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Cost-effectiveness of implementing objective diagnostic verification of asthma in the United States

Open AccessPublished:December 11, 2019DOI:https://doi.org/10.1016/j.jaci.2019.11.038

      Background

      Asthma diagnosis in the community is often made without objective testing.

      Objective

      The aim of this study was to evaluate the cost-effectiveness of implementing a stepwise objective diagnostic verification algorithm among patients with community-diagnosed asthma in the United States.

      Methods

      We developed a probabilistic time-in-state cohort model that compared a stepwise asthma verification algorithm on the basis of spirometry testing and a methacholine challenge test against the current standard of care over 20 years. Model input parameters were informed from the literature and with original data analyses when required. The target population was US adults (≥15 years old) with physician-diagnosed asthma. The final outcomes were costs (in 2018 dollars) and quality-adjusted life years (QALYs), discounted at 3% annually. Deterministic and probabilistic analyses were undertaken to examine the effect of alternative assumptions and uncertainty in model parameters on the results.

      Results

      In a simulated cohort of 10,000 adults with diagnosed asthma, the stepwise algorithm resulted in removal of the diagnosis of 3,366. This was projected to be associated with savings of $36.26 million in direct costs and a gain of 4,049.28 QALYs over 20 years. Extrapolating these results to the US population indicated an undiscounted potential savings of $56.48 billion over 20 years. The results were robust against alternative assumptions and plausible changes in values of input parameters.

      Conclusion

      Implementation of a simple diagnostic testing algorithm to verify asthma diagnosis might result in substantial savings and improvement in patients’ quality of life.

      Key words

      Abbreviations used:

      ICS (Inhaled corticosteroids), LTRA (Leukotriene receptor antagonist therapy), MCT (Methacholine challenge test (bronchoprovocation test)), MEPs (Medical Expenditure Panel Survey), QALY (Quality-adjusted life years)
      Asthma is a common chronic respiratory disease, globally and in the United States.
      • Nunes C.
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      • Morais-Almeida M.
      Asthma costs and social impact.
      According to the US Centers for Disease Control and Prevention, asthma prevalence continues to rise; the age-standardized prevalence increased by 1.5% per year since 2001, reaching 8.4% in 2010.
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      • et al.
      National surveillance of asthma: United States, 2001-2010.
      There are approximately 11 million patients with physician-diagnosed asthma in the US,
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      and the total cost of asthma in the US was estimated to be $81.9 billion in 2013.
      • Nurmagambetov T.
      • Kuwahara R.
      • Garbe P.
      The economic burden of asthma in the United States, 2008-2013.
      The annual incremental direct medical costs of adult asthma were reported to be $3,266 per patient per year (in 2016 dollars).
      • Nurmagambetov T.
      • Kuwahara R.
      • Garbe P.
      The economic burden of asthma in the United States, 2008-2013.
      Evidence-based guidelines recommend that the diagnosis of asthma be made on the basis of objective testing for reversible airflow obstruction or variability in lung function.
      Global Initiative for Asthma (GINA)
      Global Strategy for Asthma Management and Prevention.
      In some patients spirometry testing may be inconclusive; such patients may require provocative testing to document the presence of airway hyperresponsiveness. In reality, for many Americans, the diagnosis of asthma is made on clinical grounds alone.
      • Sokol K.C.
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      • Lin Y.-L.
      • Goldblum R.M.
      Choosing wisely: adherence by physicians to recommended use of spirometry in the diagnosis and management of adult asthma.
      ,
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      • Panettieri R.A.
      Attitudes of physicians toward objective measures of airway function in asthma.
      This approach can be inaccurate and can result in labeling individuals with asthma who otherwise have occasional respiratory symptoms without airflow obstruction. In addition, many patients with asthma experience spontaneous clinical remission.
      ScienceDaily
      Asthma not found in high percentage of adults who were previously diagnosed.
      Although the underlying inflammatory process can remain active, such patients may not experience symptoms of asthma for long periods of time even if they discontinue their therapies.
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      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
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      Because of these factors, a significant proportion of asthmatic patients in the community might be inappropriately treated. In a multicenter, population-based prospective Canadian cohort study, Aaron et al followed 613 participants who reported a physician diagnosis of asthma within the previous 5 years and applied an objective algorithm to verify the existing asthma diagnosis. They found that more than 30% of participants could have their current diagnosis of asthma ruled out and safely discontinue their medications.
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      Extrapolating these figures to the US indicates that there are potentially more than 3 million adults with an overdiagnosis of asthma. As such, the economic burden of overdiagnosed asthma warrants attention. Medication costs are the largest component of the direct economic burden of asthma, contributing to more than half of the disease-related costs.
      • Nurmagambetov T.
      • Kuwahara R.
      • Garbe P.
      The economic burden of asthma in the United States, 2008-2013.
      Patients with misdiagnosed asthma will incur these costs without gaining benefit and are subject to harm owing to the adverse effects of therapy as well as to the lost opportunity to appropriately treat other health conditions that might be responsible for their symptoms.
      In this context, a pressing public health question is whether a secondary verification of asthma diagnosis can be considered an efficient use of health care resources. A previous study on the economic impact of asthma screening strategies was limited to assessing asthma-related cost savings from implementing a secondary screening program in Canada.
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      • Sumner A.
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      • Vandemheen K.
      • Aaron S.
      (Correcting) misdiagnoses of asthma: a cost effectiveness analysis.
      This study did not evaluate the effects on health outcomes, such as asthma control and quality of life.
      The purpose of the current study was to evaluate the cost-effectiveness of objective diagnostic testing for asthma among previously diagnosed adults in the US. We calculated the incremental average costs and quality-adjusted life years (QALYs) associated with the implementation of objective diagnostic testing. We extrapolated the results to the entire population of US adults with asthma to evaluate the population-level impact of implementing such a strategy.

      Methods

      In reporting on the study’s methodology and results we followed the Consolidated Health Economic Evaluation Reporting Standards.
      • Husereau D.
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      • Carswell C.
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      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.
      The target population for this cost-effectiveness analysis was US adults (≥15 years old) with self-reported physician-diagnosed asthma. The diagnostic verification was assumed to have been conducted during routine outpatient encounters (eg, during a scheduled follow-up visit). The main outcomes of the analysis were the incremental costs and QALYs associated with the use of diagnostic verification, compared with the current standard of care (status quo [no further verification of diagnosed asthma]). We adopted a third-party payer’s perspective (eg, a health maintenance organization) in the main analysis and a societal perspective in a secondary analysis. The time horizon was 20 years, and costs and QALYs were discounted at the rate of 3% on the basis of recommendations of the US Panel on Cost-Effectiveness in Health and Medicine.
      • Weinstein M.C.
      • Siegel J.E.
      • Gold M.R.
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      Recommendations of the Panel on Cost-effectiveness in Health and Medicine.

       The intervention

      The comparator, the status quo, was the continuation of asthma management without any further evaluation of diagnosis. The intervention was defined as a 2-stage diagnostic verification algorithm, as illustrated in Fig 1. In accordance with care standards set by the Global Initiative for Asthma,
      • Weiler J.M.
      • Brannan J.D.
      • Randolph C.C.
      • Hallstrand T.S.
      • Parsons J.
      • Silvers W.
      • et al.
      Exercise-induced bronchoconstriction update-2016.
      the first step is spirometry with reversibility testing before and after inhaled bronchodilation. Asthma is verified in this step if the FEV1 improves by at least 12% and 200 milliliters.
      • Weiler J.M.
      • Brannan J.D.
      • Randolph C.C.
      • Hallstrand T.S.
      • Parsons J.
      • Silvers W.
      • et al.
      Exercise-induced bronchoconstriction update-2016.
      Those who do not exhibit reversible airflow obstruction undergo a single methacholine challenge test (MCT) at a second visit. Individuals whose FEV1 decreases by 20% or more after breathing up to 8 mg/mL of methacholine (in a stepwise fashion based on doubling of the methacholine dose) are considered to have their asthma confirmed. Individuals whose MCT result is negative are considered to have had their asthma ruled out, and it was assumed that their asthma-related medications could be tapered off. The use of 1 MCT, as opposed to up to 3 MCTs implemented in the research context, was considered to be the most realistic scenario for clinical practice.
      Figure thumbnail gr1
      Fig 1Algorithm for stepwise asthma verification testing.

