bmj open 2014 scholes

8112019 BMJ Open 2014 Scholes

httpslidepdfcomreaderfullbmj-open-2014-scholes 113



comorbidities and mortality Estimation of the diseaseburden has been hindered however b y differences inmethods including spirometric cut-offs5ndash8 Fixed thresh-olds (FTs) use cut-offs for lung function measurements(eg forced expiratory volume in 1 sforced vital capacity (FEV 1FVC) rat io lt07) regardless of age sex height and ethnicity9 An additional threshold for per

cent-of-predicted FEV 1 (expected for persons of a givenage sex height and ethnicity) is also commonly usedfor severity classi1047297cation In contrast a lower limit of normal (LLN) cut-off uses a statistical de1047297nition of abnormalnormal (eg belowabove the lower 5thcentile of the distribution of age-speci1047297c sex-speci1047297cheight-speci1047297c and ethnic-speci1047297c FEV 1FVC v aluesfrom a healthy lifelong non-smoking population)10

At present applying FTs such as FEV 1FVC lt07 is thestandard approach However the European Respiratory Society (ERS) Task Force on epidemiology recently advo-cated using the LLN in epidemiological studies as FTsoverestimate air1047298ow obstruction in older populations

due to the physiological reduction of FEV 1FVC withage and underestimate in young adults compared withLLN11ndash16 The controversy over FT versus LLN thresh-olds is well known with no signs of a consensus among expert groups being agreed17ndash21

Partly as a result of this controversy the COPD epi-demiological database shows heterogeneity in de1047297nit ionsand consequential estimates of the disease burden5 22

Two nationally representative samples Wave 2 (2010ndash2012) of the UK Household Longitudinal Survey (UKHLS lsquoUnderstanding Society rsquo) and the HealthSurvey for England (HSE) 2010 collected lung function

data using identical measurement protocols and special-ist equipment providing an opportunity to increase stat-istical precision by combining both data sets Thereforethe primary objective of the present study was tocompare the prevalence of lsquopotentialrsquo air1047298ow obstruc-tion according to FT and LLN thresholds among persons aged 40ndash95 years living in England and Walespotential in the sense that the administration of bronch-odilators to measure the extent of reversibility in air1047298ow obstruction was not used As a secondary aim we com-pared the sensitivity of associations with risk factorsincluding age sex smoking history and socioeconomicposition Using the same variables we also examined thecharacteristics associated with spirometry in connection with self-reported physician-diagnosed COPD

METHODOLOGYStudy design and settingThe UKHLS and HSE selected participants using strati-1047297ed multistage probability sampling designs23

Self-reported health information risk factors and demo-graphics were collected through face-to-face interviewsfollowed by a visit from a trained nurse during whichlung function was measured Response rates for the Wave

2 interview (among individuals issued) and nurse visit

(among eligible participants in the Wave 2 interview) were 61 and 59 respectively in UKHLS In HSE2010 interview (among the estimated total number of adults in sampled households) and nurse-visit (adults inco-operating households) response rates were 59 and57 Sampling methods are described elsewhere24ndash26

Eligible participants gave written consent to participate

in spirometry

Questionnaire and proceduresParticipants were excluded from spirometry for the fol-lowing safety reasons pregnancy had in the past 3 months abdominalchest surgery a heart attackdetached retina or eye or ear surgery admitted to hos-pital with a heart complaint in the preceding month aresting pulse rate gt120 bpm or currently taking medica-tions for the treatment of tuberculosis Spirometry without bronchodilator use was conducted using NDDEasyOne PCC spirometers (NDD Medical TechnologiesZurich Switzerland) Quality control was summarised in

a session grade based on the number of technically acceptable blows and their reproducibility Grades A (three acceptable manoeuvres two highest FVC andFEV 1 within 100 mL) B (three acceptable manoeuvrestwo highest FVC and FEV 1 within 150 mL) and C (twoor three acceptable manoeuvres within 200 mL) wereconsidered good quality Full det ails on measurement procedures are available elsewhere25ndash27

The highest values for FEV 1 and for FVC from at least three and up to eight blows were used Age-speci1047297c sex-speci1047297c height-speci1047297c and ethnic-speci1047297c predicted values and z-scores (FEV 1 FVC and FEV 1FVC) were

computed using the ERS Global Lungs Initiative (GLI2012 httpwwwlungfunctionorg ) reference equa-tions These have been prepared by an international col-laboration based on data spanning 26 countries fromgt70 000 healthy individuals across four ethnic groups(Caucasian African-American and North-East Asianand Sout h-East Asian) valid for persons aged 3ndash95 years28 29 and have been sho wn to 1047297t contemporary Australasian spirometric data30

FT and LLN spirometric cut-offsUsing FTs we applied the 2007 Global Initiative forChronic Obstructive Lung Disease (GOLD) classi1047297ca-tion31 which was designed for use with postbronchodila-tor spirometry potential air1047298ow obstruction was de1047297nedas FEV 1FVC lt07 (FT) Disease stage was de1047297ned by the reduction in FEV 1 relative to per cent-of-predicted values as follows stage I (FEV 1FVC lt07 and FEV 1ge80 of predicted) stage II (FEV 1FVC lt07 and FEV 150ndash79 of predicted) and stage III+ (FEV 1FVC lt07and FEV 1 lt50 of predicted)32 Participants withFEV 1FVC ge07 were de1047297ned as non-obstructed

Participants with FEV 1FVCltLLN (below the lower5th centile of the distribution of z-scores) were de1047297nedas obstructed (LLN) To examine possible heterogeneity

among participants with FEV 1FVCltLLN disease stage

2 Scholes S et al BMJ Open 20144e005685 doi101136bmjopen-2014-005685

Open Access

groupbmjcomon August 3 2014 - Published by bmjopenbmjcomDownloaded from



was de1047297ned by FEV 1 relative to LLN as follows stage I(FEV 1FVCltLLN and FEV 1geLLN) and stage II(FEV 1FVCltLLN and FEV 1ltLLN)33 Participants withFEV 1FVCgeLLN were de1047297ned as non-obstructed The1047297fth centile was chosen due to its established associa-tions with respiratory symptoms and all-cause mortality34

