Eur Resplr J 199, 6, 55:H559 Time trends in repeted spirometry in children G. Hoek*t, B. Brunekreef* Time trends in repeted spirometry in children. G. Hoek, B. Brunekreef. BSTRCT: In study on cute helth effects of ir pouutlon In the Netherlnds, pulmonry function hs been mesured repetedly In children ged 7-11 yrs. In study periods of pproximtely 3 months, 6-1 tests hve been mde In group of 1,61 children. The spirometric dt hve been exmined for the presence of trends of pulmonry function with dy of study, independent of ir pollution. Pek expirtory Oow (PEF) incresed more thn expected from norml lung growth, wheres for mximl mid-expirtory Oow (MMEF) decrese with time ws observed. For forced vitl cpcity (FVC) nd forced expirtory volume In one second (FEV } 1. smller thn expected Increse with time ws observed. The observed devition from the expected pttern ws lrger for the children with one week intervl between successive tests thn for the children with three week intervl. For FVC nd non-liner reltionship with time ws observed, for PEF nd MMEF this reltionship ws pproximtely liner. The prticulr chnges of spirometric vribles with time need to be tken into ccount when repeted lung function tests re performed to Investigte cute effects of ir pollution exposure. Eur Respir J., 199, 5, 553-559. Dept of Epidemiology nd Public Helth, nd t Dept of ir Pollution, University of Wgeningen, Wgeningen, The Netherlnds. Correspondence: G. Hoek Dept of Epidemiology nd Public Helth University of Wgeningen P.O. Box 38 67 E Wgeningen The Netherlnds Keywords: children growth lung function trining Received: July 4 1991 ccepted fter revision Jnury 199 Epidemiologicl studies of cute helth effects of ir pollution frequently employ repeted testing of pulmonry function [1]. Spirometry is widely used. These studies re chrcterized by limited number of tests, usully 1 or less, in reltively short time period (typiclly few weeks to months). In the sttisticl nlysis of the dt from such studies, individul regression nlysis is often used [-4]. For ech subject, pulmonry function is regressed on ir pollution exposure. In these studies there my be confounding effects due to trends of pulmonry function with time, unrelted to environmentl physicl, chemicl or biologicl gents [5, 6]. In summer cmp studies, with dily mesurements of pulmonry function, decrese of forced vitl cpcity (FVC) nd forced expirtory volume in one second (FEV ) hs been noted during the 1 first 5-6 tests [5]. The imtil decrese ws followed by n increse [5). In nother summer cmp study, n increse of pek expirtory flow (PEF) nd decrese of FEV ws observed during the first week [ 6]. In study of pek flow vribility, using mini-wright pek flow meters between -4 times dily during two weeks, significntly lower vlues were observed on the first two dys [7]. In the subsequent nlysis the dt obtined on these two dys were not used [7]. Fctors which my contribute to these trends re lung growth in children, lung geing in dults, lerning effects in the performnce of the test nd decresing motivtion of the subjects performing the test. Even for the typiclly short study period the effect of lung growth in children cn be comprble to the mgnitude of helth effects observed in erlier ir pollution episode studies [8]. The nnul decrese of pulmonry function in dults is less thn the growth observed in children. Lerning nd motivtion effects cn ply role in these studies, due to the short intervl between tests nd the nture of spirometry. Spirometry depends upon the effort nd co-opertion of the subject performing the test. Growth nd geing would be expected to led to pproximtely liner chnges in these short studies. lerning effect would be expected to led to lrger increse of pulmonry function during the first tests. Decresing motivtion would led to lower pulmonry function vlues with time. This pper presents n evlution of the occurrence of time trends in spirometric vribles in study of the cute effects of ir pollution on pulmonry function of children living in the Netherlnds [9]. This epidemiologicl study is n extension of erlier ir pollution episode studies conducted in the Netherlnds [8, 1). Study design Methods Our erlier episode studies consisted of one bseline mesurement, followed by mesurements during nd some time fter n episode. To obtin more
