Historically, occupational epidemiology studies have often been initiated in response to concerns

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1 Eduation SELECTING APPROPRIATE STUDY DESIGNS TO ADDRESS SPECIFIC RESEARCH QUESTIONS IN OCCUPATIONAL EPIDEMIOLOGY Harvey Chekoway, Neil Peare, David Kriebel 633 Oup Environ Med 2007; 64: doi: /oem BASIC See end of artile for authors affiliations Correspondene to: Professor H Chekoway, University of Washington, Department of Environmental and Oupational Health Sienes, Box , Seattle, WA 98195, USA; heko@ u.washington.edu Aepted 13 Otober 2006 Historially, oupational epidemiology studies have often been initiated in response to onerns about apparent workplae hazards. Suh onerns typially are motivated by observations of disease lusters in a workfore, findings from previous epidemiologial studies of similar workplae settings, or evidene derived from other disiplines, suh as toxiology, suggesting potential health impairment from workplae exposures. Oupational epidemiologists employ a variety of study approahes to investigate work-related illness and injuries. Many of these are familiar designs that are ommonly applied in other branhes of epidemiology, but some are harateristi to oupational studies. The hoie of study design is nearly always determined by the researh question of interest, and by feasibility onstraints. In this brief review, we will summarise some study design features, inluding partiular strengths and limitations, with an emphasis on seleting the design that should be most appropriate for investigating the exposure/health outome assoiation of interest. Readers seeking more in-depth disussions of study designs are enouraged to onsult text books on oupational epidemiology 1 3 or general epidemiology texts. 4 5 PRINCIPLES OF STUDY DESIGN A fundamental onept that underpins all epidemiologial researh is the requirement for learly defining the soure population, also known as the study base. 6 In studies of oupational risk fators for disease and injuries, the soure population should be a ohort of workers from one or more industries. Identifying the soure population is relatively straightforward when onduting a study of a well-defined ohort of workers from a partiular industry or faility, as is typial of most oupational ohort mortality studies. Less well appreiated is that a study that fouses on a ertain health outome, and seeks to identify multiple possible oupational risk fators, suh as a population-based ase-ontrol study, has an impliit soure population that generated the ases, namely the general population that inludes workers from the industries and oupations of interest, workers from other industries, and non-employed persons. For example, onsider a ommunitybased ase-ontrol study of oupational risk fators for Parkinson s disease in whih assoiations are estimated for employment in various oupations, suh as farming, welding, and teahing, as well as assoiations with ertain exposures that may span numerous oupations, suh as pestiides, metals and infetious agents. In this situation, the soure population would inlude a number of different subpopulations defined by oupation (farmers, welders, teahers) or by exposure (pestiides, metals, infetious agents). An underlying validity priniple is that the ontrols exposures in the aseontrol study should represent the exposure experiene of the soure population. A seond important point is that the new ourrene of disease, inidene, is the basi measure of disease ourrene that epidemiologists seek to estimate. Measuring new onset of illness or injury is largely unambiguous for aute health outomes, suh as non-fatal workplae injuries. Mortality is a speial type of inidene in whih the event is death rather than the ourrene of (non-fatal) disease or injury. It therefore is often used as a surrogate for disease inidene for diseases that are usually fatal (for example, aner), but may also be affeted by fators that affet survival as well as risk fators for disease inidene. Determining disease inidene is espeially hallenging for onditions that do not have sharp times of onset, even when serial health measurements are made. Coal worker s pneumooniosis is a disease that fits this desription. Many health outomes develop over prolonged time periods in whih onset times an only be inferred from indiret evidene. This is the ase for onditions suh as hroni obstrutive lung disease, but is also true for diseases suh as aner for whih there is generally a single diagnosti point in time, but the underlying disease

