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Abstract
Rationale: Computed tomography (CT)-based lung density is used to quantitate the percentage of emphysema-like lung (hereafter referred to as percent emphysema), but information on its distribution among healthy nonsmokers is limited.
Objectives: We evaluated percent emphysema and total lung volume on CT scans of healthy never-smokers in a multiethnic, population-based study.
Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study investigators acquired full-lung CT scans of 3,137 participants (ages 54–93 yr) between 2010–12. The CT scans were taken at full inspiration following the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) protocol. “Healthy never-smokers” were defined as participants without a history of tobacco smoking or respiratory symptoms and disease. “Percent emphysema” was defined as the percentage of lung voxels below −950 Hounsfield units. “Total lung volume” was defined by the volume of lung voxels.
Measurements and Main Results: Among 854 healthy never-smokers, the median percent emphysema visualized on full-lung scans was 1.1% (interquartile range, 0.5–2.5%). The percent emphysema values were 1.2 percentage points higher among men compared with women and 0.7, 1.2, and 1.2 percentage points lower among African Americans, Hispanics, and Asians compared with whites, respectively (P < 0.001). Percent emphysema was positively related to age and height and inversely related to body mass index. The findings were similar for total lung volume on CT scans and for percent emphysema defined at −910 Hounsfield units and measured on cardiac scans. Reference equations to account for these differences are presented for never, former and current smokers.
Conclusions: Similar to lung function, percent emphysema varies substantially by demographic factors and body size among healthy never-smokers. The presented reference equations will assist in defining abnormal values for percent emphysema and total lung volume on CT scans, although validation is pending.
Computed tomography (CT) of the lung has long been used to provide an index of regional lung density (1–3), which, when acquired at full inspiration, yields measures of the presence and distribution of emphysema-like lung (4–7). The percentage of emphysema-like lung (also called “percent low attenuation area” and hereafter referred to as “percent emphysema”) correlates with the presence and extent of emphysema on autopsy (3, 8, 9) and is associated with a poor prognosis in chronic obstructive pulmonary disease (COPD) (10–14), among smokers (15), and in the general population (16) independent of lung function.
Percent emphysema, in addition to lung volumes and airway measures (17–19), is being obtained on scans from tens of thousands of participants in research studies. In some of these studies, the researchers have inferred differences in disease susceptibility by sex and race/ethnicity using percent emphysema (20–23). To interpret variation in disease, however, it is helpful to understand the variation of percent emphysema in the nonsmoking, normal population (24).
In a normal population including never-smokers, differences in percent emphysema may occur because of altered stretch or compression of the lung related to gravity, height of the lung and support of the heart (1, 25), variation in residual peripheral airway structures (a voxel inside an airway will be emphysema-like), and scatter effects (26), which differ by scanner manufacturer, or may represent the presence of subclinical emphysema due to secondhand smoke exposure during childhood and other environmental exposures, as well as genetic factors (27–32). Indeed, researchers in small studies have suggested that percent emphysema varies among healthy never-smokers by demographic factors (33–36); however, these studies were limited by modest sample sizes, restricted racial and ethnic distributions, and lack of population-based sampling. Investigators in a larger study recently reported that lobar lung volumes on CT scans vary by sex, height, and race (37); however, that study included mostly older smokers, who are unlikely to have structurally normal lungs, and the researchers did not address percent emphysema or total lung volumes.
In the present article, we describe normal variation in percent emphysema in a large sample of nonsmokers recruited from the general population and provide normal reference equations for the four major racial and ethnic groups in the United States using a highly standardized lung CT protocol used in several other large research studies. For completeness, we provide in the online supplement similar equations for percent emphysema acquired on cardiac scans, which were previously presented in abstract form (38).
