Investigating the Natural History of Lung Function

Investigating the Natural History of Lung Function* Facts, Pitfalls, and Opportunities Robab Kohansal, MD; Joan B. Soriano, MD, PhD; and Aluar Agusti, MD, PhD COPD is currently defined as a progressive, preventable, and treatable disease that is characterized by an accelerated decline of lung function. However, contrary to other common chronic conditions like cardiovascular disease or cancer, there are no lifelong populationbased studies describing the natural history of lung function and COPD. In this review, we describe the methodology used in population-based studies, both American and European, that have formed the basis of our current understanding of the “natural history” of COPD, including studies with serial pulmonary function testing, which hold potential for further investigations. We highlight the methodological limitations of longitudinal studies and suggest possible solutions. Finally, some characteristics of an “ideal” study on the natural history of lung function decline are recommended, both in health and disease. (CHEST 2009; 135~1330-1341)

I Key

words: COPD; epidemiology; longitudinal study; natural history

Abbreviations: ARIC = Atherosclerosis Risk in Communities; ATS = American Thoracic Society; CARDIA = Coronary Artery Risk Development in Young Adults; CHS = Cardiovascular Health Study; CV = cardiovascular; CVD = cardiovascular disease; ECRHS = European Community Respiratory Health Survey; LHS = Lung Health Study; MRC = Medical Research Council; NAS = Normative Aging Study; NHLBI = National Heart, Lung, and Blood Institute; NIH = National Institutes of Health; PFT = pulmonary function testing; SAPALDIA = Swiss Study on Air Pollution and Lung Diseases in Adults; VA = Veterans Administration

c

OPD is currently defined as a preventable and treatable disease that is characterized by air flow limitation that is not fully reversible and is usually progressive.1.2 This definition implies that the “natural history” of COPD involves a steady progression and worsening of health in patients. ‘From the Program of Epidemiology and Clinical Research (Drs. Kohansal, Soriano, and Agusti), Fundacidn Caubet-International Centre for Advanced Respiratory Medicine (CIMERA) Illes Balears, Bunyola, Illes Balears, Spain; the Department of Pulmonary and Critical Care Medicine and Ludwig Boltzmann Institute for COPD (Dr. Kohansal), Otto Wa er Hospital, Vienna, Austria; Centro de Investigacfon Biomega en Red de Enfermedades Respiratorias (Drs. Soriano and Agusti), Illes Balears, Mallorca, Spain; and Servei Pneumologia (Dr. Agusti), Hospital Universitari Son Dureta, Illes Balears, Mallorca, Spain. Dr. Kohansal was the reci ‘ent of a 2007 European Respiratory Society/Spanish Society o~pulmonology and Thoracic Surgery Long-Tern Fellowship No. 123 at Fundaci6n Caubet-International Centre for Advanced Respiratory Medicine (CIMERA) IUes Balean, Bunyola, IUes Balean, Spain (www.caubet4mera.es). 1330

I

One way to define the natural history of COPD is by the fall in FEV, that occurs from 20 to 25 years of age onward. Contrary to other common chronic or cancer, conditions like cardiovascular disease (0) there are no lifelong population-based studies describing the natural history of lung function and COPD. It is therefore not surprising that one of the first priorities The authors have reported to the ACCP that no significant conflicts of interest exist with any corn aniedorganizations whose products or services may be discussel in this article. Manuscript received July 15, 2008; revision accepted July 31, 2008. Reproduction of this article is rohibited without Mtten permission from the American College ofchest Physicians (www.chestjoumal.