2 634 proess may have developed over many years. It should also be appreiated that hroni disease onset times are typially lassified as single events, suh as dates of disease diagnosis or death, although true disease onset is a ontinuous phenomenon that is diffiult to haraterise epidemiologially. In ertain situations (for example, ognitive impairment), determining the onset of inident disease may be impratial, and thus disease prevalene is studied instead. Although disease prevalene may be a surrogate for inidene, it is also affeted by fators that determine the duration of disease (inluding fators that affet survival or treatment effiay) in addition to risk fators for disease inidene. This is not to say that studies based on prevalene are inherently flawed or invalid, although distinguishing assoiations of health outomes with oupational exposures that pertain to disease aetiology from those that may be related to disease severity, prognosis and duration an be diffiult, if not impossible, when prevalent ases are inluded in a study. STUDY DESIGN OPTIONS As we will review below, eah study design option has various features that make it more or less suitable for investigating partiular exposure/disease relations. A summary of the types of health outomes and the orresponding study design hoies is shown in table 1. It should be appreiated that some researh questions an be investigated by more than one epidemiologial approah, but one design is usually learly preferable for providing diret ausal evidene. CONVENTIONAL STUDY DESIGNS Cohort studies The ohort design entails follow-up of a population and determination of the subsequent inidene of health outomes. Cohort studies an be lassified aording to their temporal sequene, either historial (retrospetive) or prospetive. Prospetive ohort studies are partiularly well suited for investigations of relatively short-term phenomena, suh as pregnany outomes, in whih the temporal relation between exposure and subsequent risk is relatively short. The span of a prospetive ohort study may be as short as a single work shift (for example, aross-shift lung funtion hange), a work-week (for example, exaerbation of symptoms), or may extend to years or deades (for example, inidene of injuries). The logistial diffiulties of performing prospetive ohort studies, espeially following study subjets and updating exposure data, over many years, represents a serious feasibility onstraint. The historial ohort design was originally developed as a more pratial alternative to prospetive studies for investigating diseases with long indution and lateny periods, and has sine beome the mainstay of oupational studies of mortality and inidene from hroni diseases. Typially, historial ohort studies are limited to mortality outomes beause, unlike data for non-fatal outomes, mortality data are readily available in most ountries. An exeption would be an industry that maintains a health surveillane database that would aommodate investigations of non-fatal onditions. A ommon prominent limitation of historial ohort studies is absent or sparse data on past exposures. The ohort design has an intuitive logial appeal in that the temporal sequene from exposure to disease outome mimis the widely reognised approah of an experimental paradigm, suh as a randomised linial trial. Nonetheless, temporality of exposure and outome an also be determined validly with other study designs. Cross-setional studies The ross-setional design involves omparisons of disease prevalene among exposed and non-exposed groups, or among groups lassified aording to exposure type and level. Subjet seletion is usually based on exposure status. It is also possible to selet subjets on the basis of health status, but in this situation the study is really a ase-ontrol study of prevalent health onditions rather than a standard ross-setional study (whih would inlude exposed and non-exposed subjets irrespetive of their health status). Cross-setional studies are most appropriate for studying relatively persistent onditions, rather than transient or reversible effets of exposure. Typial health outomes investigated with the ross-setional design are repetitive motion musuloskeletal disorders, hroni respiratory impairment, and the pneumoonioses. In addition, physiologial abnormalities, suh as diminished lung funtion or elevated liver enzymes, and indiators of biologial damage at the ellular level, suh as hromosome abnormalities, are also amenable to study with the ross-setional design. Cross-setional studies are often ritiised for providing limited ausal inferene beause exposure and health outomes are usually assessed onurrently. In other words, suh studies may be prone to a reverse ausation bias that is, the exposure status may be an effet of the disease rather than a Table 1 Design options for studies of oupational exposures and ategories of health outomes Health outome Example Study design options* Chroni disease (rare) Stomah aner 1. Historial ohort (inl. nested ase-ontrol) 2. Community-based ase-ontrol 3. Prospetive ohort Chroni disease (not rare) Asthma onset (not asthma attak or exaerbation) 1. Prospetive (ineption) ohort 2. Case-ontrol 3. Historial ohort Aute fatal Injury 1. Historial ohort 2. Case-rossover 3. Nested ase-ontrol Aute non-fatal Neurologial symptoms 1. Case-rossover 2. Cross-setional *Listed in desending priority order.