The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study initially designed to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (39). The MESA investigators recruited 6,814 men and women ages 45–84 years old from six U.S. communities from 2000–02: Forsyth County, NC; northern Manhattan and Bronx, NY; Baltimore City and Baltimore County, MD; St. Paul, MN; Chicago, IL; and Los Angeles, CA. Exclusion criteria included clinical cardiovascular disease, weight >300 lbs., pregnancy, or impediment to long-term participation. The protocols of MESA and all studies described herein were approved by the institutional review boards of all collaborating institutions and the National Heart, Lung, and Blood Institute (NHLBI).
The MESA Lung Study researchers enrolled 3,965 MESA participants of the 4,484 selected who were sampled randomly from among those who consented to genetic analyses, underwent baseline measures of endothelial function, and attended an examination during the MESA Lung recruitment period from 2004–06. Asians, who were predominantly of Chinese background, were oversampled to improve the precision of estimates for that group.
We selected the following sample to undergo full-lung CT scans between 2010–12: (1) all MESA participants who were enrolled into the MESA Lung Study from 2004–06, (2) all MESA participants who were selected for participation but were not enrolled into the MESA Lung Study from 2004–06, and (3) a random sample of MESA participants selected for magnetic resonance imaging. Of these participants, 3,137 underwent full-lung CT scans between 2010–12 (Figure 1).
Figure 1. Flow diagram of Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent full-lung computed tomography (CT) scanning between 2010–12. COPD = chronic obstructive pulmonary disease.
[More] [Minimize]The selection of healthy never-smoker MESA Lung participants followed the strategy for the derivation of spirometry reference equations recommended for use in the United States (40) and previously validated in this cohort (41). Participants with a history of tobacco smoking, respiratory symptoms or diagnoses, and poor CT scan acquisition were excluded (Figure 1). Participants with a recent respiratory infection or body mass index (BMI) >40 kg/m2 were also excluded to avoid, respectively, potential infiltrates or the effects of severe obesity on inspiration level and beam attenuation.
Because active smoking affects CT lung density measurements (42), we also defined a healthy active smoker sample to estimate reference equations for percent emphysema for current smokers. This sample met the same exclusion criteria as the healthy never-smoker sample, except that it was limited to participants who reported active smoking.
The full-lung scans were acquired at six centers in 2010–12 using four models of 64-slice multidetector row CT (MDCT) scanners from two manufacturers (four Siemens SOMATOM Sensation and one Siemens SOMATOM Definition [Siemens Medical Solutions, Erlangen, Germany], two GE LightSpeed and one GE Discovery [GE Healthcare, Waukesha, WI]) following the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)/MESA Lung CT protocol (0.984 pitch, 0.5 seconds, 120 kVp) (43, 44). Scans were acquired at suspended full inspiration following coaching to inspire to total lung capacity. The milliampere level was based on BMI: 145 mA for <20 kg/m2, 180 mA for 20–30 kg/m2, and 270 mA for >30 kg/m2. Images were reconstructed at 0.625 mm. Scanner calibration was confirmed throughout the study with monthly lung phantom measures. All participants also underwent cardiac CT scans between 2000 and 2002. The cardiac scan acquisition and reading protocol are described in the online supplement.
Image attenuation was assessed on full-lung scans using APOLLO Version 1.2 software (VIDA Diagnostics, Coralville IA) at a single reading center by trained readers without knowledge of other participant information. All voxels in the lung were identified, and lung volume was calculated. “Percent emphysema” is defined as the percentage of total voxels within the lung field that fell below −950 Hounsfield units (HUs) based upon pathological comparisons (3), and also the percentage below −910 HU, as the latter has also been validated compared with pathology (2) and is often used in cohorts of less severe disease. These thresholds were not corrected for tracheal or outside air attenuation for the main analyses. The apical and basal regions were defined as the apical and basal one-thirds of the lung and the apical/basal ratio in percent emphysema was calculated. In addition, lobes were segmented, and the ratio of upper/lower lobe percent emphysema was calculated.