org/sitdmisc/reprints.xhtml). Correspondence to: Robab Kohansal, MD, Program of Epidemiology ht Clinical Research, Fundacio’n Caubet-CIMERA llles Balears, Recinte Hospital Joan March, Carretera Soller Km 12, 07110 Bunyola, l h Baleam, Spain; e-mad: r.kohansal@

gtnx.at

DOI: 10.137Wchest.08-1750 Special Featwe

for respiratory research identified by a recent panel of experts from the British Thoracic Society3 was “. . . to better study the natural history of early development of the respiratory tract and immune system and the techniques needed to understand normal air growth, development, and decline in health and disease.” Eleven years ago, a workshop from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) reviewed the already huge amount of lung function data on NHLBI-sponsored cohorts to highlight the availability of these data, and to publish recommendations for future data collection and analytic eff0rts.4 We aimed to update this work, including European evidence. Therefore, the objectives of this review were the following: (1) to briefly summarize studies investigating the natural history of lung function decline and/or studies with serial pulmonary function testing (PFT) holding the potential for further investigations on the natural history of COPD; (2) to identify and discuss the main methodological limitations in the studies that have been carried out to date; and (3) to propose a number of characteristics that the “ideal” study on the natural history of lung function decline should consider.

REVIEW OF AVAILABLEEVIDENCE Several studies (Table 1 and the “Appendix”) have produced substantial, but partial, results on the natural history of lung function and COPD. A summary of their main characteristics is presented next.

US NHLBZ-NZH-Sponsored Studies All NHLBI-NIH data are public and available (Fig l),although investigators wishing to analyze it have to formally request and sign a distribution agreement including a brief description of the research project, the required data set, and an Institutional Review Board ap~roval.~

Framingham Heart Study In 1948, this study was initiated primarily to identify cardiovascular (CV) risk factors. At that time, little was known about the main causes of heart disease and stroke, but the death rates for patients with chronic vascular disease had been increasing progressively since the beginning of the 20th century and turned out to be a rising worldwide phenomenon. There are three cohorts within the Framingham study (Original,Offspring, and the Third Generation cohorts). www.chestjoumal.org

Original Cohort: Researchers recruited 5,209 men and women between 28 and 62 years of age from the town of Framingham, MA, and began the first round of extensive physical examinations and lifestyle interviews. Since 1948, the subjects have continued to return to the study center for follow-up every 2 years. Oj$ming Cohort: In 1971, the study enrolled a second generation of subjects, made up of 5,124 of the original participants’ adult children and their spouses between 5 and 70 years of age to participate in similar examinations.5 ’

Generation ZZZ Cohort: A third generation of subjects was enrolled in 2002 that included participants who had at least one parent in the Offspring Study aimed to further understand how genetic factors relate to CVD. These participants are being given an extensive CV examination similar to that given to their parents and grandparents. The fmt phase was completed in July 2005 and involved 4,095 participants.6 Spirometry was performed in the majority of the follow-up examinations and is already publicly available for the original and the offspring cohorts (Fig 1).

The Chiklhood Respiratory Study and the Nonnative Aging Study The Childhood Respiratory Study was carried out from 1981 to 1991, and it was aimed at characterizing the role of allergy and airway responsiveness in modifylng the growth of lung function in children and young adults. A community-based, stratified, random sample of children aged 5 to 9 years living in the east area of Boston, MA, were recruited for the study. Each member of the inception cohort and all family members 2 5 years of age residing in the household were visited at home annually by study personnel. The Childhood Respiratory Study was later expanded from 1992 to 1997 (becoming the Normative Aging Study) to examine the relationship of respiratory symptoms and illnesses, cigarette smoking, airway responsiveness, and markers of inflammation to the growth and decline in lung function in two well-characterized and investigated community-based populations of children and adults. Data were available in the following two populations: the Childhood Respiratory Disease Study in East Boston population7; and the Normative Aging Study (NAS) population. CHEST! 135/ 5 1 MAY. 2009

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Table 1-Summary of Characteristics of Several Reepiratory Cohorts* Cohort American Framingham Heart Study Original cohort Offspring cohort Third generation NAS cohort NAS (adults) Honolulu Heart Program LHS 1 I1 I11 ARIC CARDIA CHS European M RC MIDSPAN Main study cohort Tiree Study Collaborative Study RenfrewRaisley Study Family Study Vlagtwedde-Vlaardingen Study Vlagtwedde Vlaardingen ECRHS 1 I1 PiSam0 Delta Studies Po Delta Cohort Pisa Cohort OLIN SAPALDIA Copenhagen City Heart Study

Seven Countries Study-The Finnish Cohort

Period

Participants, No.

