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First published online on June 15, 2007
Chest, doi:10.1378/chest.06-2325
doi:10.1378/chest.06-2325
(Chest. 2007; 132:617-623)
© 2007 American College of Chest Physicians
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The Effects of Radiation Dose and CT Manufacturer on Measurements of Lung Densitometry*

Ren Yuan, MD; John R. Mayo, MD; James C. Hogg, MD, PhD, FCCP; Peter D. Paré, MD; Annette M. McWilliams, MD; Stephen Lam, MD, FCCP and Harvey O. Coxson, PhD

* From the James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research (Drs. Yuan, Hogg, and Paré,), St. Paul’s Hospital, Vancouver, BC, Canada; the Department of Radiology (Drs. Mayo and Coxson), Vancouver General Hospital, Vancouver, BC, Canada; and the British Columbia Cancer Agency (Drs. McWilliams and Lam), Vancouver, BC, Canada.

Correspondence to: Harvey O. Coxson, PhD, Department of Radiology, Vancouver General Hospital, 855 West Twelfth Ave, Room 3350 JPN, Vancouver, BC, Canada V5Z 1M9; e-mail: harvey.coxson{at}vch.ca

Abstract

Background: To evaluate the effect of radiation dose and scanner manufacturer on quantitative CT scan measurements of lung morphology in smokers.

Methods: Low-dose and high-dose, inspiratory, multislice CT scans were obtained in 50 subjects at intervals of approximately 6 months (mean [± SD] interval, 0.5 ± 0.2 years). In another 30 subjects, multislice CT scans were acquired first using a GE LightSpeed Ultra (General Electric Healthcare; Milwaukee, WI), followed a mean time of 1.2 ± 0.4 years later by using a Siemens Sensation 16 scanner (Siemens Medical Solutions; Erlangen, Germany). Custom software was used to measure lung volume, mass, mean density, and the extent of emphysema using threshold cutoffs of –950, –910, and –856 Hounsfield units (HU) and the lowest 15th and 5th percentile points.

Results: The change in radiograph dose significantly affected measurements of emphysema assessed using mean lung density, threshold, or percentile methods. There were also interactions between dose and total lung volume for all of the measurements except the –950-HU threshold and the lowest fifth percentile point. These two emphysema measurements suggest that there was more emphysema found in the CT scans obtained using a lower radiograph dose. Only the mean lung density and –856-HU threshold showed significant effects between CT scanner manufacturers and interactions between total lung volume and scanner. All other measures of lung structure were not different between the two CT scanners.

Conclusion: CT scan measurements of very low density lung structures are significantly affected by radiation dose but are less sensitive to the lung volume. Image acquisition parameters including radiation dose, scanner type, and the subject’s breath size should be standardized to estimate emphysema severity in longitudinal studies.

Key Words: CT scan • emphysema • lung expansion • radiation dose

Quantitative CT scanning has become a very popular method for quantifying the extent and severity of pulmonary emphysema.123 Previous studies have shown that CT scan estimates of total lung volume, mass, mean lung density, and percentage of emphysema (%Emphysema) are reproducible4567 and are significantly correlated with both lung function test891011 and pathology findings.12131415161718 Furthermore, two advantages of CT scan image analysis are that it allows the assessment of lung structure in vivo and is relatively easy to obtain in most centers. These are important features because it is now possible to investigate the pathogenesis of lung destruction and/or the effect of interventions on the disease process in large multicenter cohorts of subjects. Examples of these multicenter applications are the National Emphysema Treatment Trial19 and the Lung Tissue Repository Consortium (Presented at the 2005 Annual Meeting of the Radiologic Society of North America) in the United States and the {alpha}1-Antitrypsin Deficiency Network in Europe. Additionally, many centers are actively involved in the longitudinal follow-up of suspicious lung nodules in subjects who are susceptible to lung cancer. As these subjects are also at risk for the development of emphysema, there is great interest in using these cohorts for more comprehensive studies of smoking-related lung disease.

However, before large-scale longitudinal studies are undertaken it is important to assess the possible effect that parameters such as scanner manufacturer, slice thickness, reconstruction algorithm, and lung volume control have on both image quality and comparability of quantitative CT scan data. Therefore, the purpose of this study was to evaluate the effect of CT radiation dose (radiograph tube current) and scanner manufacture on quantitative CT scan measurements of lung morphology in smokers with emphysema.