Total lung volume visualized on full-lung scans was defined as the number of voxels within the lung mask times the voxel volume, as determined by the slice spacing and the reconstructed field of view. Air and tissue volume were determined by the mean lung HU and the reconstructed HU values of pure air and blood (1). Knowing the value of air and blood, and assuming the HU scale is linear between air and water, coupled with the assumption that lung voxels represent only air or tissue (blood), allows attribution of a percent air and tissue value to the lung based upon the mean lung HU. Multiplying percent air or percent tissue by the total lung provides a total air or tissue volume.
Spirometry was conducted from 2010–12 in accordance with the American Thoracic Society/European Respiratory Society guidelines (45) on a dry-rolling-sealed spirometer (Occupational Marketing, Inc., Houston, TX). One investigator reviewed all spirometry examinations and graded each test for quality (41).
Race/ethnicity was defined by self-report during the baseline MESA examination according to 2000 U.S. census criteria as race (white, African-American, Asian) and ethnicity (Hispanic or non-Hispanic) (39). Any smoking history was defined by self-report as a lifetime history of >100 cigarettes, >20 cigars, or >20 pipefuls of tobacco. Respiratory diagnoses and symptoms were assessed with standard questionnaire items (46). Height, weight, and waist and hip circumferences were measured using standometers, calibrated scales, and metal tapes, respectively.
Measures of percent emphysema and lung volumes were stratified by categorical variables of interest and are expressed as medians or means, as appropriate. The distribution of the CT measures was examined using the PROC TRANSREG statement, and appropriate transformations were made to yield approximate normal distributions. The λ value of log-transformed percent emphysema at −950 Hounsfield units was 0.030, suggesting that a log transformation was appropriate for this outcome. The relationships between the CT-based measures and the demographic, anthropomorphic, and scanner variables were examined in linear regression models. Variables that were significantly related to CT-based measures at P < 0.05 were considered for inclusion, although consideration was also made for consistency across models and variables previously related to pulmonary function (40).
Reference equations were estimated in the healthy never-smoker sample using linear regression for transformed percent emphysema measures. Analyses were repeated in the combined sample of healthy never-smoker and healthy current smoker samples. Interactions by age, sex, race and ethnicity, milliamperes, manufacturer, and smoking status were tested, and none were found. Quadratic and other nonlinear terms were also tested and did not improve the model fit. The intercept for the upper limit of normal was calculated as the intercept of the predicted equation plus 1.645 multiplied by the standard error of the estimate of the prediction equation. Analyses were performed using SAS 9.2 software (SAS Institute, Cary, NC).
The 3,137 participants who underwent full-lung CT scans were similar to the 1,580 participants who completed the MESA examination between 2010 and 2012 but did not have full-lung CT scans, except for being slightly younger and comprising a lower proportion of women and whites and a higher proportion of Asian Americans, the latter by design (see Table 1 in the online supplement).
Of the 3,137 participants who underwent full-lung CT scanning, 854 had never smoked, reported no respiratory diagnoses or symptoms, had a BMI below 40 kg/m2 and had adequate-quality scans (Figure 1). The characteristics of these participants are shown in Table 1. They had a mean age of 69 ± 9 years, and 62% were female. Most were between 54 and 89 years of age (see Supplement 2 online for distribution by decade of age). The racial and ethnic distribution was 32% white, 23% African American, 20% Hispanic, and 25% Asian American. Lung function was normal, as expected. The median percent emphysema was 1.1% at a −950 HU threshold and 16% at a −910 HU threshold. The mean total lung volume was 4,412 ml.
