Department of Occupational Medicine

Copenhagen University Hospital

Glostrup, Denmark

The sick building syndrome

revisited

PhD thesis

Charlotte Brauer, MD

University of Copenhagen 2005

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PhD thesis

The sick building syndrome revisitedBy Charlotte Brauer, MDDepartment of Occupational MedicineCopenhagen University HospitalGlostrup, Denmark

Supervisors:Sigurd Mikkelsen, MD, DMScDepartment of Occupational MedicineCopenhagen University HospitalDK-2600 Glostrup, Denmark

Henrik Kolstad, MD, PhDDepartment of Occupational MedicineAarhus University HospitalDK-8000 Aarhus C, Denmark

Palle Ørbæk, MD, DMScNational Institute of Occupational HealthDK-2100 Copenhagen Ø, Denmark

Opponents:Finn Gyntelberg, Professor, MD, DMScClinis of Occupational and Environmental medicineBispebjerg HospitalDK-2400 Copenhagen NV, Denmark

Jens Peter Bonde, Professor, MD, DMScDepartment of Occupational MedicineAarhus University HospitalDK-8000 Aarhus C, Denmark

Åke Thörn, MD, DMScThe Norrbotten County CouncilS-971 89 Luleå, Sweden

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This PhD thesis is based on three manu-scripts: • The context of a study influences the re-

porting of symptoms. Int Arch Occup Envi-ron Health 2003; 76: 621-624.

• No consistent risk factor pattern for symp-

toms related to the sick building syndrome: a prospective population based study. Int Arch Occup Environ Health 2006.

• The sick building syndrome - a chicken and

egg situation? Int Arch Occup Environ Health 2006.

PREFACE

This thesis was done at the Department of Occu-pational Medicine, Copenhagen University Hospi-tal in Glostrup during my employment as a staff specialist (2002-2005). First, I want to thank my three supervisors. I want to thank Sigurd Mikkelsen who made me inter-ested in the subject and made it possible for me to carry out this study. He has taught me so much and given me an indescribable support throughout the study. Thank you very much for your encour-agement and patience. I am also grateful to Henrik Kolstad and Palle Ørbæk for their thorough re-marks and inspiring discussions. I also wish to thank Peder Skov for his collabora-tion in the validation study, his good discussions and his friendship. To the secretaries at our department, especially Gitte Grubbe Baunsgård, I would like to say a big thank you for your assistance in co-ordinating the questionnaire survey. And to my colleagues and fellow members of the Center for Indoor environment and Stress re-search, thank you for your interest, support and discussions. Last but not least, I would like to thank all the participants. Charlotte Brauer, Copenhagen, July 2005 The study has received financial support from the Danish Working Environment Authority, The Danish Working Environment Council and the Danish Medical Research Council.

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CONTENTS

BACKGROUND __________________________________________________ 7Introduction _________________________________________________________7

History of health aspects related to the indoor environment __________________8

Definition of the sick building syndrome __________________________________9

Previous research on SBS ______________________________________________9

Comparison of SBS with other conditions with non-specific symptoms_________9

Factors influencing the SBS symptoms __________________________________10

PRESENT STUDY AND AIMS _____________________________________ 11

VALIDATION STUDY ____________________________________________ 12Study population ____________________________________________________12

The Glostrup Questionnaire ___________________________________________12

Statistical analyses ___________________________________________________12

Results _____________________________________________________________14

Discussion __________________________________________________________14

THE PROSPECTIVE STUDY ______________________________________ 16Study population ____________________________________________________16

Questionnaire _______________________________________________________16

Statistical analyses ___________________________________________________18

Results _____________________________________________________________21

Discussion __________________________________________________________22

OVERALL CONCLUSIONS AND IMPLICATIONS____________________ 26

ENGLISH SUMMARY____________________________________________ 27

DANSK RESUMÉ________________________________________________ 29

REFERENCES __________________________________________________ 31

APPENDICES___________________________________________________ 39Tables and manuscripts

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BACKGROUND

IntroductionThe Department of Occupational Medicine,Copenhagen University Hospital, Glostrup, wasestablished in 1989. The uptake area is theCopenhagen County with a population ofapproximately 600,000 persons. During theyears quite a few of the patients referred to usby general practitioners had symptomsattributed the indoor environment.

We were also regularly contacted byworkplaces because of suspected indoor climateproblems and symptoms among the employees.In many of these workplaces complaints aboutthe indoor environment had persisted for a longtime, even years. Often the occupational healthservices or the Labour Inspection Authority hadbeen involved and frequently surveys aboutsymptom prevalence already have beenconducted. These surveys were conducted witha number of different questionnaires. Thequestionnaires varied considerably with respectto the symptoms queried about, the time framesof perceived symptoms and how to evaluatetheir work- or building-relatedness.Furthermore, they had no well-establishedreference values with which to compare thesurvey results of complaints in a specificbuilding. This resulted in different expertassessments of whether a specific building was“sick” or not and consequently in differentdecisions on the action to be taken to “cure” thebuilding.

On this background we established aworking group in 1995 in order to develop astandardised Danish questionnaire on symptomsand perceived indoor environment. The groupconsisted of specialists in occupationalmedicine and public health medicine as well asrepresentatives from the occupational healthservices and the Danish Working EnvironmentAuthority. I became involved in this process in1996 when the questionnaire was to be pilottested and validated. I conducted the validationstudy and a subsequent study that includedcollection of normative data [22]. Thequestionnaire is now called "the GlostrupQuestionnaire". It can be downloaded in Danishon the website: www.cis.suite.dk.

During the validation study, approximately175 employees at four different workplaceswere interviewed by two of my colleagues and

me. The interviews began with an open-endedquestion about symptoms that the employeeconsidered related to the indoor environmentand were followed by systematic questionsabout the character, frequency and work-relatedness of the symptoms. In the open-endedquestions almost 25% of the interviewedpersons mentioned well-defined diseases causedby microorganisms or symptoms without abiologically plausible explanation in the indoorenvironment, for example herpes zoster,candida infection, a taste of metal, irregularmenstrual cycles, dental problems, ear ache,sinusitis, pneumonia, and cystitis. When Icompared interview information with theemployees’ responses in questionnaires, I foundonly a moderate agreement concerning theresponses as to whether the symptoms wereexperienced especially at work. I experiencedthat statements about this work-relatednessoften seemed vague, when they were exploredin detail. Instead of referring to the presence ofsymptoms when staying in the specific building,a common argument for perceiving thesymptoms as work-related was that many oftheir colleagues had similar symptoms. Some ofthe employees described their symptoms inalmost identical words or sentences. However,many of the symptoms that the employeesperceived as similar turned out to be ratherdifferent when specified further. In two of theworkplaces another argument for perceiving asymptom as work-related was that mouldgrowth had been discovered in the workplace.Many of the employees told that they had notattributed the symptoms to the indoorenvironment until they were informed of themould, but now they were certain that theirsymptoms were caused by the mould.

Thus the in-depth interviews indicated thatemployees may ascribe their symptoms to theindoor environment in the workplace, if theircolleagues report apparently similar symptomsor if they have become aware of a potentialindoor environment problem. It seemed toinclude not only non-specific symptoms, butalso clinically defined diseases that had otherwell-known causes. Hence the interplaybetween perceived health and indoorenvironment may be very complex. Theexperience from these interviews made meinterested in studying whether awareness affectsthe reporting of symptoms and whether

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perceived exposures in the indoor environmentis associated with symptoms with a biologicallyplausible explanation in the indoor environmentas well as with symptoms without such anexplanation.

History of health aspects related to theindoor environmentThe health impact of the indoor environmenthas attracted much interest of hygienists, publichealth scientists and engineers for centuries. Inthe 19th century the importance of living in goodsanitary conditions to prevent the spread ofinfectious diseases was well known, althoughthe direct cause of the infections was unknown.The German hygienist Max von Pettenkofer,who was closely involved in investigatingcholera epidemics, claimed that cleanliness, anutritious diet and fresh air were important toimprove public health. In the 1850s he proposedthat the indoor air was unclean due to volatileorganic substances from the occupants' breathand skin and suggested a limit value of carbondioxide in the indoor air as a measure of anadequately ventilated room [86]. In 1881 EliasHeyman, the first professor of Hygiene inSweden, wrote the book "The indoor air of ourhomes" in which he discussed health effects ofindoor air in rooms that were insufficientlyventilated [51]. In his experience unclean air,draught and dry air could cause nausea,headache, rheumatism, pain in the nerves,common cold, catarrh or irritation in the lowerrespiratory system and a sensation of dryness inthe throat. He recommended that a dwelling waskept dry, clean, well ventilated, and not toocrowded.

In the 20th century concern about allergicdiseases related to indoor allergens hasappeared. The role of fungi and mould growthin asthma and hay fever has been consideredsince the 1930s and the house dust mite wassuspected as being a producer of house dustallergens in 1964 [68, 96]. Since then the risk ofallergic sensitisation of house dust mite andmould spores in dwellings has been extensivelystudied [44, 48, 62]. In the 1970s muchattention was drawn to asbestos and radon inbuildings due to the cancer risk of theoccupants. The energy crisis in 1973-1974resulted in energy-conserving measures beingtaken with insulation of buildings and reductionin ventilation. This in turn led to concern aboutan increasing risk of exposure to indoor airpollutants, because emissions from the

construction materials now tended to remain inbuildings longer and at higher concentrations.

A working group was assembled by theWorld Health Organization (WHO) in 1979 toevaluate health aspects related to indoor airquality [126]. Apart from the cancer risk relatedto asbestos and radon, the group describedhealth effects in terms of irritation of the eyeand respiratory tract due to release offormaldehyde from building material as well aseye irritation, coughing and possibly nausea dueto environmental tobacco smoke. In 1982 aWHO working group once more discussed theimpact of indoor air pollutants on health [127].The group reported that an increasing numberof case stories especially from the Scandinaviancountries and the United States reported similarnon-specific symptoms that they attributed toindoor climate problems. The groupdistinguished between temporarily sickbuildings and permanently sick buildings. Theformer category comprised newly constructedor newly remodelled buildings, where thesymptoms would decrease in time and mostlydisappear. The latter category comprisedbuildings, where normally no obvious causewas evident and where the symptoms wouldpersist for years and sometimes would beresistant to extensive remedial action. Thesymptoms described were: eye, nose and throatirritation; sensation of dry mucous membranesand skin; erythema; mental fatigue; headaches,high frequency of airway infections and cough;hoarseness, wheezing, itching and unspecifichypersensitivity; nausea and dizziness. TheWHO group found it reasonable to assume thata true environmental health problem hademerged and introduced the term sick buildingsyndrome.

In 1994, a dramatic change in suspectedadverse health effects of the indoor environmentwas seen when a cluster of the serious disease"acute pulmonary haemorrhage" was reportedamong infants in Cleveland, Ohio. Initially,water-damage with growth of a toxin-producingmould in the homes of the infants was suspectedto have caused these outbreaks of disease.However, a subsequent thorough review of thecase studies found inadequate evidencesupporting a causal relationship between thesecases of illness and the mould [3]. Since theCleveland cluster of disease, mould in theindoor environment has received extensivemedia coverage and is often mentioned insensational headlines. In Denmark, buildingshave been evacuated and torn down due to

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mould and a few lawsuits have been brought tocourt because of chronic diseases ascribed tomould in the workplace. In the United States,mould litigation is frequently occurring, andinsurance companies have paid millions ofdollars in claims to occupants of moulddamaged buildings [55]. Thus, despite aconsiderable improvement in the building andhousing standard in the industrial countriesduring the past centuries, the indoorenvironment is still considered a potentialhealth hazard and almost a more serious healthhazard than a hundred years ago.

Definition of the sick building syndromeThe WHO group did not state a precisedefinition of the sick building syndrome (SBS)and even today there is no general consensus ona definition. There is no agreement on how thetemporal relationship between the building andthe symptoms is defined and on how often theoccupants have to experience the symptoms.There is also disagreement about whether theterm refers to a population or an individual.Some researchers define the SBS as apopulation in a specific "sick" building andrequire an excess of symptoms in the building[39, 85]. Others make a case definition of SBSon an individual basis, and some define aconstellation of core symptoms as diagnostic ofSBS [13, 38, 52, 71, 73, 74, 110, 115].However, there seems to be agreement that theSBS typically includes mucous membranesymptoms, general symptoms such as fatigueand headache, and possibly skin symptoms.Some authors also include lower respiratorysymptoms. In the following this group ofsymptoms will be referred to as SBS symptoms.