Materials and Methods

Subject Selection
Subjects for this study were selected from the British Columbia Cancer Agency Lung Health Study.20 The study was approved by the clinical ethics review boards of the British Columbia Cancer Agency and the University of British Columbia. All subjects signed informed consent forms to allow their spirometry and CT scan images to be used for research. This study comprises a cohort of heavy smokers who have been screened for the presence of lung nodules using "low-dose" CT scans. If suspicious nodules are noted, the subjects receive follow-up "high-dose" CT scans for up to 2 years. At entry into the study, smoking status was documented and baseline spirometry data were collected using American Thoracic Society criteria. Subjects also underwent periodic spirometry testing over the next 2 years. Fifty consecutive subjects who had received a baseline low-dose CT scan and a high-dose follow-up CT scan and spirometry tests within 6 months of the CT scan dates were selected from this cohort to investigate the effect of radiation dose (ie, radiograph tube current) on CT scan measurements of lung structure. In addition, 30 consecutive subjects who underwent baseline CT scans using a General Electric scanner and follow-up CT scans using a Siemens scanner were selected to study the effect of CT scanner manufacturer on lung densitometry measurements. Subjects were not selected for the study on the basis of lung function or the presence and extent of emphysema. There were seven subjects who were involved in both studies.

CT Scan Technique
All CT scans were acquired in the volume-scan mode at suspended full inspiration without the use of IV contrast media while the subject was in the supine position, resulting in > 200 images per CT scan (range, 212 to 323 images). The low-dose CT scans were acquired using a GE Lightspeed Ultra multislice CT scanner (General Electric Healthcare; Milwaukee, WI). Image acquisition parameters were an x-ray tube potential of 120 kVp, a tube current of 80 to 100 mA (100 mA, 48 of 50 cases; 80 mA, 2 of 50 cases), 0.5-s gantry rotation time, pitch 1.35 (average effective mA, 30 mA), and 1.25-mm slice thickness; images were reconstructed using an intermediate spatial frequency reconstruction algorithm (ie, "standard"). The high-dose CT scans were acquired approximately 6 months after the low-dose scans (mean [± SD] time, 0.5 ± 0.2 years) using the same GE scanner and image parameters with the exception of the tube current, which was set at 320 mA (average effective mA, 320 x 0.5/1.35 = 118 mA). In the second set of subjects, images were acquired first using the GE Lightspeed Ultra scanner, and the high-dose (average effective mA, 320 x 0.5/1.35 = 118 mA) protocol followed a mean time of 1.2 ± 0.4 years later with images acquired using a Siemens Sensation 16 multislice scanner (Siemens Medical Solutions; Erlangen, Germany). The Siemens protocol consisted of an x-ray tube potential of 120 kVp, a tube current of 250 mA, a rotation time of 0.5 s, and a pitch of 1.25 (average effective mA, 250 x 0.5/1.25 = 100 mA). Images were reconstructed using a slice thickness of 1 mm and an intermediate spatial frequency reconstruction algorithm ("b35f").

Quantitative CT Analysis
CT scan images were analyzed using custom software (EmphylxJ; University of British Columbia; Vancouver, BC, Canada), as previously described.182122 Briefly, the lung parenchyma was segmented from the chest wall and large central blood vessels in all CT scan images using a modified border-tracing algorithm with a prior position-knowledge algorithm. Lung volume was calculated by summing the segmented pixel area in each slice and multiplying by the slice thickness to acquire the total lung volume. The mean CT scan attenuation of the lung (in Hounsfield units [HU]) was calculated and converted to a measure of density (in grams per milliliter) by adding 1,000 to the HU number and dividing by 1,000.18212223 The mean density of the lung was then multiplied by the lung volume to estimate lung mass. The extent of low-attenuating voxels was estimated using both the threshold (ie, %Emphysema) and percentile techniques, as previously described.712131415161718242526 The cutoff values chosen for the threshold technique were –950, –910, and –856 HU, and the lowest 5th and 15th percentile points were used for the percentile technique. The mean, median, mode, SD, and variance of CT attenuation (in HU) values was also calculated to test the effect of dose and CT scanner manufacturer on the pattern of HU distribution.

Statistical Analysis
Total lung mass, mean lung density, %Emphysema, and percentile points derived from images with different doses or CT scanner manufacturers were tested using repeated measures analyses of variance (SPSS, version 10.0.5; SPSS, Inc; Chicago, IL) where radiograph dose and CT scanner manufacturer were considered to be independent variables and total lung volume was used as a covariate to test for interactions. A probability level of 0.05 was considered to be significant.

