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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introduction</span><p id="par0020" class="elsevierStylePara elsevierViewall">Chronic obstructive pulmonary disease &#40;COPD&#41; is a progressive disease characterized by persistent airflow limitation and chronic respiratory symptoms&#46; As a chronic disease&#44; COPD interventions aim to reduce the risk of acute exacerbation and relieve symptoms in overt&#44; advanced disease&#46; Cigarette smoke inhalation is the main risk factor for developing COPD&#59; other factors include poor lung growth and subsequently low maximal forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s &#40;FEV<span class="elsevierStyleInf">1</span>&#41;&#44; biomass exposure&#44; and air pollution&#44; especially in those who are at risk&#46; Several recent studies have focused on patients with early disease&#59; those with symptoms or physiological or radiological abnormalities are more likely to progress to COPD&#46; To aid early identification and preventive measures&#44; the Global Initiative for COPD &#40;GOLD&#41; suggested several definitions of early COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">1&#44;2</span></a> COPD is recognized as a condition that progresses from upstream to downstream&#44; and attention has focused on elucidating prodromal conditions preceding disease progression&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Preserved ratio impaired spirometry &#40;PRISm&#41; is defined as a FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>80&#37; of the predicted value without airflow limitation&#44; i&#46;e&#46;&#44; with a normal FEV<span class="elsevierStyleInf">1</span>&#47;forced vital capacity &#40;FVC&#41; ratio&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">3</span></a> This was previously defined as restrictive pulmonary function&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">4&#44;5</span></a> GOLD-unclassifiable&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">6</span></a> or even nonspecific findings&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">7&#44;8</span></a> PRISm is associated with more severe respiratory symptoms<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">4&#44;5&#44;9</span></a> and a higher risk of all-cause and respiratory mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">9&#8211;13</span></a> It is regarded as a transitional state&#44; either progressing to overt airflow obstruction &#40;AFO&#41; or reverting to normal spirometry in longitudinal studies<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">6&#44;10</span></a> in a significant proportion of individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Studies have found associations between respiratory symptoms&#44; such as chronic mucus production&#44;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">15&#8211;17</span></a> and abnormalities on chest images&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">18</span></a> The concept of pre-COPD encompasses not only symptoms but also structural abnormalities compatible with those found in COPD &#40;e&#46;g&#46;&#44; emphysema&#41;&#46; Formerly referred to as GOLD 0&#44; the most recent GOLD document labeled these symptoms and abnormalities pre-COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">2</span></a> Although it is associated with a higher risk of developing COPD&#44; pre-COPD can transition to other airway disease statuses&#44; including normal spirometry&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">While these airway diseases are acknowledged as precursors to COPD&#44; not all patients progress to COPD&#46; Indeed&#44; many patients transition to normal lung function&#44; as alluded to above&#46; We examined the outcomes of individuals at risk of developing COPD by analyzing data collected prospectively from the general population&#46; This well-constructed longitudinal cohort enables us to identify lung function trends over time and factors related to the development of airflow limitation&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Study population and eligibility criteria</span><p id="par0040" class="elsevierStylePara elsevierViewall">We used data from a longitudinal&#44; population-based observational cohort study &#40;the rural Ansung and urban Ansan cohort&#41; that was a part of the Korean Genome Epidemiology Study &#40;KoGES&#41;&#46; This project recruited individuals from the general population aged 40&#8211;69 years to assess the incidence and risk factors of various chronic disorders&#46; The initial baseline survey ran from 2001 to 2002&#44; and subjects were followed biannually until 2014&#46; At each visit&#44; data on lifestyle characteristics&#44; medical history&#44; subjective symptoms&#44; and disease incidence were collected&#46; Methodological information was published