Previous research on SBSExtensive research has tried to identify factorsin the indoor environment, which could be thecause(s) of SBS symptoms. Several large scalestudies have been performed, especially in theUnited States and Europe but also in Asia [1, 4,9, 17, 20, 25, 26, 34, 36, 39, 52, 58, 65, 70, 72,78-80, 83, 85, 87, 103, 109, 112, 120, 121,128]. Several investigations have beenperformed in so-called "sick" buildings inwhich a high proportion of workers haveexperienced symptoms, which they attributed tothe indoor environment already before the studytook place [11, 33, 53, 69, 81]. However, a highprevalence of symptoms has also been found inbuildings without pre-existing assumptions thatthese symptoms were building related [39, 77,

79, 85, 103]. Some studies have examined theindoor environment in dwellings, but moststudies have concentrated on non-industrialworkplaces such as offices, schools, day-carecentres and hospitals. In the 1980s focus was onventilation, particulates, formaldehyde,temperature, relative humidity, number ofpersons occupying the room, man made mineralfibres, and wall-to-wall carpeting. In the 1990sattention was drawn to volatile organiccompounds, visual display units, and damp andmouldy buildings.

Cross-sectional studies examining the SBShave found numerous associations betweenreported symptoms and self-reported exposuresin the indoor environment. Mucous membranesymptoms have been associated with perceptionof dry air, too little air movement, noise, staticelectricity, and dust [79, 80, 83]. Generalsymptoms have been related to reported odours,humidity, temperature, too little air movement,static electricity, and noise [11, 79, 83].

Cross-sectional studies with objectivemeasurements of exposures have often foundstatistically significant associations, but there islittle consistency in the findings. Ventilationseems to be associated with perceived airquality and SBS symptoms [9, 57, 58, 113,123]. Signs of dampness appear to increase therisk of pulmonary symptoms and SBSsymptoms [18, 19, 61]. However, the evidencethat indoor mould growth plays a role as acausative agent for health effects in terms ofSBS symptoms is weak [18, 19, 47, 61, 91].Studies about health effects due to airborneparticles in non-industrial buildings areinconclusive [98].

The only longitudinal epidemiological studyof which I am aware found only a fewstatistically significant associations betweenSBS symptoms and an extensive panel ofobjectively measured exposure variables [26],notably mould in seat dust, but not in airsamples or floor dust. Mechanical ventilation,floor dust and other “established” indoorenvironmental factors had no significantassociation with SBS symptoms. Thus, despiteextensive research no objectively measuredfactors in the indoor environment haveconsistently been associated with SBSsymptoms.

Comparison of SBS with otherconditions with non-specific symptomsThe symptoms associated with SBS are non-specific symptoms that are quite common in the

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general population and are seldom accompaniedby pathological abnormalities. They canaccompany other illnesses and can occurwithout connection to the environment [17, 37,56, 63, 64]. Not only the indoor environment,but also other environmental exposures withlow-level concentrations of chemicals oremissions have been associated with theoccurrence of non-specific symptoms. Some ofthe conditions have been described as clinicalentities or syndromes such as Gulf warsyndrome, waste disposal site syndrome,multiple chemical sensitivity, and electricalhypersensitivity [27, 50, 102, 106, 124]. Asresearch has failed to establish a link betweenthe suspected environmental cause and thesymptoms, a working group convened by WHOrecommended in 1996 to use the term idiopathicenvironmental intolerance (IEI) instead ofmultiple chemical sensitivity [2]. Today thisterm usually also includes the other above-mentioned conditions [50, 107]. In spite of thefact that the exposures are rather different,many of the symptoms are quite similar to thesymptoms related to the SBS. Several theorieshave been formulated for the mechanismsbehind IEI [60, 107]. According to thetoxicogenic theory, chemical sensitivity to verylow levels of almost any environmental agentaccounts for the multi-system symptoms, whilethe psychogenic theory suggests that it is afunctional somatic syndrome characterised byan overvalued idea attributing symptoms toenvironmental agents [108]. Provocationchallenge studies of IEI have demonstrated thatsymptoms could only be reliably associatedwith chemical exposures at levels above theolfactory or irritant threshold, suggesting thatperception and cognition mediate symptoms[29]. Likewise a provocation test of personswith alleged electrical hypersensitivity did notshow relationships between symptoms and theactual presence of electromagnetic fields [6].

Many of the symptoms in the SBS cantheoretically be explained by some chemical orphysical exposures in the environment e.g.headache by noise, eye irritation by dust.Provocation challenge studies of SBSsymptoms have shown that exposure to lowconcentrations of volatile organic compounds,office dust or office equipment is associatedwith reported mucous membrane symptoms andheadache [12, 49, 76, 89, 122]. However, onlyindications of objective health effects have beenfound, and some of these indications were inbiologically unexplainable directions [49].

Symptoms for which there is no biologicallyplausible explanation in the indoor environmenthas also been reported in buildings withreported problems in the indoor environment,for example bad nerves, constipation, low backpain or other musculoskeletal symptoms [11,87, 88].

Thus the SBS has many similarities with theother environmental illnesses: The symptomsare related to multiple organs and no specificcause can be identified. Nevertheless, thesymptoms are attributed to environmentalfactors that are tolerated by the majority ofpeople.

Factors influencing the SBS symptomsPsychosocial work characteristics have beenassociated with the SBS symptoms in severalstudies [79, 80, 84, 104, 120, 128]. Thesepsychosocial factors included work satisfactionin general, dissatisfaction with superiors orcolleagues, quantity of work, a high level ofstress, and climate of co-operation. Only a fewauthors have examined the impact ofpersonality traits on SBS symptoms [11, 14, 94,95]. A low sense of coherence was associatedwith a higher prevalence of SBS symptoms, butthe personality trait negative affectivity was not.Female sex, low age and atopy have also beenassociated with an increased prevalence ofsymptoms [16, 80, 95, 104, 109].

Studies on psychosomatic symptoms haveshown that persons with a general tendency toexaggerate or overrate their work stress mayreport more symptoms [41]. A tendency toreport physical and emotional stress symptomshas been associated with chronic heart disease[45]. Among 264 patients presenting withsupposed environmental illness, symptomreporting was associated with psychiatric andsomatic conditions rather than an environmentalexposure in the majority of the cases [21].Toxic chemicals were regarded as the mostprobable cause in only five of these cases. Therelationship between symptom reporting andSBS symptoms has not been investigated.

Several studies have shown thatenvironmental worry and awareness of apotential environmental hazard may influencethe reporting of non-specific symptoms [30, 66,75, 93, 106]. Assuming that SBS symptoms arerelated to the indoor environment in a building,the symptoms presumably either are presentonly when a person stays in that specificbuilding or get worse in that building. Henceresearch on the SBS should attempt to get a

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description of the temporal relationship betweenthe occurrence of symptoms and staying in thebuilding, for example the workplace. However,if worry and awareness influence the reportingof symptoms, is it then possible to get a validdescription of this relationship?

In only a few published studies, the validityof an SBS questionnaire is described [7, 24, 35,73, 125]. Most of these studies have eithercompared questionnaire information with aphysician's diagnosis or assessed the test-retestagreement. One study took account of"awareness” and found that the prevalence ofwork-related SBS symptoms increased whenthe employees were informed that a study of theindoor environment was going on [73]. Thissuggests that awareness and beliefs mayinfluence self-reports on the building-relatedness of SBS symptoms.

PRESENT STUDY AND AIMSThe thesis includes a 1-year prospective studyof a random sample of the Danish adultpopulation as well as a validation study. Theresults of the prospective study are reported inthe three manuscripts, which are included in thisthesis (appendix II to IV). Parts of thevalidation study are mentioned in one of themanuscripts. Initially, I will describe thevalidation study in further details. After this, theprospective study is described.

The main aims of this PhD thesis were toexamine:

1. Whether symptoms are more likely to bereported as work-related, if attention isfocused on the indoor environment at work(Appendix II).

2. How the perceived indoor environment isassociated with the prevalence, incidenceand persistence of the non-specificsymptoms that are traditionally included inthe sick building syndrome (SBSsymptoms) (Appendix III).

3. How a general tendency to reportsymptoms may influence the reporting ofSBS symptoms (Appendix III).

4. Whether perceived exposures in the indoorenvironment is associated with symptomswith a biologically plausible explanation inthe indoor environment as well as withsymptoms without such an explanation(Appendix IV).

Validation of the questions about SBSsymptoms and perceived indoor environmentwas another purpose of the study (Appendix IIIand thesis).

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VALIDATION STUDYPrior to the prospective study, the questionsfrom the Glostrup Questionnaire aboutsymptoms related to the SBS and the indoorenvironment were validated.

Study populationThe validation took place in eight workplacesthat had contacted our department in the years1998-2000 because of suspected indoor climateproblems and symptoms among the employees.All the workplaces were located in GreaterCopenhagen. In all, 947 employees participated.They had a mean age of 44 years (range 18-68)and were predominantly women (73%). Thecharacteristics of the eight workplaces andemployees are shown in table 1.

The Glostrup QuestionnaireThe “Glostrup Questionnaire” comprisedquestions about the following 13 symptoms: eyeirritation, nose irritation, nasal congestion,irritation of the throat, hoarseness, cough,wheezing in the chest, breathlessness, dry skinon the hands or arms, flushing face, fatigue,headache, and difficulty in concentrating. Thesymptoms were chosen as relevant for SBS onthe basis of the existing literature. Theparticipants were asked to consider symptomsexperienced during the past four weeks, andeach question had four response options: "no","yes, sometimes", "yes, several times a week",and "yes, daily". Data were dichotomised sothat a symptom occurring several times a weekor daily was a positive answer. In addition, theparticipants had to specify for each symptom, ifthat particular symptom was more pronounced"on days off" or "on working days". Alternativeresponse options were "no difference daysoff/working days" and "I don't know". Figure 1shows an example of a question about SBSsymptoms. If a symptom was more pronouncedon working days, it was considered to be work-related.

We constructed four symptom indices by thesum of the dichotomised variables, irrespectiveof the symptoms being reported as work-relatedor not. The symptom indices were: mucousmembrane index (eye irritation, nose irritation,nasal congestion, irritation of the throat, andhoarseness; range 0-5); pulmonary index(cough, wheezing in the chest, andbreathlessness; range 0-3); skin index (dry skinon the hands or arms, and flushing face; range0-2); and general symptom index (fatigue,

headache, and difficulty in concentrating; range0-3).

Perceived exposures in the indoorenvironment (17 items) were assessed with thefollowing question: "Have you been exposed toany of the following factors in your workenvironment during the past four weeks?" withthe same four response options as for thequestions on symptoms. Exposures wereregarded as relevant if they were present severaltimes a week or daily. Based on previousresearch the questions were grouped into athermal index (draught, too low temperature,too high temperature, temperature variationsand draught along the floor), a stuffy air index(stuffy air and unpleasant odour), a noise index(noise in the room, noise from other rooms andnoise from outside), and a light index(illumination problems and reflective surfaces)[28]. The remaining 5 perceived exposures (dryair, static electricity, environmental tobaccosmoke, cramped for space and poor cleaning)were not initially grouped, but were tested fordimensionality to assess whether these could begrouped in an index.

In addition the questionnaire includedquestion about age, sex and allergic diseases.Atopy was defined as reporting either allergy topollen, furry animals or house dust mite or ahistory of asthma, hay fever or childhoodeczema.

Statistical analysesThe constructed indices of symptoms andperceived indoor environment were examinedwith respect to item bias, unidimensionality,and internal consistency. These analyses werecarried out in the validation sample (N=947)and were cross-validated in the baseline studysample from the prospective study (N=2164),see below. The test-retest reliability wasassessed in two of the eight workplaces fromthe validation sample. The tests forunidimensionality and item bias were conductedwith the software program DIGRAM, whichcan be downloaded on the web sitehttp://www.biostat.ku.dk/~skm/skm/. All otherstatistical analyses were done with SAS®

System version 8.2.