Age Range, yr

Sex

1948-present 1971-present 2002-present 1981-1997 1963-present 196-1993

5,209 5,124 4,095 5,209 2,280 8.006

28-62 5-70 19-72 5-62 21-80 21-80

Male and female Male and female Male and female Male and female Male Male

1984-2005 199p1999 1998-2002 1987-1998 1985-present 1989-present

5,887 1,116

35-60

15,792 5,115 5,201

45-64

18-30 265

Male and female Male and female Male and female Male and female Male and female Male and female

1961-1969

1,136

30-59

Male

1964-1968 1968 197&1977 1972-1979 1996

Approximately 4,000 532+230 7,028 15,402 2,338

15-70 14-92

Male and female Male and female Male and female Male and female Male and female

1965-1994 1967-1995 196-1995 1969-1995

1,793 859 1,590

1991-1993 1998-2002 1988-1991 1991-1993 1985-2003 1991-present 19761978 1981-1983 1991-1994 2001-2003 1959-2000

45-64 30-59

15-39

Male and female Male and female Male and female Male and female

137,619 Approximately 18,000

20-44 28-52

Male and female Male and female

2,841 2,841 1,237 9,651 14,223 500 3,000

8-75 8-97 18-60 2 20 20-25 20-39

Male and female Male and female Male and female Male and female Male and female Male and female Male and female

1,711

40-59

Male

450

40-44 15-39 40-54

*OLIN = Obstructive Lung Disease in Northern Sweden.

The Veterans Administration NAS

The Veterans Administration (VA) NAS is a multidisciplinary longitudinal study of aging in men established by the VA in 1963.8The VA NAS subjects have undergone physical examinations and filled out questionnaires every 3 to 5 years to evaluate the aging process in healthy men. It recruited 2,280 men without any known chronic medical condition from the greater Boston area 1332

whose ages ranged from 21 to 80 years.8 Some of the examinations included reliable lung function testing. Honolulu Heart Program

This prospective studye was initiated in 1965 as an investigation of the causes of CVD among Japanese Americans living in Hawaii. This population was known to have a low incidence of Special Feature

FIGURE1. American cohort studies with PIT and/or respiratory symptoms by examinations.

www.chestjournal.org

CHEST/ 135 / 5 / MAY, 2009

1939

coronary heart disease and a high incidence of stroke. The study provided opportunities to investigate CV end points, pathologic findings, and disease predictors in the cohort, and to compare the findings in this population with those in other populations. Overall, 11,148 men were identified, of whom 8,006 participated in baseline examinations from 1965 to 1968 followed by three more examinations (the last in the period from 1991 to 1993). Examinations included lung function testing, among others (Fig 1).

Lung Health Study Initiated in 1984, the Lung Health Study (LHS)lOJl aimed to investigate the effectiveness of smoking cessation and bronchodilator administration in smokers aged 35 to 60 years with mild lung function impairment. Participants were randomly assigned to one of the following three groups: (1) no intervention; (2) smoking intervention with the inhaled bronchodilator ipratropium bromide; and (3) smoking intervention with an inhaled placebo. The effect of the intervention was evaluated by the rate of decline of FEV1.lOJ1 The LHS 1112 was started in 1994 with 1,116 participants from the population of LHS I who were either currently smoking or had smoked within the previous 2 years, aiming to evaluate the effect of the inhaled corticosteroid triamcinolone or placebo on lung function decline. More recently, the LHS I11 study13aimed to determine the long-term effects of smoking cessation and continued smoking on heart and lung disease, and the rate of decline of FEV, in ~ m m with s early COPD by following up the LHS I participants.