| Characteristics | Healthy, Never-Smoker Sample (n = 854) |
|---|---|
| Age, mean ± SD, yr | 69 ± 9 |
| Male sex, % | 38 |
| Race, % | |
| White | 32 |
| Asian | 25 |
| African-American | 23 |
| Hispanic | 20 |
| Height, mean ± SD, cm | 163 ± 9 |
| Weight, mean ± SD, lbs. | 159 ± 34 |
| Body mass index, mean ± SD, kg/m2 | 27 ± 4 |
| Waist circumference, cm | 94 ± 13 |
| Hip circumference, cm | 102 ± 10 |
| Waist/hip ratio, mean ± SD | 0.93 ± 0.09 |
| Educational attainment, % | |
| Less than high school | 14 |
| High school graduate | 18 |
| Some college | 25 |
| College graduate | 20 |
| Less than bachelor's degree | 22 |
| Scanner, % | |
| Siemens SOMATOM Sensation 64 | 60 |
| Siemens SOMATOM Definition 64 | 7 |
| GE LightSpeed VCT 64 | 20 |
| GE Discovery 64 | 14 |
| Lung function | |
| Percent predicted FVC, mean ± SD* | 99 ± 17 |
| Percent predicted FEV1, mean ± SD* | 99 ± 18 |
| FEV1/FVC ratio, mean ± SD* | 76 ± 8 |
| Emphysema measurements | |
| Percent emphysema−950 median (IQR) | 1.1 (0.49–2.49) |
| Percent emphysema−910 median (IQR) | 15.8 (7.5–26.9) |
| Apical/basal ratio of percent emphysema−950 median (IQR) | 0.90 (0.54–1.42) |
| Ratio of upper/lower lobe percent emphysema−950 median (IQR) | 1.31 (0.94–1.93) |
| Volumes | |
| Total lung volume, mean ± SD, ml | 4,526 ± 1,216 |
| Total air volume, mean ± SD, ml | 3,797 ± 1,109 |
| Total tissue volume, mean ± SD, ml | 730 ± 143 |
The characteristics of the 99 healthy current smokers are shown in online supplement Table 3. Compared with healthy nonsmokers, these participants were younger and more likely to be male, African American, and of lower socioeconomic status and also had lower lung function and greater percent emphysema.
Percent emphysema increased with age and was substantially greater among men than among women, although there was considerable overlap between individuals (Figure 2A). Percent emphysema increased with height and was greater among whites than among other racial and ethnic groups, again with great overlap (Figure 2B). In addition, percent emphysema varied by weight, educational attainment, and scanner manufacturer (all P < 0.05).
Table 2 shows the multivariate relationships of percent emphysema to these factors. Percent emphysema varied substantially by age, sex, race and ethnicity, height, and BMI. Despite efforts to standardize the protocol across scanner manufacturers and phantom data confirming calibration, participants scanned on GE scanners had a lower average percent emphysema than those scanned on Siemens scanners. In contrast, the apical/basal ratio in percent emphysema varied significantly by age and height only, whereas the upper/lower lobe ratio in percent emphysema varied by age, sex, height, BMI, and scanner manufacturer.
| Sample Demographics (N = 854) | Total Percent Emphysema−950 (%) | Apical/Basal Ratio of Emphysema−950 | Ratio of Upper/Lower Lobe Emphysema−950 | Total Lung Volume (ml) |
|---|---|---|---|---|
| Age, per 10 yr | 0.2* | −0.1* | −0.1* | −54 |
| Male sex | 1.3* | 0.2 | 0.3* | 577* |
| Race and Ethnicity | ||||
| White | Reference | Reference | Reference | Reference |
| Asian | −1.1* | 0.1 | −0.2 | −681* |
| African-American | −0.7* | 0.1 | −0.3 | −783* |
| Hispanic | −0.9* | −0.1 | −0.1 | −406* |
| Height per 10 cm | 0.21 | −0.3* | −0.2* | 654* |
| BMI, kg/m2 | ||||
| <20 | 0.3 | −0.2 | 0.2 | 234 |
| 20–30 | Reference | Reference | Reference | Reference |
| >30 | −0.6* | −0.2 | −0.5* | −235* |
| GE scanner (vs. Siemens) | −1.3* | −0.2 | −0.4* | −10 |
Total lung volume also varied by age, sex, race and ethnicity, height, and BMI, but was unaffected by scanner manufacturer.
