Operational definitions of asthma in studies on its aetiology

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1 Eur Respir J 2005; 26: DOI: / CopyrightßERS Jourals Ltd 2005 Operatioal defiitios of asthma i studies o its aetiology J. Pekkae*, J. Suyer # J.M. Ato # ad P. Burey ", o behalf of the Europea Commuity Respiratory Health Study (ECRHS) ABSTRACT: The most popular way to defie asthma based o questioaires is to use defiitios take from cross-sectioal iteratioal studies o asthma. These defiitios may ot, however, be optimal for future studies focusig o risk factors of asthma. The curret authors, therefore, compared the performace of differet operatioal defiitios of asthma. The Europea Commuity Respiratory Health Study I was a cross-sectioal study of 21,924 subjects aged betwee yrs i 18 coutries. Operatioal defiitios of asthma compared icluded differet combiatios of symptoms of asthma ad brochial hyperresposiveess. A cotiuous asthma score, ragig from 0 8, was defied as the sum of positive aswers to eight mai symptom questios. There was o threshold i the associatios of asthma symptoms with severity or risk factors of asthma, which would have suggested a dichotomous defiitio of asthma. Usig dichotomous defiitios requirig the presece of several asthma symptoms stregtheed associatios with studied risk factors, ad also icreased the estimated specificity ad positive predictive value. Usig a cotiuous asthma score also improved the power of the aalyses. I coclusio, dichotomous defiitios of asthma yieldig higher odds ratios are achieved by requirig positive resposes to several questios o symptoms. However, symptoms of asthma are possibly best aalysed as a cotiuous asthma score. KEYWORDS: Asthma, defiitio, epidemiology, methods, risk factor AFFILIATIONS *Natioal Public Health Istitute, Kuopio, Filad, ad # Ist. Muicipal D Ivestigacio Medica (IMIM), Barceloa, Spai, ad " Dept Public Health Scieces, Kig s College, Lodo, UK. CORRESPONDENCE J. Pekkae Uit of Evirometal Epidemiology Natioal Public Health Istitute P.O. Box Kuopio Filad Fax: Juha.Pekkae@ktl.fi Received: October Accepted after revisio: March Curretly there is disagreemet o the exact pathophysiology of asthma ad, therefore, it is uclear how asthma should be exactly defied i future studies [1, 2]. I epidemiology, the most commo solutio has bee to adopt questioaires ad dichotomous operatioal defiitios of asthma developed for large cross-sectioal prevalece studies, such as the Europea Commuity Respiratory Health Study (ECRHS) [3], ad the Iteratioal Study of Asthma ad Allergies i Childhood (ISAAC) [4]. However, defiitios of asthma used i these studies may ot be optimal for future studies focusig o risk factors of asthma. Choosig a cut-off poit for a dichotomous defiitio of disease is a difficult trade-off betwee sesitivity ad specificity. This has bee repeatedly show for cotiuous traits, such as brochial hyperresposiveess (BHR) [5]. The best cut-off poit depeds largely o the aims of the study. Dichotomisig a cotiuous variable also leads to a loss i power [6]. For editorial commets see page 3. Cliical diseases, e.g. asthma, are usually treated as dichotomies i epidemiological research. However, most, if ot all, chroic diseases are ot true dichotomies [7]. This was first recogised for physiological traits, such as blood pressure [8], but has bee later recogised for several chroic diseases, for istace demetia [9, 10]. Amog asthmatics, cotiuous symptom scores have bee used to measure asthma severity ad asthma-related quality of life [11]. However, the possibility of combiig differet symptoms [12] or usig a cotiuous asthma score [13] to defie asthma has bee less explored. I the preset study, the performace of several dichotomous operatioal defiitios of asthma ad a cotiuous score of asthma symptoms were compared usig data from a large iteratioal cross-sectioal study o asthma i adults, the ECRHS-I [14]. The aim of the preset study was to idetify possibilities of usig existig ad future data o symptom questioaires more efficietly whe explorig risk factors of asthma, ad to idetify the eeds for future developmet of asthma questioaires. SUPPORT STATEMENT The coordiatio of the preset study ad the fellowship of J. Pekkae at the Istitute Muicipal D Ivestigacio Medica (Barceloa, Spai), were supported by the Europea Commissio. Europea Respiratory Joural Prit ISSN Olie ISSN VOLUME 26 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