554 G. HOEK, B. BRUNEKREEF informtion bout both the vrition of pulmonry function independent of ir pollution nd the time course of n effect during nd fter n episode, it ws decided to perform spirometry more frequently. Pulmonry function ws, therefore, mesured t regulr intervls, independent of the ir pollution concentrtion. When high concentrtions of S, N or 3 were expected, dditionl mesurements were mde. In the first prt of the study, ech child ws tested 1 times, with n intervl of 1 week between successive tests. In the second prt of the study, 6-1 tests were mde with n intervl of -3 weeks. Finlly, t two schools, mesurements hve been performed ccording to our erlier protocol (8, 1). It consisted of one bseline mesurement, shm episode mesurement pproximtely.5 months lter nd follow-up test pproximtely.5 weeks fter the shm episode mesurement. Popultion From October, 1987 until Mrch, 199, 17 primry schools were entered in the study sequentilly. ll children of grdes 4 to 7 (ge 7-11 yrs) were invited to prticipte. Out of 1,693 children eligible for the study, 1,61 children (96%) prticipted. The children were living in four different towns in the Netherlnds. Deurne nd Venlo re non-industril communities in the south-est of the country, Enkhuizen is non-industril community in the north-west. In Nijmegen, city of 15, inhbitnts in the est of the country, school in the inner city ws selected. Pulmonry function mesurements Spirometry ws performed in the schools of the prticipting children ccording to the criteri of the Europen Community for Col nd Steel (ECCS) [11). Briefly, Victest-5 dry spirometer ws used to obtin volume nd (through differentition) flow prmeters of forced expirtory mnoeuvre. The spirometer ws connected with utomtic dt cquisition equipment. For ech child t lest three cceptble efforts hd to be collected. The highest forced vitl cpcity (FVC), forced expirtory volume in one second (FEV ) 1 nd pek expirtory flow rte (PEF) were selected from the vilble curves. The highest mximl mid-expirtory flow (MMEF) ws selected from mnoeuvre with FVC within 5% or 1 ml of the highest FVC. The lung function technicin evluted the volume time curves on pper recorder nd the utomticlly clculted pulmonry function vribles of the present nd previous mnoeuvres. more detiled description of the protocol hs been published previously [1). The tests were performed between 8.3 m nd 4 pm. The order of testing of the different school grdes ws the sme ech test dy. In this pper only FVC, FEV, 1 PEF nd MMEF will be discussed. Sttisticl methods The reltionship between pulmonry function nd dy of study ws nlysed by individul liner regression. For ech child liner regression model ws clculted, with pulmonry function vrible s the dependent, nd dy of study s the independent vrible. The distribution of individul regression coefficients ws then evluted. Devition of the men of the distribution of individul regression coefficients from zero hs been tested with t-test. Two-sided significnce levels re reported in this pper. Dy of study ws entered s the number of dys since the strt of the study for the child. liner regression nlysis ws performed, becuse the expected chnge is smll, liner increse with time due to lung growth. The distribution of coefficients ws evluted seprtely for children mesured with n intervl of 1 week nd children mesured with n intervl of or 3 weeks between successive tests. To obtin some stbility of the estimted individul regression coefficients, only children with more thn four mesurements were included in the nlysis. These nlyses were repeted tking into ccount two mesures of the qulity of the informtion obtined from n individul child. Ech coefficient ws weighted with the inverse of the stndrd error of the regression coefficient or the root men squre error of the individul regression model. The distribution of the weighted coefficients ws compred to the unweighted distribution. The observed chnges with time hve been compred with dt obtined from longitudinl study, in which children were mesured four times over.5 yr period [13]. In tht study, children ged 6-11 yrs were tested with the sme equipment nd protocol [1). The study ws designed to evlute respirtory effects of indoor ir pollution. more detiled description of the study hs been published previously [14]. The lung growth dt from tht study hve been shown to gree closely with regression coefficients of cross-sectionl nlyses of pulmonry function on ge in the sme ge group [8). The