Most measures of percent emphysema and total lung volume were associated with lung function, even in this healthy never-smoker sample (Table 3).
| Statistics | Total Emphysema (SD) | Apical/Basal Ratio of Emphysema (SD) | Upper/Lower Ratio of Emphysema (SD) | Total Lung Volume (ml) (SD) |
|---|---|---|---|---|
| Sample size n = 767 | Mean Difference | Mean Difference | Mean Difference | Mean Difference |
| FVC, ml | 126 | 8 | 62 | 463 |
| (<0.001) | (0.69) | (<0.001) | (<0.001) | |
| FEV1, ml | 37 | 2 | 35 | 292 |
| (0.025) | (0.87) | (0.017) | (<0.001) | |
| FEV1/FVC ratio, % | −1.55 | 0.34 | −0.47 | −2.43 |
| (<0.001) | (0.29) | (0.094) | (<0.001) |
Given the large and significant differences by demographic and body size variables, we derived reference equations for percent emphysema that included terms for age, sex, race and ethnicity, height, BMI category as defined in the protocol, and manufacturer (Table 4). Reference equations for apical-basal emphysema included terms for age, height, and BMI and those for total lung volume on CT scans included all terms except scanner manufacturer. Equations for percent emphysema were stratified by current smoking status due to the large artifactual effect of current smoking on percent emphysema. The variables included in the equations accounted for approximately one-third of the variation in percent emphysema and almost two-thirds of the variation in total lung volume in these normal individuals.
| Statistics | Intercept (Predicted) | Intercept (Upper Limit of Normal) | Intercept (Lower Limit of Normal) | Covariates | R2 |
|---|---|---|---|---|---|
| Percent Emphysema−950 for former smokers and never-smokers | |||||
| % Emphysema | 0.140 | 0.534 | — | Age0.336⋅Height2.160⋅Sex0.996⋅AA−0.451⋅Hispanic−1.022⋅Chinese−0.838⋅Manufacturer−1.017⋅Low BMI0.579⋅High BMI−0.647 | 0.32 |
| Apical/basal ratio | 31.218 | 119.104 | — | Age−0.662⋅Height−1.640 | 0.02 |
| Percent emphysema−950 HU for current smokers | |||||
| % Emphysema | 0.081 | 0.322 | — | Age0.453⋅Height2.345⋅Sex0.977⋅AA−0.444⋅Hispanic−1.022⋅Chinese−0.902⋅Manufacturer−1.087⋅Low BMI0.741⋅High BMI−0.663⋅Cigarettes/day−0.102 | 0.34 |
| Apical/basal ratio | 15.705 | 61.252 | — | Age−0.510⋅Height−1.554⋅Cigarettes/day−0.051 | 0.02 |
| Lung volumes: all for all persons | |||||
| Total lung volume | 2,805 | — | 2,105 | Age−0.145⋅Height2.285⋅Sex0.180⋅AA−0.241⋅Hispanic−0.157⋅Chinese−0.233⋅Low BMI0.069⋅High BMI−0.086 | 0.59 |
| Total air volume | 2,535 | — | 1,814 | Age−0.170⋅Height2.368⋅Sex0.194⋅AA−0.263⋅Hispanic−0.195⋅Chinese−0.253⋅Low BMI0.090⋅High BMI−0.122 | 0.54 |
The reference equations provide one intercept for the calculation of predicted values and a different intercept for the calculation of the limits of normal. Use of the predicted values to remove residual variation by scanner manufacturer and BMI makes clear the need for reference equations to account for sex, height, race and ethnicity, and, to a lesser extent, age (Figure 3).
Figure 2. Observed values of percent emphysema among healthy never-smoker adults by sex, and age (A) and by race, ethnicity, and height (B). Note: Lines in the figure are regression lines. HU = Hounsfield units.