2 J. PEKKANEN ET AL. OPERATIONAL DEFINITIONS OF ASTHMA METHODS The protocol for the ECRHS has bee described elsewhere [14, 15]. Briefly, participatig cetres selected a area defied by pre-existig admiistrative boudaries, with a populatio of o150,000 idividuals. A up-to-date samplig frame was used to radomly select o1,500 males ad 1,500 females, aged betwee yrs. I stage I, subjects were set a questioaire equirig about respiratory symptoms. A 20% radom sample of subjects was selected to take part i stage II i which they were ivited to aswer a more detailed admiistered questioaire, ad to take part i blood tests, ski tests, assessmet of lug fuctio by spirometry ad airway challege with methacholie. The preset study icluded oly subjects radomly selected to stage II from 34 cetres i 15 coutries (Belgium (2), Germay (2), Spai (5), Frace (4), Irelad (1), Italy (3), Netherlads (3), UK (3), Icelad (1), Norway (1), Swede (3), Switzerlad (1), New Zealad (3), USA (1), ad Australia (1)). For the preset aalyses, subjects with missig data o ay of the questios o asthma symptoms, BHR testig or o atopy were excluded, leavig a total of 11,297 subjects. The study protocol was approved by the Istitutioal Review Board of the participatig cetres. Participats gave iformed writte coset. The ECRHS questioaire at stage II was adapted from a preexistig questioaire [16]. The questios were tested for comprehesibility ad traslated, with back traslatio ito Eglish. The results from the questioaire have bee reported elsewhere [17], icludig respiratory symptoms, questios o asthma diagosis ad asthma treatmet. Curret smokig was defied as those reportig havig smoked durig the last moth ad atopy as a specific immuoglobuli E.0.35 ku?l -1 to ay of the followig allerges: house dust mite (Dermatophagoides pteroyssiius), cat, timothy grass ad Cladosporium Herbarum. Operatioal defiitios of asthma used At stage II of the ECRHS questioaire, there were 12 mai questios o asthma symptoms (Appedix 1; umberig take from the origial questioaire) [14]. Differet combiatios of these questios were used to devise differet operatioal defiitios of asthma. Wheeze was defied i three differet ways: 1) wheeze, positive aswer to questio 1; 2) wheeze ad breathlessess, positive aswers to questios 1 ad 1.1; ad 3) wheeze ad breathlessess, o cold, positive aswers to questios 1, 1.1 ad 1.2. The above variables were combied i additio to positive results from the BHR test (dose of methacolie causig a 20% fall i forced expiratory volume i oe secod (PD20 ),1 mg) [18] to create the followig variables: 1) wheeze ad BHR; 2) wheeze ad breathlessess ad BHR; ad 3) wheeze ad breathlessess, o cold, ad BHR. BHR was also aalysed by itself, usig three differet defiitios of abormal result from the BHR test: a slope.25%, a slope.10% or PD20,1 mg [18]. The questios used i the ECRHS to select subjects with possible asthma [15] were questios 5, 13.5 ad 13.6 (attack of shortess of breath, attack of asthma, ad use of asthma medicatio). Usig these questios, three ECRHS defiitio combiatio variables were defied. 1) Ay oe of three variables: positive aswer to at least oe of the above questios. 2) Ay two of three variables: positive aswer to at least two of the above questios. 3) All three variables: positive aswer to all three questios. Asthma score To explore cotiuous combiatios of the asthma questios, a pricipal compoet aalyses was ru with all the 12 mai questios o asthma symptoms available (Appedix 1). Three mai factors i the pricipal compoet aalyses had Eige values of 4.57, 1.69, ad 1.12, respectively. All three factors were explored i a attempt to aalyse pheotypes of asthma (see results). However, give the stregth of the first factor ad the mai aim of the preset study, the decisio was made to use oly oe factor to build the mai asthma score. First, a effort was made to reduce the umber of questios used to build the score. This was doe to avoid categories of score with very few observatios. Questio 6 o cough was excluded first, as it had a very low factor loadig (0.27). The wheezig questios were highly correlated, so