Results

Subjects
The subjects’ demographic data are summarized in Table 1 . There were more men in the CT dose study than in the CT scanner manufacture study, and there were more current smokers than former smokers in each study group. There were no significant differences (p > 0.05) in the spirometry measurements between study groups.


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  		Table 1.. Anthropomorphic and Spirometric Characteristics of Subjects in the Radiation Dose and CT Scanner Manufacturer Studies*

 
Radiation Dose Study
A summary of the measurements of total lung volume, total lung mass, mean lung density, %Emphysema, and percentile points obtained using the low-dose and high-dose CT scan images are shown in Table 2 . There were significant differences in all of the quantitative measurements (p < 0.05) except for total lung volume (p = 0.68). There was a significant main effect for dose on measurements of mean lung density and total lung mass (p = 0.037 and p = 0.024, respectively). There was also a significant interaction between radiation dose and total lung volume for mean lung density and total lung mass (p = 0.035 for both). This interaction indicates that at the low radiation dose a low total lung volume results in an increased mean lung density. Conversely, at the high radiation dose an increased total lung volume results in an increased mean lung density. The same pattern was observed for total lung mass.


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  		Table 2.. Comparison of Quantitative CT Scan Measurements Between Low-Dose and High-Dose CT Scan Images (n = 50)*

 
There was a similar main effect of dose on measurements of emphysema at the –910-HU and –856-HU thresholds (p < 0.001 and p = 0.030, respectively), and an interaction between radiation dose and total lung volume (p < 0.001 and p = 0.017, respectively), as there was for mean lung density. For both cutoff values at low lung volumes, the low-dose scan indicated more emphysema than the high-dose scan; at high volumes, the high dosage was suggestive of more disease. The –950-HU cutoff did not interact with lung volume, indicating that the %Emphysema identified with low-dose radiation was significantly higher than with high-dose radiation. The 15th percentile point also showed a significant main effect due to dose and an interaction between total lung volume and radiograph dose (p < 0.001 for both), indicating that at low lung volumes a low-dose CT scan identified a greater degree of emphysema than a high-dose scan. At high volumes, the high-dose CT scan was indicative of greater pathology than the low-dose scan. The fifth percentile point was free of this interaction and occurred at a significantly lower HU value on the low-dose CT scan images compared with those on high-dose CT scan images. The HU frequency distribution histogram from a representative subject shows that in a subject a CT scan performed at the same lung volume, the histogram from the low-dose CT scan was broader than that from the high-dose CT scan (Fig 1 ).


Figure 1
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  		Figure 1.. The HU distribution histograms derived from a representative subject who underwent both a low-dose CT scan (solid line) and a follow-up high-dose CT scan (dashed line) whose total lung volume was very similar at two CT scan time points (low-dose CT scan, 5,285 mL; high-dose CT scan, 5,381 mL). Note that the distribution of the HU is broader in the low-dose CT scan than it is in the high-dose CT scan.

 
CT Manufacturer Study
The quantitative CT scan measurements derived from different CT scanner manufacturers are shown in Table 3 . Most of the measures of emphysema (–910-HU and –950-HU thresholds, and the 5th and 15th percentile points) did not differ significantly between the two scanner types. However, there was a significant main effect for scanner type, and an interaction between scanner type and total lung volume for mean lung density (p = 0.010 and 0.023, respectively) and %Emphysema at –856 HU (p = 0.005 and 0.016, respectively), such that at low lung volumes the GE scanner yielded higher estimates of mean lung density and a smaller proportion of emphysema. At high lung volumes, the Siemens scanner tended to estimate higher mean lung densities and a smaller proportion of emphysema. The HU frequency distribution histograms (Fig 2 ) from a representative subject at a comparable lung volume were very similar between the two CT scanner manufacturers.


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  		Table 3.. Comparison of Quantitative CT Scan Measurements Between CT Scan Images Acquired Using a GE Lightspeed Ultra (8-Slice) and a Siemens Sensation 16 (16-slice) Scanner (n = 30)*

 

Figure 2
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  		Figure 2.. The HU distribution histograms derived from using a GE scanner (solid line) and a Siemens scanner (dashed line) in a representative subject whose total lung volume was very similar at the two CT scan time points (GE scanner, 4,965 mL; Siemens scanner, 4,928 mL). Note that the distribution of HU obtained from both scanners is almost identical.