       Modeling approach

      We constructed a decision tree to model the diagnostic steps and a time-in-state model to follow individuals at terminal branches of the tree over the analysis’ time horizon in annual cycles. The model stratified US adults (≥15 years old) with diagnosed asthma into age (with 5-year intervals) and sex groups. A schematic illustration of the decision tree, with point estimates of branch probabilities, is provided in Fig 2. The major input parameters for the model are provided in Table I.
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      ,
      • Nurmagambetov T.
      • Kuwahara R.
      • Garbe P.
      The economic burden of asthma in the United States, 2008-2013.
      ,
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      ,
      Centers for Disease Control and Prevention
      National Center for Health Statistics. Products. Life tables homepage.
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      • Suruki R.Y.
      • Daugherty J.B.
      • Boudiaf N.
      • Albers F.C.
      The frequency of asthma exacerbations and healthcare utilization in patients with asthma from the UK and USA.
      • Zafari Z.
      • Sadatsafavi M.
      • Marra C.A.
      • Chen W.
      • FitzGerald J.M.
      Cost-effectiveness of bronchial thermoplasty, omalizumab, and standard therapy for moderate-to-severe allergic asthma.
      • Torrego A.
      • Solà I.
      • Munoz A.M.
      • Roqué I Figuls M.
      • Yepes-Nuñez J.J.
      • Alonso-Coello P.
      • et al.
      Bronchial thermoplasty for moderate or severe persistent asthma in adults.
      • Castro M.
      • Rubin A.S.
      • Laviolette M.
      • Fiterman J.
      • De Andrade Lima M.
      • Shah P.L.
      • et al.
      Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.
      • Williams L.K.
      • Pladevall M.
      • Xi H.
      • Peterson E.L.
      • Joseph C.
      • Lafata J.E.
      • et al.
      Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma.
      • Wu A.C.
      • Butler M.G.
      • Li L.
      • Fung V.
      • Kharbanda E.O.
      • Larkin E.K.
      • et al.
      Primary adherence to controller medications for asthma is poor.
      • Chauhan B.F.
      • Ducharme F.M.
      Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children.
      • Bansal V.
      • Mangi M.A.
      • Johnson M.M.
      • Festic E.
      Inhaled corticosteroids and incident pneumonia in patients with asthma: systematic review and meta-analysis.
      • Campbell J.D.
      • Spackman D.E.
      • Sullivan S.D.
      The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective.
      • Park H.
      • Adeyemi A.O.
      • Rascati K.L.
      Direct medical costs and utilization of health care services to treat pneumonia in the United States: an analysis of the 2007-2011 Medical Expenditure Panel Survey.
      American Thoracic Society
      ATS coding & billing quarterly.
      US Department of Health and Human Services
      Agency for Healthcare Research and Quality. Statistical brief 517: Expenses for office-based physician visits by specialty and insurance type, 2016.
      • Cisternas M.G.
      • Blanc P.D.
      • Yen I.H.
      • Katz P.P.
      • Earnest G.
      • Eisner M.D.
      • et al.
      A comprehensive study of the direct and indirect costs of adult asthma.
      • Kleinman N.L.
      • Yu H.
      • Beren I.A.
      • Sato R.
      Work-related and health care cost burden of community-acquired pneumonia in an employed population.
      Agency for Healthcare Research and Quality
      Medical Expenditure Panel Survey home page.
      • Lee L.K.
      • Obi E.
      • Paknis B.
      • Kavati A.
      • Chipps B.
      Asthma control and disease burden in patients with asthma and allergic comorbidities.
      • Lloyd A.
      • Price D.
      • Brown R.
      The impact of asthma exacerbations on health-related quality of life in moderate to severe asthma patients in the UK.
      • Andrade L.F.
      • Saba G.
      • Ricard J.-D.
      • Messika J.
      • Gaillat J.
      • Bonnin P.
      • et al.
      Health related quality of life in patients with community-acquired pneumococcal pneumonia in France.
      • Fryback D.G.
      • Dunham N.C.
      • Palta M.
      • Hanmer J.
      • Buechner J.
      • Cherepanov D.
      • et al.
      U.S. norms for six generic health-related quality-of- life indexes from The National Health Measurement Study.
      United States Census Bureau
      Population projections.
      Figure thumbnail gr2
      Fig 2Decision tree combined with an open population time-in-state model. Model used for evaluating costs and health-related outcomes of an asthma verification national program compared with the status quo.
      Table IInput parameters
      ItemParametersValueSDDistributionSource
      Epidemiologic parameters and proportions of the population in the submodels
      Background mortality in the US across age and sexUS life table
      Centers for Disease Control and Prevention
      National Center for Health Statistics. Products. Life tables homepage.
      Proportion of individuals with positive spirometry testing0.15Beta (86, 527)
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      Proportion of individuals with positive MCT result0.56Beta (297, 230)
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      Proportion of individuals with negative MCT who have asthma0.10Beta (38, 344)
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      Proportion of individuals with a current diagnosis of asthma who do not actually have asthma0.33Beta (203, 410)
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      Distribution of asthma control and other risk factors
      Association between asthma control and age/sex
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      Well controlled (vs very poorly controlled)
       OR for age1.091.23Log-normal
       OR for sex (female vs male)0.741.32
      Not well controlled (vs very poorly controlled)
       OR for age0.991.28
       OR for sex (female vs male)1.101.47Log-normal
      Association between asthma control and asthma reassessment method (reference, asthma verifiable by 1 spirometry)
       OR for asthma that is verifiable by 1 MCT2.310.44
       OR for asthma that cannot be verified by 1 MCT2.360.45Log-normalAnalysis of data from the Economic Burden of Asthma Study (see this article's Online Repository at jacionline.org)
      Mean annual exacerbation rate per patient year (poorly controlled)1.020.081Normal
      • Suruki R.Y.
      • Daugherty J.B.
      • Boudiaf N.
      • Albers F.C.
      The frequency of asthma exacerbations and healthcare utilization in patients with asthma from the UK and USA.
      Mean annual exacerbation rate per patient year (controlled)0.150.002Normal
      • Suruki R.Y.
      • Daugherty J.B.
      • Boudiaf N.
      • Albers F.C.
      The frequency of asthma exacerbations and healthcare utilization in patients with asthma from the UK and USA.
      Relative frequency of exacerbation by severity
      • Zafari Z.
      • Sadatsafavi M.
      • Marra C.A.
      • Chen W.
      • FitzGerald J.M.
      Cost-effectiveness of bronchial thermoplasty, omalizumab, and standard therapy for moderate-to-severe allergic asthma.
      • Torrego A.
      • Solà I.
      • Munoz A.M.
      • Roqué I Figuls M.
      • Yepes-Nuñez J.J.
      • Alonso-Coello P.
      • et al.
      Bronchial thermoplasty for moderate or severe persistent asthma in adults.
      • Castro M.
      • Rubin A.S.
      • Laviolette M.
      • Fiterman J.
      • De Andrade Lima M.
      • Shah P.L.
      • et al.
      Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.
       Mild0.48Log-normal (–0.73, 0.09)
       Moderate0.19Log-normal (–1.64, 0.12)
       Severe0.30Log-normal (–1.21, 0.14)
      Proportion of patients taking ICS0.51
      • Williams L.K.
      • Pladevall M.
      • Xi H.
      • Peterson E.L.
      • Joseph C.
      • Lafata J.E.
      • et al.
      Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma.
      Ratio of patients taking LTRA to those taking ICS0.05
      • Wu A.C.
      • Butler M.G.
      • Li L.
      • Fung V.
      • Kharbanda E.O.
      • Larkin E.K.
      • et al.
      Primary adherence to controller medications for asthma is poor.
      Relative risk of exacerbation associated with 25% decrease in ICS use1.260.18Log-Normal
      • Williams L.K.
      • Pladevall M.
      • Xi H.
      • Peterson E.L.
      • Joseph C.
      • Lafata J.E.
      • et al.
      Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma.
      Relative risk of exacerbation associated with LRTA use vs ICS use1.510.20Log-Normal
      • Chauhan B.F.
      • Ducharme F.M.
      Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children.
      Risk of pneumonia with an ICS
      To model reduction in quality of life, we assumed that mild exacerbations last 1 week on average, whereas moderate or severe exacerbations last 2 weeks on average.
      in patients with asthma
      0.22Beta (3,517, 12,286)
      • Bansal V.
      • Mangi M.A.
      • Johnson M.M.
      • Festic E.
      Inhaled corticosteroids and incident pneumonia in patients with asthma: systematic review and meta-analysis.
      Risk of pneumonia without an ICS in patients with asthma0.13Beta (3,733, 24,480)
      • Bansal V.
      • Mangi M.A.
      • Johnson M.M.
      • Festic E.
      Inhaled corticosteroids and incident pneumonia in patients with asthma: systematic review and meta-analysis.