oly oe questio o wheezig was selected, wheeze ad breathlessess, sice it had slightly higher loadig (0.72) tha other wheezig questios (0.68 ad 0.65, respectively). Based o the same reasoig, the questio o doctor-diagosed asthma (loadig 0.73) was dropped, but questio 13 was retaied (loadig 0.74). The stadardised Crobach s alpha, which measures the iteral cosistecy of the compoets of a score, was 0.82 for the previously metioed eight questios. Deletig ay of the other questios o asthma dropped the Crobach s alpha to ; so all three questios were retaied. Addig ay of the questios that were previously dropped did ot icrease the Crobach s alpha higher tha 0.83, except for the doctor diagosis of asthma, which icreased it to However, asthma ad doctor diagosis of asthma cotai essetially the same iformatio (92% of subjects with ever asthma have a diagoses of asthma); therefore, diagosis of asthma was ot icluded i the score. The curret authors also used pricipal compoet aalyses to determie a sigle cotiuous score o asthma usig optimal weightig for the previous eight questios. However, there was high correlatio betwee this cotiuous score ad a simple sum of the eight questios (Spearma correlatio coefficiet was 0.99). Therefore, oly results for a simple asthma score, calculated as the sum of the eight idividual questios, were preseted. The fial asthma score used i the aalyses cosisted of a simple sum of the positive aswers to the eight questios, i.e. the score raged from 0 8 (Appedix 2). Statistical aalyses The differet operatioal defiitios were compared with the questio Have you ever had asthma ad with BHR (PD20). Sesitivity was the proportio of true asthmatics correctly classified by the test, ad specificity the proportio of true oasthmatics correctly classified by the tests. Positive predictive value (PPV) was the proportio of true asthmatics c EUROPEAN RESPIRATORY JOURNAL VOLUME 26 NUMBER 1 29

3 OPERATIONAL DEFINITIONS OF ASTHMA J. PEKKANEN ET AL. amog test positives. I order to be able to compare the differet PPV i table 1, a theoretical PPV for a situatio, where true prevalece of asthma was 10%, was calculated. The asthma score was a cout, which suggested a Poisso regressio model. However, the mea (0.67) was lower tha the stadard deviatio (1.32), which required the use of a egative biomial model. Compariso of the observed distributio of the score with a simulated distributio usig this model showed a almost exact match. Therefore, i multivariate aalyses, the score was aalysed usig a egative biomial model, which models the ratio of the mea score amog exposed ad oexposed, e.g. a ratio of mea score of 1.63 for materal asthma meat that those with materal asthma had a 63% higher mea score, as compared with those without materal asthma. The size of this estimate was difficult to compare with results from the logistic regressio models used for dichotomous outcomes as they model the relative odds of havig the biary outcome. However, z-values were comparable. RESULTS Differet defiitios gave very differet estimates of the prevalece of asthma (table 1). Whe more positive symptoms were required to defie asthma, the sesitivity ad prevalece decreased, but specificity icreased. Also, requirig a higher asthma score icreased the specificity, but decreased the sesitivity of the defiitio of asthma i a cotiuous fashio. Although i may very strict defiitios the specificity became very high, the PPV remaied oly moderate, as the sesitivity was so low. The best Youde s idex (sesitivity + specificity- 1) was observed with less strict defiitios, especially with wheeze i the last 12 moths (data ot show). Whe more positive symptoms were required to defie asthma, the estimated prevalece differeces of the associatio of atopy with asthma were reduced, but the odds ratios (OR) were icreased (table 2). However, the statistical sigificace (measured as z-values) chaged very little or was eve reduced for defiitios with very low prevaleces. The highest OR s were achieved defiig asthma as a positive aswer to all ECRHS defiitio questios (woke by attack of shortess of breath, attack of asthma ad medicatio for asthma), ad the highest levels of score. Similar results were obtaied for materal asthma, but the icrease i OR s were somewhat less