Item biasItem bias analyses test whether each item in anindex functions in the same way, irrespective of

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Figure 1. An example of a question about SBS symptoms in the questionnaire

During the past 4 weeks have you been bothered by stuffy or runny nose?no.......................................................................□yes, sometimes..................................................□yes, several times a week..................................□yes, daily............................................................□If yes, Are the symptoms most pronounced?on days off .........................................................□on working days.................................................□no difference days off / working days ................□I don’t know........................................................□

subgroup investigated. Because age, sex, andatopy have been shown to influence thereporting of SBS, we examined item bias inrelation to these subgroups. Variables like sexand age are called exogenous variables, as theyare not included in the items or index. We useda method based on three-way contingencytables of item score by the exogenous variablesof interest stratified by the index score [15, 43].Item bias analyses were done on the foursymptom indices: mucous membrane index,pulmonary index, skin index, and generalsymptom index. Respondents who had one ormore items in the index unanswered wereexcluded from the analysis. The partial gammawas calculated for each three-way table. Thegamma coefficient ranges from -1 to +1, and agamma outside the interval -0.31 to +0.31 canbe interpreted as moderate to large item bias[15]. Two sided p-values<0.05 estimated by theMonte Carlo approximation (1000 simulations)were regarded as significant. If the gamma wassignificantly outside the interval -0.31 to +0.31in any of the populations, I considered the itembias to be of importance.

UnidimensionalityRegarding dimensionality, we examinedwhether the 13 symptoms represented one latentvariable such as "the sick building syndrome"or whether it was composed of more underlyingdimensions as the four proposed groups ofsymptoms (mucous membrane, pulmonary, skin

and general symptoms). Initially, we cross-tabulated the symptom indices two by twochecking the standardised residuals. Largeresiduals at the edges and small residuals at thediagonal suggested different dimensions,corresponding to more than expected scoringlow on one index and high on the other index.Subsequently, we used the Martin-Löf test totest the hypothesis that the two indices were onedimension [119]. The Martin-Löf test is aconfirmatory test that is suitable fordichotomous items in contrast to factor analysis.The same procedure was followed for thequestions on perceived exposures in the indoorenvironment.

Internal consistencyInternal consistency in the symptom indices andthe indoor environment indices was assessedwith Spearmans correlations and the Cronbachcoefficient alpha. Values of the Cronbachcoefficient alpha above 0.70 are usuallyregarded satisfactory [111]. However, the alphais dependent not only on the magnitude of thecorrelations among the items, but also on thenumber of items in the scale. Hence an indexconsisting of only two or three items may yieldlower values.

Test-retest reliabilityThe questionnaire was applied twice with aninterval of one week among 110 employees(88%). The test-retest reliability was assessed as

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the percentage of full agreement and as thechance corrected agreement by the kappacoefficient and the 95% confidence interval(CI). The simple kappa coefficient was used forthe 13 dichotomised symptoms, while theweighted kappa coefficient was used for theindices that consisted of more than two levels.Values of the kappa coefficient greater than0.75 were regarded to represent excellentagreement beyond chance, values between 0.40and 0.75 fair to good agreement, and values lessthan 0.40 were considered to represent pooragreement [40].

Results

Item bias There was no evidence of important item biaswith respect to sex, age or atopy as regards themucous membrane index and the generalsymptom index.

However, concerning the pulmonary indexthe items "cough" and "breathlessness" werebiased in relation to atopy in the validationsample with a significant gamma of -0.55(p=0.01) and 0.58 (p=0.03), respectively. At agiven index score persons with atopy had adecreased tendency to report cough and anincreased tendency to report breathlessness witha negative and positive gamma coefficient,respectively. In the baseline study sample thesame tendency was seen with a gamma of -0.17for cough and 0.24 for breathlessness, but it wasnot statistically significant. Table 2 illustratesthis bias by showing the three-way table of theitem "breathlessness" by atopy stratified by theindex score.

The skin index was significantly biased inrelation to sex as well as age in the baselinestudy sample. Women (gamma=-0.41, p=0.002)and older persons (gamma=0.33, p<0.001) weremore likely to report dry skin on hand or armthan men and younger persons. In the validationsample, the same tendency was seen as regardssex, but it was not statistically significant(gamma -0.25, p=0.38 for dry skin).

UnidimensionalityTest for unidimensionality rejected that any ofthe four symptom indices could be combinedwith each other to form a common dimensionwith highly significant Martin-Löf tests in bothsamples (p<0.001).

Likewise for the indoor environment indices,the stuffy air index, the noise index and the light

index represented separate dimensions. Thethermal index turned out to consist of twodifferent dimensions. Hence it was divided intoa draught index (draught, too low temperatureand draught along the floor) and a temperatureindex (too high temperature and temperaturevariations). The remaining exposures groupedas follows: a dry air index (dry air and staticelectricity) and a space/dust index (cramped forspace and poor cleaning). Environmentaltobacco smoke could not be combined with anyof the other exposures. These indices weretested with respect to internal consistency andreliability.

Internal consistencyAll symptom variables were positivelycorrelated. In the validation sample (N=947) theCronbach coefficient alpha was 0.71 for themucous membrane index, 0.61 for thepulmonary index, 0.49 for the skin index, and0.66 for the general symptom index. In thebaseline study sample from the prospectivestudy (N=2164) the Cronbach coefficients werea little lower (table 3). For the indoorenvironment indices the Cronbach coefficientalpha ranged between 0.44 and 0.64 in thevalidation population and between 0.41 and0.72 in the baseline study sample. In bothsamples the coefficients were lowest for the dryair index and space/dust index and highest forthe draught index.

Test-retest reliabilityFor the 13 symptoms analysed separately, thesimple kappa coefficient ranged from 0.48(breathlessness) to 0.87 (nose irritation) with amean on 0.68. The kappa coefficients for thefour symptom indices as well as for the eightindoor environment indices indicated good toexcellent agreement, the symptom indicesranging between 0.65 (pulmonary index) and0.93 (general symptom index) and the indoorenvironment ranging between 0.58 and 0.79(table 3).

DiscussionThe item bias analyses showed evidence of biasas regards the pulmonary index and the skinindex with respect to sex, age and atopy.Consequently, a score on these indices hasdifferent meanings depending on whether aperson has atopy, is a woman or is young. Thismay lead to false conclusions, if the symptomindices for different groups are to be compared.Item bias analysis was developed in educational

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research and from the 1980s it has been used inmedical research as well [10, 43, 99]. To myknowledge it has not yet been used in researchon SBS. In the present study the bias was notstatistically significant in both samples, but asthe gamma was moderate in the other sampleand the tendency to bias was in the samedirection, I concluded that the bias was ofimportance. A solution to the problem could beto remove the most severely biased item fromthe index or to analyse the items separatelyinstead of using an index construction. Theindices consisted of only three and two items,respectively, so the most obvious solutionwould be to analyse the items separately.However, only the symptom "dry skin on handsor arm" was sufficiently prevalent to beinganalysed separately. Hence I decided to includeonly the mucous membrane index and thegeneral symptom index in the followinganalyses of data from the prospective study.

The test for unidimensionality showed thatthe four symptom indices represented differentdimensions in both samples. It means that aperson may have a high score on one dimensionand a low score on another dimension. Forexample, a questionnaire measuring thefunctional ability may turn out to be composedof two different dimensions corresponding tolower limb function and upper limb function, asit is possible to have a good function of theupper limbs, but not being able to walk [10].Thus the upper and lower limb function shouldbe measured separately; otherwise informationabout the poor function of the lower limbsmight be blurred among the items of thefunction of the upper limbs. If an index isformed by items belonging to differentdimensions, information is diluted and thequestionnaire is less sensitive. Until now thedimensionality of the SBS symptoms has notbeen investigated. Nevertheless, severalresearchers have made case definition for anSBS case. Some require one general symptom,one mucous membrane symptom and one skinsymptom, others require one general symptomand either a mucous membrane symptom or askin symptom, and others require at least twosymptoms among a long list of symptoms [38,72, 74, 85, 110]. However, according to mystudy mucous membrane symptoms, skinsymptoms and general symptoms should not begrouped to form an "SBS index".

The internal consistency showed fair to goodhomogeneity, considering that some indicesconsisted of only two items. In both samples the

mucous membrane index and general symptomindex showed the highest degree of internalconsistency.

The test-retest reliability analyses indicatedgood to excellent agreement as regards thesymptom indices and indoor environmentindices. The kappa coefficients were at the samelevel as for other questionnaires measuringindoor environment and SBS symptoms [8,125].

In conclusion, the mucous membrane index,the general symptom index and the indoorenvironment indices showed a high degree ofreliability and a satisfactory internalconsistency. The mucous membrane index andthe general symptom index comprised twodifferent dimensions and were not biased withrespect to sex, age or atopy. Thus I believe thatthe questionnaire used in the study is asatisfactorily reliable and valid tool.

16

THE PROSPECTIVE STUDY

Study populationThe study population comprised 4000 personsaged 18 to 59 years who were selectedrandomly from the Danish Civil RegistrationSystem with the same number of women andmen and an equal number in each year group.Data collection was made by postalquestionnaires in April 2001 and April 2002.The time lag of one year was chosen to controlfor seasonal changes. Non-respondents werereminded once. The participants were invited bymail to take part in "a study about indoorenvironment, stress and health related to theworkplace and dwelling". The general purposeof the study was to assess the associationbetween non-specific symptoms and the indoorenvironment at work and in dwellings. Thisinformation was given to all participants in aone-page information letter. In order to assesswhether awareness influences the reporting ofsymptoms, a slight change was made in two ofthe sentences in the letter. In the letter to studygroup W (Work) we stated that knowledge wasespecially lacking about health effects related tothe indoor climate at work. In the letter to studygroup H (Home) the word "work" was replacedwith "home". The letter was identical to allparticipants except for this one word in twosentences. Study participants were randomlyallocated to the two study groups. However, inaddition to being a part of the prospective study,the baseline study also served the purpose toobtain normative data for the GlostrupQuestionnaire so that work environmentprofessionals could use the results as areference. Thus I had to be sure to collect asufficient number of responses to representnormative data for workplaces. Consequentlytwo thirds were allocated to group W (n=2667)and one third to group H (n=1333). At follow-up, all participants received identicalinformation letters explaining that the purposeof this extra survey was to examine whether theindoor environment was associated withsymptoms becoming chronic. It did not mentionthe workplace or the home.

At baseline 2710 participants (68%)completed the questionnaire, but 546participants were not eligible for inclusionbecause of being unemployed or receivingeducation. Thus at baseline the study groupcomprised 2164 participants with 1468participants in group W and 696 participants in

group H corresponding to the information letterabout the indoor climate at work and at home,respectively. At baseline, all participants wereasked whether they would accept to receiveanother questionnaire one year later. A total of2065 of the 2164 baseline participants agreed toparticipate in the follow-up study. At follow-up1740 participants (80% of the baselinepopulation) completed the questionnaire, ofwhom 1402 were eligible for participationbecause they were still working and living inthe same place as at baseline. Figure 2 showsthe flowchart of the study.

The 2164 persons in the baseline populationwere comprised of 1114 women (52%), themean age was 41 years (range 18-59), 38% hadatopy and 32% were current smokers. Thegeneral mental and physical health of theparticipants was like the average generalpopulation when measured with the SF-12 [42].The majority of the participants were non-manual workers (64%), 28% were manualworkers and 8% were self-employed. Group Wand group H were comparable with respect torate of participation, age, sex, marital status,occupation, smoking habits, general health,personality traits, and perception of physicaland psychosocial work environment. The non-respondents at baseline were more likely to bemen, but did not differ from the respondentswith respect to age or geographical region.Among the non-respondents at follow-up therewas an overrepresentation of young persons(<30 years), unmarried persons, smokers, self-employed persons and unskilled manualworkers, but there was no notable difference inbaseline characteristics on perceived indoorenvironment, mucous membrane symptomindex or general symptom index. The baselinecharacteristics of the respondents and non-respondents are shown in table 4.