previously&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">21</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">We included only participants who underwent spirometry at the baseline survey and attended at least two follow-up visits&#46; Moreover&#44; the participants had to have completed a questionnaire on respiratory symptoms&#44; and radiological data used to define pre-COPD had to be available&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical variables</span><p id="par0050" class="elsevierStylePara elsevierViewall">At the baseline assessment&#44; demographic and socioeconomic data were obtained&#44; including age&#44; sex&#44; body mass index &#40;BMI&#41;&#44; smoking history and pack-years&#44; biomass exposure&#44; residence &#40;urban vs&#46; rural&#41;&#44; education level&#44; and income&#46; Anthropometric parameters &#40;height and weight&#41; were measured&#46; A systematic questionnaire was used to assess medical history at the baseline visit&#44; including symptoms &#40;chronic bronchitis symptom and modified Medical Research Council &#91;mMRC&#93; dyspnea score&#41;&#44; quality of life &#40;EQ-5D-5L&#41;&#44; and comorbidities &#40;hypertension&#44; diabetes mellitus&#44; coronary artery disease &#91;CAD&#93;&#44; congestive heart failure &#91;CHF&#93;&#44; dyslipidemia&#44; kidney disease&#44; cerebrovascular disease&#44; arthritis&#44; thyroid disease&#44; and metabolic syndrome&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Lung function measurements</span><p id="par0055" class="elsevierStylePara elsevierViewall">Pulmonary function tests were performed by a skilled technician using a standard spirometer &#40;Vmax-2130&#59; Sensor Medics&#44; Yorba Linda&#44; CA&#44; USA&#41;&#46; Calibration and quality control were performed regularly based on guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">22</span></a> Pre-bronchodilator values of FEV<span class="elsevierStyleInf">1</span> and FVC &#40;in liters and percentage of the predicted value&#44; respectively&#41;&#44; the FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio&#44; and forced expiratory flow between 25&#37; and 75&#37; of vital capacity &#40;FEF25&#8211;75&#41; were obtained&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Radiologic findings</span><p id="par0060" class="elsevierStylePara elsevierViewall">Radiologic findings from chest X-rays were collected from radiologists&#46; Patients who were reported to have emphysema&#44; interstitial lung abnormalities&#44; hyperinflation&#44; or bronchiectasis at least once were considered to possess these features&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Definition of airway disease</span><p id="par0065" class="elsevierStylePara elsevierViewall">Airway disease is classified into distinct respiratory disorders&#46; COPD is defined by a pre-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;7&#46; PRISm is defined as a pre-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>0&#46;7 and a FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>80&#37;&#46; The preclinical stage&#44; called pre-COPD&#44; is characterized by respiratory symptoms and structural or functional abnormalities&#44; without obvious airflow limitation at any age&#46; Incorporating criteria for Pre-COPD were as follows&#58; the absence of airflow limitation &#40;FEV<span class="elsevierStyleInf">1</span>&#47;FVC<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>0&#46;7&#41; and FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>80&#37;&#59; abnormal imaging findings like bullae&#44; emphysema&#44; or hyperinflation suggestive of air trapping&#59; or the presence of respiratory symptoms such as chronic bronchitis &#40;defined as cough and phlegm occurring for &#62;3 months per year for &#62;2 years&#41; or dyspnea&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">All statistical analyses were conducted using R software &#40;ver&#46; 4&#46;3&#46;1&#59; R Development Core Team&#44; Vienna&#44; Austria&#41;&#46; The results are expressed as the mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation for continuous variables and as numbers &#40;percentages&#41; for categorical variables&#46; Clinical parameters were compared among normal&#44; pre-COPD&#44; PRISm&#44; and COPD patients using ANOVA for continuous variables and the <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test for categorical variables&#46; Linear mixed models were used to analyze group differences in annual rates of lung function decline over a 12-year period&#44; as indicated by FEV<span class="elsevierStyleInf">1</span>&#44; FVC&#44; the FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio&#44; and FEF25&#8211;75&#59; covariates included age&#44; sex&#44; BMI&#44; smoking history&#44; and baseline FEV<span class="elsevierStyleInf">1</span>&#46; Changes in airway disease categories during follow-up are shown using Sankey diagrams&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Survival analysis was