proouced, especially for operatioal defiitios icludig BHR (data ot show). TABLE 1 Sesitivity (Ses), specificity (Spec) ad positive predictive value (PPV) of differet operatioal defiitios of asthma, as compared with ever asthma ad with brochial hyperreactivity Prev % Ever asthma Brochial hyperreactivity # Ses Spec PPV " Ses Spec PPV " Wheeze Wheeze Wheeze, breathlessess Wheeze, breathlessess, o cold Brochial hyperresposiveess Slope.25% % at 1 mg Slope.10% Wheeze ad BHR # Wheeze, BHR Wheeze, breathlessess, BHR Wheeze, breathlessess, o cold, BHR ECRHS defiitio Ay 1 of 3 variables Ay 2 of 3 variables All 3 variables Score Ay 1 of 8 questios Ay 2 of 8 questios Ay 3 of 8 questios Ay 4 of 8 questios Ay 5 of 8 questios Ay 6 of 8 questios Ay 7 of 8 questios All 8 questios Data are preseted as, uless otherwise stated. Prev: prevalece; BHR: brochial hyperresposiveess; ECRHS: Europea Commuity Respiratory Health Study. # :.20% fall i FEV1 at 1 mg; " : theoretical PPV, if true prevalece of asthma 10%; + : woke by shortess of breath, attack of asthma or asthma medicatio; 1 : part of the defiitio. 30 VOLUME 26 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

4 J. PEKKANEN ET AL. OPERATIONAL DEFINITIONS OF ASTHMA This was ot uexpected as brochial resposiveess has a associatio with atopy idepedet of asthma [19]. There was o evidece of a threshold i the associatio of asthma score with demographic factors, idicators of severity of asthma ad risk factors of asthma (table 3). Most idicators of severity ad risk factors icreased cotiuously with icreasig score, icludig BHR (fig. 1). For variables measurig tobacco smoke exposure, especially active smokig, there was first a icrease i prevalece, the a declie, suggestig a more complex associatio with the score. I a multivariate model assessig a combiatio of risk factors (table 4), the largest z-values were obtaied for the risk factors whe aalysig the cotiuous asthma score (usig egative biomial model), as compared with logistic regressio of the usual dichotomous defiitios. This suggests a icrease i the power of the aalyses with the use of the score. To aalyse more directly the additioal iformatio provided by the asthma score, multivariate logistic regressio models were also ru with BHR as a depedet variable, ad the three defiitios of asthma i table 4, age, sex, ad cetre as idepedet variables. The adjusted OR (z-value) for asthma score was 1.50 (10.9). The same models for atopy ad for materal asthma gave adjusted OR s (z-values) for asthma score of 1.25 (7.3) ad 1.30 (5.2), respectively. These aalyses show that, eve whe adjustig for the other two defiitios of asthma, the asthma score provides additioal iformatio o all of the three variables (BHR, atopy ad materal asthma) used. I a attempt to aalyse risk factors of differet pheotypes of asthma (table 5), the curret authors udertook further aalyses retaiig all the three mai factors idetified i the iitial pricipal compoet aalysis. After varimax rotatio, good separatio of the factors was obtaied. The first factor, asthma, had loadigs betwee 0.76 ad 0.91 with the four questios o asthma (questio 13 ad its subquestios), but loadigs,0.26 with other questios. The secod factor, wheeze, had loadigs betwee 0.73 ad 0.90 with the three questios o wheeze (questio 1 ad its subquestios), but loadigs,0.36 with other questios. The third factor, shortess of breath, had loadigs betwee 0.60 ad 0.74 with questios 2, 3, ad 5, a loadig of,0.35 with questios 4 ad 6, ad loadigs,0.26 with other questios. For aalyses o risk factors, the scores were dichotomomised at,90th percetile. Due to discotiuities i the distributios of the scores, this resulted i a prevalece of 7.6% for the asthma factor (all subjects with ever asthma), a prevalece of 8.6% for wheeze ad a prevalece of 10.0% for the dichotomised shortess of breath factor. TABLE 2 Associatio of atopy with differet operatioal defiitios of asthma Operatioal defiitio of asthma Noatopic % Atopic % Adj OR # Lower z-value Subjects Wheeze Wheeze Wheeze, breathlessess Wheeze, breathlessess, o cold Brochial hyperresposiveess Slope.25% % at 1 mg Slope.10% Wheeze ad BHR " Wheeze, BHR Wheeze, breathlessess, BHR Wheeze, breathlessess, o cold, BHR ECRHS Defiitio + Ay 1 of 3 variables Ay 2 of 3 variables All 3 variables Score Ay 1 of 8 questios Ay 2 of 8 questios Ay 3 of 8 questios Ay 4 of 8 questios Ay 5 of 8 questios Ay 6 of 8 questios Ay 7 of 8 questios All 8 questios Adj: adjusted; OR: odds ratio; CI: cofidece iterval; BHR: brochial hyperresposivess; ECRHS: Europea Commuity Respiratory Health Study. # : adjusted for age, sex ad cetre; " :.20% fall i forced expiratory volume i oe secod at 1 mg; + : woke by shortess of breath, attack of asthma or asthma medicatio. c EUROPEAN RESPIRATORY JOURNAL VOLUME 26 NUMBER 1 31