Physician-diagnosed COPDIn UKHLS disease status was ascertained through ques-tions asking ldquoHas a doctor or other health professionalever told you that you have [disease]rdquo Diagnosed COPD was de1047297ned as a positive response to either chronicbronchitis or emphysema In HSE diagnosed COPD wasde1047297ned as a positive response to the question ldquoDid adoctor ever tell you that you had chronic bronchitisemphysema or COPDrdquo

Risk factors measurements of lung function andcomorbiditiesKey subgroups were de1047297ned by age (40ndash54 55ndash64

65ndash74 75ndash95) sex smoking status (current formernever) pack-years of cigarette smoking (a cumulativetotal re1047298ecting the amount and duration of consump-tion with 1 pack-year equating to an average of 20 cigar-ettes smokedday for 1 year) and socioeconomicposition de1047297ned by the National Statistics Socio-Economic Classi1047297cation (NS-SEC) grouped into profes-sional intermediate and routine occupations

FEV 1 FVC and FEV 1FVC on a continuous scale were expressed as per cent-of-predicted values Additional variables included current use of respiratory medicine area of residence (urbanrural) body mass

index (weight in kilograms divided by the square of height in metres) grouped into normal weight (185ndash249 kgm2) overweight (25ndash299 kgm2) and obese(ge30 kgm2) diagnosed diabetes poor self-rated healthand reported cardiovascular disease (stroke anginamyocardial infarction) In HSE participants were askedto name any long-standing illness respiratory diseases were identi1047297ed using International Classi 1047297 cation of Diseases

Tenth Revision codes J00-J99 In the HSE presence of respiratory symptoms was de1047297ned as usually coughing 1047297rst thing in the morning for at least 3 monthsyearand bringing up phlegm from the chest most days forthree consecutive months in a year In the HSE partici-pants with some limitation of activity due to breathless-ness during daily living were identi1047297ed by a score of 3+on the Medical Research Council (MRC) dyspnoeascale Exposure to passive smoking in the HSE was mea-sured by reported number of hoursweek currently exposed to cigarette smoke (0 1ndash9 and ge10 h)

Statistical analyses A lower age limit was used of 40 years due to the low prevalence of non-ast hma air1047298ow obstruction in the youngest age groups35 As bronchodilators were not used w e excluded participants who reported diagnosed

asthma34 36ndash

38 Five sets of analyses were conducted

across the categories of diagnosed COPD FT and LLNFirst participantsrsquo characteristics (demographics risk factors comorbidities and per cent-of-predicted FEV 1FVC and FEV 1FVC) were summarised as means accom-panied by SD or as counts accompanied by percentagesParticipants were counted under each relevant de1047297n-ition Participants withwithout obstruction were com-

pared using the χ

2

test and analysis of variance forcategorical and continuous variables respectively39

Second prevalence estimates were computed for asubset of sociodemographic variables de1047297ned by agesex smoking status pack-years of cigarette smoking andNS-SEC Third in the absence of a gold standard wecalculated the sensitivity and speci1047297city of each spiro-metric criterion using the alternative cut-off as the refer-ence standard40

Fourth regression analyses were performed using agesex pack-years of smoking and NS-SEC as independent variables with air1047298ow obstruction as outcome Current smoking status could not be entered in the same model

as pack-years due to signi1047297cant collinearity The depend-ent variable based on FTs had four categories non-obstructed stage I stage II and stage III+ TheLLN-derived outcome had three categories non-obstructed stage I and stage II In each case multi-nomial logistic regression was used to estimate relativerisk ratios (RRRs) with non-obstructed as the referencecategory Multinomial logistic regression generaliseslogistic regression to outcomes with more than two pos-sible discrete outcomes The RRR is interpreted as therelative risk of one outcome in relation to the referencecategory for a speci1047297ed category of an independent vari-

able compared with the reference41 42

DiagnosedCOPD was analysed as a binary outcome (not reportedreported) logistic regression was therefore used to esti-mate ORs39 41 The overall association for independent variables with gt2 categories was computed using theadjusted Wald test The likelihood ratio test was used toestimate the statistical signi1047297cance of interaction termsnon-signi1047297cant terms were excluded and models re1047297t-ted with only the main effects

Fifth to examine risk factors associated with possibleunderdiagnosis a four-category outcome variable wascreated combining diagnosed COPD and spirometriccriteria as follows (1) neither diagnosed nor spirometri-cally de1047297ned obstruction (2) physician-diagnosedCOPD but no obstructive spirometry (3) spirometrically de1047297ned but no diagnosed COPD and (4) both diag-nosed and obstructive spirometry43 FT and LLN cut-offs were analysed separately RRRs generated from multi-nomial logistic regressions were used to examine associa-tions between the same set of risk factors listed aboveand the composite dependent variable

Participants with missing values on covariates wereexcluded from relevant analyses Tests of statistical sig-ni1047297cance were based on two-sided probability (plt005)Data set preparation was performed in SPSS V200

(SPSS IBM Inc Chicago Illinois USA) Stata V131

Scholes S et al BMJ Open 20144e005685 doi101136bmjopen-2014-005685 3

Open Access




(StataCorp College Station Texas USA) and R (V303R Foundation httpwwwr-projectorg ) Analysis wasconducted in Stata accounting for the complex designof both surveys using the appropriate weighting vari-ables and primary sampling units Both datasets areavailable via the UK Data Service (httpwwwukdataserviceacuk )

Sensitivity analyses Analyses were initially undertaken excluding participants with reported diagnosed asthma and then repeatedincluding those with asthma In accordance with the previous UK National Institute for Health and CareExcellence (NICE) recommendations44 comparisonsbetween FT and LLN were rerun de1047297ning only thesubset of FT participants with FEV 1 lt80 of predicted(ie stage II+) as having obstructed air1047298ow