ppropriteness of the liner trend ssumption ws investigted by repeting the regression nlysis without the first nd the first two tests, respectively. Moreover, plots of group men pulmonry function level versus dy of study were mde. Since interindividul vrition of pulmonry function is lrge, the sme group of children hs been compred for the different dys of study. Therefore, only children with vlid mesurements for ll tests were included in the grphicl nlysis. Finlly, the distribution of regression slopes hs been investigted in subgroups defined by sex, ge nd presence or bsence of chronic respirtory symptoms, respectively. The group of children with chronic respirtory symptoms comprised children with doctor dignosed sthm ever, wheeze in the lst yer, shortness of breth in the lst yer or ttcks of shortness of breth with wheeze in the lst yer, s reported by
TIME TRENDS IN REPETED SPIROMETRY IN CHILDREN 555 the prents of the children on self-completion version of the World Helth Orgniztion (WHO) children's questionnire [15]. The independent influence of these three vribles hs been evluted by performing multiple liner regression nlysis, with the regression slope s the dependent vrible nd sex, ge nd symptom sttus s independent vribles. Results t the first eight schools, tests were performed once week. ir pollution levels were low during ll test sessions t seven of the eight schools. Therefore, only the dt from these seven schools were further nlysed for evlution of time trends. t the other nine schools pulmonry function tests were mde every two or three weeks. There were insufficient numbers of children mesured with two weeks intervl who experienced low ir pollution during the whole test period. There were three schools which were visited every three weeks with low ir pollution levels during nd before ll test sessions. Therefore, only these three schools were included in subsequent nlyses. t these three schools, six test sessions were performed. In tble 1 description of the popultions used for the presented nlyses is given. The three winters included in the study were mild with only few dys with minimum tempertures slightly below C. Dily verge S concentrtion during the pulmonry function test dys rnged from -81 J.tg m 3, well below concentrtion levels t which helth effects cn be expected [16). In tble the results of the liner regression nlysis of pulmonry function on dy of study re shown. ll regression coefficients hve been trnsformed in estimted chnges per yer. The observed men chnge with dy of study ws different for the vrious pulmonry function vribles. For PEF n increse ws observed, for MMEF decrese ws observed. For FVC nd the results were more mixed. There Tble 1. - Popultion chrcteristics of ir pollution cute pulmonry function effects study, the Netherlnds; children Included In nlysis of trends of pulmonry function 1 week intervl 3 week intervl Men (sn) Rnge Men (sn) Rnge ge yrs 9 (1.) 6.8-1.4 9 (1.) 7-1.4 Vlid tests n 9 (1.3) 5-1 6 (.5) 5~ Children with >4 679 (95%) 44 (8%) vlid tests n (%) : percentge of ll prticipting children. sn: stndrd devition. Tble. - Men chnge of pulmonry function with dy of study, in reltion to the intervl between repeted tests Intervl Unweighted Weighted by Weighted by 1/sE(B) 1/RMSE 1 week (n=679) FVC rnl yr 1 7 1 (5) 11 8 (1) 1 (3) ml yr 1-38 () -39 (18) -44 (19) PEF mi-s 1 yr 1 18 (115) 3' (1) 51 (18) MMEF rnl s 1 yr 1-65 (6) -317 (46) -3 (49) 3 weeks (n=4) FVC rnl yr 1 79 () n (1) 65 (1) rnl yr 1 3 () 43 () 35 (1) PEF ml s 1 yr-1 79 (11) 665 (11) 668 (111) MMEF ml s 1 yr 1-148 (66) -1 (51) -13 (5) 6 weeks (n=75) FVC ml yr 1 54 (39) -58 (13)' -51 (93)' ml yr 1 51 (4) 137 (44) 13 (4) PEP mj-s 1 yr 1 543 (51) 784 (8) 1111 83 (316)"' MMEF rnl s 1 yr 1-54 (11) 37 (176)"' 383 (179)"' 1 : men of individul regression coefficients; tt: stndrd error (se) of the men of individul regression coefficients; 1/s(B): coefficients weighted with the inverse of the stndrd error of the coefficients; 1/RMSE: coefficients weighted with the inverse of the root men squre error of the individul regression model; -: without one extreme negtive outlier men (se) were 43 (6) nd 4 (9), respectively; "': severl positive outliers, not present in the unweighted distribution; : p<.5 (two-sided t-test); FVC: forced vitl cpcity; FEV : 1 forced expirtory volume in one second; PEF: pek expirtory flow; MMEF: mximl mid-expirtory flow.
