Respiratory impairment is most often defined spirometrically as: 1) airflow limitation (e.g. COPD), based on a reduced FEV1/FVC, with severity then defined by FEV1 alone;or 2) restrictive-pattern (e.g. interstitial lung disease), based on a reduced FVC but normal FEV1/FVC. The diagnostic thresholds for FEV1/FVC and for FEV1 and FVC alone are usually established by the Global Initiative for Obstructive Lung Disease (GOLD) or the American Thoracic Society (ATS).5-7 These thresholds have serious age-related limitations, however, and will frequently misidentify respiratory impairment in aging populations.8-22 GOLD, for example, uses a threshold of 0.70 for FEV1/FVC, but an FEV1/FVC <0.70 frequently occurs in healthy, asymptomatic never-smokers, aged >50.6-15 GOLD additionally uses percent predicted (%Pred) thresholds for FEV1 and FVC but, because these do not account for the age-related variability in spirometric performance, a given %Pred threshold is not equivalent for all persons.9,16,17In contrast, the ATS sets thresholds for FEV1/FVC and FVC at the lower limit of normal (ATS-LLN5).5-7 This approach also has serious limitations, because the ATS-LLN5 is frequently calculated from regression equations that incorrectly assume a linear relationship between predictors and spirometric measures, and/or incorrectly assume that reference values have a normal distribution and constant variability across the lifespan.9 Otherwise, the ATS also uses %Pred thresholds for FEV1. Consequently, we propose an alternative approach for defining respiratory impairment, using spirometric Z- scores as calculated by Lambda-Mu-Sigma (LMS).1,9,10 The LMS-calculated Z-scores account for age-related changes, including variability in spirometric performance and skewness of reference data.9 Using this approach, we have shown that LMS-defined respiratory impairment is associated with multiple health outcomes,15,18-23 but our prior work did not address several gaps in knowledge. First, we evaluated only whites aged <80, because LMS-calculated Z-scores were not previously available for non-whites and those aged >80. This task is now possible because new LMS equations have been published for multiple ethnicities and age up to 95.10,24 Second, as health outcomes of interest, we did not evaluate exercise capacity, use of respiratory medications, or hospitalizations other than for COPD. Third, we did not evaluate """"""""pulmonary phenotypes,"""""""" specifically those defined by physiology or CT imaging. Lastly, we did not evaluate spirometric change over time. Accordingly, the objective of this proposal is to address these gaps in knowledge. Using new LMS equations and databases from multiple aging populations, including U.S. Veterans and a broad array of health outcomes and pulmonary phenotypes, we propose the following specific aims:
Aim 1. To evaluate the association between respiratory impairment and health outcomes. We hypothesize that: 1) the LMS approach, compared to GOLD or ATS, will show a greater association between respiratory impairment and health outcomes;and 2) discordant designations of respiratory impairment (GOLD and ATS abnormal, respectively, but LMS normal) will not be associated with health outcomes.
Aim 2. To evaluate the association between respiratory impairment and pulmonary phenotypes. We hypothesize that: 1) the LMS approach, compared to GOLD or ATS, will show a greater association between respiratory impairment and various pulmonary phenotypes;and 2) discordant designations of respiratory impairment (as defined in Aim 1) will not be associated with a pulmonary phenotype.
Aim 3. To evaluate spirometric change over time, with FEV1 and FVC expressed as LMS-calculated Z- scores, %Pred, and absolute volumes (mL). These analyses will include group-based trajectory modeling and key time-varying risk factors that may affect spirometric trajectories. We hypothesize that: 1) aging is associated with declining trajectories of spirometri measures;and 2) LMS-calculated Z-scores, rather than %Pred and absolute volumes (mL), will show a greater association with time-varying risk factors.

Public Health Relevance

It is essential that respiratory impairment be established with a high level of diagnostic relevance, because respiratory and non-respiratory factors can both lead to respiratory symptoms, especially when multimorbidity is prevalent (as in aging populations). Consequently, using existing databases from multiple aging populations, including U.S. Veterans, we propose to evaluate and compare the validity of an alternative, more age- appropriate spirometric method for establishing respiratory impairment, termed Lambda-Mu-Sigma (LMS), relative to the current spirometric standards from the Global Initiative for Obstructive Lung Disease and the American Thoracic Society. Our proposed research has high clinical relevance for the Veterans Health Administration (VHA). In particular, because VHA patients are older and have increased multimorbidity, they are at high risk of poor outcomes, if respiratory symptoms are incorrectly attributed to a spirometric respiratory impairment such as COPD, and if respiratory therapies such as bronchodilators are inappropriately prescribed.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Respiration (PULM)
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VA Connecticut Healthcare System
West Haven
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