      Prevalence of major alternative diagnoses among individuals in whom asthma was ruled out
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
       Coronary heart disease1.9%
       Allergic rhinitis25.3%
       Gastroesophageal reflux disease8.5%
       Anxiety3.8%
       Acute bronchitis2.8%
       COPD1.9%
      Pneumonia death rate (per 100,000)15.10Global Burden of Disease
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      Sever exacerbation death rate (per 100,000)See the text and Table E1 in this article's Online Repository at jacionline.orgGlobal Burden of Diseases
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      Hearth disease death rate (per 100,000)164.13Global Burden of Diseases
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      COPD death rate (per 100,000)52.12Global Burden of Diseases
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      Cost and utility parameters
      Annual direct costs of well-controlled asthma2,372458Normal
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      Annual direct costs of not–well-controlled asthma2,965211Normal
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      Annual direct costs of uncontrolled asthma3,127268Normal
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      Direct costs of exacerbation by severity
      • Zafari Z.
      • Sadatsafavi M.
      • Marra C.A.
      • Chen W.
      • FitzGerald J.M.
      Cost-effectiveness of bronchial thermoplasty, omalizumab, and standard therapy for moderate-to-severe allergic asthma.
      ,
      • Campbell J.D.
      • Spackman D.E.
      • Sullivan S.D.
      The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective.
       Mild130Gamma (100,0.77)
       Moderate594Gamma (98.01,0.17)
       Severe9900Gamma (100.08,0.01)
      Direct costs of pneumonia5,006520Normal
      • Park H.
      • Adeyemi A.O.
      • Rascati K.L.
      Direct medical costs and utilization of health care services to treat pneumonia in the United States: an analysis of the 2007-2011 Medical Expenditure Panel Survey.
      Annual costs of asthma medications1,938214.8Normal
      • Nurmagambetov T.
      • Kuwahara R.
      • Garbe P.
      The economic burden of asthma in the United States, 2008-2013.
      Cost of spirometry (with reversibility)248Fixed
      American Thoracic Society
      ATS coding & billing quarterly.
      Cost of MCT444Fixed
      American Thoracic Society
      ATS coding & billing quarterly.
      Cost of office-based general practitioner visit26566.3Normal
      US Department of Health and Human Services
      Agency for Healthcare Research and Quality. Statistical brief 517: Expenses for office-based physician visits by specialty and insurance type, 2016.
      Annual indirect costs of well-controlled asthma2,666
      • Cisternas M.G.
      • Blanc P.D.
      • Yen I.H.
      • Katz P.P.
      • Earnest G.
      • Eisner M.D.
      • et al.
      A comprehensive study of the direct and indirect costs of adult asthma.
      Annual indirect costs of not–well-controlled asthma3,206389Normal
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      Annual indirect costs of uncontrolled asthma3,608496Normal
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      First-year costs of alternative diagnosesMedical Expenditure Panel Survey
      Agency for Healthcare Research and Quality
      Medical Expenditure Panel Survey home page.
      (See this article's Online Repository at jacionline.org)
       Coronary heart disease19,506
       Allergic rhinitis6,202
       Gastroesophageal reflux disease14,797
       Anxiety9,917
       Acute bronchitis12,456
       COPD22,520
      Utility of well-controlled asthma0.700.04Normal
      • Lee L.K.
      • Obi E.
      • Paknis B.
      • Kavati A.
      • Chipps B.
      Asthma control and disease burden in patients with asthma and allergic comorbidities.
      Utility of non–well-controlled asthma0.660.05Normal
      • Lee L.K.
      • Obi E.
      • Paknis B.
      • Kavati A.
      • Chipps B.
      Asthma control and disease burden in patients with asthma and allergic comorbidities.
      Utility of uncontrolled asthma0.610.05Normal
      • Lee L.K.
      • Obi E.
      • Paknis B.
      • Kavati A.
      • Chipps B.
      Asthma control and disease burden in patients with asthma and allergic comorbidities.
      Utility of exacerbation by severity
      To model reduction in quality of life, we assumed that mild exacerbations last 1 week on average, whereas moderate or severe exacerbations last 2 weeks on average.
      • Zafari Z.
      • Sadatsafavi M.
      • Marra C.A.
      • Chen W.
      • FitzGerald J.M.
      Cost-effectiveness of bronchial thermoplasty, omalizumab, and standard therapy for moderate-to-severe allergic asthma.
      ,
      • Campbell J.D.
      • Spackman D.E.
      • Sullivan S.D.
      The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective.
      ,
      • Lloyd A.
      • Price D.
      • Brown R.
      The impact of asthma exacerbations on health-related quality of life in moderate to severe asthma patients in the UK.
       Mild0.57Beta (23.57,17.78)
       Moderate0.45Beta (17.59,22.39)
       Severe0.33Beta (2.32,4.72)
      Utility of pneumonia in men0.630.31Normal
      • Andrade L.F.
      • Saba G.
      • Ricard J.-D.
      • Messika J.
      • Gaillat J.
      • Bonnin P.
      • et al.
      Health related quality of life in patients with community-acquired pneumococcal pneumonia in France.
      Utility of pneumonia in women0.580.33Normal
      • Andrade L.F.
      • Saba G.
      • Ricard J.-D.
      • Messika J.
      • Gaillat J.
      • Bonnin P.
      • et al.
      Health related quality of life in patients with community-acquired pneumococcal pneumonia in France.
      Mean utility of US adults by sex and age
      • Fryback D.G.
      • Dunham N.C.
      • Palta M.
      • Hanmer J.
      • Buechner J.
      • Cherepanov D.
      • et al.
      U.S. norms for six generic health-related quality-of- life indexes from The National Health Measurement Study.
       Male, 15-44 y0.810.01Normal
       Male, 45-74 y0.800.01Normal
       Male, 75-89 y0.770.01Normal
       Female, 15-44 y0.800.01Normal
       Female, 45-74 y0.770.01Normal
       Female, 75-89 y0.750.01Normal
      Parameters pertaining to the extrapolation of results to the entire US population
      US adult population size in 2018266,861,858
      United States Census Bureau
      Population projections.
      Prevalence of asthma in US across age and sexSee the text and Table E2 in this article's Online Repository at jacionline.org
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      COPD, Chronic obstructive pulmonary disease; OR, odds ratio.
      To model reduction in quality of life, we assumed that mild exacerbations last 1 week on average, whereas moderate or severe exacerbations last 2 weeks on average.
      The proportion of individuals at each branch of the decision tree was directly taken from the population-based study by Aaron et al.
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      In the status quo scenario, 33% of individuals were assumed to not have asthma. These are the individuals who responded negatively to spirometry testing and 3 subsequent MCTs in the aforementioned study. Given that there would be no verification of diagnosis, these individuals remained "overdiagnosed" throughout the time horizon of the study (and as such, continued to be treated for asthma) under the status quo strategy.
      In the diagnostic verification scenario, 15% of patients would have their asthma confirmed through a positive spirometry test result; of the remaining patients, 48% would have their asthma confirmed through a positive MCT result. A diagnosis of asthma in individuals with a negative spirometry test result and a negative MCT result would be considered to have been ruled out and these individuals would be advised to taper their medications. In the study by Aaron et al,
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      in 10% of such individuals the asthma diagnosis was later confirmed with a positive result of a second or third MCT, after tapering of controller medications (Table I). This figure is similar to that in the study by Luks et al
      • Luks V.P.
      • Vandemheen K.L.
      • Aaron S.D.
      Confirmation of asthma in an era of overdiagnosis.
      (9%) and reflects the imperfect sensitivity of the MCT, especially when the patient is receiving asthma medications.
      • Luks V.P.
      • Vandemheen K.L.
      • Aaron S.D.
      Confirmation of asthma in an era of overdiagnosis.
      ,
      • Sumino K.
      • Sugar E.A.
      • Irvin C.G.
      • Kaminsky D.A.
      • Shade D.
      • Wei C.Y.
      • et al.
      Methacholine challenge test: diagnostic characteristics in asthmatic patients receiving controller medications.
      Given that only 1 MCT is modeled in the diagnostic verification scenario in the present study, such individuals constitute the false-negative subgroup (those in whom an asthma diagnosis was erroneously reversed), with the rest of individuals under this branch of the decision tree constituting the "true negative" subgroup (Fig 2). Compared with their counterparts in the status quo scenario, individuals in the false-negative asthma subgroup would cease their controller medication and as such, would generally have worse asthma control.

       Modeling asthma status over time

      At terminal branches of the decision tree, each of these subpopulations was linked to its corresponding time-in-state model. Such models simulated the transition of a sex- and age-stratified population across mutually exclusive health states. For individuals with either true asthma or misdiagnosed asthma (the true positive and false-negative subgroups in Fig 2), the model contained 3 states pertaining to the 3 levels of asthma control that were assigned, in addition to a state representing death. The distribution of levels of asthma control within a given sex and age group was derived by using calibration techniques from a recent study based on the US National Health and Wellness Survey, as described in our previous work
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      ,
      • Lee L.K.
      • Obi E.
      • Paknis B.
      • Kavati A.
      • Chipps B.
      Asthma control and disease burden in patients with asthma and allergic comorbidities.
      (for more the information on the distribution of asthma control, see this article’s Online Repository at www.jacionline.org). The levels of asthma control were defined on the basis of the results of the Asthma Control Test. This test classifies a patient’s asthma status as poorly controlled (scores ≤15), not well controlled (score 16-19), or well controlled (score 20-25).
      • Nathan R.A.
      • Sorkness C.A.
      • Kosinski M.
      • Schatz M.
      • Li J.T.
      • Marcus P.
      • et al.
      Development of the asthma control test: a survey for assessing asthma control.
      In addition to asthma control, we modeled asthma exacerbations for individuals with true asthma as an event that is likely to be affected by controller therapy (for more the information on modeling asthma exacerbation, see this article’s Online Repository at www.jacionline.org). On the other hand, in the subgroup with true negative and false-positive asthma, the model consisted of only 2 states: alive and dead. Aside from mortality due to severe exacerbations, the probability of transitioning to death for all populations was equal to the age- and sex-specific background mortality rates, derived from the US life tables.
      Centers for Disease Control and Prevention
      National Center for Health Statistics. Products. Life tables homepage.
      It is likely that the degree of airway reactivity is an independent determinant of asthma control. As such, the distribution of asthma control levels can be different among individuals in whom asthma can be confirmed by using spirometry testing, those in whom asthma verification requires an MCT, and those who have asthma but do not display reversibility or have a positive MCT result. To elucidate such potential differences, we used data from the Economic Burden of Asthma study.
      University of British Columbia
      Economic burden of asthma (EBA).
      This longitudinal study used population-based sampling and followed 622 adult individuals with physician-diagnosed asthma over 1 year. Asthma status was verified with 1 prebronchodilator and 1 postbronchodilator spirometry measurement and 1 MCT (similar to the protocol evaluated in this study). Asthma control was verified at baseline and during each of the follow-up visits every 3 months. Using these data, we constructed a generalized linear model (with multinomial distribution and cumulative logit link) to estimate the odds of having controlled asthma versus the odds of having uncontrolled asthma, as well as the odds of having partially controlled asthma versus uncontrolled asthma, among the 3 aforementioned groups. The exposure was asthma verification status (response to spirometry testing, response to an MCT, or no response to spirometry testing and an MCT). The model was adjusted for sex, age at baseline, and whether the individual used any controller medication in the 12 months before the study began (see Table E1 of this article’s Online Repository at www.jacionline.org for distribution of asthma control).

       Modeling asthma treatment

      A major benefit of the objective diagnostic verification would be the removal of asthma therapies in patients who do not need them. We modeled the utilization and short-term effects of inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs), namely, in terms of improving asthma control and reducing exacerbation rates. We assumed that 51% of diagnosed patients with asthma were receiving maintenance ICS therapy at any given time,
      • Williams L.K.
      • Pladevall M.
      • Xi H.
      • Peterson E.L.
      • Joseph C.
      • Lafata J.E.
      • et al.
      Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma.
      whereas an additional 5% were taking LTRAs.
      • Wu A.C.
      • Butler M.G.
      • Li L.
      • Fung V.
      • Kharbanda E.O.
      • Larkin E.K.
      • et al.
      Primary adherence to controller medications for asthma is poor.
      The use of reliever (rescue) medications was not directly modeled, as their costs are embedded within the costs assigned to each control level, and it was assumed that their use would not have any direct impact on asthma control. To model the association between the use of controller medications and asthma control, we used the indirect evidence on the effect of ICS or LTRA use and asthma exacerbations, as performed in our previous modeling studies.
      • Williams L.K.
      • Pladevall M.
      • Xi H.
      • Peterson E.L.
      • Joseph C.
      • Lafata J.E.
      • et al.
      Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma.
      ,
      • Chauhan B.F.
      • Ducharme F.M.
      Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children.
      ,
      • Zafari Z.
      • Lynd L.D.
      • FitzGerald J.M.
      • Sadatsafavi M.
      Economic and health effect of full adherence to controller therapy in adults with uncontrolled asthma: a simulation study.
      We did not include the longer-term adverse events associated with controller medications, but in a sensitivity analysis we modeled the increased risk of acute pneumonia as an adverse effect of ICS.
      • Bansal V.
      • Mangi M.A.
      • Johnson M.M.
      • Festic E.
      Inhaled corticosteroids and incident pneumonia in patients with asthma: systematic review and meta-analysis.