556 G. HOEK, B. BRUNEKREEF were some remrkble differences between the results for the group with weekly mesurements nd the group with mesurements every three weeks. The increse in PEP ws much less for the children mesured every three weeks. For PVC nd increses were observed in the three weeks group. The MMEF decrese ws lower in the three weeks group. The results of the weighted nd unweighted regression slopes were similr. In generl, the stndrd errors were slightly lower for the weighted coefficients. However, when the number of test dys ws smll, severl extreme outliers occurred in the weighted nlyses. This ppered to be cused by children with low vribility of pulmonry function. djustment for the potentil effect of ir pollution on the observed time trends by including dily verge S concentrtion of the test dy in the individul regression models, did not mterilly chnge the presented ssocitions. For exmple, the men (se) of djusted coefficients for the children mesured every week were 1 (9), -31 (5),,6 (14) nd -4 (67) mt-s 1 per yer for PVC, FEV, 1 PEF nd MMEF, respectively. In tble 3 the estimted chnges from this study re compred with dt from longitudinl study [13] in the sme ge group mde t our deprtment with the sme equipment nd protocol. The observed PEF increse in this study ws much lrger thn would be expected from norml lung growth. The observed chnge in PVC nd ws less thn expected for ll groups. Clerly, the chnge in MMEF is contrry to wht would be expected from lung growth. The PEF chnges observed for the children mesured three times in three months study period, were only slightly lrger thn the expected chnge. The chnges for FVC, nd MMEF were still less thn expected. The time trends were similr for boys nd girls, the youngest nd the oldest children, nd for children with nd without chronic respirtory symptoms. In tble 4 the results of multiple liner regression nlysis with the regression slopes s the dependent vrible nd sex, ge nd symptom sttus nd dummy vrible defining the intervl between tests s independent vribles, re shown. None of the vribles ws significntly relted to the observed chnge of pulmonry function with time, except the time intervl between tests, which ws significntly relted to the increse of PEF with time. To djust for potentil trining effects, sometimes the first or first two tests re not included in the nlysis. In tble 5 the results of individul regression nlysis of pulmonry function on dy of study re shown for ll test dys, ll dys without the first test nd ll dys except the first two tests, respectively. For PEF nd MMEF the coefficients do not chnge much, but in the 1 week intervl group the cqefficients for FVC nd do chnge drsticlly, indicting non-linerity of their chnges with time. Tble 3. Men chnge of pulmonry function observed with different Intervls of repeted mesurements, compred to expected lung growth 1 week 3 weeks 6 weeks*.5 yrs.. FVC ml yr 1 7 (5) 79 () 54 (39) 33 (3) ml yr 1-38 () 3 () 51 (4) 18 (3) PEF ml s 1 yr' 1 18 (115) 79 (11) 543 (51) 459 (1) MMEF ml s yr' 1-65 (6) -148 (66) -51 (11) 15 (5) n 679 4 75 4 Dt re presented s men (se). : children from schools with 3 tests in 3 months period (bseline, shm episode nd follow-up test);.. : observed in longitudinl study of children [13]. For bbrevitions see legend to tble. Tble 4. - ssocition of observed chnge of pulmonry function with personl chrcteristics of the child Sex 1 ge 11 Respirtory' Intervl"' yrs symptoms FVC ml yr 1 5 (4) 1 (17) 45 (55) -55 (47) ml yr 1-3 (36) (15) 38 (5) -67 (43) PEF ml s 1 yr 1 37 (187) -7 (78) -193 (59) 156* (19) MMEF ml s 1 yr 1-111 (1) -76 (4) 64 (14) -1 (1) Dt re presented s men of individul regression coefficients (se). : p<.5 (two-sided t-test); 1 : boy=o, girl=1; 11 : ge in yers, clculted from the exct dy of birth nd the strt dy of the study for the child; ': presence of one or more chronic respirtory symptoms coded s 1, bsence of these symptoms s (text); "': one week intervl coded s 1, three week intervl s. For bbrevitions see legend to tble.
