- Email: [email protected]
Clinical implications of pulmonary function testing in preschool children
PAEDIATRIC RESPIRATORY REVIEWS (2006) 7S, S26–S29
Clinical implications of pulmonary function testing in preschool children Janet Stocks* Portex Unit: Respiratory Physiology, UCL, Institute of Child Health, London, UK KEYWORDS child; diagnostic profile; preschool; reference values; repeatability; interpretative strategies
Summary There is increasing recognition of the need for objective physiological measurements of lung function during the preschool years in order to identify and treat early lung disease before irreversible structural changes occur; monitor disease progression and efficacy of therapeutic interventions and distinguish the various wheezing phenotypes that occur in this age group, all of which require different management strategies. While preschool pulmonary function tests are undoubtedly excellent research tools , their role in the clinical management of the individual young child remains more controversial . In particular, further work is required to establish information on the within -subject , between occasion variability and the relative sensitivity and specificity of each technique, as well as developing more appropriate prediction equations for this age group, before they can be used confidently in the clinical management of individual child. This review examines the various challenges facing paediatricians who are responsible for children with respiratory diseases such as asthma, wheezing, cystic fibrosis and chronic lung disease following preterm delivery and summarises recent recommendations from an ATS/ERS Task Force. ß 2006 Elsevier Ltd. All rights reserved.
INTRODUCTION It is now recognised that, given encouragement and suitable measurement conditions, most children between 2 and 6 years can undertake a wide range of pulmonary function tests (PFTs). While there is little doubt about the value of these tests in clinical or epidemiological research, their potential to influence clinical management in an individual remains debateable. The clinical usefulness of any measurement depends on how well it can discriminate between health and disease and how reproducible it is from day to day so that disease progression and response to treatment can be assessed. It is often claimed that the assessment of PFT will help diagnosis, assist prognosis, monitor disease progress and measure the effect of therapeutic interventions. An objective
test would supplement history and physical examination in subjects with respiratory problems, known to be notoriously difficult in the childhood wheezing disorders. However, the evidence base of clinical decision making, i.e. deciding what is the best test or group of tests for the individual, lags far behind that for treatments. For the clinician, it is important to know how helpful PFT is in distinguishing health from disease and monitoring disease progress in the individual. The principal disease categories where PFT could help in diagnosis are the preschool wheezing disorders. PFTs could also be helpful in monitoring progress and response to treatment in children suffering from wheezing disorders, cystic fibrosis (CF) and chronic lung disease of infancy.
FEASIBILITY * Tel.: +44 207 905 2382; Fax: +44 207 829 8634. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.015
Under perfect conditions, many PFTs can be now be undertaken successfully in the majority of preschool chil-
CLINICAL IMPLICATIONS OF PFTs IN PRESCHOOL CHILDREN
dren over the age of 3 years. These tests were developed by researchers primarily interested in their application to groups of children in order to understand the progress of lung development, disease and the effect of interventions. For application to the management of individuals, however, feasibility depends on many factors other than just whether the patient can undertake the test. For example, while the majority of preschool children with and without CF, may be able to produce technically satisfactory forced expiratory maneuvers provided FEV is measured after 0.5 or 0.75 seconds, relatively few will be able to meet international quality control requirements for adult spirometry. In addition, in contrast to routine measurements of peak flow in a respiratory clinic by the physician managing the patient’s care, preschool tests require time and patience by individuals trained in the techniques who can help young children to perform at their best.