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Figure 3. Predicted normal values of percent emphysema among healthy never-smoker adults by sex and age (A) and by race, ethnicity, and height (B). Note: Lines in the figure are regression lines. HU = Hounsfield units.
[More] [Minimize]Reference equations are also provided for percent emphysema on full-lung scans corrected for the attenuation of outside air and defined at a −910-HU threshold, as well as for lung density measurements, including percent high attenuation areas, on cardiac scans (see Tables 4–6 in the online supplement). The equations for cardiac scans included the same variables as those derived for full-lung CT scans and explained a similar proportion of the variance in percent emphysema.
The results of the present study demonstrate significant variation in percent emphysema and total lung volume visualized on CT scans by demographic factors, body size, and scanner manufacturer among healthy never-smokers in a unique, multiethnic, population-based sample. We provide reference equations to account for this normal variation and to more accurately define abnormal values of percent emphysema and total lung volume visualized on CT scans of current, former, and never smokers. Validation of these equations in an external cohort is pending.
Although researchers in several small studies have described CT characteristics in a normal nonsmoking population (33–36), this study is the first, to the best of our knowledge, with a cohort of normal nonsmokers that is large enough to define normal variation in percent emphysema in the general population. In a relatively large number of disease-based, multicenter studies, researchers have or are using CT to define lung structure, including the National Emphysema Treatment Trial, SPIROMICS, COPDGene, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints studies in COPD, the Severe Asthma Research Project (SARP) in asthma, and the Lung Tissue Research Consortium in interstitial lung disease. Several papers on these studies have suggested differing susceptibilities to pathologic processes based upon sex, race, and demographic characteristics (20–22). On the basis of the data we present herein, we think that some of their conclusions may have been influenced by normal variation, as the differences observed for percent emphysema based upon sex, race and ethnicity, and body size among healthy never-smokers were consistent with or more extreme than those previously observed in patients with COPD (20–22).
It is of interest that the only factors in those studies that influenced differences between apical basal aspects were age and height. Because an important determination of emphysema phenotypes (α1- versus smoking-associated), as well as trigger points for lung volume (surgical or endobronchial), has been the apical and basal differences in emphysema-like lung, the homogeneity of this measure across the normal population in all but measures of age and height demonstrates the robust nature of the apical and basal phenotype (47–49). Interestingly, the more refined measure of upper/lower lobe ratio in percent emphysema varied with all factors except for race and ethnicity.
The current findings for lung structure, perhaps not surprisingly, are similar to those for spirometric measures. For example, mean normal values of the forced vital capacity (FVC) have long been recognized to decline with age and to be greater among men compared with women, among whites compared with nonwhites, and among taller compared with shorter individuals (40), as we observed for total lung volumes on CT scans.
Similar differences in percent emphysema among healthy never-smokers may reflect differences in airway size between men and women and between large compared with small individuals that persist out to the lung periphery and that contribute to “parenchymal density” in the lung periphery. CT measurements also varied by obesity, likely due to greater compression of the lung at suspended full inspiration in the supine position in obese compared with lean individuals, and, in the case of percent emphysema, beam attenuation by adipose tissue, in addition to protocol differences. Age, obesity, and other factors related to ability to attain total lung capacity (50) may also have affected our measurements. Unlike spirometric measurements, percent emphysema is known to be affected acutely by cigarette smoking (42). We did not examine this relationship directly in this study, but we present separate equations for percent emphysema for use with current smokers.
The variance explained by the current reference equations for lung volumes on CT scans was comparable to that for reference equations for volumes measured on spirometry in the Third National Health and Nutrition Examination Survey (40). Similarly, the variance explained by the reference equations for percent emphysema was similar to that for the ratio of forced expiratory volume in 1 second (FEV1) to FVC, the lower limit of normal of which is used to define airflow limitation (45). The variance explained by reference equations for the apical/basal ratio in percent emphysema was lower.