3 ause. This ould our, for example, if a worker hanged departments (from a more dusty to a less dusty job) or left employment as a result of developing respiratory disease. This shortoming is not an inherent flaw of the ross-setional design, espeially in situations where a full aounting of exposure history (rather than merely urrent exposure status) is asertained, as was done in the study by Eisen et al 7 of asthma among US automotive workers exposed to metalworking fluids. Nonetheless, the ross-setional design may be partiularly prone to the healthy worker survivor effet 8 in situations where only atively employed workers are studied. This form of bias may lead to missed or underestimated assoiations if the most heavily exposed, and onsequently the most severely affeted workers, have preferentially left employment and are hene not available for study. Attempts to identify and inlude former workers, although logistially hallenging, an mitigate this bias. Repeated measures studies There are alternatives to the ross-setional design to examine non-fatal health endpoints or physiologial damage indiators. The best developed of these is the repeated measures study in whih exposures and health status are determined at a baseline time point, and re-assessed throughout a period of follow-up. Relatively short-term follow-up (for example, several years) an provide the framework for longer-term investigations of hroni effets, suh as myoardial infartion and stroke. Repeated measures studies share the idential design as prospetive ohort studies. The distintion between the two is generally the nature of the health outomes studied with these approahes: disease inidene or mortality in prospetive ohort studies; and disease symptoms and physiologial parameter hanges in repeated measures studies. The optimal study populations for follow-up are ineption ohorts of newly hired, and hene newly exposed, workers. A good template for this approah is the 20-year prospetive follow-up of respiratory system outomes among Chinese otton textile workers onduted by Christiani et al Findings from the first five years of follow-up demonstrated aelerated loss of lung funtion, 9 and subsequent follow-up findings indiate the potential for hroni obstrutive lung disease related to otton dust and endotoxin exposure. Inlusion in this study required workers to have had a minimum of two years employment to ensure follow-up of a stable workfore; thus, this was not stritly an ineption ohort of new hires. Assembling ohorts of new hires, although desirable from the standpoint of investigating new onset disease in relation to initial and subsequent exposure, an pose logistial diffiulties. Enrolment may suffer from high turnover rates in the early weeks or months of employment, and aumulating suffiiently large numbers of new hires in industries with sporadi hiring praties may require prolonged reruitment periods. Case-ontrol studies Case-ontrol designs entail exposure omparisons made between an index ase group and a referene group of persons free of the disease of interest at the times of ases diagnoses. Typially, efforts are made to enrol all possible ases who meet study inlusion riteria, and ontrols are then seleted as a sample of the soure population that generated the ases. Caseontrol studies may be nested within defined oupational ohorts, or may be onduted in the ommunity at-large (ommunity-based studies). Both ases and ontrols in nested industry-based ase-ontrol studies are from the same ohort, defined variously as members of a partiular faility, oupation, industry or profession. In ontrast, ommunity-based ase-ontrol studies involve multiple oupational subpopulations from the population at large. In both types of study, ases may be identified from various soures, suh as hospitals, disease registers, and death or birth ertifiates. However, in nested ase-ontrol studies, ases may also be identified diretly by a survey or surveillane of the ohort. It has long been reognised that the ase-ontrol design has deided advantages in terms of effiieny, relative to full ohort studies. For studies of rare diseases (for example, most aners) ase-ontrol studies offer a ost- and time-effiient means of aruing relatively large numbers of ases, thus avoiding prolonged follow-up of