RESULTS

The analytical sample comprised 7879 participants(5936 and 1943 from UKHLS and HSE respectively)aged 40ndash95 years who resided in England and Walesdid not report diagnosed asthma had valid values of height and ethnicity and provided good-quality spirom-etry Response 1047298ow charts for the UKHLS and HSE areprovided in online supplementary 1047297gures S1 and S2respectively Excluded participants were more likely tobe older engaged in routine occupations and self-reported respiratory symptoms (data not shown)Differences between the UKHLS and HSE in terms of sex ratio age smoking history NS-SEC and objective

measurements of lung function were not materially important (see online supplementary table S1)

Descriptive characteristics of the analytical sampleaccording to physician-diagnosed COPD FT and LLN areshown in online supplementary tables S2 and S3 Overall468 of participants were men with mean age576 years (SD 123) 166 were current smokers 46had gt50 pack-years of cigarette smoking and 365 wereengaged in professional occupations Twelve (01) and265 (32) participants had missing values for pack-yearsand NS-SEC respectively The prevalence of diagnosedCOPD was similar between the sexes (p=0349) but washigher for men using FT and LLN (both plt0001)Participants with diagnosed COPDobstructive spirom-etry were more likely to be older currently smoke havehigher pack-years of smoking and be engaged in routineoccupations (all plt0001) Prevalence of diagnosedCOPD was higher in HSE versus UKHLS (plt0001) but survey-speci1047297c prevalence was similar for FT and for LLNParticipants with diagnosed COPDobstructive spiro-metry were more likely to report respiratory symptoms(chronic cough and phlegm) and disease current use of respiratory medications cardiovascular disease breath-lessness poor self-rated health and have on averagelower (per cent-of-predicted) values of FEV 1 FVC and

FEV 1FVC The prevalence of respiratory symptoms was

137 102 and 113 among participants classed ashaving air1047298ow obstruction according to diagnosedCOPD FT and LLN respectively prevalence of having ascore of 3+ on the MRC dyspnoea scale was 348 123and 159

Prevalence of airflow obstruction

The prevalence of air1047298

ow obstruction was 28 222and 131 using diagnosed COPD FT and LLN respect-ively (table 1) Using FTs 116 89 and 17 of parti-cipants were classed as stage I stage II and stage III+respectively LLN-derived obstruction was 66 (stage I)and 64 (stage II) For most subgroups prevalence washighest for FT and lowest for diagnosed COPD with LLNfalling in between The gap in prevalence between FTand LLN increased in older age groups Prevalenceamong participants aged 40ndash54 years was 119 and107 using FT and LLN respectively Prevalence among participants aged 75ndash95 was 45 and 172

Table 2 shows estimates of sensitivity and speci1047297city for

FT and LLN using the alternative spirometric cut-off asthe reference standard When using LLN as referencespeci1047297city mdashthe percentage of participants classed asnon-obstructed using LLN identi1047297ed as non-obstructedusing FTmdashdecreased from 949 among participantsaged 40ndash64 years to 744 among those aged 65ndash95

Multivariate analyses of airflow obstructionTable 3 shows the signi1047297cant risk factors for diagnosedCOPD and the FT and LLN disease stage classi1047297cations(non-obstructed as reference category) For diagnosedCOPD the signi1047297cant interaction between sex and age

group (p=0022) suggested no difference in oddsbetween the sexes among participants aged 40ndash64 yearsbut higher odds among men aged 65ndash95 Using FTsbeing male was associated with a signi1047297cantly increasedrisk of air1047298ow obstruction RRR 135 (95 CI 116 to158) RRR 135 (112 to 163) and RRR 172 (108 to276) for stages I II and III+ respectively In contrastsex differences were not signi1047297cant using LLN RRR 107 (088 to 131) for stage I and RRR 120 (096 to150) for stage II

Odds of diagnosed COPD increased signi1047297cantly withage only in men ( p=0022 for the interaction term)Using non-obstruction as reference RRRs increased sig-ni1047297cantly with age when using FTs (plt0001 for eachstage) The age-related difference using LLN was moremarked for stage II (p=0492 and plt0001 for stages Iand II respectively) A dose-related increased risk withpack-years of cigarette smoking was observed across eachde1047297nition (plt0001) The difference between NS-SEClevels was more marked with diagnosed COPD(p=0012) and the tightest FT and LLN de1047297nitions (FTp=0002 stage III+ LLN plt0001 stage II)

Combination of diagnosed COPD and spirometric cut-offsThe signi1047297cant risk factors for the two four-category

outcome variables created as a composite of diagnosed


Open Access






COPD and obstructive spirometry are shown in table 4Relative to the reference category (neither doctor-diagnosed nor spirometrically de1047297ned air1047298ow obstruc-tion) the risk of reporting COPD in the absence of

obstructive spirometry was signi1047297cantly lower in menusing either spirometric criterion (FT RRR 053 (95CI 032 to 087) LLN RRR 056 (035 to 089)) Therisk of having obstructed air1047298ow using spirometry but with no diagnosed COPDmdashthereby indicating possibleunderdiagnosismdash was signi1047297cantly higher in men and inolder age groups when using FT but not LLN For bothspirometric criterions increases in risk with increasing pack-years of cigarette smoking relative to the reference was consistent across combinations of COPDobstructivespirometry the difference between NS-SEC levels wasmore marked for obstructive spirometry

Sensitivity analysesRepeating analyses by including 1183 participants withreported diagnosed asthma increased prevalence of diagnosed COPD FT and LLN by 2ndash3 percentage points(see online supplementary 1047297gure S3) but showedsimilar patterns of association with risk factorsDiagnosed asthma was a strong predictor of diagnosedCOPD and obstructive spirometry (plt0001 data not shown) Narrowing FT-de1047297ned obstruction to the subset of FT participants with FEV 1 lt80 of predicted (iestage II+) more than halved the FT-derived prevalence(222 vs 106) Among participants aged 65ndash95 years

speci1047297city using LLN as the reference standard was

744 and 911 for FT and FT stage II+ respectively (table 2) Patterns of association with risk factors using FT stage II+ were similar to those shown for FT