       Costs

      Details on the cost parameters are provided in Table I. In the base case analysis, costs included the cost of stepwise asthma verification testing, controller medication costs, direct asthma-attributable costs across levels of control, and direct medical costs resulting from asthma exacerbations. The costs of spirometry testing and the MCT were derived from American Thoracic Society Coding and Billing Quarterly
      American Thoracic Society
      ATS coding & billing quarterly.
      for hospital-based lung function testing. In the intervention scenario, we assumed that interpreting the results of spirometry testing and an MCT would each require 1 additional physician visit. The costs of an office-based physician visit were derived from the Medical Expenditure Panel Survey (MEPS) on the basis of average expenses per visit, assuming the mixture of general practitioner and specialist visits as observed in the MEPS data.
      US Department of Health and Human Services
      Agency for Healthcare Research and Quality. Statistical brief 517: Expenses for office-based physician visits by specialty and insurance type, 2016.
      In a sensitivity analysis, we varied these costs across the entire range of speciality types to cover scenarios that are based on general practitioner or specialist management only. Annual per-person direct medical costs of asthma (including health care provider visits, emergency visits, hospitalizations, and medication use) across levels of control (not including exacerbation costs or costs of controller use, as they were explicitly modeled) were derived from our previous work.
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      The costs of exacerbations were obtained from the literature.
      • Zafari Z.
      • Sadatsafavi M.
      • Marra C.A.
      • Chen W.
      • FitzGerald J.M.
      Cost-effectiveness of bronchial thermoplasty, omalizumab, and standard therapy for moderate-to-severe allergic asthma.
      ,
      • Campbell J.D.
      • Spackman D.E.
      • Sullivan S.D.
      The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective.
      All costs were adjusted to 2018 US dollars by using historical inflation rates.
      US Inflation Calculator
      US Inflation Calculator.
      In the base case analysis we excluded indirect costs on the basis of the recommendation of the US Panel on Cost-Effectiveness in Health and Medicine.
      • Weinstein M.C.
      • Siegel J.E.
      • Gold M.R.
      • Kamlet M.S.
      • Russell L.B.
      Recommendations of the Panel on Cost-effectiveness in Health and Medicine.
      In a scenario analysis, we adopted a societal perspective and included costs due to asthma-related productivity loss (indirect costs). Indirect costs due to suboptimal asthma control were derived from multiple sources.
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      ,
      • Cisternas M.G.
      • Blanc P.D.
      • Yen I.H.
      • Katz P.P.
      • Earnest G.
      • Eisner M.D.
      • et al.
      A comprehensive study of the direct and indirect costs of adult asthma.
      ,
      • Kleinman N.L.
      • Yu H.
      • Beren I.A.
      • Sato R.
      Work-related and health care cost burden of community-acquired pneumonia in an employed population.
      These included costs due to total cessation of work as well as loss of work time. Indirect costs per level of control included loss of productivity due to exacerbations. In the base case analysis, we did not include the costs of workup required for alternative diagnoses when the asthma diagnosis was reversed. However, in a sensitivity analysis, we considered the first-year costs of 6 common and major alternative diagnoses, as reported by Aaron et al.
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      These costs were derived from a dedicated analysis of 2017 MEPS data (details are provided in this article’s Online Repository at www.jacionline.org).

       Health state utility values

      The health state utility values (utilities) associated with asthma across levels of control were derived from a study conducted on the basis of the 2011-2013 US National Health and Wellness Survey.
      • Lee L.K.
      • Obi E.
      • Paknis B.
      • Kavati A.
      • Chipps B.
      Asthma control and disease burden in patients with asthma and allergic comorbidities.
      We assigned US-specific general population utilities to individuals in whom asthma was ruled out.
      • Fryback D.G.
      • Dunham N.C.
      • Palta M.
      • Hanmer J.
      • Buechner J.
      • Cherepanov D.
      • et al.
      U.S. norms for six generic health-related quality-of- life indexes from The National Health Measurement Study.
      Utilities associated with different severities of exacerbation were derived from previous studies
      • Zafari Z.
      • Sadatsafavi M.
      • Marra C.A.
      • Chen W.
      • FitzGerald J.M.
      Cost-effectiveness of bronchial thermoplasty, omalizumab, and standard therapy for moderate-to-severe allergic asthma.
      ,
      • Campbell J.D.
      • Spackman D.E.
      • Sullivan S.D.
      The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective.
      ,
      • Lloyd A.
      • Price D.
      • Brown R.
      The impact of asthma exacerbations on health-related quality of life in moderate to severe asthma patients in the UK.
      (Table I).

       Analysis

      In the base case analysis, we ran the model separately in the intervention and status quo scenarios and estimated total discounted costs and QALYs over the 20-year time horizon. We standardized the results such that they pertained to the outcome of a hypothetical cohort of 10,000 representative individuals.
      Deterministic sensitivity and scenario analyses were conducted to investigate the impact of key parameter values and assumptions on the base case results. In addition, we performed 2 threshold analyses: 1 on the prevalence of asthma overdiagnosis and another on the first-year diagnostic and management costs of alternative diagnoses. These analyses identified the critical value of their respective parameters around which the overall findings on the cost-effectiveness of the intervention would change. To fully account for uncertainty in all parameters, probabilistic sensitivity analyses were conducted through Monte Carlo simulations. Uncertainty in each of the underlying parameters was characterized by assigning a probability distribution to the parameter, and the model was run 10,000 times; within each run, a new random value from each distribution was drawn and the results were recalculated. Cost-effectiveness was assessed by using willingness-to-pay thresholds of a willingness to pay of $50,000 per QALY.
      Furthermore, we extrapolated the result to the entire US asthma population, using the general methodology as described in our recent work estimating the burden of uncontrolled asthma in the US.
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      In summary, projections of US population by state were derived from the US Census Bureau, Population Division.
      United States Census Bureau
      Population projections.
      The prevalence of physician-diagnosed asthma stratified by age and sex was obtained from the Global Burden of Disease studies
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      (see Table E2, Table E3 in this article’s Online Repository at www.jacionline.org). The baseline year was 2019, and cumulative projections were made to 2038 (20 years).

      Results

      Table II provides the results of base case analysis for a cohort of 10,000 adults with physician-diagnosed asthma under the diagnostic verification versus status quo scenarios. In the diagnostic verification scenario, in 1,500 patients asthma diagnosis would be confirmed through spirometry testing alone. Among the 8,500 who would undergo a subsequent MCT, asthma diagnosis would be confirmed in 4,760. Asthma would be ruled out in the remaining 3,740 patients in whom the result of spirometry testing and the result of an MCT would be negative. In 374 of these patients, the asthma diagnosis would be erroneously reversed. The total costs of spirometry testing and an MCT in the diagnostic verification scenario would be $2,480,000 and $3,774,000, respectively.
      Table IIResults of cost-effectiveness analysis
      ItemInterventionStatus quoIncremental
      Total patients10,00010,0000
      No. of patients confirmed asthma by spirometry1,50001,500
      No. of patients confirmed asthma by an MCT
      The diagnostic verification scenario was associated with lower costs and higher QALYs.
      4,76004,760
      No. of erroneous rule-outs of asthma3740374
      No. of correct rule-outs of asthma3,36603,366
      Total no. of spirometry tests required10,000010,000
      Total no. of MCTs required8,50008,500
      Total patient-years across the stratum192,944192,9440
       Controlled79,40483,511–4,107
       Partially controlled23,82123,028792
       Uncontrolled27,49024,1763,314
       Asthma ruled out62,229062,229
       False-positive asthma while taking medication062,229–62,229
      Total no. of exacerbations by severity33,73632,1411,595
       Mild16,69415,905789
       Moderate6,6086,296312
       Severe10,4349,940493
      No. of patient-years on asthma medication62,90698,402-35,495
      Total cost of spirometry$2,480,0000$2,480,000
      Total cost of MCTs$3,774,0000$3,774,000
      Total cost of GP visit$4,902,5000$4,902,500
      Total cost of well-controlled asthma$144,570,236$152,046,117–7,475,881
      Total cost of non–well-controlled asthma$54,192,213$52,388,4301,803,783
      Total cost of poorly controlled asthma$65,958,334$58,005,5657,952,769
      Cost of medication in false-positive asthma0$49,850,476–$49,850,476
      Total cost of exacerbations$3,187,580$3,036,891$150,689
       Mild$31,937$30,427$1,510
       Moderate$115,525$110,063$5,461
       Severe$3,040,119$2,896,401$143,718
      Total costs$279,064,863$315,327,479–$36,262,616
      Total QALYs105,324.89101,275.614,049.28
      ICERDominant
      The diagnostic verification scenario was associated with lower costs and higher QALYs.
      ICER, Incremental cost-effectiveness ratio.
      The diagnostic verification scenario was associated with lower costs and higher QALYs.
      The total patient-years of asthma controller medication use would be 62,906 in the diagnostic verification and 98,402 in the status quo scenario. The total savings in medication costs would be $49.85 million. Under the diagnostic verification scenario, there would be an extra 3,314 patient-years with uncontrolled asthma compared with under the status quo scenario, and as a result there would be 1,595 more exacerbations. If these results were combined, for the diagnostic verification scenario, the total discounted costs and QALYs would be $279.06 million and 105,324, respectively. The corresponding values for the status quo scenario would be $315.32 million and 101,275. As such, implementation of the objective asthma verification algorithm would be associated with a $36.26 million reduction in direct costs and a gain of 4,049 in QALYs compared with the status quo over the next 20 years.

       Sensitivity and scenario analyses

      Fig 3 depicts change in incremental costs for different analyses. Diagnostic verification remained cost saving in all 1-way sensitivity analyses. Table III
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      • Pakhale S.
      • Sumner A.
      • Coyle D.
      • Vandemheen K.
      • Aaron S.
      (Correcting) misdiagnoses of asthma: a cost effectiveness analysis.
      • Bansal V.
      • Mangi M.A.
      • Johnson M.M.
      • Festic E.
      Inhaled corticosteroids and incident pneumonia in patients with asthma: systematic review and meta-analysis.
      • Park H.
      • Adeyemi A.O.
      • Rascati K.L.
      Direct medical costs and utilization of health care services to treat pneumonia in the United States: an analysis of the 2007-2011 Medical Expenditure Panel Survey.
      • Andrade L.F.
      • Saba G.
      • Ricard J.-D.
      • Messika J.
      • Gaillat J.
      • Bonnin P.
      • et al.
      Health related quality of life in patients with community-acquired pneumococcal pneumonia in France.
      presents the results of scenario analyses. Again, the overall conclusion remained the same when several alternative assumptions were explored. The threshold analysis indicated that when the proportion of falsely diagnosed cases to overall asthma cases was 6% or lower (compared with 33% in the main analysis), the diagnostic verification was no longer cost-saving. As well, the first-year costs of major alternative diagnoses had to be at least 3 times higher than their original estimates for the diagnostic intervention to not be cost-saving. The inclusion of indirect costs only slightly reduced the difference in costs between the 2 strategies, and diagnostic intervention remained dominant. Results of the probabilistic sensitivity analysis are provided in Fig 4. In more than 99% of all simulations, the intervention remained dominant.
      Figure thumbnail gr3
      Fig 3Results of deterministic 1-way sensitivity analyses.
      Table IIIResults of scenario analyses
      ScenarioIncremental costsIncremental QALYsICER
      Base case (reference analysis)–$36,262,6164,049.28Dominant
      10-y time horizon–$17,207,7552,428.53Dominant
      Including the increased risk of pneumonia due to ICS
      In this scenario we investigated increased risk of pneumonia. The probabilities of pneumonia according to ICS exposure were obtained from a recent systematic review and meta-analysis.25 Pneumonia-related death rate, direct costs of pneumonia, and utilities associated with pneumonia were derived from the literature3,27,35 (see Table I).
      –$47,159,4614,555.81Dominant
      Including indirect costs
      In this scenario we adopted a societal perspective by including costs due to loss of productivity.
      –$31,007,2904,049.28Dominant
      Modeling gradual rediagnosis of asthma in patients whose asthma was erroneously ruled out
      In this scenario we assumed that the individuals in whom asthma would be incorrectly ruled out would be rediagnosed over time (50% rediagnosis over 20 years) on account of unresolved symptoms and exacerbations after treatment withdrawal.
      –$36,772,8374,155.28Dominant
      Diagnostic verification implemented only among current ICS users
      We modeled a general decline in ICS use (from 100% in year 1 to 60% in year 20) derived from previous reports.12
      –$56,802,9294,049.28Dominant
      Including first-year costs of major alternative diagnoses
      We selected 6 major alternative diagnoses in patients in whom asthma was ruled out. See the text and Table I for details. We estimated the mean annual cost of first-time diagnosis for aforementioned diseases from the Medical Expenditure Panel Survey data for 2017.
      –$21,616,5524,049.28Dominant
      First-year costs of major alternative diagnoses
       Twice the base case–$7,088,1144,049.28Dominant
       3 times the base case$7,438,7834,049.281,837.06
      Proportion of asthma overdiagnosis (33% in the base case analysis)
       30%–$30,648,2553,554.1Dominant
       25%–$23,134,3982,893.3Dominant
       20%–$15,620,8792,232.5Dominant
       15%–$8,107,6951,571.8Dominant
       10%–$594,842911.0Dominant
       6%$1,411,089–628.0Dominated
      ICER, Incremental cost-effectiveness ratio.
      In this scenario we investigated increased risk of pneumonia. The probabilities of pneumonia according to ICS exposure were obtained from a recent systematic review and meta-analysis.
      • Bansal V.
      • Mangi M.A.
      • Johnson M.M.
      • Festic E.
      Inhaled corticosteroids and incident pneumonia in patients with asthma: systematic review and meta-analysis.
      Pneumonia-related death rate, direct costs of pneumonia, and utilities associated with pneumonia were derived from the literature
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      • Park H.
      • Adeyemi A.O.
      • Rascati K.L.
      Direct medical costs and utilization of health care services to treat pneumonia in the United States: an analysis of the 2007-2011 Medical Expenditure Panel Survey.
      • Andrade L.F.
      • Saba G.
      • Ricard J.-D.
      • Messika J.
      • Gaillat J.
      • Bonnin P.
      • et al.
      Health related quality of life in patients with community-acquired pneumococcal pneumonia in France.
      (see Table I).
      In this scenario we adopted a societal perspective by including costs due to loss of productivity.
      In this scenario we assumed that the individuals in whom asthma would be incorrectly ruled out would be rediagnosed over time (50% rediagnosis over 20 years) on account of unresolved symptoms and exacerbations after treatment withdrawal.
      § We modeled a general decline in ICS use (from 100% in year 1 to 60% in year 20) derived from previous reports.
      • Pakhale S.
      • Sumner A.
      • Coyle D.
      • Vandemheen K.
      • Aaron S.
      (Correcting) misdiagnoses of asthma: a cost effectiveness analysis.
      We selected 6 major alternative diagnoses in patients in whom asthma was ruled out. See the text and Table I for details. We estimated the mean annual cost of first-time diagnosis for aforementioned diseases from the Medical Expenditure Panel Survey data for 2017.
      Figure thumbnail gr4
      Fig 4Cost-effectiveness plan for a cohort of 10,000 individuals. ICER, Incremental cost-effectiveness ratio.

       Extrapolating the results to the entire US population

      In 2019, there will be 15.55 million adolescents and adults with asthma in the US; this value will increase by 13% by 2038. After the implementation of diagnostic verification algorithm, during the 2018-2038 period a diagnosis of asthma will be reversed in 70.29 million individuals. The total undiscounted cost saving in the intervention scenario versus in the status quo will be $56.48 billion, and there will be a cumulative gain in QALYs of 6.14 million (see the analysis by year for the entire US population in and Table E3 in this article’s Online Repository at www.jacionline.org).

      Discussion

      Our results indicate that implementation of a stepwise diagnostic verification algorithm at point of care among US adults with a self-reported diagnosis of asthma might be associated with significant savings in costs and improvements in quality of life over 20 years. In the main analysis as well as in the sensitivity and scenario analyses, this strategy was dominant against the strategy of continuing asthma management; that is, it was associated with reduced costs and improvements in quality of life. Extrapolating these results to the entire US population suggested that over 20 years, there could be a saving of $40.51 billion in direct asthma-related medical costs.
      These results are despite the fact that our modeling approach was based on several conservative assumptions against diagnostic verification. For one thing, in patients in whom asthma is ruled out, the possible causes of underlying symptoms are more likely to be verified. As such, it is likely that there would be benefits to patients and reductions in costs thanks to proper management of the underlying disease. In the study by Aaron et al,
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      more than 50% of patients in whom asthma was ruled out were ultimately diagnosed with other conditions. The most common alternative diagnoses were allergic rhinitis, gastroesophageal reflux disease, anxiety disorders, acute bronchitis, chronic obstructive pulmonary disease, and ischemic heart disease. To some extent, the overall efficiency of the asthma verification algorithms is influenced by the efficiency of management of these conditions. It is likely that the additional costs of diagnostic workup and disease management would be offset by better outcomes and an increase in quality of life under proper treatment of such conditions. In a sensitivity analysis that explored this aspect, the asthma verification test remained cost saving by incorporating the first-year costs of diagnostic and management of the 6 most common alternative diagnoses (a finding that remained valid when the prevalence of such conditions was assumed to be up to 3 times higher than their original values).
      Further, we assumed that in around 4% of individuals asthma would be ruled out incorrectly on account of the imperfect sensitivity of spirometry testing and a single MCT. In such individuals we assumed that controller medications would be discontinued and, as a result, asthma control status would deteriorate. This results in reduced quality of life and a higher rate of exacerbations that will last throughout the time horizon of the study. However, in reality it is likely that the intensification of symptoms and occurrence of exacerbations on treatment withdrawal will result in further assessments and reestablishment of the diagnosis. When we modeled this aspect in a sensitivity analysis, the diagnostic intervention scenario was even more cost saving.
      We are aware of 1 previous economic evaluation of secondary verification of asthma.
      • Ng B.
      • Sadatsafavi M.
      • Safari A.
      • Fitzgerald J.M.
      • Johnson K.M.
      The costs of misdiagnosed asthma in a longitudinal study of the general population.
      In the study by Pakhale et al,
      • Pakhale S.
      • Sumner A.
      • Coyle D.
      • Vandemheen K.
      • Aaron S.
      (Correcting) misdiagnoses of asthma: a cost effectiveness analysis.
      which was performed in the Canadian context, implementation of an asthma verification algorithm was associated with an average cost savings of $35,141 per 100 screened individuals. The main source of cost saving was medication costs, but the authors did not consider the impact of diagnostic verification and subsequent medication changes on asthma control, exacerbations, and quality of life.
      The strengths of our study include its reliance on hierarchy of evidence in estimating model parameters, considering multiple sources of evidence about the burden of uncontrolled asthma and the association between asthma control, treatment, resource use, and quality of life. Nuanced modeling of asthma control over time and how it is affected by diagnostic verification and changes in treatments further enhances the generalizability of our results compared with previous evidence. The incorporation of uncertainty in model inputs and assumptions into the results should provide reassurance that the overall findings are not materially affected by uncertain evidence.
      The limitations of our study should also be acknowledged. The main source of evidence on the rate of asthma overdiagnosis was a Canadian study.
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      We could not find any US–based study, but a recent systematic review on this topic reported that studies across different jurisdictions have consistently reported an overdiagnosis rate between 29% and 34%.
      • Aaron S.D.
      • Boulet L.P.
      • Reddel H.K.
      • Gershon A.S.
      Underdiagnosis and overdiagnosis of asthma.
      Our threshold analysis also indicated that the overdiagnosis rate in the US should be implausibly low for the diagnostic verification to not be cost-saving. We assumed that diagnostic verification would take place in the context of routine clinical practice, and as such, our results do not pertain to alternative schemes such as a systematic screening program. As well, a strict adherence to the diagnostic verification algorithm might not be achieved in the real world. For example, if spirometry testing fails to establish the diagnosis, the physician might decide on a trial of medication cessation and reevaluation of symptom burden before embarking on the assessment of airway hyperresponsiveness. Such departures from the verification protocol would inevitably affect the cost-effectiveness of diagnostic verification. Furthermore, in extrapolating the results to the entire US, we assumed immediate uptake of the diagnostic verification algorithm, whereas in reality there would be gradual adoption of such a program and imperfect implementation. We did not consider alternative diagnostic strategies such as using the measurement of exhaled nitric oxide, as the data for such a diagnostic strategy are less robust. Finally, changes in risk factors, as well as future innovations in asthma diagnosis and care, can have an impact on the efficiency of the proposed intervention.
      There are several opportunities for future research in this area. We evaluated the implementation of objective diagnostic verification in patients with a previous diagnosis of asthma. Objective diagnostic testing might also be beneficial in individuals in whom asthma is suspected for the first time. The cost-effectiveness profile of objective testing for such a population may be different from that for individuals with an existing diagnosis. Further, we did not investigate the extent to which individual characteristics can be used to refine the population for whom diagnostic verification would be beneficial. For instance, performing a diagnostic workup only among patients in whom an asthma diagnosis was not initially made through objective verification might further improve its cost-effectiveness. We did not have access to a reliable source of evidence to infer the performance of diagnostic verification across such subgroups. However, previous objective verification testing should not necessarily preclude an objective reevaluation of asthma because of potentially inaccurate recall of the initial diagnosis, and also because asthma may become clinically dormant for extended periods of time, justifying treatment cessation among individuals in whom reversible airway obstruction cannot be reproduced.
      In summary, our results indicate that secondary diagnostic verification of asthma during routine clinical encounters among adults with a self-reported asthma diagnosis may be cost-saving and may improve patients' quality of life. The overall conclusions made in this study about the merits of such diagnostic verification remained robust against changes in assumptions and parameter values. Nevertheless, the evidence on performance of diagnostic verification largely comes from research settings, including some in countries other than the US. As the "real-world" adherence to, and performance of, stepwise diagnostic algorithms remain untested, future implementation of such algorithms should also be coupled with subsequent evaluations.
      Key messages
      • Compared with current standards of practice, the implementation of an asthma verification algorithm among US adults with diagnosed asthma can be associated with a reduction in costs and gain in quality of life.
      • There is substantial room for improving patient care and outcomes through promoting objective asthma diagnosis.

      Methods

       Distributions of asthma control levels across sex and age

      The distribution of levels of asthma control within a given sex and age group was derived by using calibration techniques from a recent study based on the US National Health and Wellness Survey by Lee et al,
      • Lee L.K.
      • Obi E.
      • Paknis B.
      • Kavati A.
      • Chipps B.
      Asthma control and disease burden in patients with asthma and allergic comorbidities.
      which is explained in detail in our previous study.
      • Yaghoubi M.
      • Adibi A.
      • Safari A.
      • FitzGerald J.M.
      • Sadatsafavi M.
      The projected economic and health burden of uncontrolled asthma in the United States.
      Using model calibration, we estimated the coefficient of the following multinomial logit equations:
      Probability of non-well-controlled asthma=exp(β0+β1.age+β2.sex)1+exp(β0+β1.age+β2.sex)+exp(β3+β4.age+β5.sex)


      Probability of well-controlled asthma=exp(β3+β4.age+β5.sex)1+exp(β0+β1.age+β2.sex)+exp(β3+β4.age+β5.sex)


      Probability of very poorly controlled asthma=1(Probability of non-well-controlled asthma+Probability of well-controlled asthma)


       Modeling asthma exacerbations

      For individuals with true asthma, we modeled asthma exacerbations associated with levels of asthma control. Asthma exacerbation rates across levels of control were derived from 2 retrospective cohort studies describing exacerbation frequency for patients with asthma in the United States and United Kingdom
      • Bansal V.
      • Mangi M.A.
      • Johnson M.M.
      • Festic E.
      Inhaled corticosteroids and incident pneumonia in patients with asthma: systematic review and meta-analysis.
      (see Table I in the main text). Three levels of exacerbation severity were modeled.
      • Williams L.K.
      • Pladevall M.
      • Xi H.
      • Peterson E.L.
      • Joseph C.
      • Lafata J.E.
      • et al.
      Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma.
      • Zafari Z.
      • Lynd L.D.
      • FitzGerald J.M.
      • Sadatsafavi M.
      Economic and health effect of full adherence to controller therapy in adults with uncontrolled asthma: a simulation study.
      Exacerbations were classified as mild (an increase in the intensity of symptoms, without patients seeking care), moderate (managed on an outpatient basis, including with an emergency department visit), or severe (managed in the inpatient setting). The rate of death due to asthma exacerbation was extracted from Global Burden of Disease study
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      (Table E1).