large ohorts. Also, the redued study size of a ase-ontrol study, ompared to a full ohort study, an permit effiient resoure alloation to refining exposure assessment and obtaining data on potential onfounding fators (for example, smoking) whih may not be pratial in a ohort study. Control seletion for nested ase-ontrol studies is a relatively straightforward matter in most instanes, whereas the hoie of ontrols in ommunity-based studies is often more ompliated and subjet to unertainty. In ommunity-based studies, ontrols should be a random sample of the soure population, but this may not always be well-defined or enumerated. Ideally, ontrols should be seleted from population registers, but when these are not available, ontrols may be seleted from other soures, suh as patients in the same hospital but admitted for an illness unrelated to the exposure, neighbours or family members. There an be several alternative hoies for ontrols for a given study, eah with harateristi advantages and limitations in terms of validity, effiieny for addressing study questions of interest, and feasibility. When seleting ontrols, the underlying methodologial priniple required to maintain study validity is to selet ontrols suh that they represent the soure population that generated the ases. The onept of ounterfatual mathing of ases and ontrols, suh that ontrols would have been identified as ases had they developed the health outome of interest during the period of observation of the study base, an also be invoked as a guideline for validity. 12 In either type of ase-ontrol study, ontrols should be free of the outome of interest (to the extent that an be determined) at the times of ases diagnoses. Thus, it is possible for a subjet to be seleted as a ontrol for a given ase at one time, but subsequently be inluded as a ase if he or she develops the outome of interest subsequently. This seletion method, known as inidene density sampling, allows for ausal inferenes to be drawn with equivalent validity in nested aseontrol and full ohort analyses. 13 There are situations in whih seleting more than one ontrol group is desirable to minimise onfounding and other biases. For example, onsider a ommunity-based ase-ontrol study of lung aner in relation to exposure to dusty onstrution work. One ontrol group might be a random sample of all members of 635

4 636 the ommunity (free of lung aner), and a seond ontrol group might be patients with other types of aner not plausibly related to dusts perhaps brain and reprodutive system aners, for example. The first ontrol group would represent the general soure population from whih the ases arose, but might be biased beause of differential reall between aner ases and healthy ontrols. Comparisons of exposures between ases and the seond ontrol group would help minimise reall bias beause all subjets would be aner patients, and thus likely to be in a similar state of mind when asked to reall potentially hazardous exposures. If the results from omparisons with both ontrol groups were similar, this might strengthen arguments for ausality, although there may also be plausible reasons for disrepant findings. VARIANTS OF THE CASE-CONTROL DESIGN Over the past two deades, two variants of the ase-ontrol design, namely the ase-ohort and ase-rossover designs, have been developed that have lear effiieny and validity advantages over the onventional ase-ontrol design in some situations. Case-ohort design In a ase-ohort study, there are multiple ase groups and a ommon omparison group. 14 The latter is seleted as a random sample representative of the soure population (ohort) that generated the ases, and is termed the referene subohort. Case-ohort studies that are nested within defined oupational ohorts are far more ommon than ommunity-based aseohort studies, although a ommunity soure population would not prelude appliation of this design. The multisite aner hospital-based ase-ohort study in Montreal 15 is an example of the latter. The partiular advantage of the ase-ohort approah is that it permits effiient testing of assoiations with multiple health outomes (ase groups). In the onventional aseontrol approah, a ontrol group would have to be seleted for eah ase group, whereas the ase-ohort design allows using one omparison group