DISCUSSIONConsistent estimation of the COPD burden has beenhindered by differences in methods including disagree-ment among expert s o ver the choice of FT versus LLNspirometric cut-offs5ndash8 In this study we combined twonationally representative surveys with standardised pro-tocols and objective lung function measurements toevaluate the impact of different de1047297nitions on the preva-lence of potential air1047298ow obstruction and its associa-tions with key risk factors Participants with diagnosedCOPDobstructive spirometry were more likely to beolder currently smoke have higher pack-years of cigar-ette smoking be in lower socioeconomic groups andreport the presence of respiratory symptoms (chroniccough and phlegm) cardiovascular disease breathless-ness and poor self-rated health Among persons aged40ndash95 years without physician-diagnosed asthma preva-lence was 28 222 and 131 according to diag-nosed COPD FT and LLN respectively The gap inprevalence between FT and LLN increased in older agegroups When using LLN as the reference standard spe-ci1047297city for FT decreased from 949 among participantsaged 40ndash64 years to 744 among participants aged 65ndash95 corresponding to false-positive rates of 51 and

256 respectively Sex differences in the risk of

Table 2 Sensitivity and specificity of FTs and LLN spirometric criteria by age group persons aged 40ndash95 years without

diagnosed asthma Health Survey for England 2010 and UK Household Longitudinal Survey Wave 2 (2010ndash2012)

40ndash64 (n=5544) 65ndash95 (n=2335) 40ndash64 (n=5544) 65ndash95 (n=2335)

FT using LLN as reference standard LLN using FT as reference standard

False positives () 51 256 04 00

False negatives () 25 00 280 576

Sensitivity 0975 1000 0720 0424

Specificity 0949 0744 0996 1000

PPV 0720 0424 0975 1000

NPV 0996 1000 0949 0744

κ coefficient 0801 0479 0801 0479

Likelihood ratio positive 1898 390 20065 NA

Likelihood ratio negative 0027 0000 0281 0576

FT (stage II+) using LLN as reference

standard

LLN using FT (stage II+) as reference

standard



Sensitivity 0508 0733 0840 0609

Specificity 0987 0911 0937 0948

PPV 0840 0609 0508 0733NPV 0937 0948 0987 0911

κ coefficient 0597 0596 0597 0596

Likelihood ratio positive 3882 828 1327 1167


FTs fixed thresholds LLN lower limit of normal (below the 5th centile of z-scores) NPV negative predictive value PPV positive predictivevalue


Open Access








obstructed air1047298ow after adjustment for potential con-founders were sensitive to spirometric criteria being higher among men for FT compared with no differenceusing LLN

Strengths and limitations Analyses were based on nationally representative

samples with identical measurement protocols and spe-cialist equipment for collecting lung function dataCombining the HSE and UKHLS data sets increased stat-istical precision for spirometry-based estimates particu-larly for population subgroups and allowed detailedanalyses to be conducted Predicted values and z-scores were obtained from the ERS GLI 2012 reference equa-tions28 facilitating inclusion of older participants non- white populations and comparability with internationalstudies Our study has a number of limitationsReversibility in air1047298ow obstruction could not be assesseddue to bronchodilators not being used Spirometry-based prevalence therefore may be overestimated

Analysis of the National Health and NutritionExamination Survey (NHANES) 2007ndash2010 showed that FT and LLN prevalence estimates among US adults aged40ndash79 years decreased in relative terms by approxi-mat ely one-third after administration of bronchodila-tors45 Although recent guidelines from NICE46 andERS13 recommend use of postbronchodilator spirometry to con1047297rm the presence of air1047298ow obstruction debatecontinues over its use in epidemiological settings withthe arguments against including ethical issues such aspossible side effects and contraindications47 Potentialmisclassi1047297cation of disease status through bronchodila-

tors not being used was reduced by excluding partici-pants with physician-diagnosed asthma Someparticipants in the analytical sample however may beundiagnosed asthmatics On the other hand the diseaseburden may be underestimated through excluding parti-cipants with poor-quality spirometry Participation inspirometry and achievement of good-quality standardsamong participants with any spirometry data was higheramong participants of younger age engaged in profes-sionalmanagerial occupations non-smokers and withno physician-diagnosed COPD Lower survey participa-tion rates among sociodemographic groups at higherrisk of air1047298ow obstruction (eg older persons lowersocioeconomic groups) would also have led to an under-estimation of true prevalence These limitationshowever are unlikely to affect comparisons across de1047297ni-tions but may have led to an underestimate of risk asso-ciations The list of health conditions in the UKHLSinterview programme included chronic bronchitis andemphysema but not COPD leading to potential under-estimation of self-reported physician-diagnosed COPD

Comparisons with previous studiesEarlier analyses of HSE data36 38 48 used older referenceequations49 50 applicable only to white younger popula-

tions Nevertheless estimates of prevalence and their

substantive conclusions of higher prevalence using FT versus LLN with a widening gap in prevalence in olderage groups and sex differences when using FT but not LLN were similar to ours con1047297rming 1047297ndings reportedin the USA45 Europe51 K orea16 internationally12 andin recent literature reviews6 52 A further strength of ourstudy was the wide range of clinically relevant conditions

examined in the context of disease staging with higherprevalence of respiratory symptoms respiratory and car-diovascular diseases breathlessness and poor self-ratedhealth among participants in the tightest de1047297nitions of FT and LLN obstruction con1047297rming similar 1047297ndings inthe USA53 54 While recent guidelines13 46 55 recom-mend adopting multidimensional de1047297nitions of respira-tory disease our study outcomes were de1047297ned only using spirometry While we acknowledge the merits of amultidimensional approach and agree that neitherspirometric cut-off is able to fully characterise thecomplex diagnostic features of COPD56 our primary aim was to use up-to-date survey data to evaluate differ-

ences in prevalence according to FT and LLN thresh-olds to provide baseline data for monitoring purposesin the UK and promote comparability with internationalstudies Current recommendations regarding symptomcriteria are less speci1047297c than those for spirometry Wechose therefore to examine the associations betweendisease staging assessed only using spirometry and pres-ence of respiratory symptoms rather than broaden thede1047297nition of disease