performed to identify the time to first AFO&#44; defined as an FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;7 in the normal&#44; pre-COPD&#44; and PRISm groups&#46; Cox regression models were used to calculate hazard ratios &#40;HRs&#41; of pre-COPD and PRISm &#40;compared to the normal group&#41; for the time to first AFO&#46; Model 1 was adjusted for age&#44; sex&#44; BMI&#44; smoking history and FEV<span class="elsevierStyleInf">1</span>&#44; and model 2 was further adjusted for comorbid cardiovascular disease &#40;CVD&#59; the presence of hypertension&#44; CAD&#44; or CHF&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Multivariate logistic regression was performed to evaluate differences in the risk of future AFO among the normal&#44; pre-COPD&#44; and PRISm groups&#46; We analyzed AFO according to its occurrence at least once during the 12-year study period and its occurrence at the last visit &#40;year 12&#41;&#46; The covariates included age&#44; sex&#44; BMI&#44; and smoking history in model 1&#44; with comorbid CVD added in model 2&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Baseline characteristics of the airway disease group</span><p id="par0085" class="elsevierStylePara elsevierViewall">From the entire KOGES cohort of 10&#44;030 individuals&#44; 4762 were included in the analysis&#59; we excluded those for whom classification of airway disease&#44; and transition thereof&#44; would be challenging due to missing pulmonary function&#44; imaging&#44; and respiratory symptom data&#46; There were 66&#44; 866&#44; 289&#44; and 3541 individuals in the PRISm&#44; pre-COPD&#44; COPD&#44; and normal groups&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#sec0110">Fig&#46; S1</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the baseline characteristics of the four groups&#46; The COPD group was the oldest&#44; had the highest proportions of males &#40;80&#46;6&#37;&#41; and smokers&#44; and had the lowest levels of education and income&#46; Chronic bronchitis symptoms were most prevalent in the pre-COPD and COPD groups&#46; While dyspnea was more common in the airway disease groups compared to the normal group&#44; the severity of dyspnea did not differ significantly among the airway disease groups&#46; Comorbid hypertension was prevalent in both the PRISm and COPD groups&#44; while diabetes was more prevalent in the PRISm group&#46; Baseline spirometry in the PRISm group revealed low values FEV<span class="elsevierStyleInf">1</span> and FVC values&#46; Both the PRISm and COPD groups had low FEF25&#8211;75 values&#46; Emphysema&#44; interstitial lung abnormalities&#44; hyperinflation&#44; and bronchiectasis were more prevalent among the PRISm&#44; pre-COPD&#44; and COPD groups compared to normal group&#46; The feature of hyperinflation was more common in the pre-COPD group compared to the PRISm group&#44; while interstitial lung abnormalities were more frequent in the PRISm group than in the pre-COPD group&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Longitudinal changes of lung function parameters</span><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 1</a> shows the longitudinal trends in pulmonary function indicators&#46; For FEV<span class="elsevierStyleInf">1</span>&#44; the baseline values were higher in the normal and pre-COPD groups compared to the COPD and PRISm groups&#46; However&#44; the rate of decline was more rapid in the pre-COPD group than in the normal group&#44; and the rate was significantly lower in the PRISm group &#40;&#8722;40&#46;2&#44; &#8722;42&#46;6&#44; and &#8722;12&#46;6<span class="elsevierStyleHsp" style=""></span>mL&#47;year in the normal&#44; pre-COPD&#44; and PRISm groups&#44; respectively&#41;&#46; The rate of FEV<span class="elsevierStyleInf">1</span> decline in the PRISm group was significantly slower compared to both the normal and COPD groups&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">The baseline FVC was lowest in the PRISm group&#46; However&#44; the rate of decline was more gradual in the PRISm group &#40;&#8722;2&#46;4<span class="elsevierStyleHsp" style=""></span>mL&#47;year&#41; than in the normal &#40;&#8722;33&#46;7<span class="elsevierStyleHsp" style=""></span>mL&#47;year&#41; and COPD &#40;&#8722;49&#46;9<span class="elsevierStyleHsp" style=""></span>mL&#47;year&#41; groups&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The baseline FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio exceeded 70&#37; in all groups except the COPD group&#46; However&#44; the rate of decline was more rapid in the pre-COPD group than the normal group&#46; Compared to the COPD group&#44; the rate of decline was faster in the normal&#44; pre-COPD&#44; and PRISm groups&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The baseline FEF25&#8211;75 was lower in the PRISm and COPD groups compared to the normal and pre-COPD groups&#46; The rate of decline was more gradual in the PRISm &#40;&#8722;37&#46;9<span class="elsevierStyleHsp" style=""></span>mL&#47;year&#41; and COPD &#40;&#8722;35&#46;9<span class="elsevierStyleHsp" style=""></span>mL&#47;year&#41; groups compared to the normal &#40;&#8722;83&#46;3<span class="elsevierStyleHsp" style=""></span>mL&#47;year&#41; and pre-COPD &#40;&#8722;83&#46;5<span class="elsevierStyleHsp" style=""></span>mL&#47;year&#41; groups&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Transitions of airway group categories</span><p id="par0115" class="elsevierStylePara elsevierViewall">The transitions in airway groups among the enrollment&#44; first assessment&#44; and second assessment timepoints are shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 2</a>&#46; There was no loss to follow-up at both timepoints&#46; Of the subjects with COPD or normal findings at enrollment&#44; approximately 79&#37; and 85&#37;&#44; respectively&#44; showed no change in status at the second assessment&#46; However&#44; of those initially categorized as pre-COPD or PRISm&#44; 65&#37; and 53&#37;&#37;&#44; respectively&#44; transitioned to the normal group&#46; Notably&#44; there were higher rates of transition from PRISm to COPD &#40;13&#46;6&#37;&#41; or pre-COPD &#40;9&#46;1&#37;&#41; compared to the transition from pre-COPD to COPD &#40;4&#46;4&#37;&#41; or PRISm &#40;0&#46;7&#37;&#41;&#46; At subsequent assessments&#44; the majority of subjects in the COPD and normal groups showed no change in status&#46; However&#44; among those classified as pre-COPD&#44; approximately 66&#37; transitioned to normal status&#44; while 3&#46;5&#37; transitioned to COPD&#46; In the PRISm group&#44; 21&#46;6&#37; transitioned to normal status&#44; while 16&#46;2&#37; transitioned to pre-COPD and 10&#46;8&#37; to COPD&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Differences in time to first AFO among the normal&#44; pre-COPD&#44; and PRISm groups</span><p id="par0120" class="elsevierStylePara elsevierViewall">Significant group differences were observed in time to first AFO&#44; in the order of the PRISm&#44; pre-COPD&#44; and normal groups &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 3</a>&#41;&#46; Univariate and multivariate Cox regression analyses were used to evaluate factors influencing the time to first AFO &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; In the univariate analyses&#44; the pre-COPD and PRISm groups had HRs indicating elevated risk compared to the normal group&#46; Old age&#44; male sex&#44; smoking status&#44; low BMI&#44; respiratory symptoms&#44; comorbid CVD&#44; and lower lung function parameters had significant associations with COPD progression&#46; According to multivariate model 1&#44; which considered age&#44; sex&#44; smoking status&#44; BMI&#44; smoking history&#44; education level&#44; income&#44; and chronic bronchitis symptoms&#44; both pre-COPD and PRISm significantly increased the risk of progression to COPD&#46; However&#44; in model 2&#44; which also considered the presence of CVD&#44; the impact of PRISm became non-significant&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Differences in future risk of developing COPD among the groups</span><p id="par0125" class="elsevierStylePara elsevierViewall">To compare the risk of future AFO among groups&#44; we used a multivariate logistic regression model &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; In the univariate analyses&#44; the pre-COPD and PRISm groups had higher risks of developing AFO at least once during the 12-year follow-up &#40;OR 1&#46;89&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; OR 5&#46;14&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; and at the last visit &#40;year 12&#41; &#40;OR 1&#46;66&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; OR 4&#46;31&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41;&#46; In the multivariate analysis adjusting for age&#44; sex&#44; BMI&#44; and smoking history &#40;model 1&#41;&#44; both groups had significantly higher risks of future AFO at least during the 12-year follow-up &#40;OR 1&#46;80&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; OR 4&#46;26&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; and at the last visit &#40;year 12&#41; &#40;OR 1&#46;54&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; OR 3&#46;21&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#44; respectively&#41;&#46; After adding the presence of CVD as a covariate&#44; the significance remained for the pre-COPD group developing AFO at the last visit &#40;OR 1&#46;63&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;019&#41; but was lost for the PRISm group &#40;OR 3&#46;29&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;079&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0130" class="elsevierStylePara elsevierViewall">This prospective cohort study sought to classify a substantial sample of the general population into airway groups based on lung