repeatedly. Beause the referene subohort is simply a random sample of the ohort or soure population, it may ontain subjets who are also in one of the ase groups. Inlusion of ases in the referene subohort will not introdue bias provided that exposures for subohort members are trunated at the times when they develop the disease of interest in a speifi analysis. For example, in a aseohort analysis of stomah aner in whih the subohort inludes one or more subjets with stomah aner (by virtue of random sampling), the overlapping ases would also be inluded in the ase group, and their exposure histories would be inluded with the exposure experiene of the referene subohort up to the dates of their diagnoses. This is equivalent to inidene density mathing. 14 Appliation of the ase-ohort design is illustrated by a study of oupational risk fators for various aners among women workers in the Shanghai textile industry. The study was originated as an intervention trial of breast self-exam in a ohort of over women workers. 16 Exposure assessments were performed for numerous textile industry hemials and dusts, inluding fibre dusts, solvents and endotoxin Table 2 provides a summary of ase-ohort omparisons for umulative exposure to endotoxin by various lag intervals, for seleted gastrointestinal aners In these analyses, eah ase group s exposures was ompared with exposures experiened by a ommon referene subohort of approximately 3200 workers. These findings indiate that the highest umulative endotoxin exposures were assoiated with redued risks for several different aners, espeially when exposures were lagged by 20 years, suggesting possible early-stage antiarinogeni effets. Case-rossover design The ase-rossover design was formulated to haraterise risk fators for health outomes that our in lose temporal sequene to exposure, espeially for so-alled disease triggers. 23 To date, most appliations of this design have been in studies of aute outomes related to environmental air pollution; thus, methodologial aspets of ase-rossover studies have been developed in that ontext. Typially, the outomes of interest are aute events, suh as injuries or disease symptoms with abrupt onsets. This design only inludes an index ase group, and involves the omparison of ases exposures immediately before (or very lose in time to) their events with exposures that our at other typial times. Consequently, eah ase serves as his or her own individually mathed ontrol in whih the index interval before the event is treated as the ase and the referene interval representing typial exposures is the ontrol. The prinipal advantage of the ase-rossover design, relative to a onventional aseontrol study, is that mathing eah ase with himself or herself greatly failitates ontrol of potential onfounders that are time invariant and possibly diffiult to measure, suh as geneti fators. However, potential onfounders that are not time invariant, espeially over the relatively short period of observation in a ase-rossover study, suh as reent infetion status, will require ontrol by onventional methods. A study of risk and protetive fators among for aute hand injuries 24 offers a good illustration of this approah. Cases provided details on the extent and timing of transient work fators during the 90 min preeding their injuries, and were lassified as exposed if they experiened these fators at the time of the injury. Referene period exposures were estimated as averages for the month preeding the injury. As shown in table 3, working with unusual equipment or materials was strongly assoiated with inreased risks, and glove use Table 2 Relative risks for gastrointestinal aners assoiated with highest umulative exposures to endotoxin, by lag interval, among women textile workers in Shanghai, China Caner site (ases) 0-year lag 20-year lag RR (95% CI)* trend pà RR (95% CI)* trend pà Oesophagus (102) 0.5 (0.2 to 1.2) (0.2 to 0.8) 0.01 Stomah (646) 0.8 (0.6 to 1.1) (0.5 to 0.9),0.001 Colon (477) 1.2 (0.8 to 1.6) (0.6 to 1.1) 0.32 Retum (274) 1.1 (0.7 to 1.7) (0.4 to 1.0) 0.08 Panreas (180) 0.8 (0.5 to 1.2) (0.3 to 0.9),0.001 Liver (360) 0.8 (0.6 to 1.1) (0.4 to 0.9) 0.02 *Relative risk (95% CI) for the highest versus lowest exposure strata, adjusted for age and igarette smoking. ÀExposure-response trend p value.