Atherosclerosis Risk in Communities This prospective epidemiologic study was conducted in 1987 in four US communities. The Atherosclerosis Risk in Communities (ARIC) study aimed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and the variation in CV risk factors, medical care, and disease by race, gender, location, and date.14 The ARIC study includes the following two parts: the Cohort Component; and the Community Surveillance Component. The Cohort Component began in 1987. A total of 15,792 participants aged 45 to 64 years received an extensive examination, included obtaining medical, social, and demographic data, and, in some examinations, spirometry (Fig 1). These participants were reexamined every 3 years (the last in the period from 1996 to 1998). 1334

Coronary Artery Risk Development in Young Adults The Coronary Artery Risk Development in Young Adults (CARDIA) study is a longitudinal study of the antecedents and risk factors for CVD in a cohort of 5,115 black and white men and women aged 18 to 30 years at the time of their initial examination (1985 to 1986). The sample was recruited to achieve approximately balanced subgroups of race, gender, education, and age in the United States.15 Six more examinations (the last conducted in the period from 2005 to 2006) have been completed in this cohort. A majority of subjects in the group has been examined at each of the follow-up examinations, .and lung function testing was performed in the majority of the follow-up examinations (Fig 1).

Cardiovascular Health Study The Cardiovascular Health Study (CHS)16J7was a longitudinal study that was initiated in 1989 to investigate the risk factors for coronary heart disease and stroke in men and women 2 65 years of age. The main objective of the study was to identify factors related to the onset and progression of coronary heart disease and stroke.16J7 The CHS was designed to determine the importance of conventional CVD risk factors in older adults, and to identify new risk factors in this age group. There was particular interest in identifjmg participants with subclinical CVD and in investigating the relationships among risk factors, subclinical disease, and the development of overt CVD. In June 1990, four field centers completed the recruitment of 5,201 participants. Between November 1992 and June 1993, an additional 687 African Americans were recruited using similar methods. This study completed a total of 11 examinations (first in 1989 to 1990 and the last in 1998 to 1999) and included spirometry in some of the examinations (Fig 1). EUROPEAN COHORTS Medical Research Council Cohort In 1960, the UK Medical Research Council (MRC) commissioned a cohort study18 to explore how smoking interacts with other factors (eg, phlegm volume, chest infections,and pollution) in causing air flow obstruction and m glung function decline (Fig 2). This landmark MRC cohort study investigatedlung function and respiratory events in 1,136working men aged 30to 59 years starting in 1961 and followed them up for a maximum of 8 years. At that time, nearly two thirds of the population were current smokers. Even with all Sp&ial Feature

FIGURE2. European cohort studies with PIT and/or respiratory symptoms by examinations.

these limitations the so-called Fletcher and Pet0 &gram,suggested from the MRC cohort data,l9 is still widely considered to accurately represent “the natural history of COPD.”

MIDSPAN: The Studies MIDSPAN is a framework for a number of occupational and general population health studies that began in the 1960s and involved nearly 30,000 people in Scotland and elsewhere in the United Kingdom. The study involved, the Main and Collaborative Studies, which were based mainly in factories and other workplaces in Scotland, the www.chsstjoumal.org

Tiree Study, which was a general population study in this Hebridean island, and finally two more studies centered in the towns of Paisley and Renfrew (the Renfrew/Paisley Study and the Family Study). Findings from the MIDSPAN studies are representative for populations living and working in areas exposed to high rates of socioeconomic deprivation and early mortality. Lung function testing was performed in all MIDSPAN studies (Fig 2).20

Main and Tiree Study: The primary purpose of this study was to measure cardiorespiratoryhealth in the population at a time when tuberculosis was CHEST / 135 / 5 / MAY. 2009

’la

increasing continuously. Nearly 4,000 men and women aged 15 to 70 years were recruited and observed between 1964 and 1968. In May 1967, the MIDSPAN team visited the Hebridean island of Tiree in order to register health details of all residents over the age of 15 years. In total, 532 islanders (age range, 14 to 92 years) took part in this study, and later 230 of their relatives who had settled on the mainland were also recruited into the study in 1968.