QuestionnaireThe questionnaire included items concerningsymptoms related to the SBS, perceived indoorenvironment at work, psychosocial workcharacteristics, and personal characteristics.

The symptoms related to the SBS, the work-relatedness of the symptoms and the perceivedindoor environment were assessed with the"Glostrup Questionnaire", which is described indetails in the section about the validation study.A positive symptom was a symptomexperienced several times a week or daily.

17

In accordance with our validation study, thesymptoms were grouped in two indices, mucousmembrane index and general symptom index.The indices were formed by the sum of thesymptom variables that were dichotomisedcorresponding to symptoms experienced severaltimes a week or daily, irrespective of work-relation. If a symptom was more pronounced onworking days, it was considered to be work-related. Questions on the perceived indoorenvironment were grouped into the followinggroups: a draught index (range 0-3), atemperature index (range 0-2), a stuffy air index(range 0-2), a dry air index (range 0-2), a noiseindex (range 0-3), a light index (range 0-2), aspace/dust index (range 0-2), environmentaltobacco smoke (range 0-1). This grouping wasdone according to our validation study andcovered perceptions reported present severaltimes a week or daily. In addition, a question

designed for the study was asked whether therewere patches of damp or mildew in theworkplace.

A general tendency to report symptoms wasmeasured with a symptom checklist including19 somatic, emotional and cognitive symptomsexperienced during the past four weeks(stomach ache, chest pain, heart palpitations,shortness of breath, vertigo, muscle tension,sweating, powerlessness, depression,restlessness, nervousness, fatigue, sleepingproblems, tendency to cry, unable to relax,concentration problems, difficulty in makingdecisions, forgetfulness, and difficulty inthinking clearly, table 7) [100]. However, in theanalyses four of the symptoms were excluded,as they were symptoms that are often includedin the SBS (fatigue, concentration problems,forgetfulness and difficulty in thinking clearly).A variable denoting "symptom reporting

546 persons excluded(unemployed and students)

338 persons were excluded:86 were unemployed or students

230 had changed job22 had moved to a new home

1402 participantsat one-year follow-up

1740 respondents(80% of the baseline participants)

2065 agreed to participate in the follow-up study

2164 participants at baseline:1468 received a letter with emphasis on "work"

696 received a letter with emphasis on the "home"

2710 (68%)respondents

4000 persons selected randomly,aged between 18-59 years

Figure 2. Flowchart of the study population

18

tendency" was defined as present if at least fourof the remaining 15 symptoms were reported tooccur very often or often.

Psychosocial work characteristics weremeasured with four global questions designedfor the present study addressing job demands,job control, support from colleagues orsupervisors, and effort-reward imbalance [59][101]. The personality traits “negativeaffectivity” and “type A behaviour” weredetermined by two questions used in a previousstudy [5]. A question about self-efficacy, aquestion covering a tendency to worry abouthealth and a question about support from familyor friends were designed for the study. Table 5shows the questions on psychosocial workcharacteristics and personality traits. Decisionson where to dichotomise the responses weremade a priori on the basis of the wordings in theresponse options to indicate a high degree of thecharacteristic.

Information about age, sex and municipalityof living was obtained from the Danish CivilRegister; all other covariates were self-reported.Atopy was defined as reporting either allergy topollen, furry animals or house dust mite or ahistory of asthma, hay fever or childhoodeczema. A person who reported smokingtobacco daily was regarded a current smoker.General health was assessed by the Short Form12 Health Survey (SF-12) [42]. It was scoredaccording to the manual resulting in a physicaland a mental summary score, where a score of50 is the average and a score above 50 is aboveaverage.

The follow-up questionnaire consisted of thequestions on symptoms and potential riskfactors that were identical to the questions atbaseline.

Statistical analyses

PowerPower calculations were done before the study.It was computed that if an outcome occurredwith a prevalence of 5%, it would require asample size of approximately 1160 persons todetect an odds ratio (OR) of 2 [alpha=0.05 andbeta=0.90]. With an expected participation rateof 70% and assuming that 80% of theseparticipants were in employment at baseline, thesample size of 4000 persons was consideredsufficient.

Focus on the indoor environment at workand work-related symptomsWe used multiple logistic regression to examinethe effect of the two different informationletters on reporting a symptom as work-relatedallowing for potential confounders. A symptomwas considered work-related if it was morepronounced on working days. The associationswere analysed for the separate symptoms, notthe symptom indices. In the model we includedsex, age, allergy, smoking, negative affectivity,social support at home, a symptom reportingtendency, job demands, job control, socialsupport at work, social climate at work, andperceived indoor environment at work. Thecovariates were chosen a priori and entered inthe model in one step.

Perceived indoor environment andprevalence, incidence and persistence ofSBS symptomsLogistic regression was used to examine theassociation between perceived indoorenvironment at work and mucous membranesymptoms and general symptoms. Theoutcomes were the mucous membrane index(range 0-5) and general symptoms index (range0-3) described in the section about thequestionnaire. At baseline the prevalence ofmucous membrane symptoms and generalsymptoms was assessed as a score>0 on thesymptom index. At follow-up, the outcomes ofinterest were the incidence and the persistenceof mucous membrane symptoms and generalsymptoms. Incidence of symptoms was definedas a score>0 on the symptom index at follow-upamong participants with a score=0 on therespective score index at baseline. Persistenceof symptoms was defined as having a score>0at follow-up as well as at baseline.

Analyses were done in a three-stage process.Firstly, we examined the effect of each of theindoor environment indices, adjusting for sex,age, atopy and symptom reporting tendency.These potential confounders were kept in allsubsequent models whether significant or not.

Secondly, we in addition adjusted for otherpersonal factors and factors in the psychosocialwork environment. Potential personal orpsychosocial confounders comprised maritalstatus, smoking, negative affectivity, type Abehaviour, a tendency to worry about health,self-efficacy, support from family and friends,job demands, job control, job strain, worksupport, and effort-reward imbalance. We usedbackward elimination to choose which of these

19

covariates to keep in the model and chose 0.10as the significance level of the Wald chi-squarefor keeping a variable in the model.

Finally, we additionally adjusted each indoorenvironment index for the other indoorenvironment indices, testing whether the effectfor individual environment factors could beexplained by the other indoor environmentfactors. Again we used backward elimination ata 0.10 significance level to decide which of theother indoor environment indices to keep in thefinal model together with the potentialconfounders chosen at stage two.

To test for a dose-response effect we used atest for trend analysing the models with theindoor environment indices as continuousvariables in the models. An association wasregarded as significant if the top level of theindex had a 95% CI not including 1.0 or if thep-value was below 0.05 in the linear tests fortrend. In analyses of follow-up data, we usedinformation from the baseline questionnaire onthe indoor environment and other risk factors aspredictors of developing new symptoms orhaving persistent symptoms after one year. Inorder to keep the indoor environment asconstant as possible, analyses at follow-up wererestricted to the participants who were stillemployed in the same company and who stilllived in the same dwelling as they did atbaseline. The models were tested for goodnessof fit with the Hosmer and Lemeshow method[54].

The influence of a symptom reportingtendencyIn the models described above, symptomreporting tendency was forced in all models as apotential confounder. In order to test whetherthis was an over-adjustment, we repeated theanalyses without symptom reporting tendencyin the models.

Perceived indoor environment, SBSsymptoms and “dummy” symptomsLogistic regression was used to examine theassociation between perceived indoorenvironment at work and SBS symptoms aswell as other symptoms that cannot plausibly belinked to the indoor environment. The SBSsymptoms were grouped into mucousmembrane symptoms and general symptoms,and the outcomes of interest were theprevalence and incidence of these symptomgroups as described above. The other symptomsthat were considered not to be SBS symptoms

are referred to as dummy symptoms in thefollowing. None of the dummy symptoms wereincluded in the WHO description of the SBSsymptoms. The dummy symptoms were thesame as the symptoms used to describesymptom reporting tendency (table 7), but nowthey were used as an outcome and not as apotential confounder. The variable for symptomreporting tendency was defined as at least fourof the 15 symptoms that were reported to occurvery often or often. However, in order to have asufficient number of incident cases with dummysymptoms it was necessary to re-define apositive outcome. Responses of "never" or"seldom" were assigned a value of 0, while"sometimes", "often" and "very often" wereassigned a value of 1, 2 and 3, respectively. Thescores were summed to obtain an overall scorefor "dummy" symptoms ranging from 0 to 45.At baseline the prevalence of dummy symptomswas defined as having a score of at least 7,which corresponds to reporting 7 or morespecific symptoms at least "sometimes". Theincidence was defined as a score of at least 7 atfollow-up among persons with a score less than7 at baseline. This cut-off point corresponded tothe 75th percentile and was chosen because itparalleled the dichotomization of the mucousmembrane symptoms and general symptoms. Itwas fixed before any analyses were doneregarding relationships between exposure andoutcome.

Baseline data were used to examine thecross-sectional association between theperceived indoor environment and theprevalence of mucous membrane symptoms,general symptoms, and dummy symptoms.Longitudinal data were used to examine theassociation between indoor environment atbaseline and the incidence of SBS symptomsand dummy symptoms at 1-year follow-up aswell as the reverse association: whethersymptoms at baseline predicted that a personbegan to report new exposures in the indoorenvironment at follow-up (figure 3). Newreports of exposures in the indoor environmentwas defined as having at least a score of one onthe index at follow-up among persons who hada score of zero on the respective index atbaseline.

Analyses were done in the same three stageprocess as described above adjusting for sex,age, atopy, other personal factors, psychosocialwork characteristics and indoor environmentindices. The only difference was that analyseswere performed without symptom reporting

20

Baseline

SBS symptoms:mucous membrane symptoms

and general symptoms

Follow-up

Figure 3. Models on the predictive relationships between the perceived indoorenvironment and symptoms. "1" indicates cross-sectional analysis at baseline, "2"indicates longitudinal analysis with normal causal direction between exposure andoutcome, and "3" indicates the reverse causation in longitudinal analysis.

SBS symptoms:mucous membrane symptoms

and general symptoms

Perceived indoor environment Perceived indoor environment

Other symptoms:"dummy" symptoms

Other symptoms:"dummy" symptoms

21

tendency as a covariate in the models. In theanalyses of the reverse association, we adjustedonly for sex, age, and atopy because the smallnumber of cases did not permit furtheradjustments in the models. To test for trend wealso analysed the models with the indoorenvironment indices as continuous variables inthe models. An association was regarded assignificant if the top level of the index had a95% CI not including 1.0 or if the p-value wasbelow 0.05 in the linear tests for trend. Analysesat follow-up were restricted to the 1402participants who worked and lived in the sameplace as they did at baseline.

All data processing were done with the SAS®

System version 8.2 [97].

Results

Focus on the indoor environment at workand work-related symptoms (appendix II)A slight difference in the accompanying letterreplacing the word "work" with "home" in twosentences influenced the responsesconsiderably. The prevalence estimates ofsymptoms were similar in group W and groupH, but differences were found as regards thereporting of work-relatedness and home-relatedness. If the information letter focusedslightly more on the indoor environment at theworkplace than in the home, the participantswere more likely to report that their symptomswere work-related (significant unadjusted oddsratios (OR) between 1.8 and 5.5). Adjusting theresults for several potential confounders mainlyled to higher estimates of OR. Likewise, theparticipants were more likely to report that theirsymptoms were more pronounced at home, iffocus was on the environment at home(significant unadjusted OR between 5.7 and20.6). As regards the psychosocial workcharacteristics, persons who reported to havehigh job demands and low support at work alsotended to report work-related general symptoms(significant adjusted OR ranging between 1.9and 4.0). Work-related mucous membranesymptoms were associated only with high jobdemands (significant adjusted OR between 1.9and 2.6).