5 Table 3 Relative risks for hand injury assoiated with transient workplae onditions Worker group Unusual work task or equipment Glove use All subjets 11.0 (9.4 to 12.8)* 0.4 (0.3 to 0.5) Oupational group Mahine/assembly 10.6 (18.5 to 13.3) 0.5 (0.4 to 0.6) Constrution trades 17.4 (9.3 to 32.3) 0.3 (0.2 to 0.4) Pakaging 5.1 (3.8 to 6.9) 0.4 (0.3 to 0.7) Servie, prof, mgmt 15.7 (11.1 to 22.3) 0.4 (0.3 to 0.6) Job experiene (years) ( (9.1 to 19.2) 0.4 (0.3 to 0.6) 1 to (11.4 to 23.3) 0.2 (0.2 to 0.4) (7.4 to 11.0) 0.5 (0.4 to 0.6) *Relative risk (95% CI) exposed versus non-exposed. onferred protetion. Similar findings were noted among various oupational groups and job tenures. The seletion of index and referene intervals is not neessarily lear ut, and an pose some methodologial hallenges. The width of the index interval will depend on the harateristis of the exposure and the health outome and the nature of their presumed relation. In the simplest ase of a very aute severe injury, the index interval an be as short as several minutes or hours, whereas for an outome with a longer indution time (for example, myoardial infartion), the index period may be defined as one or more days. In addition, it may be neessary to inlude a lag interval between the index interval and the event onset time for outomes that may be delayed manifestations of exposure. For example, the effets of sensitising hemials may appear hours or days after relevant exposures. The plaement and width of referene intervals an be soures of unertainty. Referene intervals are generally seleted as time periods preeding index intervals, suh as the preeding day, or the same day of the week during the past month. 25 Alternatively, a bi-diretional ontrol sampling sheme an be adopted suh that referene intervals are seleted both before and after the event ourrene times in order to ontrol for preditable temporal hanges in exposure, as might our when air pollution levels are known to be dereasing. 26 Uni-diretional sampling should be most appropriate for the majority of oupational studies for several reasons. In a workplae setting, there may be preditable hanges in exposure due to hanges in ventilation or use of protetive equipment, although the time sale of these hanges will ordinarily exeed the duration of observation of a aserossover study. Furthermore, the bi-diretional referent sampling sheme requires the assumption that ase events will not influene subsequent exposures, whih may hold in studies of air pollution or limati hanges, but may be violated in a workplae setting if, for example, safety enforement poliies are modified after a fatal aident ourrene. DISCUSSION When onfronted with the task of answering questions about the relative safety of the workplae environment, oupational epidemiologists prefer to design and implement studies that allow testing of very speifi exposure/disease assoiations. Deiding whih study design is most suitable for addressing a partiular oupational health question will depend on the nature of the health outome(s) and exposure(s) of interest and, to a Main messages Various epidemiologial study designs have partiular strengths and limitations for investigating partiular exposure/disease relations. Study design seletion should be guided by the suitability of the design for the researh question at hand, and by feasibility onstraints. Conventional approahes, inluding ohort, ase-ontrol, and ross-setional designs, should ontinue to be mainstay methods; appliation of newer variants of the ase-ontrol design ase-ohort and ase-rossover studies for speifi purposes should be enouraged. A series of oordinated epidemiologial studies whose designs are tailored to investigate speifi researh questions, will inevitably be required to address a wide range of oupational health onerns. Poliy impliations Seletion of the most suitable epidemiologial study designs for speifi researh questions will be required for maximising knowledge on illness and injury risk fators, and ultimately for informing disease prevention programmes. great extent, on feasibility. In pratie, logistial onsiderations frequently are the ritial determinants of study design hoie. By way of illustration, onsider a situation where there is onern about potential ardiovasular toxiity of a ertain workplae hemial. This onern would be addressed optimally by a prospetive ohort study of hanges in ardiovasular disease inidene and related linial parameters among urrent and former workers, whose exposures to the hemial of interest and potential onfounders are assessed with a high degree of auray. Inlusion of newly hired workers as ineption ohorts would be espeially valuable for identifying early hanges in health status. It beomes readily apparent, however, that the requirements of time, ost and data for suh a study may far exeed available resoures, thus neessitating alternative approahes. Among