Collaboratiue Study: The Collaborative Study was a cohort study of 6,022 men and 1,006 women who were recruited from 27 workplaces throughout the central belt of Scotland. The study took place between 1970 and 1973. In 1977, the workplaces were revisited and participants were requested to attend for follow-up a second time. RenfreWPaisley Study: The Renfrew/Paisley Study was a general population study of 15,402 men and women conducted from 1972 to 1976. All residents aged 45 to 64 years living in the large boroughs of Renfrew and Paisley, situated in the west of Scotland, were asked to complete a questionnaire and were invited to attend screening examinations at clinics set up nearby. In 1973, a return visit was made to Renfrew. All the participants were invited for a further visit between 1977 and 1979. Family Study: The Family Study is an investigation of two generations. The Renfrewflaisley cohort contained 4,064 married couples. From 1993 to 1994, their offspring aged 30 to 59 years were invited to take part in this cardiorespiratory study. In total, 2,338 offspring participated in the examination in 1996. Vlagtwedde-Vlaardingen This investigation was set up to determine the effects in early adulthood of asthma, increased bronchial responsiveness, markers of allergy, and smoking on pulmonary function level, and the effects of these same risk factors on a subsequent decline in pulmonary function, because these early adult factors presumably profoundly influence the risk of COPD.21 This was a longitudinal study of host factors and environmental determinants of COPD, based on a random sample of populations from two Dutch villages, Vlagtwedde and Vlaardingen. The Vlagtwedde cohort consisted of 450 subjects, 40 to 44 years of age, who were enrolled in 1965, and 1,793 subjects, 15 to 39 years of age, who were enrolled in 1967. The Vlaardingen cohort consisted of 859 subjects, 40 to 54 years 1336

of age, who were enrolled in 1965, and 1,590 subjects, 15 to 39 years of age, who were enrolled in 1969. After the baseline survey, the two cohorts have been reexamined every 3 years. Lung function testing was performed in the majority of the follow-up examinations (Fig 2).

Pisa and Po Delta I d o r Epidemiologic Studies The Po Delta and Pisa studies aimed to accomplish the following: (1) to evaluate the short-term effects of home environment on respiratory health in two sample populations from an Italian general population living in an urban and a rural area that were characterized by different levels of outdoor air pollution; (2) to examine the relationship between home characteristics and the quality of the indoor environment; and (3) to investigate the relationship between indoor and outdoor environments (Fig 2). Two prospective studies were carried out in the rural area of the Po delta from 1988 to 1991 (2,841 subjects; age range, 8 to 75 years) and in the urban area of Pisa from 1991 to 1993 (2,841 subjects; age range, 8 to 97 years). Subjects aged < 76 years were invited to perform lung function tests.22

European Community Respiratoy Health Survey In the early 1980s, the European Community Respiratory Health Survey (ECRHS) 123was the first study aimed to assess the prevalence of asthma and allergic disease in young adults in many countries using a stanprotocol (Fig 2). Adults between 20 and 44 years of age were selected randomly. The study was initiated to explore the worldwide increase in asthma prevalence, which pointed to environmental factors being important in the development of the disease. The primary aims of the study were to estimate variations in the prevalence of asthma, asthma-like symptoms, and atopic sensitization, and bronchial responsiveness; to estimate the variation in exposure to known or suspected risk factors for asthma and to assess how they explain the variations in asthma prevalence across Europe; and to estimate variations in the treatment of asthma in Europe. This multicenter, multinational study23 started in 1990, collecting data mainly from European countries. It was a two-stage study, with around 200,000 participants in stage 1, and 26,000 in the clinical stage 2. A follow-up study, ECRHS 11, was carried out from 1998 to 2002. Overall, 56 centers from 25 countries took part in stage 1 of ECRHS I, and 45 centers took part in atleast part of stage 2. Special Feature