       Distribution of asthma control in the true positive asthma in intervention arm

      We used the longitudinal North Economic Burden of Asthma study to estimate these parameters. Asthma control was based on the Global Initiative for Asthma definition.
      Global Initiative for Asthma (GINA)
      Global Strategy for Asthma Management and Prevention.
      Although this definition of control is different from the definition based on the Asthma Control Test (ACT), which is the basis of the definition of asthma control in the model, the clinical experts on our team deemed it acceptable to use the Global Initiative for Asthma–based definition to examine the difference in the distribution of asthma control across different groups while modeling the overall distribution of control according to ACT. A recent analysis of these data, which was based on an algorithm similar to the one used by Aaron et al,
      • Aaron S.D.
      • Vandemheen K.L.
      • FitzGerald J.M.
      • Ainslie M.
      • Gupta S.
      • Lemière C.
      • et al.
      Reevaluation of diagnosis in adults with physician-diagnosed asthma.
      has demonstrated that in the Economic Burden of Asthma study, 24.9% of patients with a self-reported physician diagnosis of asthma did not have asthma.
      • Ng B.
      • Sadatsafavi M.
      • Safari A.
      • Fitzgerald J.M.
      • Johnson K.M.
      Direct costs of overdiagnosed asthma: a longitudinal, population-based cohort study in British Columbia, Canada.
      Asthma status in this survey was verified with 1 prebronchodilator and 1 postbronchodilator spirometry measurement and 1 MCT (as in the protocol evaluated in this study). Asthma control was verified by using the ACT at the baseline visit and during each of the follow-up visits every 3 months. Using these data, we constructed a generalized linear model (multinomial distribution, cumulative logit link) to calculate the odds of having controlled asthma versus uncontrolled asthma, as well as the odds of having partially controlled asthma versus uncontrolled asthma, among the following groups: patients in whom asthma was diagnosed with spirometry testing, patients in whom asthma was diagnosed with an MCT, and patients in whom asthma was erroneously ruled out. The model was adjusted for sex, age at baseline, and whether the individual had used any ICSs in the 12 months before the study began. We used generalized estimating equations to account for the clustering of observations within individuals.

       Estimating costs of alternative diagnosis

      To estimate the costs of alternative diagnoses for patients in whom asthma was ruled out, we calculated the mean annual costs of first-time diagnosis for selected diseases from Medical Expenditure Panel Survey. We considered patients who had a diagnosis of these conditions in 2017 (based on the International Classification of Diseases, 10th Revision [ICD-10] codes) and did not report the same condition in 2016 to calculate mean annual costs of first-time diagnosis. The following diseases were selected according to the corresponding ICD-10 codes: chronic ischemic heart disease (ICD-10 code I25); vasomotor and allergic rhinitis (ICD-10 code J30); gastroesophageal reflux disease (ICD-10 code K21); phobic anxiety disorder (ICD-10 code F40) or other anxiety disorder (ICD-10 code F41); acute bronchitis (ICD-10 code J20) or unspecified chronic bronchitis (ICD-10 code J42) or bronchitis, not specified as acute or chronic (ICD-10 code J40); and chronic obstructive pulmonary disease (ICD-10 code J44). The results are provided in the main text.

       Analysis by year for the entire US population

      Sex- and age-specific asthma prevalence in the United States (per 100,000) were derived from the Global Burden of Disease study
      GBD 2016 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      and are provided in Table E2.
      Table E3 provides the undiscounted costs and QALYs in the intervention and status quo groups (2018-2038). The undiscounted costs of intervention and status quo will total $20.80 billion and $24.54 billion, respectively, in 2019; these values will increase to $21.95 billion and $25.42 billion in 2027 and to $24 billion and $27.22 billion in 2038. The undiscounted QALYs of intervention and status quo scenarios in 2019 will total 8.20 million and 7.89 million, respectively; these values will increase to 8.30 million and 8.01 million in 2027 and to 8.63 and 8.36 million in 2038. The total undiscounted incremental costs of spirometry testing and MCTs for the entire US asthma adult population will be $2.86 billion and $4.35 billion, respectively.
      Table E1Asthma exacerbation death rate per 100,000 across age and sex
      Source: Institute for Health Metrics and Evaluation (IHME). GBD Compare, Seattle, Wash: IHME, University of Washington, 2015. Available at: http://vizhub.healthdata.org/gbd-compare.
      Sex (age)Death rate per 100,000
      Male (15-49 y)0.65
      Male (50-69 y)1.16
      Male (≥70 y)2.99
      Female (15-49 y)0.66
      Female (50-69 y)1.92
      Female (≥70 y)6.08
      Table E2Sex- and age-specific asthma prevalence in the United States (per 100,000)
      Source: Institute for Health Metrics and Evaluation (IHME). GBD Compare, Seattle, Wash: IHME, University of Washington, 2015. Available at: http://vizhub.healthdata.org/gbd-compare.
      Age (y)SexValueLower 95% CI boundUpper 95% CI bound
      15-19Male43274002.24678.3
      20-24Male28962691.53136.8
      25-29Male27022550.32893.2
      30-34Male28812683.83106.7
      35-39Male29772805.23145.6
      40-44Male29922798.93197.6
      45-49Male29362762.63101.8
      50-54Male29052688.33109.5
      55-59Male31582986.03337.7
      60-64Male35403291.83786.1
      65-69Male40333815.64276.9
      70-74Male44114088.84758.1
      75-79Male43334083.64577.2
      80-84Male41153792.84413.1
      85-89Male39833704.74260.6
      90-94Male38873611.54194.2
      ≥95Male38013380.04308.4
      15-19Female51294798.65511.9
      20-24Female42583967.14568.4
      25-29Female41763946.44440.4
      30-34Female45084227.44806.4
      35-39Female48464603.45105.6
      40-44Female51184828.35418.0
      45-49Female52524987.55511.3
      50-54Female53454998.25661.4
      55-59Female56785403.05976.7
      60-64Female61595764.76547.1
      65-69Female67726442.37138.1
      70-74Female70406565.37536.8
      75-79Female62895950.46637.6
      80-84Female53134907.45680.4
      85-89Female47994463.45105.4
      90-94Female44584170.14774.0
      ≥95Female41813697.94748.6
      Table E3The total undiscounted costs and QALYs of intervention group versus status quo (2018-2037)
      YearTotal cost (million)Total QALYs (million)Total cost (million)Total QALYs (million)
      2018$33,560.848.20$24,467.707.89
      2019$20,801.368.20$24,549.457.89
      2020$20,932.248.21$24,638.377.90
      2021$21,066.878.21$24,733.757.91
      2022$21,205.358.22$24,835.157.92
      2023$21,347.778.23$24,942.297.93
      2024$21,494.228.25$25,055.007.95
      2025$21,644.818.26$25,173.167.97
      2026$21,799.638.28$25,296.747.99
      2027$21,958.798.30$25,425.698.01
      2028$22,122.398.32$25,560.048.03
      2029$22,290.558.34$25,699.818.05
      2030$22,463.388.37$25,845.038.08
      2031$22,641.008.40$25,995.768.11
      2032$22,823.538.42$26,152.078.14
      2033$23,011.108.45$26,314.038.17
      2034$23,202.378.49$26,481.738.21
      2035$23,401.868.52$26,655.268.24
      2036$23,605.328.56$26,834.738.28
      2037$23,814.368.59$27,020.248.32
      2038$24,004.368.63$27,221.248.36
      Total$479,192175.47$538,897169.33

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