5 OPERATIONAL DEFINITIONS OF ASTHMA J. PEKKANEN ET AL. TABLE 3 Associatio of asthma score with demographic factors, idicators of severity of asthma ad risk factors of asthma Father smokes Mother smokes No sibligs BHR + Atopy Materal asthma Curret smokig Atopic eczema Hay fever Doctor diagosis medicatio # of asthma o4 asthma attacks?yr -1 Asthma Score " Female o35 yrs of age Data are preseted as %, uless otherwise stated. BHR: brochial hyperresposivess. # : icluded i the defiitio of score; " : based o aalyses of sex; + :.20% fall i forced expiratory volume i oe secod at 1mg. Prevalece % Asthma symptoms FIGURE 1. Prevalece (%) of subjects with a give umber of asthma symptoms (&) ad the associatio with prevalece (%) of brochial hyperresposiveess (PD20; ). Materal asthma, atopy ad BHR were most strogly associated with the asthma factor, but there was also clear associatio with the other two factors (table 5). Smokig was associated maily with the wheeze factor, whereas older age ad female sex were mostly associated with the shortess of breath factor. DISCUSSION The most commo operatioal defiitios of asthma i epidemiological studies today are based o the questioaires ad defiitios of asthma developed for iteratioal prevalece studies, such as the ECRHS [3] i adults ad ISAAC [4] amog childre. The ECRHS defies asthma usually as the presece of either a attack of shortess of breath, a attack of asthma or use of asthma medicatio [15]. ISAAC focuses o the presece of wheezig [4]. However, defiitios of asthma used i these studies may ot be optimal for future studies o risk factors of asthma for two reasos. First, the defiitios are dichotomous ad secodly, the defiitios have bee developed with more focus o prevalece of asthma rather tha o risk factors of asthma [20]. Whether asthma is a truly dichotomous disease is ukow. Curret kowledge o the pathophysiology ad atural history of asthma does ot strogly suggest that asthma would be differet from most other chroic diseases that exist as a cotiuum i the populatio [7]. This is especially clear whe asthma is measured usig symptom questioaires, as the reportig of symptoms is also iflueced by may other factors, such as perceptio of symptoms ad curret evirometal exposures. The preset aalyses showed o threshold i the associatio betwee icreasig umber of asthma symptoms ad ay of the markers of asthma severity, or mai risk factors of asthma, which would have suggested a dichotomous defiitio of asthma. Usig a cotiuous asthma score istead of a dichotomous defiitio of asthma is likely to icrease the power of the study [6], which is especially importat i smaller populatio based studies. This was observed i the curret aalyses. Take together this suggests that whe aalysig symptoms of asthma i epidemiological VOLUME 26 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

6 J. PEKKANEN ET AL. OPERATIONAL DEFINITIONS OF ASTHMA TABLE 4 Multivariate # associatios of selected factors with differet operatioal defiitios of asthma Wheeze, breathlessess (biary) ECRHS defiitio " (biary) Score (cotiuous) OR Lower z-value OR Lower z-value Relative chage + Lower z-value Materal asthma Atopy BHR Curret smokig Ex-smokig Age yrs Age.40 yrs Female ECRHS: Europea Commuity Respiratory Health Study; OR: odds ratio; CI: cofidece itervals; BHR: brochial hyperresposivess. # : OR calculated usig logistic regressio ad relative chage i mea score usig egative biomial model, adjustig for cetre ad all the other variables i the table; " : ay oe of the three variables (woke by shortess of breath, attack of asthma, or asthma medicatio); + : for iterpretatio of the relative chage, see statistical methods; 1 : 20% fall i forced expiratory volume i oe secod at 1 mg. studies, they are best aalysed as a