WHAT IS NORMAL? a) Choosing reference data: Reference equations are essential to express pulmonary function in relation to that which would be expected for healthy children of similar age, sex, body size and ethnic group. The choice of reference equations directly influences the interpretation of paediatric pulmonary function data and can have a significant impact on patient care and research. Most lung function data are Normally distributed or can be transformed to such, so that 90% of ‘normal’ values are found within the range; mean 1.65, to mean +1.65 SD (with 95% lying between 1.96 and +1.96 SD). In paediatrics, values outside these ranges are considered ‘unusual’ or ‘abnormal’. However, lung function variables in healthy subjects and those with respiratory symptoms and/or disease often overlap to such an extent that a ‘normal’ lung function measurement does not exclude disease. Clearly abnormal lung function parameters will often, but not necessarily, be associated with symptoms and disease. Although an increasing number of publications have reported normative preschool PFT data during the past few years, many are based on relatively few children, particularly below 4 years of age. Furthermore, display of raw data plotted against height or age, which would allow the potential user to assess the validity of statistical analysis, (such as whether linear regression is appropriate and whether data are Normally distributed about the regression line) is rarely provided. The most important consideration when choosing reference data is that the method, equipment and software used to collect the data should be the same as that used by the clinician for his/her patients, and that such data were derived from a similar population with respect to age, body size and ethnic group. Particular caution is required when using commercial equipment for techniques such as plethysmography and spirometry. The default predic-
S27
tion equations from such equipment are invariably based on reference data derived from older subjects, which can result in serious misinterpretation if extrapolated to preschool children. b) Using reference data: Once the clinician has selected the data set that satisfies the above criteria, it has been recommended that measurements be made in at least 30 (preferably 50) healthy children across the same age range, and recruited from the local community, to ensure that there are no significant differences in the local population from the reference population. If data are to be related to height as the main predictor, accurate anthropometric measurements using a carefully calibrated stadiometer must be made according to the manufacturer’s recommendations. Data which are better related to age are particularly suitable for field studies and for disabled children where height is difficult to measure. Predicted values based on age may, however, over-estimate expected values if the child suffers from any significant degree of growth retardation associated with his/her respiratory disease.
EXPRESSING RESULTS In clinical practice, PFT results are most commonly reported as percent predicted, despite the fact that the ‘cut off’ point to define the normal limits may be extremely wide for certain parameters, and such an approach gives no indication of how unusual a finding might be. For example, while <80% may be considered abnormal for FEV1, this would have to be <60% for FEF75 and >150% for Rint). An alternative and far more informative approach is to express data as Z (SD) scores. Individual values of any lung function parameter can be converted to Z scores after adjusting for significant determinants, using the formula: Z score ¼ ½observed predicted=RSD where ‘observed’ is the child’s measurement, ‘predicted’ is that calculated for the child’s sex, age and height (and other variables), and RSD is the residual standard deviation of the predicted value. The Z score indicates how many SDs a value or an individual is below or above normal. Z scores of +/1.96 respectively correspond to the 97.5th and 2.5th centile of a normally distributed population (i.e 95% of a ‘normal’ population fall within these limits, whereas +/1.64 Z scores correspond to the 95th and 5th centiles. Z scores have the advantage of clearly indicating not only how likely/unlikely a certain result is to occur within a ‘normal population (as do centiles) but how far removed the result is from that predicted, having taken the natural between-subject variability of that parameter into account. They are thus particularly useful for tracking changes in lung function with time in the presence of severe deviations and for comparing results from different tests with varying
S28
degrees of between-subject variability. Software for calculating results as Z scores should be provided with commercial equipment, though currently, rarely is. Production or use of prediction equations without an accompanying ‘prediction interval’ is of minimal use and should be strongly discouraged.
RELIABILITY OF A TEST To evaluate the reliability of a test, it is necessary to know both the within-occasion repeatability and between occasion reproducibility of the measurements in healthy children and in those with respiratory complaints. The withintest repeatability of the measurement is usually expressed as a coefficient of variation (CV%), which is the SD of repeated measures expressed as a percentage of the mean (i.e. 100 SD/mean). In addition, if PFTs are to be used to measure the effect of an intervention such as response to a bronchodilator, then the repeatability of the test over the same time interval as the expected response to treatment should be known. Only then can the clinician decide whether any observed change can be ascribed confidently to the bronchodilator (or other intervention).
MONITORING DISEASE PROGRESS AND RESPONSE TO INTERVENTIONS An understanding of the between-occasion reproducibility, both in healthy children and in those with stable lung disease, is important when assessing day-to-day change in the individual. This information is critical in order to know whether any observed change is simply due to day-to-day variability of the measurement or whether it reflects the effect of an intervention or disease progression. Very limited data are currently available for preschool children.
DIAGNOSING RESPIRATORY DISEASES Before the clinician selects a pulmonary function test, s/he must know what the results are likely to be in children with the disorder(s) s/he is considering. For example, there is considerable overlap between measurements in children with mild asthma, isolated cough and healthy children. As mentioned above, while it can be said with 95% confidence that measurements outside the reference range (i.e. >+2 or <2 Z scores) are abnormal, many of the measurements in children with respiratory disorders will lie within the reference range. The diagnostic accuracy of any test can be described by the sensitivity and specificity of the test for the disease. The specificity is the proportion of ‘true negatives’ in healthy children and so 1-specificity is the proportion of false positives in healthy children. The sensitivity is the proportion of ‘true positives’ in affected
J. STOCKS
children. Because of the overlap of measurements between healthy subjects and those with previous wheeze, the diagnostic accuracy of baseline PFT is generally very poor in any age group. Bronchodilator responsiveness (BDR) has been recommended in the work-up of adult and childhood asthmatics where measurements of BDR give a much better diagnostic profile than that obtained from baseline lung function data. While significant group differences between young children with CF and healthy controls have been observed in several studies, the number of individuals with ‘abnormal’ results is relatively low for most PFTs during early childhood, with the possible exception of parameters reflecting ventilation inhomogeneity derived from inert gas multiple-breath washout. Summary: The ATS/ERS Task force on preschool lung function have recently developed the following guidelines to facilitate clinical interpretation of Preschool PFTs: Reference data derived from older subjects should not be extrapolated for use in children below 6 years of age. Prediction equations chosen for use within a particular laboratory should have been obtained using the same method and similar equipment to that used by the laboratory that developed such reference data, and to have been derived from a similar population, particularly with respect to age, body size, sex and ethnic group. The validity of the selected reference data for use in those with respiratory disease should be checked by studying at least 30–50 healthy preschool children using identical techniques. Results should, by preference, be expressed as Z scores: and not as percent predicted. Efforts are needed to establish both the within-subject, within occasion repeatability, and the reproducibility of measurements over several days or weeks in order to monitor disease progression or response to interventions, including tests of bronchial responsiveness. The diagnostic profile of measurements made using each technique, both with respect to baseline measurements and the ability to detect change in response to an intervention, needs to be established in order to make informed decisions as to which test(s) to use under specific clinical (or research) applications. Further multidisciplinary work is required to investigate the best combination of tests and challenges to investigate specific clinical entities during early childhood. In conclusion, while pre-school PFTs are undoubtedly excellent research tools, more research is needed to monitor progress and measure the effect of interventions within the individual subject. In particular, further work is required to establish information on the within-subject repeatability and the relative sensitivity and specificity of the various ‘preschool PFTs’ as well as developing appropriate reference data for this challenging age group, before we can use them to reliably assess the effects of treatment
CLINICAL IMPLICATIONS OF PFTs IN PRESCHOOL CHILDREN
or distinguish the effects of lung disease from that of growth and development, within an individual child.10
ACKNOWLEDGEMENTS This summary is based on a document prepared by an ad hoc subcommittee of the ATS/ERS Working Group on Infant and Young Children PFTs. Members of this subcommittee were: Sheila McKenzie (Chair), Paul Aurora, Francine Ducharme, Michael Healy, Bent Klug, Paul Seddon and Janet Stocks.
FURTHER READING 1. ATS_ERS Consensus Statement: Lung function testing in preschool children: Clinical Usefulness. McKenzie S, Stocks J et al. Am J Respir Crit Care Med (under review). 2. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Resp Dis 1991; 144: 1202– 1218.
S29
3. Beelen RM, Smit HA et al. Short and long term variability of the interrupter technique under field and standardised conditions in 3–6 year old children. Thorax 2003; 58: 761–764. 4. Borrill Z, Houghton C, Sullivan PJ, Sestini P. Retrospective analysis of evidence base for tests used in diagnosis and monitoring of disease in respiratory medicine. BMJ 2003; 327: 1136–1138. 5. Chan EY, Bridge PD, Dundas I, Pao CS, Healy MJ, McKenzie SA. Repeatability of airway resistance measurements made using the interrupter technique. Thorax 2003; 58: 344–347. 6. Chinn S. Statistics in respiratory medicine. 2. Repeatability and method comparison. Thorax 1991; 46: 454–456. 7. Knottnerus JA, van Weel C. In: Knotternus JA, ed: Evaluation of diagnostic procedures. London: The Evidence Base of Clinical Diagnosis BMJ books, 2002. 8. Merkus PJ, Tiddens HA, de Jongste JC. Annual lung function changes in young patients with chronic lung disease. Eur Respir J 2002; 19: 886– 891. 9. Rosenfeld M, Pepe MS, Longton G et al. Effect of choice of reference equation on analysis of pulmonary function in cystic fibrosis patients. Pediatr Pulmonol 2001; 31: 227–237. 10. Aurora P, Bush A, Gustafsson P, Oliver C, Wallis C, Price J, Stroobant J, Carr S, Stocks J. Multiple-breath Washout as a Marker of Lung Disease in Preschool Children with Cystic Fibrosis. Am J Respir Crit Care Med 2005; 179: 249–256.
Clinical implications of pulmonary function testing in preschool children Janet Stocks* Portex Unit: Respiratory Physiology, UCL, Institute of Child Health, London, UK KEYWORDS child; diagnostic profile; preschool; reference values; repeatability; interpretative strategies
Summary There is increasing recognition of the need for objective physiological measurements of lung function during the preschool years in order to identify and treat early lung disease before irreversible structural changes occur; monitor disease progression and efficacy of therapeutic interventions and distinguish the various wheezing phenotypes that occur in this age group, all of which require different management strategies. While preschool pulmonary function tests are undoubtedly excellent research tools , their role in the clinical management of the individual young child remains more controversial . In particular, further work is required to establish information on the within -subject , between occasion variability and the relative sensitivity and specificity of each technique, as well as developing more appropriate prediction equations for this age group, before they can be used confidently in the clinical management of individual child. This review examines the various challenges facing paediatricians who are responsible for children with respiratory diseases such as asthma, wheezing, cystic fibrosis and chronic lung disease following preterm delivery and summarises recent recommendations from an ATS/ERS Task Force. ß 2006 Elsevier Ltd. All rights reserved.
INTRODUCTION It is now recognised that, given encouragement and suitable measurement conditions, most children between 2 and 6 years can undertake a wide range of pulmonary function tests (PFTs). While there is little doubt about the value of these tests in clinical or epidemiological research, their potential to influence clinical management in an individual remains debateable. The clinical usefulness of any measurement depends on how well it can discriminate between health and disease and how reproducible it is from day to day so that disease progression and response to treatment can be assessed. It is often claimed that the assessment of PFT will help diagnosis, assist prognosis, monitor disease progress and measure the effect of therapeutic interventions. An objective
test would supplement history and physical examination in subjects with respiratory problems, known to be notoriously difficult in the childhood wheezing disorders. However, the evidence base of clinical decision making, i.e. deciding what is the best test or group of tests for the individual, lags far behind that for treatments. For the clinician, it is important to know how helpful PFT is in distinguishing health from disease and monitoring disease progress in the individual. The principal disease categories where PFT could help in diagnosis are the preschool wheezing disorders. PFTs could also be helpful in monitoring progress and response to treatment in children suffering from wheezing disorders, cystic fibrosis (CF) and chronic lung disease of infancy.
FEASIBILITY * Tel.: +44 207 905 2382; Fax: +44 207 829 8634. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.015
Under perfect conditions, many PFTs can be now be undertaken successfully in the majority of preschool chil-
CLINICAL IMPLICATIONS OF PFTs IN PRESCHOOL CHILDREN
dren over the age of 3 years. These tests were developed by researchers primarily interested in their application to groups of children in order to understand the progress of lung development, disease and the effect of interventions. For application to the management of individuals, however, feasibility depends on many factors other than just whether the patient can undertake the test. For example, while the majority of preschool children with and without CF, may be able to produce technically satisfactory forced expiratory maneuvers provided FEV is measured after 0.5 or 0.75 seconds, relatively few will be able to meet international quality control requirements for adult spirometry. In addition, in contrast to routine measurements of peak flow in a respiratory clinic by the physician managing the patient’s care, preschool tests require time and patience by individuals trained in the techniques who can help young children to perform at their best.
WHAT IS NORMAL? a) Choosing reference data: Reference equations are essential to express pulmonary function in relation to that which would be expected for healthy children of similar age, sex, body size and ethnic group. The choice of reference equations directly influences the interpretation of paediatric pulmonary function data and can have a significant impact on patient care and research. Most lung function data are Normally distributed or can be transformed to such, so that 90% of ‘normal’ values are found within the range; mean 1.65, to mean +1.65 SD (with 95% lying between 1.96 and +1.96 SD). In paediatrics, values outside these ranges are considered ‘unusual’ or ‘abnormal’. However, lung function variables in healthy subjects and those with respiratory symptoms and/or disease often overlap to such an extent that a ‘normal’ lung function measurement does not exclude disease. Clearly abnormal lung function parameters will often, but not necessarily, be associated with symptoms and disease. Although an increasing number of publications have reported normative preschool PFT data during the past few years, many are based on relatively few children, particularly below 4 years of age. Furthermore, display of raw data plotted against height or age, which would allow the potential user to assess the validity of statistical analysis, (such as whether linear regression is appropriate and whether data are Normally distributed about the regression line) is rarely provided. The most important consideration when choosing reference data is that the method, equipment and software used to collect the data should be the same as that used by the clinician for his/her patients, and that such data were derived from a similar population with respect to age, body size and ethnic group. Particular caution is required when using commercial equipment for techniques such as plethysmography and spirometry. The default predic-
S27
tion equations from such equipment are invariably based on reference data derived from older subjects, which can result in serious misinterpretation if extrapolated to preschool children. b) Using reference data: Once the clinician has selected the data set that satisfies the above criteria, it has been recommended that measurements be made in at least 30 (preferably 50) healthy children across the same age range, and recruited from the local community, to ensure that there are no significant differences in the local population from the reference population. If data are to be related to height as the main predictor, accurate anthropometric measurements using a carefully calibrated stadiometer must be made according to the manufacturer’s recommendations. Data which are better related to age are particularly suitable for field studies and for disabled children where height is difficult to measure. Predicted values based on age may, however, over-estimate expected values if the child suffers from any significant degree of growth retardation associated with his/her respiratory disease.
EXPRESSING RESULTS In clinical practice, PFT results are most commonly reported as percent predicted, despite the fact that the ‘cut off’ point to define the normal limits may be extremely wide for certain parameters, and such an approach gives no indication of how unusual a finding might be. For example, while <80% may be considered abnormal for FEV1, this would have to be <60% for FEF75 and >150% for Rint). An alternative and far more informative approach is to express data as Z (SD) scores. Individual values of any lung function parameter can be converted to Z scores after adjusting for significant determinants, using the formula: Z score ¼ ½observed predicted=RSD where ‘observed’ is the child’s measurement, ‘predicted’ is that calculated for the child’s sex, age and height (and other variables), and RSD is the residual standard deviation of the predicted value. The Z score indicates how many SDs a value or an individual is below or above normal. Z scores of +/1.96 respectively correspond to the 97.5th and 2.5th centile of a normally distributed population (i.e 95% of a ‘normal’ population fall within these limits, whereas +/1.64 Z scores correspond to the 95th and 5th centiles. Z scores have the advantage of clearly indicating not only how likely/unlikely a certain result is to occur within a ‘normal population (as do centiles) but how far removed the result is from that predicted, having taken the natural between-subject variability of that parameter into account. They are thus particularly useful for tracking changes in lung function with time in the presence of severe deviations and for comparing results from different tests with varying
S28
degrees of between-subject variability. Software for calculating results as Z scores should be provided with commercial equipment, though currently, rarely is. Production or use of prediction equations without an accompanying ‘prediction interval’ is of minimal use and should be strongly discouraged.
RELIABILITY OF A TEST To evaluate the reliability of a test, it is necessary to know both the within-occasion repeatability and between occasion reproducibility of the measurements in healthy children and in those with respiratory complaints. The withintest repeatability of the measurement is usually expressed as a coefficient of variation (CV%), which is the SD of repeated measures expressed as a percentage of the mean (i.e. 100 SD/mean). In addition, if PFTs are to be used to measure the effect of an intervention such as response to a bronchodilator, then the repeatability of the test over the same time interval as the expected response to treatment should be known. Only then can the clinician decide whether any observed change can be ascribed confidently to the bronchodilator (or other intervention).
MONITORING DISEASE PROGRESS AND RESPONSE TO INTERVENTIONS An understanding of the between-occasion reproducibility, both in healthy children and in those with stable lung disease, is important when assessing day-to-day change in the individual. This information is critical in order to know whether any observed change is simply due to day-to-day variability of the measurement or whether it reflects the effect of an intervention or disease progression. Very limited data are currently available for preschool children.
DIAGNOSING RESPIRATORY DISEASES Before the clinician selects a pulmonary function test, s/he must know what the results are likely to be in children with the disorder(s) s/he is considering. For example, there is considerable overlap between measurements in children with mild asthma, isolated cough and healthy children. As mentioned above, while it can be said with 95% confidence that measurements outside the reference range (i.e. >+2 or <2 Z scores) are abnormal, many of the measurements in children with respiratory disorders will lie within the reference range. The diagnostic accuracy of any test can be described by the sensitivity and specificity of the test for the disease. The specificity is the proportion of ‘true negatives’ in healthy children and so 1-specificity is the proportion of false positives in healthy children. The sensitivity is the proportion of ‘true positives’ in affected
J. STOCKS
children. Because of the overlap of measurements between healthy subjects and those with previous wheeze, the diagnostic accuracy of baseline PFT is generally very poor in any age group. Bronchodilator responsiveness (BDR) has been recommended in the work-up of adult and childhood asthmatics where measurements of BDR give a much better diagnostic profile than that obtained from baseline lung function data. While significant group differences between young children with CF and healthy controls have been observed in several studies, the number of individuals with ‘abnormal’ results is relatively low for most PFTs during early childhood, with the possible exception of parameters reflecting ventilation inhomogeneity derived from inert gas multiple-breath washout. Summary: The ATS/ERS Task force on preschool lung function have recently developed the following guidelines to facilitate clinical interpretation of Preschool PFTs: Reference data derived from older subjects should not be extrapolated for use in children below 6 years of age. Prediction equations chosen for use within a particular laboratory should have been obtained using the same method and similar equipment to that used by the laboratory that developed such reference data, and to have been derived from a similar population, particularly with respect to age, body size, sex and ethnic group. The validity of the selected reference data for use in those with respiratory disease should be checked by studying at least 30–50 healthy preschool children using identical techniques. Results should, by preference, be expressed as Z scores: and not as percent predicted. Efforts are needed to establish both the within-subject, within occasion repeatability, and the reproducibility of measurements over several days or weeks in order to monitor disease progression or response to interventions, including tests of bronchial responsiveness. The diagnostic profile of measurements made using each technique, both with respect to baseline measurements and the ability to detect change in response to an intervention, needs to be established in order to make informed decisions as to which test(s) to use under specific clinical (or research) applications. Further multidisciplinary work is required to investigate the best combination of tests and challenges to investigate specific clinical entities during early childhood. In conclusion, while pre-school PFTs are undoubtedly excellent research tools, more research is needed to monitor progress and measure the effect of interventions within the individual subject. In particular, further work is required to establish information on the within-subject repeatability and the relative sensitivity and specificity of the various ‘preschool PFTs’ as well as developing appropriate reference data for this challenging age group, before we can use them to reliably assess the effects of treatment
CLINICAL IMPLICATIONS OF PFTs IN PRESCHOOL CHILDREN
or distinguish the effects of lung disease from that of growth and development, within an individual child.10
ACKNOWLEDGEMENTS This summary is based on a document prepared by an ad hoc subcommittee of the ATS/ERS Working Group on Infant and Young Children PFTs. Members of this subcommittee were: Sheila McKenzie (Chair), Paul Aurora, Francine Ducharme, Michael Healy, Bent Klug, Paul Seddon and Janet Stocks.
FURTHER READING 1. ATS_ERS Consensus Statement: Lung function testing in preschool children: Clinical Usefulness. McKenzie S, Stocks J et al. Am J Respir Crit Care Med (under review). 2. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Resp Dis 1991; 144: 1202– 1218.
S29
3. Beelen RM, Smit HA et al. Short and long term variability of the interrupter technique under field and standardised conditions in 3–6 year old children. Thorax 2003; 58: 761–764. 4. Borrill Z, Houghton C, Sullivan PJ, Sestini P. Retrospective analysis of evidence base for tests used in diagnosis and monitoring of disease in respiratory medicine. BMJ 2003; 327: 1136–1138. 5. Chan EY, Bridge PD, Dundas I, Pao CS, Healy MJ, McKenzie SA. Repeatability of airway resistance measurements made using the interrupter technique. Thorax 2003; 58: 344–347. 6. Chinn S. Statistics in respiratory medicine. 2. Repeatability and method comparison. Thorax 1991; 46: 454–456. 7. Knottnerus JA, van Weel C. In: Knotternus JA, ed: Evaluation of diagnostic procedures. London: The Evidence Base of Clinical Diagnosis BMJ books, 2002. 8. Merkus PJ, Tiddens HA, de Jongste JC. Annual lung function changes in young patients with chronic lung disease. Eur Respir J 2002; 19: 886– 891. 9. Rosenfeld M, Pepe MS, Longton G et al. Effect of choice of reference equation on analysis of pulmonary function in cystic fibrosis patients. Pediatr Pulmonol 2001; 31: 227–237. 10. Aurora P, Bush A, Gustafsson P, Oliver C, Wallis C, Price J, Stroobant J, Carr S, Stocks J. Multiple-breath Washout as a Marker of Lung Disease in Preschool Children with Cystic Fibrosis. Am J Respir Crit Care Med 2005; 179: 249–256.