A major strength of the current study is that the acquisition protocol and the software used for the full-lung analyses are identical to those used in other major NHLBI-supported studies, including SPIROMICS and SARP; hence, the reference equations developed in our study are likely directly applicable to those studies and other research studies using the same CT scan data acquisition protocol. The reference equations for percent emphysema on cardiac scans presented in the online supplement are likely to be applicable in studies using cardiac CT protocols based upon the MESA protocol, including the Framingham Heart Study, the Coronary Artery Risk Development in Young Adults Study, and the Reykjavik Study. As manufacturers, and presumably protocols, did not affect total lung volume, the reference equations for lung volumes visualized on CT scans apply broadly, potentially including well-performed clinical scans.
As reconstructed CT scan-visualized densities are influenced by scanner manufacturer and model, slice thickness, reconstruction kernel, and more (51–54), the equations for percent emphysema may or may not be applicable directly to studies in which other techniques are used; however, the current equations provide a benchmark against which other studies can test their results. The differences by manufacturer and model reinforce the need for scanner manufacturers to standardize measurements for lung imaging.
No other similarly large cohort of nonsmokers is available for validation of the full-lung equations, although the authors of a recent publication on lobar volumes visualized on CT scans of smokers found somewhat similar differences by sex, height, and African-American race/ethnicity, but not age and body mass index (other racial and ethnic groups were not included) (37).
Similarly to findings for spirometry (55), we found no evidence that the relationship of age and height to percent emphysema varied by race or ethnicity. This observation implies that separate reference equations for quantitative CT-based lung measurements for separate racial and ethnic groups are unnecessary, although terms for race and ethnicity in the equations are still needed.
The limitations of the present study include its modest sample size after stratification by race, ethnicity, and sex and the lack of an independent validation set. Nonetheless, the sample sizes for most race-, ethnicity-, and sex-specific cells were comparable to those for spirometry reference equations (40), and the sample size of the present study was considerably larger than those of prior studies on reference equations for lung volumes on phlethysmography (56, 57). We did not validate the reference equations in an independent cohort, owing to the absence of an appropriate cohort with full-lung scans; however, we anticipate future validation in the control group in SPIROMICS.
In conclusion, herein we present a large population-based assessment of percent emphysema and total lung volume measured on CT scans among healthy never-smokers. We demonstrate that there are significant differences based upon sex, age, race, ethnicity, body habitus, and scanner manufacturer with regard to percent emphysema, and we provide reference equations to account for these differences. The reference equations were not validated in an independent cohort, owing to the current lack of a large cohort of healthy never-smokers with CT scans. It is possible that changes in scanning protocols and scanners might alter the coefficients in the equations for percent emphysema; however, the relative differences between the subsets of the population identified in our study should remain unchanged. Scanner factors did not affect equations for total lung volume. Thus, the equations represent the present state-of-the-art definition of abnormal values for percent emphysema in research settings and, for total lung volume on CT, in clinical research and settings.
The authors thank Megha Parikh, Tess Pottinger, and Joe Schwartz for assistance with statistical analyses, David Lederer for high attenuation area analyses, and the participants of the MESA and MESA Lung studies for their valuable contributions. A full list of participating MESA investigators and institutions can be found at www.mesa-nhlbi.org
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Supported by the National Heart, Lung and Blood Institute, National Institutes of Health (R01 HL077612, R01 HL093081, N01 HC95159-HC95169, BRP HL064368, and HL112986).
Author Contributions: drafting the manuscript: E.A.H., R.G.B.; collecting the data: E.A.H., H.B., M.B., J.J.C., R.K., S.R., R.G.B.; obtaining funding: E.A.H., R.G.B., R.K.; statistical analysis: F.S.A.; oversight of statistical analysis: R.G.B., R.K.; final review: all authors.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Author disclosures are available with the text of this article at www.atsjournals.org.