Perceived indoor environment andprevalence, incidence and persistence ofSBS symptoms (appendix III)Mucous membrane symptoms and generalsymptoms were common, as 28% of thepopulation at baseline reported to have mucousmembrane symptoms regularly and 23%reported to have general symptoms. The mostcommon symptoms were nasal congestion(16%) followed by fatigue (15%), headache(12%), nose irritation (11%) and eye irritation(10%). At follow-up the incidence of mucousmembrane symptoms and general symptomswas 15% and 9%, respectively, andapproximately 50% recovered from symptomsduring the one-year follow-up period. Nodifference was found between manual and non-manual workers in prevalence or one-yearincidence of mucous membrane symptoms orgeneral symptoms. In the indoor environment atbaseline the most common reported exposurewas noise (46%) followed by reports aboutcramped space or dust (38%) and perception ofdry air (30%). The majority of participantsremained at the same level of indoorenvironment complaints (63% to 94%), andonly few changed more than one score on anindex (1% to 7%). Table 6 shows the changes inperceived indoor environment between baselineand follow-up.

We found no consistent risk factor pattern inthe cross-sectional and the longitudinal analysesfor the associations between perceived indoorenvironment factors at work and symptoms.Whereas mucous membrane symptoms in thecross-sectional analysis were significantlyassociated with self-reported high temperatureand dry air, the prospective analyses showedthat onset of mucous membrane symptoms wasassociated with the sensation of draught, dry air,and noise. Persistent mucous membranesymptoms were associated only with perceptionof stuffy air. General symptoms were associatedwith self-reported stuffy air and dry air in thecross-sectional analysis, while draught was theonly predictor of onset of general symptoms.We found no predictors in the indoorenvironment for the persistence of generalsymptoms.

The influence of a symptom reportingtendency (appendix III and thesis)Table 7 shows the symptom check list used torecord a symptom reporting tendency, whichwas defined as having at least four of the 15

22

symptoms that cannot plausibly be linked to theindoor environment. Symptom reportingtendency was associated with the prevalence ofmucous membrane symptoms as well as generalsymptoms with odds ratios of approximately 2.3and 7.2, respectively (table 8). In addition,symptom reporting tendency was similarlyassociated with the incidence and persistence ofmucous membrane symptoms. Elevated oddsratios were also found regarding the incidenceand persistence of general symptoms, but theassociations were of borderline significance(table 8). When the analyses were repeatedwithout symptom reporting tendency as acovariate in the models, the estimates of theeffects of the indoor environment factorschanged only slightly (table 9 and table 10).

Perceived indoor environment, SBSsymptoms and dummy symptoms(appendix IV and thesis)In the cross-sectional analysis, the perceivedindoor environment was associated withsymptoms that are traditionally included in theSBS as well as with dummy symptoms. Mucousmembrane symptoms were associated with dryair, dust, temperature and stuffy air (table 9,model without symptom reporting tendency).General symptoms were associated with stuffyair and light (table 10, model without symptomreporting tendency). Dummy symptoms wereassociated with stuffy air index, dry air index,noise index and patches of dampness (appendixIV).

In the longitudinal analysis only few of theperceived indoor environment factors predictedthe development of any of the symptom groups.Draught, dry air and noise were associated withincident mucous membrane symptoms, anddraught was associated with incident generalsymptoms (table 9, table 10 and appendix IV).Incident dummy symptoms were associatedwith dry air. Although many were notstatistically significant, the patterns ofassociation for the dummy symptoms resembledthose of the mucous membrane symptoms andgeneral symptoms.

In the reverse longitudinal analysis, wefound that persons with symptoms at baselinewere more likely to report exposures in theindoor environment than persons withoutsymptoms were. Both the SBS symptoms andthe dummy symptoms predicted several newreported exposures in the indoor environment(appendix IV). Persons with mucous membranesymptoms at baseline began to report exposures

to temperature conditions, stuffy air, noise, andlight conditions. Persons with generalsymptoms began to report exposures to draught,temperature conditions, stuffy air, noise, andlight conditions while persons with dummysymptoms reported draught, temperatureconditions, and stuffy air.

DiscussionIn my study there was no risk factor in theperceived indoor environment that wasconsistently and plausibly associated with theprevalence, incidence and persistence ofmucous membrane or general symptoms.

Some of the perceived indoor environmentfactors predicted not only mucous membrane orgeneral symptoms, but also symptoms without abiologically plausible explanation in the indoorenvironment (dummy symptoms). However,SBS symptoms and dummy symptoms alsopredicted that the participants began to reportexposures in the indoor environment at follow-up.

Even a small increase in focus on theworkplace influenced the responses as towhether a symptom was reported as work-related or not.

A general tendency to report symptoms wasan independent risk factor of mucous membranesymptoms and general symptoms, but not aconfounder in this study.

Comparison with other findingsExcept for a few intervention studies and onelongitudinal epidemiological study, previousstudies on the SBS are cross-sectional. In thesecross-sectional studies several self-reportedexposures, but no objective measurements haveconsistently been associated with mucousmembrane symptoms and general symptoms.The only findings from previous studies thatcould be reproduced in the present study werethat mucous membrane symptoms wereassociated with the perception of dry air andnoise, and that general symptoms wereassociated with perceived stuffy air. There is,however, no obvious biological pathwaybetween noise and mucous membranesymptoms. In a recent longitudinalepidemiological study mould in seat dust, self-reported lack of office cleanliness and self-reported number of people working in the officewere associated with SBS symptoms [26].Perceived exposure to dust or dirt was not a riskfactor in my study. The participants were askeda question about the number of people working

23

in the office or workroom, but the validity ofthis question was doubtful. Hence I did notinclude this variable in the models. Thisvariable, however, was not statisticallysignificant in univariate analyses.

A few other studies on SBS symptoms havefocused on the association between exposures inthe indoor environment and other symptoms,which cannot plausibly be related to the indoorenvironment. Wallace et al. found that pain inthe back, hands or shoulder/neck was associatedwith glare, noise and odour of cosmetics [120].Platt et al. found an increased frequency ofbackache and constipation among adults livingin houses with visible damp or mould [88].Pirhonen et al. found that self-reporteddampness or mould problems in homes wereassociated not only with many different SBSsymptoms, but also with backache and recurrentstomach ache [87]. These biologically unlikelyresults seem to be in good agreement with theresults of my study.

There exists no other study on the SBS thathas examined the reverse association assessinghow the presence of symptoms influences futurereporting of exposure. However, inoccupational stress research the reversecausation hypothesis has been used examiningthe impact of mental health on future reportingof work characteristics [31, 32, 41, 118]. DeLange et al found that health affected perceivedwork characteristics both positively andnegatively, and the study by van Hoof et al.suggested that health and work characteristicsmay act reciprocally, similar to the findings inmy study.

One other study on SBS has also takenaccount of "awareness" by informing only someof the participants that a study about the indoorenvironment was going on [73]. They foundthat the prevalence of work-related SBSsymptoms was three times higher amongworkers aware of the study relative to thoseblinded. Another study examined an outbreak ofSBS in a school with mould growth and alsofound that the perception of symptomsincreased after the problem was publicised [46].This is in good accordance with my results.

Thus altogether, studies that have examinedthe same type of problems seem to support myresults.

Strenghts and limitations of the studyThe strengths of the present study are the largepopulation and the prospective design. Theprospective design made it possible to evaluate

a temporal relationship measuring the exposurebefore the outcome, on the assumption that theexposure was relatively stable during the one-year follow-up period. Longitudinal studies aremore informative in etiological analyses.However, cross-sectional studies may support acausal relationship, if the studied symptoms ordisease develop shortly after the exposure. SBSsymptoms are believed to be acute reactions tofactors in the indoor environment rather thanchronic symptoms. Hence cross-sectionalstudies could be suitable to assess acutereactions to the indoor environment, if it waspossible to measure the outcome objectivelyand thus reduce reporting bias. I chose alongitudinal design because of the possibility toassess whether the reported exposures precededthe symptom.

A limitation is the interval of one yearbetween baseline and follow-up. This choicewas made to control for seasonal variations. Ihave no information about changes in theindoor environment during the one-year follow-up period, but I excluded participants who hadchanged job in order to keep exposureconditions as constant as possible. However,fluctuations in the exposure are likely to occur.Thus, misclassification of the exposure mayhave occurred, which would reduce theassociations towards the null hypothesis of noassociation. More follow-up rounds with acloser interval than a year would have made itpossible to assess more precisely how thesymptoms emerged and disappeared in relationto exposure. This approach has been used in theonly other longitudinal epidemiological study[26]. In that study, environmentalmeasurements and questionnaire survey weredone every six weeks during a year andincluded 98 participants. My power calculationsbefore the study indicated that approximately1160 participants were needed in a study withone follow-up round. It is difficult to assess,however, if a design with more repeatedmeasurements would have been more cost-effective. In addition, repeated measurementsmay influence the reporting of symptoms. Forexample, if the participants are moreenthusiastic in the beginning of a study, adecrease in symptom prevalence will beobserved during the follow-up period, whichmay affect the observed associations [26].

A limitation in the study is that I have onlyself-reports on the exposure. However, it was ofcourse neither practically nor financiallypossible to make objective measurements in

24

more than two thousand workplaces and homes.Although self-reports seem to reflectobjectively measurable factors in the indoorenvironment to some degree [1, 23, 82, 90, 92,114, 117], a risk of reporting bias existsresulting in bias towards more significantpositive associations with symptoms. However,in the analyses of follow-up data the exposureand outcome is measured on different points intime. Assuming that the participants are unableto remember what they answered a year before,this will reduce but not eliminate reporting bias.

As the cohort is a random sample of thegeneral population it is possible that thecontrasts in exposure are insufficient to detecttrue associations, because only few presumablywork in buildings with severe indoor climateproblems. The prevalence of perceivedexposures in the present study populationcorresponded to the prevalences I have found in41 non-problem buildings [22]. The distributionof reported exposures in these 41 non-problembuildings showed a large or complete overlapwith the similar distribution in the 8 problembuildings in my validation study [unpublisheddata]. Thus, it may be assumed that also theparticipants from the general population areexposed to a wide variation in physical orchemical factors in the indoor environment. Infact, a large variation in perceived indoorenvironment factors was found in the presentstudy.

The possibility of selection bias must beconsidered. The participants who were lost tofollow-up did not differ from the cohort inbaseline characteristics on perceived indoorenvironment and symptoms. Thus I consider thedrop out to be less important. A response rate of68% at baseline and 80% at follow-up can beconsidered satisfactory for a population study, ifthere is no selection bias.

Possible explanations for the findingsIn the longitudinal analyses I chose to use thesymptoms as an outcome without consideringwhether the participants reported them as morepronounced at work or not. This choice wasmade because the baseline study had shown thatinformation about work-relatedness may beseriously biased. Nevertheless, this might leadto underestimation of possible effects, becausethe work-related symptoms are diluted withsymptoms that are not temporarily related to theworkplace.

I had expected that the same factor in theindoor environment would induce symptoms aswell as maintain symptoms, yielding aconsistent risk factor pattern in the prevalence,incidence and persistence of SBS symptoms.However, as SBS symptoms are supposed to beacute recurrent symptoms, the symptoms maydisappear and reappear during the follow-upperiod, which may reduce the estimates ofincidence and persistence. Nevertheless, aconsistent risk factor pattern would havesupported a causal relationship, assuming thatpersons who are sensitive to develop SBSsymptoms still exists in the population, thatpersons do not become immune to SBSsymptoms once they have got it, and that theexposure still persists at follow-up. In thepresent study, the most consistent finding wasthat dry air was associated with the prevalenceand incidence of mucous membrane symptoms.The prevalence could be explained by problemsin distinguishing the sensation of dry air withirritation of the eye, but not the incidence.

If there is a true biological relation betweenindoor environmental factors and SBSsymptoms, one would expect these variables tobe stronger associated with SBS symptoms thanwith other symptoms for which there is noplausible explanation. Thus, the lack ofspecificity of associations found in my studymay speak against a true causal relation.Furthermore, a number of associations betweenthe reported indoor exposures and SBSsymptoms were also biologically implausible.The association between mucous membranesymptoms and noise, for example, was noteasily understood. Pirhonen et al. found anincreased prevalence of backache and stomachache in damp buildings [87]. However, whenthey analysed data on a sample consisting solelyof persons not complaining of backache orstomach ache, the strength of the associationsbetween the indoor environment and SBSsymptoms were significantly reduced. Thisindicates that some associations between SBSsymptoms and perceived indoor environmentfactors could be due to over-reporting. In mystudy symptom reporting tendency was stronglyrelated with both mucous membrane symptomsand general symptoms in the cross-sectionalanalysis. This may reflect persons withdisorders in several organs, but may also be dueto over-reporting.

A possible explanation for the reverseassociation, showing that persons withsymptoms were likely to begin to report

25

exposures in the indoor environment, is thatsymptomatic persons may be more susceptiblein that specific organ to irritants or otherproblems in the indoor environment [67].However several of the findings in my study arenot easily understood, if such a mechanism isthe explanation of “reversed causation”. It is,for example, difficult to explain why personswith symptoms such as stomach ache or heartpalpitation should begin to complain moreabout draught or temperature conditions. Itseems reasonable that persons with irritatedeyes could be more bothered by glare andreflections, but it is not conceivable that personswith irritation in the nose or throat shouldcomplain about the light. Repeating theanalyses with eye irritation and nose/throatirritation separately did not alter theassociations [data not shown]. Thus it does notseem likely that individual susceptibility solelyexplains the reverse associations. An alternativeexplanation is that people who have manyhealth complaints look for potential causes forexample stress at work or problems in theindoor environment. The result is an increasedawareness on external factors, which mayproduce a spurious association between e.g. theindoor environment and health.

I chose to study SBS symptoms in a randomsample of the general population instead ofstudying occupants of a “sick building”. Basedon my experience from interviewing employeesin problem buildings, I presumed that self-reports could be biased in cases initiated byconcern about health effects among theoccupants of a building. Subsequently my studyhas shown that even little awareness mayintroduce bias in self-reported health. Otherresearchers have proposed that the sick buildingsyndrome could be due to or modified by stress-related factors at work or a group behaviour as a"contagious" condition [105, 116]. In my studythe participants completed the questionnaire athome out of context with the workplace, so nogroup behaviour ought to be present.

In the term "sick building syndrome" thecause of the syndrome is incorporated in thedefinition of the syndrome. This easily leads toarguing in a circle: a "sick" building may bedefined as a building where many occupantshave similar symptoms and, conversely, theSBS are symptoms occurring in a sick building.Does this mean that an excess of symptoms in abuilding is required to call it SBS, and that SBSsymptoms can be investigated only in a sickbuilding? My results suggest that bias with

respect to work-relatedness of symptoms islikely to occur when surveys are conducted inbuildings with suspected indoor environmentproblems, because attention has already beendrawn to the problems, and a survey will onlyfurther increase the focus on the problems. Inparticular the risk of bias exists when theexposure and outcome are measuredsimultaneously, and especially if information onexposures as well as outcomes reliesexclusively on the participants' subjectiveevaluation. Thus, a study conducted in aproblem building may not be suitable fordetecting causal effects of indoor environmentfactors, even if a non-problem building isincluded as a control, which has been the designof some other studies [11, 53]. Studiesexamining problem buildings may, however, beuseful to generate important hypotheses andprovide information from extreme exposuresituations that are rarely encountered insystematic studies. In addition, cases initiatedbecause of concern about health effects amongthe occupants of a building may also be usefulfor qualitative studies, including personal andcontextual factors in the models as mediators oreffect modifiers in order to explain the causalpathway from environmental exposure tooutcome.

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OVERALL CONCLUSIONS ANDIMPLICATIONS In my study three important criteria of causalassociations between the indoor environmentand symptoms could not be met: temporality,biological plausibility, and consistency. Theresults suggest that many people experiencemucous membrane symptoms and generalsymptoms regularly. As the reporting of work-relatedness is severely biased, many symptomsmay be misclassified as "building relatedsymptoms" and the term should be avoided. Thevalidation study showed that the symptomsincluded in the SBS represent differentdimensions and thus should not be grouped toform an SBS index or an SBS-diagnosis. Thereverse associations found in my study indicate

bias towards a tendency to over-report.According to my study symptoms such asstomach ache, heart palpitations and muscletension were also associated with perceivedfactors in the indoor environment. This suggeststhat these symptoms just as well as mucousmembrane symptoms and general symptomscould have been included in the SBS, if theoccupants of a building were of the conceptionthat these symptoms were related to the indoorclimate. This does not exclude that there may beassociations between specific indoorenvironment factors and health. However, itsuggests that the SBS symptoms do notconstitute a well-defined syndrome.

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ENGLISH SUMMARYThis PhD thesis was done during myemployment at the Department of OccupationalMedicine at the Copenhagen UniversityHospital in Glostrup.

During the last 20 years several cross-sectionalstudies have examined relationships betweenindoor environment factors and symptoms suchas irritation of the mucous membranes, irritationof the skin, fatigue and headache. If thesymptoms are attributed to the indoorenvironment, this constellation of symptoms hasbeen described as the sick building syndrome(SBS). However, the cause(s) of the SBSsymptoms are unknown and little is knownabout the temporal relationship betweenexposures in the indoor environment and thedevelopment of symptoms. In addition, it hasbeen suggested that awareness of a potentialenvironmental hazard and a personal tendencyto overrate exposures or symptoms caninfluence how people report SBS symptoms andthus affect the association between theperceived indoor environment and SBSsymptoms.

The main aims of the present study were toexamine the temporal relationship betweenreported exposures and SBS symptoms and toexamine whether awareness of the indoorenvironment and a tendency to overrate mayaffect the association between the perceivedindoor environment and SBS symptoms.Another aim was to validate the questionnaireused for the study.

The study was designed as a follow-up studywith two questionnaire surveys conducted withan interval of one year in a random sample ofthe general population aged 18-59 years. Thestudy population consisted of 2164 participantsat baseline, of whom 1402 were also eligible forinclusion at the one-year follow-up. Theoutcomes of interest were the prevalence,incidence and persistence of mucous membranesymptoms (an index consisting of eye irritation,nose irritation, nasal congestion, throat irritationand hoarseness) and general symptoms (anindex consisting of fatigue, headache anddifficulty in concentrating).

At baseline a slight difference in theintroduction letter was made so that someparticipants received a letter with a bit moreattention on the indoor environment at work,and other participants received at letter that

focused slightly more on the indoorenvironment at home. In two sentences of theletter the word "work" was replaced with"home". I found that persons who had beenfocused on the workplace were more likely toreport their symptoms as more pronounced atwork. In addition, persons who received theother letter with focus on the home were morelikely to report their symptoms as morepronounced at home. The findings suggestedthat reports on work-relatedness may beseverely biased.

Some statistically significant associationswere found between reported exposures in theindoor environment and the prevalence ofmucous membrane symptoms and generalsymptom. However, not all associations werebiologically plausible, and no consistent patternwas found between the associations found asregards the prevalence, incidence andpersistence of these symptoms.

I also examined the association betweenreported exposures in the indoor environmentand a group of other symptoms that werebiologically implausible to associate with theindoor environment (dummy symptoms).Several of the indoor environment factors wereassociated also with the dummy symptoms, thusindicating reporting bias.

Furthermore I investigated the reverse orderrelationship: that symptoms may predict futurereports of exposures in the indoor environment.I found that persons having mucous membranesymptoms, general symptoms or dummysymptoms were more likely to begin to reportexposures in the indoor environment thanpersons without symptoms. Finally, a tendencyto report many symptoms in general was relatedwith mucous membrane symptoms and generalsymptoms at baseline. The findings suggest abias towards a tendency to over-report.

The validation study took place prior to thefollow-up study in 8 workplaces with suspectedindoor environment problems (N=947). It wascross-validated in the baseline sample from theprospective study. It showed a high degree ofreliability of the questionnaire. However, itembias was found related to sex, age and atopy asregards the construction of two symptomindices, a skin index and a pulmonary index.Hence these indices were not used in thesubsequent analyses of the follow-up study.Testing for unidimensionality showed thatmucous membrane symptoms, skin symptoms,

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pulmonary symptoms and general symptomsbelong to different dimensions and thus shouldnot be combined in a common index.

In conclusion, the results indicates a ratherconfusing web of pathways between thesymptoms and perceived exposures, where it isdifficult to determine what existed first: theoutcome or the exposure. In addition, thereported indoor environment exposures wereassociated with symptoms that cannot plausiblybe explained by the indoor environment. Thefindings do not exclude that there may beassociations between specific indoorenvironment factors and health. However, itsuggests that there is a risk of reporting biaswhen assessing non-specific symptoms and thatthe SBS symptoms do not constitute a well-defined syndrome.

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DANSK RESUMÉPh.d. afhandlingen er udarbejdet under minansættelse på Arbejdsmedicinsk Klinik,Amtssygehuset i Glostrup.

I de seneste 20 år har adskillige tværsnitsstudierundersøgt mulige sammenhænge mellemforhold i indeklimaet og symptomer somirritation af slimhinder og hud, træthed oghovedpine. Hvis man mener, at symptomerneskyldes indeklimaet, kalder man ofte dennesammensætning af symptomer for"indeklimasyndrom". Årsagen eller årsagerne tilindeklimasyndrom er imidlertid ukendt, og mankender kun lidt den tidsmæssige sammenhængmellem udsættelse for kemiske eller fysiskeforhold i indeklimaet og udviklingen afsymptomer. Desuden er der noget, der tyder på,at forhold som opmærksomhed omkring årsagertil indeklimaproblemer og en tendens til atoverrapportere kan påvirke angivelsen af, omman har disse symptomer.

Formålet med nærværende undersøgelse harværet at undersøge den tidsmæssigesammenhæng mellem en persons oplevelse afindeklimaet og de uspecifikke symptomer, somer blevet beskrevet ved indeklimasyndromet,samt at undersøge hvorvidt opmærksomhedomkring indeklimaet og enoverrapporteringstendens er associeret medsymptomerne. Et andet formål var at valideredet spørgeskema, som er blevet anvendt iundersøgelsen.

Undersøgelsen er en opfølgnings-undersøgelse baseret på spørgeskemaer fra entilfældig stikprøve af danske statsborgere ialderen 18-59 år. Spørgeskemaerne er udfyldt togange med et års mellemrum. I alt 2164personer deltog ved førstespørgeskemaundersøgelse. Af disse var der1402 personer, der også besvarede det andetspørgeskema og som kunne indgå iopfølgningsundersøgelsen, idet de stadig varansat på samme arbejdsplads og boede sammested. De helbredsmål, der havde interesse forundersøgelsen, var slimhindesymptomer (etindex bestående af øjenirritation, næseirritation,stoppet/løbende næse, irritation i svælget oghæshed) samt almensymptomer (et indexbestående af hovedpine, træthed ogkoncentrationsbesvær).

Ved den første spørgeskemaundersøgelseblev populationen delt op i to grupper, som blevpræsenteret for formålet med undersøgelsen påen lidt forskellig måde. I ledsagebrevet til den

ene gruppe blev der lagt lidt mere vægt påindeklimaet på arbejdspladsen end i hjemmet. Iden anden gruppe var det omvendt. Det drejedesig om at ordene "på arbejde", der blev skiftetud med "i hjemmet" i to sætninger i brevet. Detviste sig, at personer, som havde fået brevetmed mere vægt på arbejdspladsen, var meretilbøjelige til at angive, at deres symptomer varværst, når de var på arbejde. Desuden var depersoner, der havde fået det andet brev, meretilbøjelige til at angive at symptomerne varværst i hjemmet. Disse resultater tyder på, at derkan være store fejlkilder forbundet med de svarman får på spørgsmål, der vedrører om etsymptom er værst på arbejdspladsen.

I den første spørgeskemaundersøgelse blevder fundet flere statistisk signifikantesammenhænge mellem selv-rapporteredefaktorer i indeklimaet og slimhindesymptomersamt almensymptomer. Der var imidlertid ikkenoget konsistent mønster mellem disse fund ogde longitudinelle analyser med hensyn til hvilkefaktorer i indeklimaet, der var associeret medforekomsten af indeklimasymptomer ellerudvikling eller vedligeholdelse af symptomer.