cotiuum, ot as a dichotomy. If it is accepted that asthma symptoms exist as a cotiuum i the populatio, choosig the cut-off poit to classify subjects ito asthmatics ad oasthmatics is a somewhat arbitrary decisio, which depeds maily o the aims of the classificatio, e.g. whe screeig for a disease, the defiitio eeds to be very sesitive. Iteratioal studies comparig prevalece of asthma have focused o questios o asthma symptoms, such as wheeze, which have a high combiatio of specificity ad sesitivity [3]. I aetiological research ad i cliical practise, there is more emphasis o specificity ad PPV [20, 21]. The preset study idicates that requirig positive aswers to several questios o symptoms of asthma icreases the specificity ad PPV, but reduces sesitivity of the defiitio, whe compared agaist self-report of ever asthma or BHR. The estimated sesitivities ad specificities should, however, be iterpreted more as measures of agreemet tha as a true validatio study, give the lack of a true gold stadard for asthma [2]. However, as expected based o theory, the observed OR icreased with icreasig PPV of the defiitio [21]. PPV is a fuctio of true prevalece of the disease, specificity, ad sesitivity [22 24]. I geeral, whe the specificity is,95%, there is substatial bias i the estimated risk ratios. I the mai aalyses of the preset study, a sigle asthma score was used. This was doe as asthma is usually treated as a sigle disease i epidemiological studies. Previous aalyses [13] also suggest that the asthma symptom questios i the ECRHS mostly measure oe sigle uderlyig factor or latet trait. This was supported by the preset pricipal compoet TABLE 5 Multivariate # associatios of selected factors with differet pheotypes " of asthma Asthma factor Wheeze factor Shortess of breath factor OR Lower z-value OR Lower z-value OR Lower z-value Materal asthma Atopy BHR Curret smokig Ex-smokig Age yrs Age.40 yrs Female OR: odds ratio; CI: cofidece iterval; BHR: brochial hyperresposivess. # : OR calculated usig logistic regressio, adjustig for cetre ad all the other variables i the table. " : pheotypes based o dichotomised scores from pricipal compoet aalysis of the 12 questios o asthma symptoms. The first factor correspods closely to the questio o ever asthma, secod factor to questios o wheeze, ad third factor o questios o chest tightess ad shortess of breath. c EUROPEAN RESPIRATORY JOURNAL VOLUME 26 NUMBER 1 33

7 OPERATIONAL DEFINITIONS OF ASTHMA J. PEKKANEN ET AL. aalyses. The curret authors used oly the simple sum of the eight asthma questios, due to simplicity ad the high correlatio (r50.99) betwee the simple sum ad a cotiuous score that ca be calculated based o the pricipal compoet aalysis. However, it is possible that asthma is a more heterogeeous disease etity with several differet pheotypes. Earlier aalyses of the ECRHS questioaire [25] separated two differet pheotypes of asthma, amely asthma ad wheeze. The preset aalyses o pheotypes cofirmed the earlier fidigs o the risk factors of these two pheotypes. The preset aalyses icluded, i additio, a third pheotype, shortess of breath, which was most strogly associated with female sex ad older age. The possibility to separate differet pheotypes of asthma ad to create cotiuous scores of these pheotypes usig oly the curret questios is, however, limited. Two-thirds of the subjects had o positive replies to the questios o asthma symptoms. Future aalyses should try to obtai iformatio o loger symptom histories (ot just the past 12 moths), use symptom questios, which are ot dichotomised, but have cotiuous scales, ad also iclude iformatio o possible objective markers of asthma. Whe the asthma score is used i epidemiological aalyses, it is importat to explore if the risk factor uder study icreases i a cotiuous maer with icreasig level of the score. I the preset study this was observed for all risk factors of asthma except smokig. As observed before [25], smokig was also more strogly associated with questios o wheezig tha with questios o asthma. Therefore, it is probably advisable to stratify future aalyses by smokig, at least as a sesitivity aalyses. For example, i the preset aalyses, the associatio betwee asthma score ad BHR was slightly weaker amog smokers tha amog osmokers. However, the