TIME TRENDS IN REPETED SPIROMETRY IN CHILDREN 557 Tble 5. - Men chnge of pulmonry function with dy of study; effect of excluding the first or first two tests Intervl ll tests Test 1 Test 1 nd excluded excluded 1 week (n=679) FVC ml yr 1 7 (5) 115 (9) 187 (3) ml yr 1-38 () 3 (5) 75 (9) PEF ml's' 1 yr1 18 (115) 83 (13) 8 (15) MMEF ml s 1 yr 1-65 (6) -175 (7) -185 (84) 3 weeks (n 4) FVC ml yr 1 79 () 66 (3) 4 (39) ml yr 1 3 () 9 (9) (38) PEF mt-s ' yr 1 79 (11) 686 (149) 578 (198) MMEF ml s 1 yr 1-148 (66) -159 (77) -43 (93) Dt re presented s men of individul regression coefficients (se). For bbrevitions see legend to tble. fter exclusion of the first two mesurements, pproximtely the expected growth rte is observed for FVC. The increse of is still less thn expected from lung growth. In figures 1 nd the men pulmonry function versus dy of study is shown for the group of children hving vlid test results for ll dys of study. These plots confirm the results shown in tble 5. litres (l).3r------- ------- --,. -..1 1.9 + + + + + + + + + + litres (l).3r------------- -----,.-.1 1.9 + + + + + I 3 4 5 6 PEF / s 1 MMEF / s 1 4.9r-------------------..4 4.8 + 4 6 8 1 PEF l s 1 MMEF /-s' 1 4.8r---------------,.3 4.7 4.6 ll.3. 4.7 4.6 4.5 4.4 4.3 o== 4 6 8 =r=o 1.5..15 Fig. 1. - Group men pulmonry function nd test number: 1 week intervl (n=334). e : FVC: +: FEV ; 1 : PEF; o: MMEF. FVC: forced vitl cpcity; FEV : 1 forced expirtory volume in one second; PEF: pek expirtory flow; MMEF: mximl mid-expirtory flow. 3 Fig.. - Group men pulmonry function nd test number: 3 week intervl (n=lss). e: FVC; +: FEV ; 1.6: PEF; : MMEF. For bbrevitions see legend to figure 1. 4 Discussion This study hs shown tht repeted pulmonry function testing with short time intervls between successive tests yielded estimted chnges of pulmonry function with time which were different from those expected from norml lung growth. Pek flow incresed more thn expected. For MMEF decrese with time ws 5 6 =~o
558 G. HOEK, B. BRUNEKREEF observed. For FVC nd smller thn expected increse with time ws observed. The observed devition from the pttern expected from norml lung growth ws lrger for the children with one week intervl between successive tests thn for the children with three week intervl. The chnges with dy of study for PEF nd MMEF could be described by liner reltionship. For FVC nd this ws only possible fter ignoring the first two tests. When exposure vribles of interest re lso ssocited with time since strt of the study, the observed reltionship between pulmonry function nd exposure cn be bised. n exmple of this my be study of the cute helth effects of mbient ozone pollution, in which ozone concentrtions my be higher or lower t the end of the study due to meteorologicl fctors. djustment for this bis hs to tke into ccount the observed ptterns with time. The presented nlyses suggest tht PEF nd MMEF cn be detrended by including liner reltionship with time since the strt of the study. For FVC nd FEV, 1 either non-liner reltionship with time needs to be modelled or, probbly more ppropritely, the first two observtions need to be ignored. Trining effects in repeted pulmonry function testing hve been described previously [5-7). In number of summer cmp studies, with dily mesurements of pulmonry function, decrese of FVC nd nd MMEF during the first 5-Q tests hs been noted. The initil decrese ws followed by n increse [ 5, 17]. In one of the three study popultions described, n increse of pek flow ws observed in the ltter phse of the two week study period [17). In nother summer cmp study, n increse of PEF nd decrese of ws observed during the first week [6). This pttern is lmost identicl to the pttern in our study. In two other studies mde t our deprtment, mini-wright pek flow meters were used for repeted testing, with n intervl of pproximtely one week between successive tests [9, 18]. In these studies