ImplicationsRecent UK studies used administrative primary care

databases to report the number of diagnosed andtreated patients thereby missing undiagnosed casesSuch studies have reported prevalence below 25 7 58

The disparity in prevalence from clinical versus epi-demiological studies led to the development of theCOPD prevalence model with the HSE 2001 used asinput data to more accurately estimate prevalence59 Inaccordance with previous NICE recommendations44

COPD is currently de1047297ned in the model as FT stage II+(FEV 1FVC lt07 and FEV 1 lt80 of predicted) with thelogistic regression models showing sharp increases withage and a modifying effect of gender60 61 Similar to the1047297ndings reported by Jordan et al 36 our study shows that the strength of association between risk factors andair1047298ow obstruction varies according to spirometric criter-ion with age and sex differences in risk being moremarked for FT and for FT stage II+ than LLN In theabsence of agreement among experts policymakersclinicians and researchers building the COPD epidemio-logical database it is important to appreciate the sensi-tivity of estimates of the disease burden and itsdistribution across sociodemographic groups to differ-ences in methods including spirometric cut-offs

The prevalence of reported physician-diagnosedCOPD in our study was 28 considerably lower

than spirometry-based estimates possibly indicating


Open Access




considerable under-recognition by participants and phy-sicians Using the tightest de1047297nitions prevalence of physician-diagnosed COPD among participants withobstructive spirometry was 302 (FT stage III+) and147 (LLN stage II) Similar low rates of physiciandiagnosis among participants meeting spirometric cri-teria have been reported in New Zealand62

Spirometrically de1047297

ned air1047298

ow obstruction but no diag-nosed COPD does not necessarily indicate underdiagno-sis De1047297nitive diagnosis requires further information onall relevant clinical factors particularly respiratory symp-toms and smoking history as well as postbronchodilatorspirometry

CONCLUSIONIn summary we have enhanced the COPD epidemio-logical database by evaluating the impact of different de1047297nitions on the prevalence of potential air1047298ow obstruction and its associations with key risk factors and

comorbidities With no gold standard currently availablelongitudinal studies examining differences in unsched-uled hospital admissions and risk of death between FTand LLN may inform the choice as to the best way toinclude spirometric data in multidimensional assess-ments of air1047298ow obstruction in clinical and epidemio-logical settings

Acknowledgements The authors thank Deborah Jarvis Janet Stocks and

Jessica Sheringham for helpful comments

Contributors SS AM and JSM participated in study concept and design

analysis and interpretation of data SS performed data acquisition and

management SS participated in drafting of the manuscript AM and JM aided

revision of the manuscript and provided relevant intellectual input SS is thedata guarantor All authors have approved the final version of the manuscript

Funding The Health Survey for England 2010 was funded by the Health and

Social Care Information Centre (HSCIC)

Competing interests None

Ethics approval Ethical approval for collecting biosocial data in UKHLS was

obtained from the Oxfordshire A Research Ethics Committee (10H06042)

approval for HSE 2010 was obtained from the Oxfordshire B Research Ethics

Committee (09H060573)

Provenance and peer review Not commissioned externally peer reviewed

Data sharing statement Both datasets are available via the UK Data Service

(httpwwwukdataserviceacuk ) Statistical code is available from the

corresponding author at sscholesuclacuk

Open Access This is an Open Access article distributed in accordance with

the Creative Commons Attribution Non Commercial (CC BY-NC 40) license

which permits others to distribute remix adapt build upon this work non-

commercially and license their derivative works on different terms provided

the original work is properly cited and the use is non-commercial See http

creativecommonsorglicensesby-nc40

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prevalence and future trends Lancet 2007370765ndash732 Raherison C Girodet PO Epidemiology of COPD Eur Respir Rev

200918213ndash213 Lozano R Naghavi M Foreman K et al Global and regional

mortality from 235 causes of death for 20 age groups in 1990 and

2010 a systematic analysis for the Global Burden of Disease Study2010 Lancet 20123802095ndash128

4 Department of Health An Outcomes Strategy for COPD andasthma NHS Companion Document 2012 httpswwwgovuk governmentuploadssystemuploadsattachment_datafile216139 dh_128428pdf

5 Atsou K Chouaid C Hejblum G Variability of the chronic obstructivepulmonary disease key epidemiological data in Europe systematicreview BMC Med 201197

6 Rycroft CE Heyes A Lanza L et al Epidemiology of chronicobstructive pulmonary disease a literature review Int J Chron Obstruct Pulmon Dis 20127457ndash94

7 McLean S Wild SH Simpson CR et al Models for estimatingprojections for the prevalence and disease burden of chronicobstructive pulmonary disease (COPD) systematic review protocolPrim Care Respir J 201322S8ndash21

8 Salvi SS Manap R Beasley R Understanding the true burden ofCOPD the epidemiological challenges Prim Care Respir J 201221249ndash51

9 Pauwels RA Buist AS Calverley PM et al Global strategy for thediagnosis management and prevention of chronic obstructivepulmonary disease NHLBIWHO Global Initiative for ChronicObstructive Lung Disease (GOLD) Workshop summary Am J Respir Crit Care Med 20011631256ndash76

10 Miller MR Hankinson J Brusasco V et al Standardisation ofspirometry Eur Respir J 200526319ndash38

11 Miller MR Quanjer PH Swanney MP et al Interpreting lung functiondata using 80 predicted and fixed thresholds misclassifies more

than 20 of patients Chest 201113952ndash912 Swanney MP Ruppel G Enright PL et al Using the lower limit of

normal for the FEV1FVC ratio reduces the misclassification ofairway obstruction Thorax 2008631046ndash51