Copenhagen City Heart Study The Copenhagen City Heart Study is a prospective study that was initiated in 1976. A sample comprising 19,698 individuals who were 20 years of age was drawn from the Copenhagen Population Register in January 1976. The first examination round lasted from 1976 to 1978. A total of 14,223 individuals were examined. The whole population sample, together with a new sample of 500 younger subjects 20 to 25 years of age, were invited for a second examination between 1981 and 1983, resulting in a total of 12,698 subjects being examined. A third examination of the cohort, together with an additional sample of 3,000 subjects aged 20 to 39 years was performed between 1991 and 1994. A total of 10,127 subjects participated in this examination. After the exclusion of subjects with incomplete data, which were required for the longitudinal analyses of lung function, the final sample consisted of 17,506 subjects, who attended at least one of the three examinations of the survey.24 A fourth examination providing lung function data within 25 years of follow-up proceeded from 2001 to 2003.25 Spirometry was assessed in all follow-up examinations (Fig 2).

Obstructive Lung Disease in Northern Sweden The Obstructive Lung Disease in Northern Sweden studies26 have collected epidemiologic data since 1985 with a focus on allergy and obstructive lung disease. Initially, in 1985 to 1986, a postal questionnaire was sent to 6,610 men and women aged 35 to 66 years in eight representative areas of northern Sweden. In 1996, a random sample of 1,500 subjects were invited to undergo a structured interview and spirometry, of whom 1,282 subjects participated and 1,237 performed an acceptable spirometry maneuver.27 Participants were invited to undergo a second examination in 2003, of whom 1,009 subjects participated and 979 had adequate lung function test results. The study sample consisted of the 963 subjects who had technically performed spirometry adequately in both 1996 and 2003 (Fig 2).

Swiss Study on Air Pollution and Lung Diseases in Adults Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) is a multicenter cohort study investigating the relationship between exposure to air pollutants and respiratory symptoms or diseases. The eight study areas participating in the project represent the variety of environmental conditions found in Switzerland.28 For the crosswww.chestioumal.org

sectional part of the study, adults were drawn in 1991 from the registry of inhabitants of eight areas in Switzerland representing a range of air pollution exposure, urbanization, altitude, and meteorologic conditions. A total of 9,651 subjects completed a standardized questionnaire on respiratory health and attended a health assessment. Participants were invited for reexamination between 2001 and 2003 (Fig 2). An ongoing follow-up will investigate the mortality profile of the SAPALDIA cohort.

Finnish Cohort in the Seven Countries Study The Seven Countries Study was primarily initiated to investigate coronary heart disease and included 16 cohorts located in eight nations (the United States, Finland, the Netherlands, Italy, Croatia, Serbia, Greece, and Japan) with > 12,000 subjects at study entry (Fig 2). In this review, we introduce the Finland cohort as a representative cohort. The original Finnish cohorts started in 1959, and consisted of all men (n = 1,711) aged 40 to 59 years from two rural areas in the east and southwest of Finland. Reexaminations were performed in 1964, 1969, 1974, 1984, and 1989, and 2000.29.3O POTENTIAL LIMITATIONS A number of methodological issues have to be considered when assessing or analyzing the changes in lung function from large, prospective cohorts (Table 2). First, most old cohorts had their main interest in CV end points. Therefore, pulmonary measurements and questionnaires were often missing and/or had low quality control. Accordingly, they should be critically reviewed and validated before their use in respiratory research. Often, cohort studies involve different generations, and cohort-related changes in population structure and risk factors due to changes in diet, smoking, or other factors might distort any results. Differences in lung function between generations can be observed in segregation analysis,31 and should be considered when pooling the data of longitudinal studies and/or starting new cohort studies.32 Population studies conducted during the 1950s and later that included spirometry did not include post-bronchodilator therapy values, simply because bronchodilator drugs were not available at that time. Current guidelines33 recommend that all lung function data be post-bronchodilator therapy because of validity and repeatability factors. Notwithstanding, old data still have precious value, but authors using pre-bronchodilator therCHEST I 135 1 5 I MAY, 2009

Table 2-Ut

of Limitations of Cohort Studiee With Pulmonary Function Data: Methalobgical Problems and Recommendations Problems

Data-related Effort-related, censored data (right-censored, interval-censored, and left-censored)

Pre-bronchodilator therapy vs post-bronchodilator therapy measurements Measurement-related Technology and machines Changes in techniques and maneuvers

Protocol Cohort-related Changes in population structure and risk factors

Reference population Pooling groups vs individuals Analysis-related Statistical analyses

Bias

apy data cannot claim to use the thresholds and staging recommended by the current Global Initiative for Chronic Obstructive Lung Disease guidelines2 or European Respiratory Society/ American Thoracic Society (ATS) guidelines.' However, in population studies the use of bronchodilator drugs may produce logistic and perhaps safety problems. That is why some authors pragmatically suggest the use of pre-bronchodilator therapy values in population studies.34 Predicted values of lung function are usually estimated by gender, age and height, but there are often few data on the very young or the elderly.% The choice of the adequate reference equations by 1338

Recommendations Use of adequate statistical methods (Kaplan-Meier suMval analysis or other) to counter the failure rate among noncensored patients vs censored patients Balancing extrapolation or not, as most informative individuals produce few or no data Use pre-bronchodilator therapy values in case post-bronchcdilator therapy values are unavailable Document and assess any changes in spirometric measurements and devices. Use of ATS guidelines standardizing spirometry were used first in 1979 and were updated several times, the last time in 2005; Use of valid evidence-based techniques and trained personnel to standardize the same techniques, centerdabor, and staff; and an (I posteriori objective quality control of data should be available Record of questionnaire or technical protocol changes including appropriate and relevant respiratory end points Differences in lung function between generations have been shown in segregation analysis elsewhere and should be considered when pooling data from different studies and/or starting new cohort studies The choice of a healthy control population of never-smokers and of appropriate reference equations for spiromehy Decide according to prespecified end point on whether individual slopes or grouped values will be analyzed Inclusion of subjects whose lung function did not meet the ATS reproducibility criterion should be carried out, at least in the first main analysis; Modeling by ARIMA, seasonal trends, or other proper statistical tools; Detectionhe of the same questionnaire variables (often labeled differently through time) and pooling them; Bivariate analysis: variables evaluated by, eg, gender, age, or smoking status for quality control; and Multivariate analysis to determine confounding and effect modification No representative cohorts, no correct reference values, no correct methddtechniques

geographic area and ethnic origin, and generational effects when assessments take decades, are an additional methodological concern. Optimal data (so-called complete data) imply that the value of each measurement is observed or known all over the observation time. Because spirometry is individually effort related, by blowing in or out as hard as possible for seconds and following instructions from a technician, this criterion is hard to fulfil in cohort studies. For example, infants and young children are unable to comply with voluntary respiratory maneuvers, and alternative testing methods are needed to indirectly measure pulmonary function during inSpecial Feature

!