differece i the OR was small (1.37 versus 1.52). I coclusio, the preset study suggests that there is o threshold i the associatio betwee icreasig umber of asthma symptoms ad ay of the markers of asthma severity or mai risk factors of asthma. Usig defiitios that require positive aswers to several asthma symptom questios stregtheed the associatios with the studied risk factors ad also icreased the estimated specificity ad positive predictive value of the defiitio. However, statistical power differed very little. I cotrast, usig a cotiuous asthma score both improved the power of the aalyses ad gave additioal iformatio to the dichotomous defiitios of disease. This suggests that symptoms of asthma are possibly best aalysed as a cotiuous asthma score i epidemiological studies. ACKNOWLEDGEMENTS The pricipal participats of the Europea Commuity Respiratory Health Study (ECRHS) are as follows. Australia: M. Abramso, J. Kuti (Melboure); Belgium: P. Vermeire, F. va Bastelaer (Atwerp South, Atwerp Cetral); Frace: J. Bousquet (Motpellier), F. Neukirch, R. Liard (Paris), I. Pi, C. Piso (Greoble), A. Taytard (Bordeaux); Germay: H. Magusse, D. Nowak (Hamburg), H.E. Wichma, J. Heirich (Erfurt); Icelad: T. Gislaso, D. Gislaso (Reykjavik); Irelad: J. Prichard, S. Allwright, D. MacLeod (Dubli); Italy: M. Bugiai, C. Bucca, C. Romao (Turi), R. de Marco, V. Lo Cascio, C. Campello (Veroa), A. Marioi, I. Cerveri, L. Casali (Pavia); The Netherlads: B. Rijcke, A. Kremer (Groige, Berge-op-Zoom, Gelee); New Zealad: J. Crae, S. Lewis (Welligto, Christchurch, Hawkes Bay); Norway: A. Gulsvik, E. Omeaas (Berge); Spai: J. Ató, J. Suyer, J. Soriao, A. Tobías, J. Roca, M. Kogevias (Barceloa), N. Muiozgure, J. Ramos Gozález, A. Capelastegui (Galdakao), J. Martiez-Moratalla, E. Almar (Albacete), J. Maldoado, A. Pereira, J. Sáchez (Huelva), F. Payo, I. Huerta (Oviedo); Swede: G. Boma, C. Jaso, E. Bjorsso (Uppsala), L. Rosehall, E. Norrma, B. Ludback (Umea), N. Lidholm, P. Plaschke (Goteborg); Switzerlad: U. Ackerma-Liebrich, N. Küzli, A. Perruchoud (Basel); Uited Kigdom: M. Burr, J. Layzqll (Caerphilly), R. Hall (Ipswich), B. Harriso, (Norwich), J. Stark (Cambridge); Coordiatig Cetres, Lodo, UK: P. Burey, S. Chi, C. Luczyska, D. Jarvis, E. Lai; USA: S. Buist, W. Vollmer, M. Osbore (Portlad, OH). The followig grats helped to fud the local studies. Australia: Alle ad Habury s; Belgium: Belgia Sciece Policy Office, Natioal Fud for Scietific Research; Frace: Miistère de la Saté, Glaxo Frace, Istitut Peumologique d Aquitaie, Cotrat de Pla Etat-Régio Laguedoc- Rousillo, CNMATS, CNMRT (90MR/10, 91AF/6), Miistre delegué de la saté, RNSP; Germay: GSF ad the Budesmiister für Forschug ud Techologie, Bo; Greece: The Greek Secretary Geeral of Research ad Techology, Fisos, Astra, Boehriger-Igelheim; Idia: Bombay Hospital Trust; Italy: Miistero dell Uiversità e della Ricerca Scietifica e Tecologica, CNR, Regioe Veeto grat RSF. 381/05.93; New Zealad: Asthma Foudatio of New Zealad, Lotteries Grat Board, Health Research Coucil of New Zealad; Norway: Norwegia Research Coucil project o /310; Portugal: Glaxo Farmacêutica Lda, Sadoz Portugesa; Spai: Miistero Saidad y Cosumo FIS grats #91/ /00E-05E ad #93/0393, Red Respira RTIC 03/ 11, ISC III, ad grats from Hospital Geeral de Albacete, Hospital Geeral Jua Ramó Jiméez, Cosejeria de Saidad Pricipado de Asturias; Swede: The Swedish Medical Research Coucil, the Swedish Heart Lug Foudatio, the Swedish Associatio agaist Asthma ad Allergy; Switzerlad: Swiss atioal Sciece Foudatio grat ad PROSPER (NK); Uited Kigdom: Natioal Asthma Campaig, British Lug Foudatio, Departmet of Health, South Thames Regioal Health Authority; USA: Uited States Departmet of Health, Educatio ad Welfare Public Health Service grat o. 2 S07 RR APPENDIX 1 Questios used to devise differet operatioal defiitios of asthma 1. Wheezig or whistlig i your chest i the last 12 moths 1.1 If yes to 1, breathless whe wheezig soud preset 1.2 If yes to 1, wheezig ad whistlig without cold 2. Woke up with a feelig of chest tightess i the last 12 moths 3. Attack of shortess of breath at rest i the last 12 moths 34 VOLUME 26 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