Den vigtigste risikofaktor for at udvikle nyeindeklimasymptomer var, at man havde mangeandre symptomer, som ikke er biologiskplausible at relatere til indeklimaet. Der fandtesendvidere også flere statistisk signifikantesammenhænge mellem disse uplausiblesymptomer og rapporterede påvirkninger iindeklimaet. Dette kunne tyde på rapporteringsbias.

Der syntes at være en vekselvirkning mellemklager over indeklimaet og symptomer, idetpersoner som havde symptomer vedundersøgelsens begyndelse, men som på dettetidspunkt ikke klagede over indeklimaet,begyndte at opleve problemer i indeklimaet iløbet af den 1-årige opfølgningsperiode.

Undersøgelsen af validiteten blev udført på 8arbejdspladser, hvor man mistænkte at der varindeklimaproblemer (N=947) samt istudiepopulationen fra den førstespørgeskemaundersøgelse. Der blev fundet enhøj grad af reproducerbarhed. To indexeromfattende hhv. hudsymptomer og nedreluftvejssymptomer viste sig at være forbundetmed item-bias i forhold til køn, alder og atopi.Derfor blev disse to indexer ikke anvendt ianalyserne af opfølgningsundersøgelsen.Analyser af dimensionalitet viste, at slimhinde-indexet, hud-indexet, luftvejs-indexet ogalmensymptom-indexet tilhørte forskellige

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dimensioner og derfor ikke bør samles i etfælles index.

Sammenfattende viste resultaterne etkomplekst netværk af sammenhænge mellemsymptomer og oplevede påvirkninger iindeklimaet, hvor det er vanskeligt at adskillehvad der kom først: eksponering ellersymptomer. Desuden, var de rapporteredeindeklimapåvirkninger associeret medsymptomer som ikke er biologisk plausible atkæde sammen med indeklimaet. Disse fundudelukker ikke, at specifikke forhold iindeklimaet kan påvirke helbredet, men viser atder kan være bias forbundet med om manangiver disse symptomer og at symptomerne iindeklimasyndromet ikke udgør et veldefineretsyndrom.

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Table 1. Characteristics of the participants in the validation study, N=947.Type of workplace Suspected indoor environment

problem N Participationrate (%)

Women(%)

Agemean (range)

School No. 1 Mould growth in the roof construction 69 97 68 49 (26-63)

Hospital ward Dust after renovation of the building 40 91 100 42 (24-68)

Social and health

care college

Mould growth in the outside walls 26 >85* 100 45 (26-63)

School No. 2 Dust and mineral fibres from ceilings 52 95 67 45 (25-63)

Nursing home Water damage 204 93 96 42 (18-66)

Technical University Dust after renovation of the building

and ventilation problems

64 100 59 39 (22-65)

School No. 3 Water damage and ventilation

problems

62 >85* 68 46 (24-63)

Town hall Dust after renovation of the building

and ventilation problems

430 94 63 44 (18-65)

* The exact number of employees was not reported, only an approximate number

Table 2. Illustration of item bias with respect to atopy of the item “breathlessness” in thepulmonary symptom index.If there was no item bias the percentage of positive answers to the item "breathlessness" at theindex scores 1 and 2 would be the same for non-atopics and atopics. However, here atopics aremore likely to have a positive answer to the item "breathlessness" (shown in the hatched fields).At a score=0 and a score=3, both non-atopics and atopics, by definition, have 0% and 100%,respectively.

Breathlessness

n* No (%) Yes (%)

Index score 0Non-atopic 483 100 0Atopic 250 100 0

Index score 1Non-atopic 72 94 6Atopic 52 81 19

Index score 2Non-atopic 7 57 43Atopic 18 44 56

Index score 3Non-atopic 5 0 100Atopic 11 0 100

χ2=6.0 d.f.=2 p=0.044 gamma=0.58 p=0.032 (two-sided)

*N=898, because respondents with any item unanswered in the index are excluded.

Table 3. Test-retest reliability and internal consistency of symptom indices and indoorenvironment indices

Test-retest reliability, N=110 Internal consistency.Cronbach coefficient alpha

Full agreement(%) kappa (95% CI) Validation

sample, N=947Baseline study

sample, N=2164Symptom indices

Mucous membrane index 76 0.78 (0.70 - 0.86) 0.71 0.64Pulmonary index 89 0.65 (0.46 - 0.84) 0.61 0.53Skin index 84 0.69 (0.56 - 0.83) 0.49 0.41General symptom index 94 0.93 (0.88 - 0.98) 0.66 0.57

Indoor environment indicesDraught index 80 0.64 (0.49 - 0.78) 0.64 0.72Temperature index 77 0.58 (0.43 - 0.73) 0.58 0.58Stuffy air index 73 0.63 (0.51 - 0.74) 0.60 0.61Environmental tobacco smoke 85 0.79 (0.63 - 0.94)* - -Dry air index 88 0.77 (0.65 - 0.89) 0.44 0.50Noise index 76 0.67 (0.55 - 0.79) 0.59 0.68Light index 87 0.63 (0.45 - 0.81) 0.58 0.57Space/dust index 77 0.74 (0.62 - 0.86) 0.45 0.41

* Simple kappa. All other kappa values are the weighted kappa.

Table 4. Baseline characteristics according to status at one-year follow-up. P-values computed with the Chi Square test unless otherwise noted.

Non-respondents, N=424 Respondents, N=1740

n (%) n (%) P-valueWomen 207 (48.8) 907 (52.1) 0.22Marital status, living as married 283 (73.3) 1307 (80.7) 0.001Age, years

18-2930-3940-4950-59

107113105

99

(25.2)(26.7)(24.8)(23.4)

290484508458

(16.7)(27.8)(29.2)(26.3)

0.001

Employmentself-employednon-manualsskilled manual workerunskilled manual worker

46232

5571

(11.4)(57.4)(13.6)(17.6)

1291107

224231

(7.6)(65.5)(13.3)(13.7)

0.005

Smoking, daily 156 (37.1) 539 (31.1) 0.02Atopy 164 (38.9) 658 (37.9) 0.72

SymptomsMore than one mucous membrane symptom* 122 (28.8) 485 (27.9) 0.72

More than one general symptom† 104 (24.5) 396 (22.8) 0.45

Symptom reporting tendency‡ 49 (11.6) 150 (8.7) 0.06

Perceived indoor environment§Draught index 107 (26.8) 464 (27.5) 0.77Temperature index 108 (27.3) 467 (27.7) 0.86Stuffy air index 92 (23.2) 387 (23.0) 0.94Environmental tobacco smoke 113 (28.5) 421 (25.1) 0.17Dry air index 104 (26.2) 527 (31.2) 0.05Noise index 193 (48.6) 757 (44.9) 0.18Light index 54 (13.6) 293 (17.4) 0.07Space/dust indext 147 (37.1) 650 (38.5) 0.60Patches of damp/mildew 26 (6.7) 108 (6.5) 0.91

Psychosocial work characteristicsHigh job demands 156 (38.3) 668 (39.4) 0.68Low job control 77 (19.1) 245 (14.4) 0.02Poor support, co-workers and supervisors 141 (34.8) 601 (35.4) 0.83Effort-reward imbalance 61 (15.1) 311 (18.3) 0.13Poor social climate 44 (10.9) 244 (14.4) 0.07

Personality traitsNegative affectivity 53 (12.6) 158 (9.1) 0.03Type A behaviour 87 (20.7) 307 (17.7) 0.16Self-efficacy 52 (12.4) 167 (9.7) 0.10Worry about health 52 (12.3) 204 (11.8) 0.76

Poor family support 102 (24.5) 338 (19.6) 0.02

SF12Physical Health Summary Scale (mean) 50.8 51.8 0.02¶

Mental Health Summary Scale (mean) 50.3 50.2 0.87¶

* Mucous membrane symptoms: eye irritation, nose irritation, nasal congestion, throat irritation, and hoarseness.† General symptoms: fatigue, headache, and concentration difficulty‡ At least four symptoms among 15 "non-SBS" symptoms§ A score of one or more on the index¶ T-test

Table 5. Questions about psychosocial work characteristics and personality traits.

Characteristic measured Questions Answers

Job demands How demanding do you find your workaltogether?

Extremely demanding, verydemanding, rather demanding,somewhat demanding, not verydemanding, very little demanding

Job control How much influence do you have in planningand carrying out your work?

Very much, rather much, moderate,not so much, rather little, very little

Job strain*

Support at work If you have problems, is it possible to obtain thenecessary support from colleagues orsuperiors?

Always, often, sometimes, seldom,never

Effort-reward imbalance Do you think that your job performance issufficiently appreciated?

To a very high degree, to a highdegree, to some degree, to a minordegree, to a low degree, to a verylow degree

Social climate at work How is the atmosphere and psychologicalclimate at your workplace?

Very good, rather good, quite good,not so good, rather poor, very poor

Negative affectivity Do you as a person tend to be worried,nervous, or somewhat pessimistic?

Not at all, very little, a little, somewhat,quite a bit, rather much, very much

Type A behaviour Do you as a person tend to be competitive,jealous, ambitious, and somewhat impatient

Not at all, very little, a little, somewhat,quite a bit, rather much, very much

Self-efficacy Are you a person who is usually able to solvedifficult problems, manage unexpectedsituations and reach your goals?

Not at all, very little, a little,somewhat, quite a bit, rather much,very much

Worry about health Do you as a person tend to be worried aboutyour health?

Not at all, very little, a little, somewhat,quite a bit, rather much, very much

Social support If you have problems, is it possible to obtain thenecessary support from family or friends?

Always, often, sometimes, seldom,never

Bold indicates response alternatives with a hypothesized high risk of non-specific symptoms compared to non-bold responsealternatives.* Job strain defined as the combination of high job demands and low job control

Table 6. Changes in perceived indoor environment between baseline and follow-up.Number and (%).

Better Unchanged Worse

A change>1 A change=1 A change=1 A change>1Draught 63 (4.7) 159 (12.0) 945 (71.1) 114 (8.6) 48 (3.6)

Temperature 49 (3.7) 160 (12.1) 955 (72.0) 121 (9.1) 41 (3.1)

Stuffy air 41 (3.1) 137 (10.4) 1010 (76.3) 107 (8.1) 28 (2.1)

Environmentaltobacco smoke

- 155 (11.8) 1063 (80.7) 99 (7.5) -

Dry air 28 (2.1) 187 (14.1) 990 (74.6) 111 (8.4) 11 (0.8)

Noise 95 (7.2) 154 (11.6) 828 (62.6) 176 (13.3) 70 (5.3)

Light 27 (2.0) 101 (7.6) 1086 (82.0) 85 (6.4) 25 (1.9)

Space/dust 37 (2.8) 176 (13.3) 943 (71.0) 155 (11.7) 17 (1.3)

Patches ofdamp/mildew

- 50 (3.8) 1225 (93.7) 32 (2.5) -

Table 7. The symptom check list used to record “symptom reporting tendency”. Results from baseline questionnaire. N=2164. Symptoms marked in bold are omitted from thetotal score of "symptom reporting tendency", because they are often included in the SBS.

Prevalence

Symptom Mean score* SD very often/often(%)

sometimes(%)

Stomach ache or problem with the stomach 4.1 1.0 6.6 20.1Chest pain 4.6 0.7 1.6 9.9Heart palpitations 4.6 0.8 2.8 8.8Shortness of breath 4.6 0.8 2.7 8.5Vertigo 4.5 0.8 3.0 11.9Muscle tension 3.4 1.3 24.5 31.8Sweating 4.0 1.1 10.8 21.1Powerlessness or helplessness 4.4 0.9 4.3 12.2Sadness or depression 4.1 1.0 5.2 20.6Restlessness 4.1 1.0 7.3 20.9Nervousness 4.1 1.0 7.1 20.4Fatigue and weakness 3.8 1.1 12.1 27.7Sleeping problems 4.1 1.1 9.6 19.8Tendency to cry 4.3 0.9 4.8 14.0Unable to relax 3.9 1.1 10.4 22.9Concentration problems 4.1 1.0 5.8 21.2Difficulty in making decisions 4.2 0.9 4.1 18.1Forgetfulness 3.7 1.1 11.8 28.7Difficulty in thinking clearly 4.2 0.9 4.3 16.4

Symptoms experienced during the past four weeks. The response options were: very often, often, sometimes, seldom, never.* The score ranges from 1 to 5, where 1=very often and 5=never.