fancy.% Similarly, elderly and/or sick individuals can have problems in performing pulmonary tests, as individuals get tired, are too weak, or are unable to fulfill the technician’s instructions or to maintain the requested effort in all maneuvers. These are called, respectively, left-censored data and right-censored data, and have to be considered when analyzing and interpreting data from natural history studies or clinical trials, and can merely be minimized by using adequate statistical methods.37 Technology and protocols are usually standardized and unchanged within a single study, even if it is a multicenter study, but changes in techniques and maneuvers can occur over time and might produce “cohort effects,”38 which are systematic variations in measurements (bias) that cankannot be minimized by correction factors. For instance, the ATS guidelines standardizing spirometry were published first in 197939and were updated last in 2005,40with consecutive updates providing variations in recommendations that altered the performance of testing. Likewise, changes in thresholds for defining disease and disease severity have occurred and will produce very different outcomes if not considered properly.41

RECOMMENDATIONS: THE IDEALNATURAL HISTORY OF LUNGFUNCTION STUDY In a provocative statement in the article by Mannino et al,42 Vestbo suggested that the perfect COPD natural history study of pulmonary function has not been conducted and perhaps never will be conducted. However, from the discussion above, a number of recommendations when setting up studies on the natural history of lung function can be considered (Table 2). These recommendations may also be helpful when analyzing data from old studies. A wide range of risk, protective and modifying factors of lung function, such as active and passive smoking, respiratory infections, and comorbidities, among others, should be taken into account and included in the protocol. A recent ATS/European Respiratory Society task force43 reviewed a comprehensive list of respiratory end points, some of them to be considered in new studies or trials. Generations might grow healthier, leanerlfatter, and taller; calendar and biological age should be properly registered; and all machines and set-ups should be recorded. For the time being, postbronchodilator therapy values are considered to be a “gold standard” and should be a strong recomwww.chestjoumal.org

mendation. Using the appropriate reference equations according to the population surveyed, or even developing contemporary reference equations among healthy never-smokers from that population sample might be advisable. Other potentially relevant recommendations include using evidence-based validated techniques and adequately trained personnel; standardizing of techniques and staff; and recording of questionnaire forms and any technical or protocol changes. Storing biological samples for future biochemistry, biomarkers, or genetic considerations are to be considered as well. Finally, a sophisticated statistical analysis can be used to deal with serial measurements, missing individual examinations, and the interpolation of results, adjusted by seasonal trends or other, which may help the investigator to choose proper statistical Taking all of the above into account, it is conceivable to envisage that the ideal COPD natural history study, as Vestbo suggested in the article by Mannino et al,4* should be an enlarged pulmonary version of the Framingham Study, enabling us to do what cardiologists have already done. In addition, it should take into account our knowledge (or lack of knowledge) on genetics and the early origin of late-onset disease. From this somewhat naive viewpoint, the ideal COPD natural history study should be large; start before birth; include follow-up for life; include a few hundred pages of questionnaire forms, PFT, biomarker measurements (including imaging), and direct exposure measures, and, of course, genetics and all the “omics” (eg, genomics, proteomics, metabolomics).45 Obviously, this is not an easy task. An alternative might be pooling results from individual natural history studies, and using a metaanalytical approach could be a partial, positive solution, as it has been proposed46 for asthma and atopy birth cohorts, and is currently being explored for lung function and COPD. As a consequence, the ideal COPD natural history study might consist of multiple studies, each addressing a specific scientific question.

CONCLUSIONS A number of cohort studies that included pulmonary objectives and/or PFT are available worldwide. Some of them already have yielded valuable findings, which changed our knowledge tremendously, and modified the way that COPD is treated and diagnosed. Nevertheless, the natural history of COPD is still not completely understood, and further research, by investigating both CHEST I 135 1 5 I MAY. 2009

Appendix-Lbt of Aoaihble Web Links to Popuhtion-&Med Studies With P u l m o ~ r yComponents Institution

Web Site

NHLBI Framingham Heart Study Honolulu Heart Program NAS NAS (adults) ARK

LHS CHS ECRHS

Renfrew-Paisley MIDSPAN study Vlaagtwedde Vlaardingen study CARDIA study

old and new data, is needed. We hope that this review encourages researchers to carry out the ideal study on the natural history of COPD.

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2 Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the

3 4 5 6

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