13 Bakke PS Ronmark E Eagan T et al Recommendations for epidemiological studies on COPD Eur Respir J 2011381261ndash77

14 Hansen JE Sun XG Wasserman K Spirometric criteria for airwayobstruction use percentage of FEV1FVC ratio below the fifthpercentile not lt 70 Chest 2007131349ndash55

15 Roberts SD Farber MO Knox KS et al FEV1FVC ratio of 70misclassifies patients with obstruction at the extremes of age Chest 2006130200ndash6

16 Hwang YI Kim CH Kang HR et al Comparison of the prevalenceof chronic obstructive pulmonary disease diagnosed by lower limit ofnormal and fixed ratio criteria J Korean Med Sci 200924621ndash6

17 Quanjer PH Cole TJ COPD and GOLD stage I Chest 20121411122

18 Enright P Brusasco V Counterpoint should we abandon FEV(1) FVC lt070 to detect airway obstruction Yes Chest 20101381040ndash2

19 Quanjer PH Enright PL Miller MR et al The need to change themethod for defining mild airway obstruction Eur Respir J 201137720ndash2

20 Celli BR Halbert RJ Point should we abandon FEV(1)FVC lt070to detect airway obstruction No Chest 20101381037ndash40

21 Falaschetti E Swanney MP Crapo RO et al Diagnosis of COPDThorax 200762924ndash5

22 Halbert RJ Natoli JL Gano A et al Global burden of COPDsystematic review and meta-analysis Eur Respir J 200628523ndash32

23 Mindell J Biddulph JP Hirani V et al Cohort profile the healthsurvey for England Int J Epidemiol 2012411585ndash93

24 Joint Health Surveys Unit The Health Survey for England 2010Volume 1 Respiratory Health In Craig R Mindell J edsRespiratory health Leeds NHS Information Centre 2011 http wwwhscicgovukpubshse10report

25 Joint Health Surveys Unit The Health Survey for England 2010Volume 2 Methods and Documentation Leeds The InformationCentre for Health and Social Care 2011 httpwwwhscicgovuk cataloguePUB03023heal-surv-eng-2010-resp-heal-vol2-meth-reppdf

26 Lynn P Sample design for Understanding Society UnderstandingSociety Working Paper Series 2009-01 httpswwwunderstandingsocietyacukresearchpublicationsworking-paper understanding-society2009-01pdf

27 McFall SL Petersen J Kaminska O et al Understanding Society mdash

The UK Household Longitudinal Study Waves 2 and 3 Nurse Health Assessment 2010 ndash 2012 Guide to Nurse Health Assessment Colchester University of Essex 2012 httpswwwunderstandingsocietyacukd1007251_User_Guide_Health_Assmt_w2_w3pdf1392855567

28 Quanjer PH Stanojevic S Cole TJ et al Multi-ethnic referencevalues for spirometry for the 3ndash95-yr age range the global lung

function 2012 equations Eur Respir J 2012401324ndash

43


Open Access




29 Quanjer PH Brazzale DJ Boros PW et al Implications of adoptingthe Global Lungs Initiative 2012 all-age reference equations for spirometry Eur Respir J 2013421046ndash54

30 Hall GL Thompson BR Stanojevic S et al The Global LungInitiative 2012 reference values reflect contemporary Australasianspirometry Respirology 2012171150ndash1

31 Rabe KF Hurd S Anzueto A et al Global strategy for thediagnosis management and prevention of chronic obstructivepulmonary disease GOLD executive summary Am J Respir Crit Care Med 2007176532ndash55

32 COPD Guidelines Group of the Standards of Care Committee of theBTS BTS guidelines for the management of chronic obstructivepulmonary disease The COPD Guidelines Group of the Standardsof Care Committee of the BTS Thorax 199752 5)S1ndash28

33 Ferguson GT Enright PL Buist AS et al Office spirometry for lunghealth assessment in adults a consensus statement from theNational Lung Health Education Program Chest 20001171146ndash61

34 Vaz Fragoso CA Concato J McAvay G et al The ratio of FEV1 toFVC as a basis for establishing chronic obstructive pulmonarydisease Am J Respir Crit Care Med 2010181446ndash51

35 Centers for Disease Control and Prevention (CDC) Deaths fromchronic obstructive pulmonary diseasemdashUnited States 2000ndash2005MMWR Morb Mortal Wkly Rep 2008571229ndash32

36 Jordan RE Miller MR Lam KB et al Sex susceptibility to smokingand chronic obstructive pulmonary disease the effect of differentdiagnostic criteria Analysis of the Health Survey for EnglandThorax 201267600ndash5

37 Bhatt SP Sieren JC Dransfield MT et al Comparison of spirometric

thresholds in diagnosing smoking-related airflow obstruction Thorax 201469409ndash14

38 Jordan RE Cheng KK Miller MR et al Passive smoking andchronic obstructive pulmonary disease cross-sectional analysis ofdata from the Health Survey for England BMJ Open 20111e000153

39 Woodward M Epidemiology study design and data analysis 2ndedn Boca Raton FL Chapman amp HallCRC 2004

40 Loong TW Understanding sensitivity and specificity with the rightside of the brain BMJ 2003327716ndash9

41 Rabe-Hesketh S Skrondal A Multilevel and longitudinal modeling using Stata volume II categorical responses counts and survival 3rd edn Stata Press 2012

42 UCLA Statistical Consulting Group Multinomial Logistic Regressionhttpwwwatsuclaedustatstatadaemlogithtm

43 Hill K Goldstein RS Guyatt GH et al Prevalence andunderdiagnosis of chronic obstructive pulmonary disease amongpatients at risk in primary care CMAJ 2010182673ndash8

44 Chronic obstructive pulmonary disease National clinical guideline onmanagement of chronic obstructive pulmonary disease in adults inprimary and secondary care Thorax 200459(Suppl 1)1ndash232

45 Tilert T Dillon C Paulose-Ram R et al Estimating the USprevalence of chronic obstructive pulmonary disease using pre- andpost-bronchodilator spirometry the National Health and NutritionExamination Survey (NHANES) 2007ndash2010 Respir Res 201314103