alternatives, ross-setional studies may yield some aetiologial insights, primarily among atively employed workers, although the likely absene of data for former and retired workers and the potential for healthy worker survival effet bias ould be severe limitations. A historial ohort mortality study is another option, but ould only evaluate the effets of exposure on fatal ardiovasular disease. A reasonable strategy might then be a series of epidemiologial studies, eah of whih addresses various aspets of ardiovasular system risk. Suh studies ould inlude: targeted ineption ohort studies of hanges in seleted ardiovasular health parameters (serum lipids, blood pressure, heart rate variability, et); a ross-setional study of speifi health endpoints (for example, hypertension); a ohort mortality study, initiated first as a retrospetive ohort study, and expanded to inorporate prospetive follow-up as a omponent of worker health surveillane. Nested ase-ohort studies of speifi ardiovasular diseases in whih detailed data on non-oupational risk fators are obtained and ase-rossover studies to identify aute exposure-related effets would also be benefiial

6 638 As the above hypothetial example is intended to illustrate, it is very unlikely that any single epidemiologial study design an yield data adequate to investigate a broad spetrum of oupational health questions. Instead, a rational epidemiologial strategy is to ondut separate, yet related studies whose designs are most suitably tailored to address speifi researh questions. Conventional epidemiologial study designs will no doubt ontinue to serve as the mainstay approahes. The aseohort and ase-rossover variants of ase-ontrol studies offer distint advantages, and their further appliation in oupational epidemiology should be enouraged. ACKNOWLEDGEMENTS Harvey Chekoway ontributed to this paper during a Visiting Sientist Fellowship at the International Ageny for Researh on Caner. Funding for Neil Peare s salary is from a Programme Grant from the Health Researh Counil of New Zealand.... Authors affiliations H Chekoway, Department of Environmental and Oupational Health Sienes, University of Washington, Seattle, Washington USA and International Ageny for Researh on Caner, Lyon, Frane N Peare, Centre for Publi Health Researh, Massey University Wellington Campus, Wellington, New Zealand D Kriebel, Department of Work Environment, University of Massahusetts at Lowell, Lowell, Massahusetts, USA Competing interests: None delared. REFERENCES 1 Monson RR. Oupational epidemiology, Seond edition. Boa Raton, FL: CRC Press, Hernberg S. Introdution to oupational epidemiology. Chelsea, MI: Lewis Publishers, Chekoway H, Peare N, Kriebel D. Researh methods in oupational epidemiology, Seond edition. New York: Oxford University Press, Rothman KJ, Greenland S. Modern epidemiology, Seond edition. Philadelphia: Lippinott-Raven Press, Koepsell TD, Weiss NS. Epidemiologi methods: studying the ourrene of illness. New York: Oxford University Press, Miettinen OS. Theoretial epidemiology. 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Please visit the Oupational and Environmental Mediine website [www. oenvmed. om] for a link to the full text of this artile. Evidene on asthma outome found wanting A uthors of a systemati review are advoating a large ollaborative and arefully standardised study to determine best advie for patients with oupational asthma, in the light of published findings on outome. Better evidene is needed, they say. Patients prospets seem poor, by the two outomes assessed omplete symptomati reovery and physiologial reovery after antigeni exposure has eased. About a third of patients overall ahieved omplete reovery from symptoms, based on 39 original studies overing 1681 patients with a median follow up of 31 (range 6 240) months. Potential fators affeting this outome were inreased age and lini based populations, with lower pooled prevalenes for 100% reovery. Physiologial reovery was also limited, as non-speifi bronhial hyper-responsiveness (NSBHR) persisted after diagnosis in most of the 28 studies identified, overing 695 patients with a median follow up 37(6 240) months. However, variation among studies was signifiant for both outomes and the authors suspet length of follow up may be important. Most patients were from speialist linis an important soure of bias. The few studies of workplae populations showed a higher pooled prevalene of reovery from symptoms than lini based populations and lower pooled prevalene of NSBHR but at best were only borderline signifiant. The analysis is ompromised too by variation in study size and methods, possible overlap between some study populations, and differenes in the way outomes were measured. Added snags were inability to ontrol for other important aspets like severity of asthma at diagnosis or use of protetive measures. m Rahiotis G, et al. Thorax 2007;62: