Fragoso, C.A.V. (Carlos )

Güder, G. (Gülmisal)

Hoes, A.W. (Arno)

Miller, M.R. (Martin)

Quanjer, P.H. (Philip)

Rutten, F.F.H. (Frans)

Störk, S. (Stefan)

Respiratory Research

PubMed

Quanjer, Philip

Vaz Fragoso, CA

Miller, MR

Guder, G

Stork, S

Hoes, AW

Rutten, FFH

EUR Research Repository

Quanjer et al. Respiratory Research 2012, 13:61http://respiratory-research.com/content/13/1/61LETTER TO THE EDITOR Open AccessGOLD or lower limit of normal definition? a letterand authors’ responsePhilip Quanjer1*, Carlos A Vaz Fragoso2, Martin R Miller3, Gülmisal Güder4, Stefan Störk5, Arno W Hoes4and Frans Rutten4LetterPhilip H Quanjer, Carlos A Vaz Fragoso and Martin RMiller.It is a very refreshing idea to use clinical data andhealth outcomes to decide how to best diagnose ChronicObstructive Pulmonary Disease (COPD). Therefore weread the article by Güder et al. [1] with great interest.However, upon reading the article in more detail wedeveloped reservations about the criteria used.The authors started with 405 patients aged ≥65 yearswith a general practitioner’s (GP) diagnosis of COPD. AGP and a chest physician subsequently decided that 37%did not have COPD but they were still treated as if theyhad COPD. In fact, the percentage of not-COPD sub-jects receiving inhaled corticosteroids was almost as highas in those with expert panel (EP) COPD (EP COPD+).As there was a definite COPD bias in the selection ofsubjects, the EP-COPD negative patients are not an ad-equate control group.A large mix of criteria was used to diagnose EP-COPD+. It is impossible to reconstruct how the diag-nosis was adjudicated. There does not seem to havebeen any weighting of symptoms, signs, or measure-ment results. In fact, FEV1/FVC, FEV1 percentage ofpredicted, RV/TLC were used, but no information isprovided what criteria were applied in diagnosing EP-COPD+. Presumably the GP and chest physician adju-dicated a diagnosis without a predefined algorithm,nor blinded to the assessment of their counterpart. Itis to be expected that the judgment of the chest phys-ician would predominate, because many of the mea-surements are not part and parcel of a GP’s routine.In that respect the fall in Cohen’s kappa upon re-assessing the EP-COPD diagnosis suggests that agree-ment between chest physicians is not optimal.* Correspondence: pquanjer@xs4all.nl1Department of Pulmonary Diseases and Department of Paediatrics, ErasmusMedical Centre, Erasmus University, Rotterdam, the NetherlandsFull list of author information is available at the end of the article© 2012 Quanjer et al.; licensee BioMed CentraCommons Attribution License (http://creativecreproduction in any medium, provided the orThe diagnosis of COPD was based on pulmonary func-tion indices, using unspecified cutoff criteria and an un-known reference equation. Pulmonary function criteriawere probably pivotal in establishing the diagnosis.Maintaining a diagnosis based on arbitrary lung functioncriteria rather than redefining EP-COPD + by applyingother pulmonary function criteria and prediction equa-tions is a flawed approach, particularly when studyinghow the diagnosis of COPD is affected by such criteriaand prediction equations. The exclusive use of one set ofarbitrary pulmonary function criteria for establishing adiagnosis precludes studying how the diagnosis isaffected by other criteria.The use of percent of predicted, for example for FEV1,is also flawed as the scatter is not proportional to thepredicted value; this creates an age, sex, height and eth-nic group related bias [2-6]. Stanojevic [6] was the firstto show that in adults the scatter increases with age.This means that the lower limit of normal (LLN) derivedfrom conventional regression equations cannot bederived from predicted minus 1.64RSD, because theRSD varies with age. The use of z-scores using Stanoje-vic equations [6] is the method of choice, because z-scores are free of bias. The only problem is that the ageis limited to 80 years; this will be resolved when the Glo-bal Lungs Initiative publishes its 3-95 year predictedvalues (www.lungfunction.org).The number of co-morbidities in elderly subjects isvery great and this makes it very difficult to tease out aclinical diagnosis of COPD. Cox regression (hazardratios) should not be used as a basis for comparisons ofrisk among the various definitions of COPD, becausethese differ in their reference groups and because the ex-pert panel would have had access to relevant informa-tion concerning likelihood of the tested outcomes.Moreover, the analyses make no adjustment for con-founders such as age, smoking habit and male sex whichwill affect the tested outcomes and may vary betweenthe groups.l Ltd. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.Quanjer et al. Respiratory Research 2012, 13:61 Page 2 of 3http://respiratory-research.com/content/13/1/61Finally, including criteria to which a GP does not haveaccess, such as RV/TLC, makes establishing a diagnosisof COPD out of reach of GPs.Authors’ responseGülmisal Güder, Stefan Störk, Arno W Hoes and FransH Rutten.We thank Quanjer and colleagues for their insightfulcomments regarding our article [1]. Some points, how-ever, deserve further clarification. The critique of currentCOPD definitions was not intended to specifically ad-dress the GOLD guidelines or the lower limit of normal(LLN) approach, but was a general caveat to base thediagnosis onto one single ratio derived from pulmonaryfunction testing (PFT), ie FEV/FVC. Using the Stanoje-vic equation [6] as proposed by Quanjer might indeedincrease the specificity of the LLN definition, but it willnot improve the sensitivity since the LLN approach aswell as the GOLD definition fails to acknowledge falsenegative spirometric test results. Important diagnosticneeds will still remain unsolved. E.g., how should weclassify patients who – according to the GOLD or LLNdefinition – are (borderline) normal and have abnormal-ities at diffusion testing or RV/TLC ratio, especiallythose with a smoking history and symptoms.All 405 patients in our study had a GP’s diagnosis ofCOPD and were treated accordingly. The study team didnot attempt to modify the pulmonary treatment. Wealso did not exclude patients with co-morbidities as thismight provoke selection bias, nor did we considerhealthy never-smokers as controls, since they hardlypose diagnostic problems in daily routine. According tothe GOLD definition, about 60% of all patients sufferedfrom COPD, and about 40% depending on the type ofLLN definition. Hence, the challenge was not only to dif-ferentiate true positive from false positive COPDpatients but to also consider the possibility of false nega-tives. We therefore used an expert diagnosis of a pulmo-nologist and GP (validated internally and externally) asthe reference standard. We agree that this is not a per-fect standard. However, we are still convinced that anexperienced physician will outperform a single and ra-ther rigid mathematical model in the complex process ofintegrating very heterogeneous informations from vari-ous tests, including other PFT results as well as signsand symptoms. For many diseases that lack an irrefut-able single test as a reference, the use of an expert panel(using all diagnostic information) is an excepted alterna-tive, e.g. in heart failure.Furthermore, although the LLN approach is regardedmore “physiological” than the GOLD definition, since itconsiders age-, sex-and height-dependent cut-off valuesof FEV1/FVC, the present real-world cohort illustratesthat the LLN definition is not widely used by GPs todiagnose COPD. One reason for this reluctance mightbe the lack of consistency between different LLN equa-tions [7]. In a recent review, the shortcomings ofpopulation-derived LLN equations were thoroughly dis-cussed and the need of more studies with longitudinaldata to identify markers of COPD diagnosis and progno-sis was emphasized [8].In our prospective cohort study the two most import-ant PFT parameters for identifying a positive expertCOPD diagnosis besides FEV1/FVC ratio were FEV1 as% predicted and RV/TLC. Our proposed diagnostic algo-rithm is not yet validated; however, it is the very firstmathematical attempt that considers plausibility check-ing of a COPD diagnosis.We agree with Quanjer and colleagues that in our Coxregression analysis comparing expert COPD vs. the LLNor GOLD definition information bias may be a concernand it may explain the slightly superior point estimate ofthe expert diagnosis. However, since cut-off based defini-tions do not consider other information than providedin the equation, multivariable adjustment is not justifiedto test the prognostic capacity of different LLN defini-tions as suggested by the authors. Instead, and consist-ent with general clinical practice, we advocate todeliberately use otherwise neglected clinical informationfor diagnosis and decision making.In general, the goal of making a diagnosis is to definea certain population that may benefit from certain ther-apies. The ideal diagnostic perfectly identifies the sub-group sensitive to therapy, and accurately predictsrelevant clinical outcomes (e.g., exacerbations, hospitali-zations, mortality). Our results remind us of the useful-ness of the clinical view, including signs and symptoms.Moreover, we provide some evidence that bodyplethys-mographic measurements and diffusion testing is usefulto decide whether a patient has COPD when spirometryresults are indifferent. Maybe it is time to realize thatthe definition of COPD needs to include some ‘clinicalitems’, as nearly all definitions of diseases in medicine in-clude clinical aspects of patients.Author details1Department of Pulmonary Diseases and Department of Paediatrics, ErasmusMedical Centre, Erasmus University, Rotterdam, the Netherlands.2Department of Internal Medicine, New Haven, CT, USA, and Veterans Affairs(VA) Clinical Epidemiology Research Center, Yale University School ofMedicine, West Haven, CT, USA. 3Institute of Occupational and EnvironmentalMedicine, University of Birmingham, Birmingham, UK. 4Julius Center forHealth Sciences and Primary Care, University Medical Center Utrecht, Utrecht,The Netherlands. 5Comprehensive Heart Failure Center, Department ofInternal Medicine I, University Würzburg, Würzburg, Germany.Received: 2 April 2012 Accepted: 5 July 2012Published: 26 July 2012References1. Güder G, Brenner S, Angermann CE, Ertl G, Held M, Sachs AP, Lammers J,Zanen P, Hoes AW, Stork S, Rutten FH: GOLD or lower limit of normalQuanjer et al. Respiratory Research 2012, 13:61 Page 3 of 3http://respiratory-research.com/content/13/1/61definition? A comparison with expert-based diagnosis of chronicobstructive pulmonary disease in a prospective cohort-study. Respir Res2012, 13:13.2. Sobol BJ: Assessment of ventilatory abnormality in the asymptomaticsubject: an exercise in futility. Thorax 1966, 21:445–449.3. Sobol BJ, Sobol PG: Percent of predicted as the limit of normal inpulmonary function testing: a statistically valid approach. Thorax 1979,34:1–3.4. Miller MR, Pincock AC: Predicted values: how should we use them? Thorax1988, 43:265–267.5. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC:Lung volumes and forced ventilatory flows. Report Working PartyStandardization of Lung Function Tests, European Community for Steeland Coal. Official Statement of the European Respiratory Society.Eur Respir J 1993, 6(suppl 16):5–40.6. Stanojevic S, Wade A, Stocks J, Hankinson J, Coates AL, Pan H, Rosenthal M,Corey M, Lebecque P, Cole TJ: Reference ranges for spirometry across allages: a new approach. Am J Respir Crit Care Med 2008, 177:253–260.7. Olofson J, Bake B, Tengelin MN, Houltz B: COPD 'diagnosis’ based onspirometric reference equations. Clin Respir J 2008, 2(4):214–219.8. Marks GB: Are reference equations for spirometry an appropriatecriterion for diagnosing disease and predicting prognosis? Thorax 2012,67:85–87.doi:10.1186/1465-9921-13-61Cite this article as: Quanjer et al.: GOLD or lower limit of normaldefinition? a letter and authors’ response. Respiratory Research 2012 13:61.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

English

GOLD of lower limit of normal definition? a letter and authors' response

EUR Research Information PortalGOLD of lower limit of normal definition? a letter and authors' responsePublished in:Respiratory ResearchPublication status and date:Published: 01/01/2012DOI (link to publisher):10.1186/1465-9921-13-61Document VersionPublisher's PDF, also known as Version of recordCitation for the published version (APA):Quanjer, P., Vaz Fragoso, CA., Miller, MR., Guder, G., Stork, S., Hoes, AW., & Rutten, FFH. (2012). GOLD of lower limit ofnormal definition? a letter and authors' response. Respiratory Research, 13, 61. https://doi.org/10.1186/1465-9921-13-61Link to publication on the EUR Research Information PortalTerms and Conditions of UseExcept as permitted by the applicable copyright law, you may not reproduce or make this material available to any third partywithout the prior written permission from the copyright holder(s). 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In case of a legitimate complaint,we will make the material inaccessible and/or remove it from the website.LETTER TO THE EDITOR Open AccessGOLD or lower limit of normal definition? a letterand authors’ responsePhilip Quanjer1*, Carlos A Vaz Fragoso2, Martin R Miller3, Gülmisal Güder4, Stefan Störk5, Arno W Hoes4and Frans Rutten4LetterPhilip H Quanjer, Carlos A Vaz Fragoso and Martin RMiller.It is a very refreshing idea to use clinical data andhealth outcomes to decide how to best diagnose ChronicObstructive Pulmonary Disease (COPD). Therefore weread the article by Güder et al. [1] with great interest.However, upon reading the article in more detail wedeveloped reservations about the criteria used.The authors started with 405 patients aged ≥65 yearswith a general practitioner’s (GP) diagnosis of COPD. AGP and a chest physician subsequently decided that 37%did not have COPD but they were still treated as if theyhad COPD. In fact, the percentage of not-COPD sub-jects receiving inhaled corticosteroids was almost as highas in those with expert panel (EP) COPD (EP COPD+).As there was a definite COPD bias in the selection ofsubjects, the EP-COPD negative patients are not an ad-equate control group.A large mix of criteria was used to diagnose EP-COPD+. It is impossible to reconstruct how the diag-nosis was adjudicated. There does not seem to havebeen any weighting of symptoms, signs, or measure-ment results. In fact, FEV1/FVC, FEV1 percentage ofpredicted, RV/TLC were used, but no information isprovided what criteria were applied in diagnosing EP-COPD+. Presumably the GP and chest physician adju-dicated a diagnosis without a predefined algorithm,nor blinded to the assessment of their counterpart. Itis to be expected that the judgment of the chest phys-ician would predominate, because many of the mea-surements are not part and parcel of a GP’s routine.In that respect the fall in Cohen’s kappa upon re-assessing the EP-COPD diagnosis suggests that agree-ment between chest physicians is not optimal.The diagnosis of COPD was based on pulmonary func-tion indices, using unspecified cutoff criteria and an un-known reference equation. Pulmonary function criteriawere probably pivotal in establishing the diagnosis.Maintaining a diagnosis based on arbitrary lung functioncriteria rather than redefining EP-COPD + by applyingother pulmonary function criteria and prediction equa-tions is a flawed approach, particularly when studyinghow the diagnosis of COPD is affected by such criteriaand prediction equations. The exclusive use of one set ofarbitrary pulmonary function criteria for establishing adiagnosis precludes studying how the diagnosis isaffected by other criteria.The use of percent of predicted, for example for FEV1,is also flawed as the scatter is not proportional to thepredicted value; this creates an age, sex, height and eth-nic group related bias [2-6]. Stanojevic [6] was the firstto show that in adults the scatter increases with age.This means that the lower limit of normal (LLN) derivedfrom conventional regression equations cannot bederived from predicted minus 1.64RSD, because theRSD varies with age. The use of z-scores using Stanoje-vic equations [6] is the method of choice, because z-scores are free of bias. The only problem is that the ageis limited to 80 years; this will be resolved when the Glo-bal Lungs Initiative publishes its 3-95 year predictedvalues (www.lungfunction.org).The number of co-morbidities in elderly subjects isvery great and this makes it very difficult to tease out aclinical diagnosis of COPD. Cox regression (hazardratios) should not be used as a basis for comparisons ofrisk among the various definitions of COPD, becausethese differ in their reference groups and because the ex-pert panel would have had access to relevant informa-tion concerning likelihood of the tested outcomes.Moreover, the analyses make no adjustment for con-founders such as age, smoking habit and male sex whichwill affect the tested outcomes and may vary betweenthe groups.* Correspondence: pquanjer@xs4all.nl1Department of Pulmonary Diseases and Department of Paediatrics, ErasmusMedical Centre, Erasmus University, Rotterdam, the NetherlandsFull list of author information is available at the end of the article© 2012 Quanjer et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Quanjer et al. Respiratory Research 2012, 13:61http://respiratory-research.com/content/13/1/61Finally, including criteria to which a GP does not haveaccess, such as RV/TLC, makes establishing a diagnosisof COPD out of reach of GPs.Authors’ responseGülmisal Güder, Stefan Störk, Arno W Hoes and FransH Rutten.We thank Quanjer and colleagues for their insightfulcomments regarding our article [1]. Some points, how-ever, deserve further clarification. The critique of currentCOPD definitions was not intended to specifically ad-dress the GOLD guidelines or the lower limit of normal(LLN) approach, but was a general caveat to base thediagnosis onto one single ratio derived from pulmonaryfunction testing (PFT), ie FEV/FVC. Using the Stanoje-vic equation [6] as proposed by Quanjer might indeedincrease the specificity of the LLN definition, but it willnot improve the sensitivity since the LLN approach aswell as the GOLD definition fails to acknowledge falsenegative spirometric test results. Important diagnosticneeds will still remain unsolved. E.g., how should weclassify patients who – according to the GOLD or LLNdefinition – are (borderline) normal and have abnormal-ities at diffusion testing or RV/TLC ratio, especiallythose with a smoking history and symptoms.All 405 patients in our study had a GP’s diagnosis ofCOPD and were treated accordingly. The study team didnot attempt to modify the pulmonary treatment. Wealso did not exclude patients with co-morbidities as thismight provoke selection bias, nor did we considerhealthy never-smokers as controls, since they hardlypose diagnostic problems in daily routine. According tothe GOLD definition, about 60% of all patients sufferedfrom COPD, and about 40% depending on the type ofLLN definition. Hence, the challenge was not only to dif-ferentiate true positive from false positive COPDpatients but to also consider the possibility of false nega-tives. We therefore used an expert diagnosis of a pulmo-nologist and GP (validated internally and externally) asthe reference standard. We agree that this is not a per-fect standard. However, we are still convinced that anexperienced physician will outperform a single and ra-ther rigid mathematical model in the complex process ofintegrating very heterogeneous informations from vari-ous tests, including other PFT results as well as signsand symptoms. For many diseases that lack an irrefut-able single test as a reference, the use of an expert panel(using all diagnostic information) is an excepted alterna-tive, e.g. in heart failure.Furthermore, although the LLN approach is regardedmore “physiological” than the GOLD definition, since itconsiders age-, sex-and height-dependent cut-off valuesof FEV1/FVC, the present real-world cohort illustratesthat the LLN definition is not widely used by GPs todiagnose COPD. One reason for this reluctance mightbe the lack of consistency between different LLN equa-tions [7]. In a recent review, the shortcomings ofpopulation-derived LLN equations were thoroughly dis-cussed and the need of more studies with longitudinaldata to identify markers of COPD diagnosis and progno-sis was emphasized [8].In our prospective cohort study the two most import-ant PFT parameters for identifying a positive expertCOPD diagnosis besides FEV1/FVC ratio were FEV1 as% predicted and RV/TLC. Our proposed diagnostic algo-rithm is not yet validated; however, it is the very firstmathematical attempt that considers plausibility check-ing of a COPD diagnosis.We agree with Quanjer and colleagues that in our Coxregression analysis comparing expert COPD vs. the LLNor GOLD definition information bias may be a concernand it may explain the slightly superior point estimate ofthe expert diagnosis. However, since cut-off based defini-tions do not consider other information than providedin the equation, multivariable adjustment is not justifiedto test the prognostic capacity of different LLN defini-tions as suggested by the authors. Instead, and consist-ent with general clinical practice, we advocate todeliberately use otherwise neglected clinical informationfor diagnosis and decision making.In general, the goal of making a diagnosis is to definea certain population that may benefit from certain ther-apies. The ideal diagnostic perfectly identifies the sub-group sensitive to therapy, and accurately predictsrelevant clinical outcomes (e.g., exacerbations, hospitali-zations, mortality). Our results remind us of the useful-ness of the clinical view, including signs and symptoms.Moreover, we provide some evidence that bodyplethys-mographic measurements and diffusion testing is usefulto decide whether a patient has COPD when spirometryresults are indifferent. Maybe it is time to realize thatthe definition of COPD needs to include some ‘clinicalitems’, as nearly all definitions of diseases in medicine in-clude clinical aspects of patients.Author details1Department of Pulmonary Diseases and Department of Paediatrics, ErasmusMedical Centre, Erasmus University, Rotterdam, the Netherlands.2Department of Internal Medicine, New Haven, CT, USA, and Veterans Affairs(VA) Clinical Epidemiology Research Center, Yale University School ofMedicine, West Haven, CT, USA. 3Institute of Occupational and EnvironmentalMedicine, University of Birmingham, Birmingham, UK. 4Julius Center forHealth Sciences and Primary Care, University Medical Center Utrecht, Utrecht,The Netherlands. 5Comprehensive Heart Failure Center, Department ofInternal Medicine I, University Würzburg, Würzburg, Germany.Received: 2 April 2012 Accepted: 5 July 2012Published: 26 July 2012References1. Güder G, Brenner S, Angermann CE, Ertl G, Held M, Sachs AP, Lammers J,Zanen P, Hoes AW, Stork S, Rutten FH: GOLD or lower limit of normalQuanjer et al. Respiratory Research 2012, 13:61 Page 2 of 3http://respiratory-research.com/content/13/1/61definition? A comparison with expert-based diagnosis of chronicobstructive pulmonary disease in a prospective cohort-study. Respir Res2012, 13:13.2. Sobol BJ: Assessment of ventilatory abnormality in the asymptomaticsubject: an exercise in futility. Thorax 1966, 21:445–449.3. Sobol BJ, Sobol PG: Percent of predicted as the limit of normal inpulmonary function testing: a statistically valid approach. Thorax 1979,34:1–3.4. Miller MR, Pincock AC: Predicted values: how should we use them? Thorax1988, 43:265–267.5. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC:Lung volumes and forced ventilatory flows. Report Working PartyStandardization of Lung Function Tests, European Community for Steeland Coal. Official Statement of the European Respiratory Society.Eur Respir J 1993, 6(suppl 16):5–40.6. Stanojevic S, Wade A, Stocks J, Hankinson J, Coates AL, Pan H, Rosenthal M,Corey M, Lebecque P, Cole TJ: Reference ranges for spirometry across allages: a new approach. Am J Respir Crit Care Med 2008, 177:253–260.7. Olofson J, Bake B, Tengelin MN, Houltz B: COPD 'diagnosis’ based onspirometric reference equations. Clin Respir J 2008, 2(4):214–219.8. Marks GB: Are reference equations for spirometry an appropriatecriterion for diagnosing disease and predicting prognosis? Thorax 2012,67:85–87.doi:10.1186/1465-9921-13-61Cite this article as: Quanjer et al.: GOLD or lower limit of normaldefinition? a letter and authors’ response. Respiratory Research 2012 13:61.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitQuanjer et al. Respiratory Research 2012, 13:61 Page 3 of 3http://respiratory-research.com/content/13/1/61

Undetermined

Philip Quanjer

Carlos A Fragoso

Martin R Miller

Gülmisal Güder

Stefan Störk

Arno W Hoes

Frans Rutten

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