46 National Institute for Health and Care Excellence (NICE) Chronicobstructive pulmonary disease management of chronic obstructive

pulmonary disease in adults in primary and secondary care 2010httpwwwniceorgukGuidanceCG101

47 Quanjer PH Stanojevic S Swanney MP et al Recommendationsfor epidemiological studies on COPD Eur Respir J 2012391277ndash8

48 Shahab L Jarvis MJ Britton J et al Prevalence diagnosis andrelation to tobacco dependence of chronic obstructive pulmonarydisease in a nationally representative population sample Thorax 2006611043ndash7

49 Quanjer PH Tammeling GJ Cotes JE et al Lung volumes andforced ventilatory flows Report Working Party Standardization ofLung Function Tests European Community for Steel and CoalOfficial Statement of the European Respiratory Society Eur Respir J Suppl 1993165ndash40

50 Falaschetti E Laiho J Primatesta P et al Prediction equations for normal and low lung function from the Health Survey for EnglandEur Respir J 200423456ndash63

51 Maio S Sherrill DL MacNee W et al The European RespiratorySociety spirometry tent a unique form of screening for airwayobstruction Eur Respir J 2012391458ndash67

52 Mohamed Hoesein FA Zanen P Lammers JW Lower limit ofnormal or FEV1FVC lt070 in diagnosing COPD anevidence-based review Respir Med 2011105907ndash15

53 Mannino DM Thorn D Swensen A et al Prevalence and outcomesof diabetes hypertension and cardiovascular disease in COPDEur Respir J 200832962ndash9

54 Ford ES Wheaton AG Mannino DM et al Elevated cardiovascular risk among adults with obstructive and restrictive airway functioningin the United States a cross-sectional study of the National Health

and Nutrition Examination Survey from 2007ndash2010 Respir Res 201213115

55 Vestbo J Hurd SS Agusti AG et al Global strategy for thediagnosis management and prevention of chronic obstructivepulmonary disease GOLD executive summary Am J Respir Crit Care Med 2013187347ndash65

56 Clini EM Crisafulli E Roca M et al Diagnosis of chronic obstructivepulmonary disease simpler is better Complexity and simplicityEur J Intern Med 201324195ndash8

57 Haughney J Gruffydd-Jones K Roberts J et al The distribution ofCOPD in UK general practice using the new GOLD classificationEur Respir J 201443993ndash1002

58 Simpson CR Hippisley-Cox J Sheikh A Trends in the epidemiologyof chronic obstructive pulmonary disease in England a nationalstudy of 51 804 patients Br J Gen Pract 201060277ndash84

59 Walford H Ramsey L COPD Prevalence Modelling BriefingDocument 2011 httpwwwaphoorgukresourceviewaspxRID=111137

60 Nacul LC Soljak M Meade T Model for estimating the populationprevalence of chronic obstructive pulmonary disease cross sectionaldata from the Health Survey for England Popul Health Metr 200758

61 Nacul L Soljak M Samarasundera E et al COPD in England acomparison of expected model-based prevalence and observedprevalence from general practice data J Public Health (Oxf) 201133108ndash16

62 Shirtcliffe P Weatherall M Marsh S et al COPD prevalence in arandom population survey a matter of definition Eur Respir J 200730232ndash9


Open Access




doi 101136bmjopen-2014-005685 2014 4BMJ Open

Shaun Scholes Alison Moody and Jennifer S Mindell years in England and Wales95minus

cross-sectional analysis of persons aged 40 spirometric criteria a pooled

potential airflow obstruction using different Estimating population prevalence of

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Notes










comorbidities and mortality Estimation of the diseaseburden has been hindered however b y differences inmethods including spirometric cut-offs5ndash8 Fixed thresh-olds (FTs) use cut-offs for lung function measurements(eg forced expiratory volume in 1 sforced vital capacity (FEV 1FVC) rat io lt07) regardless of age sex height and ethnicity9 An additional threshold for per

cent-of-predicted FEV 1 (expected for persons of a givenage sex height and ethnicity) is also commonly usedfor severity classi1047297cation In contrast a lower limit of normal (LLN) cut-off uses a statistical de1047297nition of abnormalnormal (eg belowabove the lower 5thcentile of the distribution of age-speci1047297c sex-speci1047297cheight-speci1047297c and ethnic-speci1047297c FEV 1FVC v aluesfrom a healthy lifelong non-smoking population)10

At present applying FTs such as FEV 1FVC lt07 is thestandard approach However the European Respiratory Society (ERS) Task Force on epidemiology recently advo-cated using the LLN in epidemiological studies as FTsoverestimate air1047298ow obstruction in older populations

due to the physiological reduction of FEV 1FVC withage and underestimate in young adults compared withLLN11ndash16 The controversy over FT versus LLN thresh-olds is well known with no signs of a consensus among expert groups being agreed17ndash21

Partly as a result of this controversy the COPD epi-demiological database shows heterogeneity in de1047297nit ionsand consequential estimates of the disease burden5 22

Two nationally representative samples Wave 2 (2010ndash2012) of the UK Household Longitudinal Survey (UKHLS lsquoUnderstanding Society rsquo) and the HealthSurvey for England (HSE) 2010 collected lung function

data using identical measurement protocols and special-ist equipment providing an opportunity to increase stat-istical precision by combining both data sets Thereforethe primary objective of the present study was tocompare the prevalence of lsquopotentialrsquo air1047298ow obstruc-tion according to FT and LLN thresholds among persons aged 40ndash95 years living in England and Walespotential in the sense that the administration of bronch-odilators to measure the extent of reversibility in air1047298ow obstruction was not used As a secondary aim we com-pared the sensitivity of associations with risk factorsincluding age sex smoking history and socioeconomicposition Using the same variables we also examined thecharacteristics associated with spirometry in connection with self-reported physician-diagnosed COPD

METHODOLOGYStudy design and settingThe UKHLS and HSE selected participants using strati-1047297ed multistage probability sampling designs23