function&#44; respiratory symptoms&#44; and radiological abnormalities&#46; Group transitions were identified by analyzing follow-up data&#46; Indicators of AFO&#44; such as FEV<span class="elsevierStyleInf">1</span>&#44; the FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio&#44; and FEF25&#8211;75&#44; declined more rapidly in the pre-COPD group than in the PRISm group&#46; Moreover&#44; while transitions to normal status or COPD occurred in both the pre-COPD and PRISm groups&#44; more transitions occurred in the PRISm group&#46; Although the risk of developing COPD was much higher in the PRISm group than in the other groups&#44; the risk was nevertheless significantly higher in both the pre-COPD and PRISm groups compared to the normal group&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">This study found that the rates of decline in FEV<span class="elsevierStyleInf">1</span>&#44; the FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio&#44; and FEF25&#8211;75 were notably higher in the pre-COPD group compared to the normal group&#44; and the decline in FEV<span class="elsevierStyleInf">1</span> and FEF25&#8211;75 was slower in the PRISm group compared to the normal group&#46; Moreover&#44; there were significantly more status transitions in the pre-COPD and PRISm groups compared to the other groups&#46; During the initial follow-up period&#44; approximately half of the individuals in both the pre-COPD and PRISm groups transitioned to normal status&#46; In the pre-COPD group&#44; a similar pattern was seen during the second follow-up period&#44; with approximately 55&#37; of patients transitioning to normal status&#46; However&#44; in the PRISm group&#44; a distinct trend emerged&#44; with 51&#37; of patients classified as &#8220;persistently PRISm&#8221; and &#62;10&#37; progressing to COPD during both the first and second follow-up periods&#46; Other cohort studies have reported frequent transitions between PRISm and other lung function groups&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">5&#44;6&#44;10</span></a> and the reported occurrence of AFO in patients with PRISm progressing to COPD is in the range of 15&#8211;40&#37;&#46; In our study&#44; however&#44; the proportion of patients transiting from PRISm to COPD was only approximately 13&#37;&#44; which is lower than that reported elsewhere&#46; Since our study included relatively young subjects &#40;average age of 50 years&#41; and many never-smokers compared to other studies&#44; which often included mainly elderly patients and smokers with &#62;10 pack-years of smoking&#44; it is plausible to attribute these differences to age-related variation in pulmonary function and the influence of cigarette smoking&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">5&#44;6&#44;8</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Given the recent interest in the earlier stages of COPD&#44; the GOLD classified individuals with a high likelihood of developing COPD into pre-COPD and PRISm groups&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">23</span></a> Recently&#44; Miguel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">24</span></a> analyzed risk factors for the progression from pre-COPD to COPD within a cohort of smokers&#44; identifying a low FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio&#44; &#8805;30 pack-years of smoking&#44; BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#44; and a history of chronic bronchitis as risk factors&#46; Our study similarly identified smoking&#44; low BMI&#44; and impaired lung function as risk factors for COPD progression&#44; and the pre-COPD and PRISm patients had higher risks of progression to COPD&#46; However&#44; it is noteworthy that all groups in this study had a mean BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25&#44; possibly reflecting ethnic variation&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Pre-COPD and PRISm contributed to an earlier time to first AFO Another interesting finding in the present study was that both pre-COPD and PRISm significantly shortened the time to first AFO&#44; although this was not seen in the PRISm group when CVD was considered&#46; CVD is thought to be a comorbid condition of COPD&#46; However&#44; a recent Danish study based on the Copenhagen City Heart study&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">25</span></a> which included 1160 individuals aged 20&#8211;40 years&#44; found that incident PRISm could increase the risk of hospitalization for CVDs&#44; such as ischemic heart disease or heart failure&#46; Furthermore&#44; PRISm was associated with obesity&#44; smoking&#44; cardiovascular comorbidities&#44; and increased CVD-related morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">12&#44;26</span></a> Not all individuals with pre-COPD or PRISm will necessarily develop fixed airflow limitation&#46; Particularly in PRISm patients diagnosed solely based on pulmonary function tests&#44; without concurrent respiratory symptoms or imaging findings suggestive of COPD&#44; clinicians should consider the presence of pre-existing CVD&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Considering the socioeconomic impact of COPD&#44; it is necessary to define early disease and examine the effects of early intervention on these patients&#46; However&#44; there are few randomized controlled trials &#40;RCTs&#41; have addressed the early detection and treatment of such individuals who are at-risk for development of COPD&#46; Moreover&#44; a recent RCT reported that the use of dual-bronchodilator inhaler treatment in the PRISm group did not reduce respiratory symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">27</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">This study had several limitations&#46; First&#44; the KoGES cohort did not include post-BD values&#44; necessitating the classification of airway groups based on pre-bronchodilator &#40;BD&#41; values&#46; However&#44; numerous studies have used pre-BD values as an alternative to post-BD values for evaluation of patients with COPD in terms of diagnosis&#44; clinical features and longitudinal outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">28&#8211;31</span></a> Recently&#44; respiratory symptoms were found to be more severe in a post-BD PRISm group compared to a pre-BD PRISm group whose post-BD values were normalized&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a> However&#44; there are few comparative studies of pre-BD and post-BD&#44; and the concept of PRISm includes patients capable of transitioning&#46; Second&#44; radiological abnormalities were ascertained using chest radiographs&#44; not chest computed tomography &#40;CT&#41;&#46; Consequently&#44; structural abnormalities indicative of COPD beyond emphysema and bullae&#44; such as airway wall thickening&#44; were not discernible&#46; However&#44; repeated CT examinations present challenges in terms of time&#44; resources&#44; and radiation exposure-related risks in the general population&#46; Third&#44; the diffusing capacity for carbon monoxide &#40;DLCO&#41; values was not known&#46; Given that DLCO can help to identify individuals with an elevated risk of developing COPD among smokers without AFO&#44; the unavailability of this metric may have resulted in underestimation of the risk of progression to COPD&#46; Fourth&#44; as this cohort did not focused primarily on airway and lung diseases&#44; there were no indicators of airway disease-specific quality of life or the severity of symptoms&#46; However&#44; we addressed this deficiency by using the mMRC dyspnea scale and EQ-5D-5L&#44; derived from multiple inquiries related to dyspnea and general quality of life&#46; Lastly&#44; we were unable to obtain mortality information&#44; and some patients may have passed away during the follow-up period&#46; We have presented the number of participants at each follow-up in <a class="elsevierStyleCrossRef" href="#sec0110">Table S1</a>&#46; From Year 0 to Year 4&#44; there were no missing data&#46; By Year 12&#44; 3352 out of 4762 patients were followed up&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">In conclusion&#44; in a large cohort drawn from the general population&#44; we found that individuals with pre-COPD and those in the PRISm group exhibited comparable differences in the longitudinal changes of lung function parameters over time&#46; Additionally&#44; a significant proportions of individuals in both groups transitioned to other lung function groups over time&#46; As well as age&#44; male sex&#44; lower BMI&#44; and low lung function&#44; pre-COPD and PRISm were identified as risk factors for progression to COPD&#46; However&#44; in PRISm patients&#44; the concurrent presence of CVD should be considered&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ethics approval and consent to participate</span><p id="par0165" class="elsevierStylePara elsevierViewall">Ethical approval was obtained from the Ethics Committee of Incheon St&#46; Mary&#39;s Hospital&#44; and the IRB number was OC23ZISI0033&#46; The requirement for informed consent was waived by the Ethics Committee of Incheon St&#46; Mary&#39;s Hospital&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0240" class="elsevierStylePara elsevierViewall">This research was supported by Basic Science Research Program through the National Research Foundation of Korea &#40;NRF&#41; funded by the Ministry of Education &#40;grant number&#41; &#40;NRF-2022R1I1A1A01063654&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Author&#39;s contributions</span><p id="par0175" class="elsevierStylePara elsevierViewall">YSJ and JYC contributed to study concept&#47;study design&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">YSJ and JYC contributed to data acquisition and analysis&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">All authors contributed to interpretation for the work&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">YSJ and JYC contributed to drafting the work&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">All authors contributed to critical revision for relevant intellectual content and final approval of this manuscript&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicts of interests</span><p id="par0200" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Data availability statement</span><p id="par0205" class="elsevierStylePara elsevierViewall">The raw data involved in this study will be available by the corresponding author to any qualified researcher&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Declaration of generative AI and AI-assisted technologies in the writing process</span><p id="par0210" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "palabras" => array:6 [
            0 => "Pre-COPD"
            1 => "PRISm"
            2 => "COPD"
            3 => "Transition"
            4 => "Lung function"
            5 => "KoGES"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Introduction</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Chronic obstructive pulmonary disease &#40;COPD&#41; is a dynamic disease with a high socioeconomic burden&#46; Using data collected prospectively from the general population&#44; we examined factors related to the transition of at-risk individuals to COPD&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Methods</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We used the Korean Genome Epidemiology Study &#40;KoGES&#41; database&#44; defining pre-COPD based on respiratory symptoms and radiological abnormalities suggestive of COPD&#59; the preserved ratio impaired spirometry &#40;PRISm&#41; was defined as a forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s &#40;FEV<span class="elsevierStyleInf">1</span>&#41;&#47;forced vital capacity ratio<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>70&#37; and FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>80&#37;&#44; as predicted by spirometry&#46; We determined group differences in the rate of lung function decline&#44; risk of future airflow obstruction &#40;AFO&#41;&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Results</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The study included 4762 individuals&#44; and longitudinal analysis revealed distinct trends in pulmonary function indicators&#46; Compared to the normal group&#44; the pre-COPD group showed a more rapid decline in lung function&#44; while the PRISm group showed a slower decline&#46; In the pre-COPD and PRISm groups&#44; 4&#46;4&#37; and 3&#46;5&#37;&#44; and 13&#46;6&#37; and 10&#46;8&#37;&#44; respectively&#44; of patients had progressed to COPD at the first and second visits&#46; Pre-COPD and PRISm contributed to an earlier time to first AFO&#44; but consideration of comorbid cardiovascular disease weakened this relationship in the PRISm group&#46; Multivariate logistic regression showed that pre-COPD and PRISm are significant risk factors for future development of COPD &#40;OR 1&#46;80&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; OR 4&#46;26&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusion</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Pre-COPD and PRISm patients showed different trends in lung function changes over time and both were significant risk factors for future development of COPD&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Conclusion"
          ]
        ]
      ]
    ]
    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic obstructive pulmonary disease &#40;COPD&#41; has been shown to be a progressive disease with various precursors&#44; including pre-COPD and preserved ratio and impaired spirometry &#40;PRISm&#41;&#46; These states were identified as potentially lead to COPD&#44; but their lung function trajectories and risks associated with their progression were not fully understood&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">This study reveals distinct trends in longitudinal lung function trajectories in patients with pre-COPD and PRISm&#46; It identifies these conditions as significant risk factors for future COPD development&#46; However&#44; in PRISm patients&#44; the concurrent presence of cardiovascular disease &#40;CVD&#41; should be considered&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Our findings emphasize the importance of early detection and intervention in individuals with pre-COPD and PRISm&#46;</p></li></ul></p></span>"
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0235" class="elsevierStylePara elsevierViewall">The followings are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix B"
            "titulo" => "Supplementary data"
            "identificador" => "sec0115"
          ]
        ]
      ]
    ]
    "multimedia" => array:9 [
      0 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1962
            "Ancho" => 3500