no unexpectedly lrge increse with time ws observed [18). In pnel study of 73 children with chronic respirtory symptoms, pek flow ws mesured t home twice dily with mini-wright pek flow meters during two months. Preliminry nlyses suggest significnt trining effects during the first few dys. This ltter observtion is consistent with the results from study of dily pek flow vribility over period of two weeks [7]. Differences between these studies re not redily explinble. It my be tht trining effects re less pronounced with mini-wright meters due to the simpler equipment or somewht different technique of performing the test. Different study settings (intervl between tests, presence of lung function technicin) my lso explin differences. The physiologicl interprettion of the observed results is not simple. We believe tht the following mechnisms ply role in explining the ptterns observed in this study: trining effect of PEF, negtive effort dependence nd lung growth. We believe the observed pttern of PEF is the driving force of the chnges noted in the other vribles, since the pttern noted for PEF is most consistent for different schools nd subgroups. It ppers tht the children were ble to increse their mximl effort in the course of the study. Mybe some physiologicl trining of (the control over) respirtory muscles occurs, resulting in higher pek flows t lter tests. This hypothesis is supported by the lrger increse of PEF observed in the group of schools with n intervl of one week. In short-term ventiltory muscle trining progrmme including 3 min of forced expirtory nd inspirtory mnoeuvres, lrge increses (55%) of expirtory nd inspirtory mximl pressures were observed. Only modest (4%) increse of VC ws noted [19, ). There re severl exmples of pulmonry function technicins improving their own pulmonry function by performing regulr pulmonry function tests themselves (]. The pttern for FVC, nd MMEF might be explined by negtive effort dependence [19, 1-3]. Negtive effort dependence is prtly n rtifct of mesuring lung volumes by exhled volumes t the mouth. Higher efforts cuse higher lveolr pressures, leding to compression of the irwy gs. When lung volumes re mesured t the mouth, the compression prt of the chnge in ctul lung volume is not mesured. second mechnism is denoted s true effort dependence (19, 1] nd hs been relted to dynmic compression of the irwys [19). Submximl efforts, therefore, led to higher flows in the effort independent portion of the flow volume curve [19, 1, 3]. The mgnitude of the effect hs been illustrted in number of studies. KRoWK et l. [1] noted tht in lrge group of dult ptients FVC, FEV, 1 MMEF nd MEF ~ were, respectively,.3,.7, 3.5 nd 3.4% less for mximl efforts compred to the vlue from the highest FEY 1 -curve. MEDINOER [] noted in group of 11 dult ptients significntly lower FEY from curves with the highest PEF. Consistent with this hypothesis is tht the devince from growth-predicted increse in this study with time is lrger for thn for FVC. This is not consistent with less inspirtion or erlier termintion of the mnoeuvre. fter removing the first two tests for FVC n increse close to expected from norml growth ws observed. For FEV, 1 the observed increse is still less thn expected from growth. This my be result of the lrger impct of the described mechnism on FEV 1 The observed decrese of MMEF my lso result from the lrger influence of negtive effort dependence on this vrible. Lung growth pprently ws not sufficiently lrge to compenste for this effect in the reltively short study periods. In summry, this study hs shown unexpected chnges of spirometric pulmonry function with dy of study, when childre~ were tested repetedly in short period. The nlyses presented here, suggest the necessity of tking into ccount potentil confounding effects of ptterns of pulmonry function with time.
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