8 J. PEKKANEN ET AL. OPERATIONAL DEFINITIONS OF ASTHMA 4. Attack of shortess of breath after exercise i the last 12 moths 5. Woke by attack of shortess of breath i the last 12 moths 6. Woke by attack of coughig i the last 12 moths 13. Have you ever had asthma 13.1 If yes to 13, diagosis by a doctor 13.5 If yes to 13, attacks of asthma i the last 12 moths 13.6 If yes to 13, medicatio for asthma APPENDIX 2 Questios from Appedix 1 used to produce a cotiuous asthma score 1. Wheeze ad breathless (yes to questios 1 ad 1.1) 2. Feelig of chest tightess (questio 2) 3. Attack of shortess of breath at rest (questio 3) 4. Attack of shortess of breath after exercise (questio 4) 5. Woke by attack of shortess of breath (questio 5) 6. Ever asthma (questio 13) 7. Attack of asthma (questio 13.5) 8. Medicatio for asthma (questio 13.6) REFERENCES 1 Pearce N, Beasley R, Burgess C, et al., Asthma epidemiology: priciples ad methods. New York, Oxford Uiversity Press, Gross NJ. What is this thig called love? or, defiig asthma. Am Rev Respir Dis 1980; 121: Burey PGJ, Laitie L-A, Perdrizet S, et al. Validity ad repeatability of the IUALTD (1984) brochial symptoms questioaire: a iteratioal compariso. Eur Respir J 1989; 2: Worldwide variatio i prevalece of symptoms of asthma, allergic rhiocojuctivitis, ad atopic eczema: ISAAC. The Iteratioal Study of Asthma ad Allergies i Childhood (ISAAC) Steerig Committee. Lacet 1998; 351: Lewis SA, Weiss ST, Britto JR. Airway resposiveess ad peak flow variability i the diagosis of asthma for epidemiological studies. Eur Respir J 2001; 18: MacCallum RC, Zhag S, Preacher KJ, Rucker DD. O the practise of dichotomizatio of quatitative variables. Psychol Methods 2002; 7: Rose G. The Strategy of prevetive medicie. Lodo, Oxford Uiversity Press, Pickerig GW. High blood pressure. New York, Rave Press, Braye C, Calloway P. Normal ageig, impaired cogitive fuctio, ad seile demetia of the Alzheimer s type: A cotiuum? Lacet 1988; 4: McDowell I, Newell C. Measurig health. A quide to ratig scales ad questioaires. New York, Oxford Uiversity Press, Curtis JR, Marti DP, Marti TR. Patiet-assessed health outcomes i chroic lug disease. Am J Respir Crit Care Med 1997; 156: Shaw RA, Crae J, Pearce NE, et al. Compariso of a video questioaire with the IUATLD writte questioaire for measurig asthma prevalece. Cli Exp Allergy 1992; 22: Biio G, Rezzai C, Grassi M, et al. ECRHS screeig questioaire scorig: a methodological suggestio for asthma assessmet. J Outcome Res ; 4: Burey PGJ, Luczyska P, Chi S, et al. The Europea Commuity Respiratory Health Survey. Eur Respir J 1994; 7: Jaso C, Ato J, Burey P, et al. The Europea Commuity Respiratory Health Survey: what are the mai results so far? Europea Commuity Respiratory Health Survey II. Eur Respir J 2001; 18: Burey PGJ, Chi S. Developig a ew questioaire for measurig the prevalece ad distributio of asthma. Chest 1987; 91: Suppl. 6, 79S 83S. 17 Europea Commuity Respiratory Health Survey. Variatios i the prevalece of respiratory symptoms, self-reported asthma attacks, ad use of asthma medicatio i the Europea Commuity Respiratory Health Survey. Eur Respir J 1996; 9: Chi S, Burey P, Jarvis D, et al. o behalf of the Europea Commuity Respiratory Health Survey. Variatio i brochial resposiveess i the Europea Commuity Respiratory Health Survey (ECRHS). Eur Respir J 1999; 10: Postma DS, Bleecker ER, Amelug PJ, et al. Geetic susceptibility to asthma brochial hyperresposiveess coiherited with a major gee for atopy. N Egl J Med 1995; 333: Pekkae J, Pearce N. Defiig asthma i epidemiological studies. Eur Respir J 1999; 14: Breer H, Gefeller O. Use of positive predictive value to correct for disease misclassificatio i epidemiological studies. Am J Epidemiol 1993; 138: Copelad KT, Checkoway H, McMichael AJ, et al. Bias due to misclassificatio i the estimatio of relative risk. Am J Epidemiol 1977; 105: Gree MS. Use of predictive value to adjust relative risk estimates biased by misclassificatio of outcome status. Am J Epidemiol 1983; 117: Poole C. Exceptio to the rule about odifferetial misclassificatio. Am J Epidemiol 1985; 122: Suyer J, Basagaa X, Burey P, et al. Iteratioal assessmet of the iteral cosistecy of respiratory symptoms. Europea Commuity Respiratory Health Study (ECRHS). Am J Respir Crit Care Med 2000; 162: EUROPEAN RESPIRATORY JOURNAL VOLUME 26 NUMBER 1 35