            "Tamanyo" => 326587
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Differences in the rate of lung function decline over time among four different airway disease status groups &#40;COPD&#44; normal&#44; pre-COPD&#44; and PRISm&#41;&#46; &#40;A&#41; FEV<span class="elsevierStyleInf">1</span>&#59; &#40;B&#41; FVC&#59; &#40;C&#41; FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio&#59; &#40;D&#41; FEF25&#8211;75&#46; &#42; vs normal &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; &#35; vs COPD &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; COPD&#44; chronic obstructive pulmonary disease&#59; FEF&#44; forced expiratory flow&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s&#59; FVC&#44; forced vital capacity&#59; PRISm&#44; preserved ratio impaired spirometry&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 2141
            "Ancho" => 3500
            "Tamanyo" => 400196
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Transitions among four different airway disease statuses &#40;COPD&#44; normal&#44; pre-COPD&#44; and PRISm&#41; shown using a Sankey diagram&#46; Transitions from the &#40;A&#41; normal&#44; &#40;B&#41; pre-COPD&#44; &#40;C&#41; PRISm&#44; and &#40;D&#41; COPD groups&#46; COPD&#44; chronic obstructive pulmonary disease&#59; PRISm&#44; preserved ratio impaired spirometry&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 2656
            "Ancho" => 2667
            "Tamanyo" => 225984
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Time to first AFO in the normal&#44; pre-COPD and PRISm groups&#46; AFO&#44; airflow obstruction&#59; COPD&#44; chronic obstructive pulmonary disease&#59; PRISm&#44; preserved ratio impaired spirometry&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">BMI&#44; body mass index&#59; CAD&#44; coronary artery disease&#59; CHF&#44; congestive heart failure&#59; COPD&#44; chronic obstructive pulmonary disease&#59; DM&#44; diabetes mellitus&#59; FEF&#44; forced expiratory flow&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s&#59; FVC&#44; forced vital capacity&#59; HTN&#44; hypertension&#59; KRW&#44; Korean won&#59; mMRC&#44; modified Medical Research Council&#59; PRISm&#44; preserved ratio impaired spirometry&#46;</p>"
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39 &#40;59&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">233 &#40;80&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">BMI &#40;kg&#47;m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">24&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">24&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">237 &#40;6&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">72 &#40;8&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;3&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">27 &#40;9&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>University or above&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Income</span></td><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;4&#44;000&#44;000 KRW&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">63 &#40;7&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;7&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Nutrition&#44; total energy&#44; kcal</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1844&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>541&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Never smoker&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2125 &#40;60&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">534 &#40;62&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32 &#40;48&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77 &#40;26&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Former smoker&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">632 &#40;17&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">146 &#40;17&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;21&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89 &#40;30&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Current smoker&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">778 &#40;22&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>DM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CHF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dyslipidemia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Metabolic syndrome&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FVC&#44; &#37;predicted&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span> FEV<span class="elsevierStyleInf">1</span>&#44; L&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span>&#44; &#37;predicted&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">113&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">115&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span>&#47;FVC &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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