacy.
      A prospective study based on cross-sectional data.

      Consent for publication

      All the participants are consented to publish their data, and the specific contents of this section are mentioned in the informed consent of this study.

      Availability of data and material

      Please contact author for data requests.

      Conflicts of interest

      All authors declare that there is no conflict of interest in the publication.

      Funding

      This work was supported by 973 program 2015CB553403(to Dr. Zhou), science and technology program of Guangzhou 201504010018(to Dr. P. Ran), the Guangzhou Healthcare Collaborative Innovation Major Project 201604020012(to Dr. R. Chen), Chinese central government key research projects of the 12th national five-year development plan grants 2012BAI05B01 (to Dr. P. Ran).

      Authors' contributions

      Project design: Ran Pixin, Li Bing, Liu Sha.
      Project implementation and data acquisition: Liu Sha, Zhou Yumin, Li Xiaochen, Zou Weifeng, Li Chenglong, Deng Zhishan, Zheng Jinzhen.
      The first draft is written by: Liu Sha, Ran Pixin,
      Statistical analysis: Liu Sha, Zhou Yumin, Liu Shiliang.

      Acknowledgments

      We thank all the participants and other assistance personnel who participated in the study. Thanks to the People's Hospital of Lianping County and the People's Hospital of Wengyuan County for providing us with a study follow-up site.

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