Self-reported health information risk factors and demo-graphics were collected through face-to-face interviewsfollowed by a visit from a trained nurse during whichlung function was measured Response rates for the Wave

2 interview (among individuals issued) and nurse visit

(among eligible participants in the Wave 2 interview) were 61 and 59 respectively in UKHLS In HSE2010 interview (among the estimated total number of adults in sampled households) and nurse-visit (adults inco-operating households) response rates were 59 and57 Sampling methods are described elsewhere24ndash26

Eligible participants gave written consent to participate

in spirometry

Questionnaire and proceduresParticipants were excluded from spirometry for the fol-lowing safety reasons pregnancy had in the past 3 months abdominalchest surgery a heart attackdetached retina or eye or ear surgery admitted to hos-pital with a heart complaint in the preceding month aresting pulse rate gt120 bpm or currently taking medica-tions for the treatment of tuberculosis Spirometry without bronchodilator use was conducted using NDDEasyOne PCC spirometers (NDD Medical TechnologiesZurich Switzerland) Quality control was summarised in

a session grade based on the number of technically acceptable blows and their reproducibility Grades A (three acceptable manoeuvres two highest FVC andFEV 1 within 100 mL) B (three acceptable manoeuvrestwo highest FVC and FEV 1 within 150 mL) and C (twoor three acceptable manoeuvres within 200 mL) wereconsidered good quality Full det ails on measurement procedures are available elsewhere25ndash27

The highest values for FEV 1 and for FVC from at least three and up to eight blows were used Age-speci1047297c sex-speci1047297c height-speci1047297c and ethnic-speci1047297c predicted values and z-scores (FEV 1 FVC and FEV 1FVC) were

computed using the ERS Global Lungs Initiative (GLI2012 httpwwwlungfunctionorg ) reference equa-tions These have been prepared by an international col-laboration based on data spanning 26 countries fromgt70 000 healthy individuals across four ethnic groups(Caucasian African-American and North-East Asianand Sout h-East Asian) valid for persons aged 3ndash95 years28 29 and have been sho wn to 1047297t contemporary Australasian spirometric data30

FT and LLN spirometric cut-offsUsing FTs we applied the 2007 Global Initiative forChronic Obstructive Lung Disease (GOLD) classi1047297ca-tion31 which was designed for use with postbronchodila-tor spirometry potential air1047298ow obstruction was de1047297nedas FEV 1FVC lt07 (FT) Disease stage was de1047297ned by the reduction in FEV 1 relative to per cent-of-predicted values as follows stage I (FEV 1FVC lt07 and FEV 1ge80 of predicted) stage II (FEV 1FVC lt07 and FEV 150ndash79 of predicted) and stage III+ (FEV 1FVC lt07and FEV 1 lt50 of predicted)32 Participants withFEV 1FVC ge07 were de1047297ned as non-obstructed

Participants with FEV 1FVCltLLN (below the lower5th centile of the distribution of z-scores) were de1047297nedas obstructed (LLN) To examine possible heterogeneity

among participants with FEV 1FVCltLLN disease stage


Open Access












asthma34 36ndash



pared using the χ

2











Open Access






RESULTS

















Open Access



















Sensitivity 0975 1000 0720 0424

Specificity 0949 0744 0996 1000

PPV 0720 0424 0975 1000

NPV 0996 1000 0949 0744

κ coefficient 0801 0479 0801 0479




standard


standard



Sensitivity 0508 0733 0840 0609

Specificity 0987 0911 0937 0948

PPV 0840 0609 0508 0733NPV 0937 0948 0987 0911

κ coefficient 0597 0596 0597 0596





Open Access

























Open Access






ned air1047298




























































43


Open Access










































Open Access










These include


Supplementary Data



Open Access



CollectionsTopic














Notes


















asthma34 36ndash



pared using the χ

2











Open Access






RESULTS

















Open Access



















Sensitivity 0975 1000 0720 0424

Specificity 0949 0744 0996 1000

PPV 0720 0424 0975 1000

NPV 0996 1000 0949 0744

κ coefficient 0801 0479 0801 0479




standard


standard



Sensitivity 0508 0733 0840 0609

Specificity 0987 0911 0937 0948

PPV 0840 0609 0508 0733NPV 0937 0948 0987 0911

κ coefficient 0597 0596 0597 0596





Open Access

























Open Access






ned air1047298




























































43


Open Access










































Open Access










These include


Supplementary Data



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CollectionsTopic














Notes












RESULTS

















Open Access



















Sensitivity 0975 1000 0720 0424

Specificity 0949 0744 0996 1000

PPV 0720 0424 0975 1000

NPV 0996 1000 0949 0744

κ coefficient 0801 0479 0801 0479




standard


standard



Sensitivity 0508 0733 0840 0609

Specificity 0987 0911 0937 0948

PPV 0840 0609 0508 0733NPV 0937 0948 0987 0911

κ coefficient 0597 0596 0597 0596





Open Access

























Open Access






ned air1047298




























































43


Open Access










































Open Access










These include


Supplementary Data



Open Access



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Notes

























Sensitivity 0975 1000 0720 0424

Specificity 0949 0744 0996 1000

PPV 0720 0424 0975 1000

NPV 0996 1000 0949 0744

κ coefficient 0801 0479 0801 0479




standard


standard



Sensitivity 0508 0733 0840 0609

Specificity 0987 0911 0937 0948

PPV 0840 0609 0508 0733NPV 0937 0948 0987 0911

κ coefficient 0597 0596 0597 0596





Open Access

























Open Access






ned air1047298




























































43


Open Access










































Open Access










These include


Supplementary Data



Open Access



CollectionsTopic














Notes































Open Access






ned air1047298




























































43


Open Access










































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These include


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ned air1047298




























































43


Open Access










































Open Access










These include


Supplementary Data



Open Access



CollectionsTopic














Notes
















































Open Access










These include


Supplementary Data



Open Access



CollectionsTopic














Notes
















These include


Supplementary Data



Open Access



CollectionsTopic














Notes










Notes








bmj open 2014 scholes

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