Table 8. Associations between "symptom reporting tendency" and the prevalence, incidenceand persistence of mucous membrane symptoms and general symptoms. Odds ratios and 95% confidence interval.

Mucous membrane symptoms (N=607) General symptoms (N=500)

Prevalence Incidence Persistence Prevalence Incidence Persistence

Min.* 2.3 (1.6 to 3.2) 2.5 (1.3 to 4.8) 2.2 (1.2 to 4.3) 7.2 (5.0 to 10.6) 2.2 (0.9 to 5.2) 1.4 (0.7 to 2.7)

Sym

ptom

repo

rting

tend

ency

Max. 2.3 (1.6 to 3.3) 2.7 (1.4 to 5.2) 2.4 (1.3 to 4.8) 7.3 (5.0 to 10.8) 2.4 (0.9 to 5.7) 1.7 (0.9 to 3.2)

*Minimum and maximum odds ratios from the models with each of the nine indoor environment indices.

Table 9. Associations between mucous membrane symptoms and perceived indoor environment. Models with and without "symptom reporting tendency".Adjusted odds ratios (OR) and 95% confidence interval (95%CI).

Mucous membrane symptoms

Prevalence, N=607 Incidence, N=152 Persistence, N=183Model with

symptom reportingtendency

Model withoutsymptom reporting

tendency

Model withsymptom reporting

tendency

Model withoutsymptom reporting

tendency

Model withsymptom reporting

tendency

Model withoutsymptom reporting

tendencyRisk factor Values OR* (95% CI) OR* (95% CI) OR* (95% CI) OR* (95% CI) OR* (95% CI) OR* (95% CI)Draught index 0 1 1 1 1 1 1

1 1.65 (1.2 to 2.2) 1.71 (1.3 to 2.3) 1.02 (0.6 to 1.8) 1.03 (0.6 to 1.8) 0.93 (0.5 to 1.6) 1.05 (0.6 to 1.8)2 1.18 (0.8 to 1.8) 1.18 (0.8 to 1.8) 1.14 (0.5 to 2.2) 1.22 (0.6 to 2.4) 1.70 (0.8 to 3.7) 1.85 (0.9 to 4.0)3 1.13 (0.7 to 1.8) 1.24 (0.8 to 2.0) 2.51 (1.2 to 5.1) 2.57 (1.2 to 5.2) 1.13 (0.5 to 2.8) 1.26 (0.5 to 3.1)

Temperature index 0 1 1 1 1 1 11 1.35 (1.0 to 1.8) 1.34 (1.0 to 1.8) 1.18 (0.7 to 1.9) 1.19 (0.7 to 1.9) 1.16 (0.7 to 2.0) 1.20 (0.7 to 2.1)2 1.67 (1.1 to 2.5) 1.68 (1.1 to 2.5) 0.98 (0.5 to 2.0) 1.01 (0.5 to 2.0) 1.16 (0.6 to 2.3) 1.30 (0.7 to 2.5)

Stuffy air index 0 1 1 1 1 1 11 1.27 (0.9 to 1.7) 1.28 (0.9 to 1.7) 1.19 (0.7 to 2.0) 1.23 (0.7 to 2.1) 1.97 (1.2 to 3.4) 2.12 (1.3 to 3.6)2 1.30 (0.9 to 1.9) 1.42 (1.0 to 2.1) 1.82 (0.9 to 3.7) 1.95 (1.0 to 3.9) 2.05 (1.0 to 4.2) 2.46 (1.2 to 5.0)

0 1 1 1 1 1 1Environmental tobaccosmoke 1 1.05 (0.8 to 1.3) 1.06 (0.8 to 1.3) 1.02 (0.7 to 1.6) 1.04 (0.7 to 1.6) 1.17 (0.7 to 1.9) 1.13 (0.7 to 1.8)

Dry air index 0 1 1 1 1 1 1

1 2.20 (1.7 to 2.8) 2.23 (1.7 to 2.9) 1.43 (0.9 to 2.3) 1.49 (0.9 to 2.3) 1.18 (0.7 to 1.9) 1.21 (0.7 to 2.0)2 3.55 (2.5 to 5.1) 3.51 (2.5 to 5.0) 1.85 (0.9 to 3.6) 1.76 (0.9 to 3.4) 1.16 (0.6 to 2.3) 1.18 (0.6 to 2.3)

Noise index 0 1 1 1 1 1 11 1.35 (1.0 to 1.8) 1.37 (1.1 to 1.8) 1.51 (0.9 to 2.4) 1.49 (0.9 to 2.4) 0.87 (0.5 to 1.5) 0.92 (0.5 to 1.6)2 1.22 (0.9 to 1.7) 1.22 (0.9 to 1.7) 1.60 (0.9 to 2.7) 1.62 (0.9 to 2.7) 0.66 (0.3 to 1.2) 0.70 (0.4 to 1.3)3 0.99 (0.7 to 1.5) 1.05 (0.7 to 1.5) 2.37 (1.2 to 4.4) 2.53 (1.3 to 4.7) 1.37 (0.6 to 3.2) 1.34 (0.6 to 3.1)

Light index 0 1 1 1 1 1 11 1.13 (0.8 to 1.6) 1.18 (0.9 to 1.6) 1.76 (1.0 to 2.9) 1.83 (1.1 to 3.0) 0.95 (0.5 to 1.8) 1.03 (0.6 to 1.9)2 1.22 (0.8 to 1.9) 1.27 (0.8 to 2.0) 0.95 (0.3 to 2.3) 0.97 (0.4 to 2.3) 0.88 (0.4 to 2.0) 0.98 (0.4 to 2.2)

Space/dust index 0 1 1 1 1 1 11 1.21 (0.9 to 1.5) 1.23 (1.0 to 1.6) 1.22 (0.8 to 1.9) 1.26 (0.8 to 1.9) 1.14 (0.7 to 1.9) 1.13 (0.7 to 1.9)2 1.26 (0.9 to 1.8) 1.30 (0.9 to 1.9) 1.28 (0.6 to 2.5) 1.31 (0.7 to 2.5) 1.72 (0.9 to 3.5) 1.71 (0.8 to 3.5)

Patches of damp/mildew 0 1 1 1 1 1 11 0.95 (0.6 to 1.4) 0.99 (0.7 to 1.5) 1.71 (0.8 to 3.3) 1.76 (0.9 to 3.4) 1.48 (0.6 to 3.9) 1.69 (0.7 to 4.4)

* OR: Odds ratios adjusted for sex, age, atopy, other personal factors and psychosocial factors according to the tables in appendix III.

Table 10. Associations between general symptoms and perceived indoor environment. Models with and without symptom reporting tendency.Adjusted odds ratios (OR) and 95% confidence interval (95% CI).

General symptoms

Prevalence, N=500 Incidence, N=103 Persistence, N=146Model with

symptom reportingtendency

Model withoutsymptom reporting

tendency

Model withsymptom

reporting tendency

Model withoutsymptom reporting

tendency

Model withsymptom reporting

tendency

Model withoutsymptom reporting

tendencyRisk factor Values OR* (95% CI) OR* (95% CI) OR* (95% CI) OR* (95% CI) OR* (95% CI) OR: (95% CI)Draught index 0 1 1 1 1 1 1

1 1.05 (0.7 to 1.5) 1.15 (0.8 to 1.6) 1.48 (0.8 to 2.8) 1.47 (0.8 to 2.7) 0.88 (0.4 to 1.8) 0.97 (0.5 to 1.9)2 1.11 (0.7 to 1.7) 1.11 (0.7 to 1.7) 1.65 (0.7 to 3.7) 1.60 (0.7 to 3.6) 1.10 (0.5 to 2.4) 1.15 (0.5 to 2.5)3 1.25 (0.8 to 2.0) 1.41 (0.9 to 2.2) 2.40 (1.0 to 5.7) 2.48 (1.0 to 5.9) 0.81 (0.3 to 2.1) 0.86 (0.3 to 2.2)

Temperature index 0 1 1 1 1 1 11 1.11 (0.8 to 1.5) 1.12 (0.8 to 1.5) 1.53 (0.8 to 2.7) 1.53 (0.8 to 2.7) 0.84 (0.5 to 1.5) 0.87 (0.5 to 1.6)2 1.07 (0.7 to 1.6) 1.09 (0.7 to 1.6) 1.21 (0.5 to 2.7) 1.22 (0.5 to 2.7) 1.33 (0.6 to 3.0) 1.38 (0.6 to 3.1)

Stuffy air index 0 1 1 1 1 1 11 1.91 (1.4 to 2.6) 1.90 (1.4 to 2.5) 1.52 (0.8 to 2.8) 1.47 (0.8 to 2.7) 1.70 (0.9 to 3.2) 1.76 (0.9 to 3.3)2 2.79 (1.9 to 4.1) 3.13 (2.2 to 4.5) 1.13 (0.4 to 2.7) 1.14 (0.4 to 2.8) 1.47 (0.7 to 3.1) 1.54 (0.7 to 3.2)

0 1 1 1 1 1 1Environmental tobaccosmoke 1 1.09 (0.8 to 1.4) 1.07 (0.8 to 1.4) 0.68 (0.4 to 1.1) 0.69 (0.4 to 1.1) 0.78 (0.4 to 1.4) 0.78 (0.4 to 1.4)

Dry air index 0 1 1 1 1 1 11 1.21 (0.9 to 1.6) 1.25 (0.9 to 1.6) 1.10 (0.6 to 1.9) 1.16 (0.7 to 2.0) 1.18 (0.7 to 2.1) 1.21 (0.7 to 2.2)2 1.41 (0.9 to 2.1) 1.32 (0.9 to 1.9) 1.75 (0.8 to 3.6) 1.75 (0.8 to 3.6) 1.02 (0.5 to 2.1) 1.02 (0.5 to 2.2)

Noise index 0 1 1 1 1 1 11 1.27 (0.9 to 1.7) 1.29 (1.0 to 1.7) 0.69 (0.4 to 1.2) 0.68 (0.4 to 1.2) 1.01 (0.5 to 1.9) 1.03 (0.5 to 2.0)2 1.66 (1.2 to 2.3) 1.65 (1.2 to 2.3) 0.96 (0.5 to 1.9) 0.93 (0.5 to 1.8) 0.55 (0.3 to 1.1) 0.55 (0.3 to 1.1)3 0.93 (0.6 to 1.4) 1.08 (0.7 to 1.6) 0.73 (0.3 to 1.7) 0.76 (0.3 to 1.7) 1.27 (0.5 to 3.2) 1.30 (0.5 to 3.3)

Light index 0 1 1 1 1 1 11 1.24 (0.9 to 1.7) 1.34 (1.0 to 1.9) 1.31 (0.7 to 2.4) 1.30 (0.7 to 2.4) 1.17 (0.6 to 2.3) 1.22 (0.6 to 2.4)2 1.54 (0.9 to 2.5) 1.66 (1.0 to 2.7) 1.29 (0.4 to 3.4) 1.25 (0.4 to 3.3) 0.46 (0.2 to 1.1) 0.49 (0.2 to 1.2)

Space/dust index 0 1 1 1 1 1 11 0.94 (0.7 to 1.2) 1.00 (0.8 to 1.3) 1.82 (1.1 to 3.0) 1.80 (1.1 to 3.0) 0.84 (0.5 to 1.5) 0.87 (0.5 to 1.5)2 0.90 (0.6 to 1.4) 1.00 (0.7 to 1.5) 1.51 (0.7 to 3.2) 1.52 (0.7 to 3.2) 0.68 (0.3 to 1.4) 0.72 (0.3 to 1.5)

Patches of damp/mildew 0 1 1 1 1 1 11 1.09 (0.7 to 1.7) 1.25 (0.8 to 1.9) 1.48 (0.6 to 3.1) 1.44 (0.6 to 3.0) 0.73 (0.3 to 1.9) 0.81 (0.3 to 2.0)

* OR: Odds ratios adjusted for sex, age, atopy, other personal factors and psychosocial factors according to the tables in appendix III