 
Discussion

Quantitative CT scan imaging has become a very important tool for quantifying the extent of emphysema in subjects with COPD. However, most published studies arise from a single institution scanning small numbers of subjects using a single CT scanner and a site-specific scanning protocol. It is now apparent that to advance the knowledge of how the lung changes with time, either in a diseased state or with an intervention, quantitative CT scanning must be applied to larger cohorts acquired from multiple centers and/or over longer time frames. Furthermore, because of increased concern over the effect of radiation exposure on subjects who are receiving numerous radiologic investigations, researchers have started to decrease the radiation dose that a subject receives as part of longitudinal studies. The results from a number of studies have shown that it is important to standardize all the components of the CT scan protocol to achieve comparable CT lung densitometry measurements.456272829

The results from our study show that different CT scan protocols can make a difference in the measurements of lung density and the extent of emphysema. While the radiograph dose and manufacturer of a CT scanner do not affect the measurements of total lung volume, which are obtained using a simple segmentation of low-attenuating regions (lung) from high-attenuating regions (chest wall and soft tissue), the volume of the lung during the scan can have significant effects on the densitometry measurements themselves through interactions with either the radiograph dose or the type of CT scanner. We think that these interactions are due, at least in part, to the noise profile of CT scan images. Other investigators53031 have shown that image noise is directly proportional to the slice thickness and radiograph dose according to the following equation:

Formula 1(1)

Where {varsigma} is image noise, f is the spatial resolution of the reconstruction algorithm, z is slice thickness, and D is radiograph dose. This equation indicates that as radiograph dose decreases (ie, lower radiograph tube current), there is an increase in the quantum noise within the image. This increased noise causes broadening of the frequency distribution of the radiograph attenuation values for an object of uniform attenuation. In the central regions of CT scan attenuation (eg, water, 0 HU), the broadening of the frequency distribution of radiograph attenuation values is symmetric, and there is no change in the mean attenuation value. However, in the extreme low-attenuation or high-attenuation ends of the HU value scale (eg, emphysematous or well-inflated lung tissue) the effect of increased noise and broadening of the frequency distribution of radiograph attenuation values is no longer symmetric as the HU scale is truncated at –1,000 HU. This truncation causes an interaction between factors that affect the shape of the distribution curve (ie, radiograph dose and scanner manufacturer) and factors that affect the mean lung density (ie, total lung volume). Therefore, since measurements are inherently imperfect, and since radiograph dose is a central part of the measurement of density, a change in this mechanistic part of the measurement process will result in a different estimate of lung density. Furthermore, since measurements of emphysema rely on choosing a threshold or percentile value at the extreme end of this frequency distribution, any change in noise will result in a change of the emphysema estimate. In this study, we show that when the effective radiograph dose was increased from 30 to 118 mA, the %Emphysema dropped from 10 to 5% using a cutoff value of –950 HU and the lowest fifth percentile point increased from –959 to –938 HU. These data suggest that if lung volume and radiation dose values are not controlled in longitudinal studies, they may interact through changes in image noise and impact on emphysema measurements, possibly falsely suggesting disease progression or improvement.

These data complement the recent work of Boedeker et al,32 who measured the mean transfer factor in different CT scanners and using different reconstruction kernels, and showed that as the spatial frequency of the kernel increases so does the image noise through the same mechanism as that shown in equation 1. These data once again illustrate the need for careful CT scan parameter setting in multicenter and longitudinal studies.

Finally, it has been shown that the fundamental differences between CT scanners produced by different manufacturers can still have complicated effects on measurements of lung morphology even if standardized acquisition protocol are used.33 Our data provide important information that two modern multidetector CT scanners using comparable scan protocols produce images with a similar noise spectrum and, therefore, have fewer interactions with lung volume. These data suggest that CT scans obtained using these scanners can be compared to assess changes in lung structure.

There are several limitations to our study. First, while we were able to obtain serial CT scans on subjects, both lung volume and the CT scan parameters were changed, thereby eliminating the opportunity to calculate a correction for lung volume such as the one that Shaker et al34 have proposed. This correction factor may make it possible to account for the interaction of lung volume on the measurements of emphysema in serial CT scan studies and to compare results between CT scanner manufactures. However, we contend that the evidence that the emphysema at the –950-HU threshold or the lowest fifth percentile decreases with decreased image noise indicates that the noise spectrum within the CT scan image is of primary importance in longitudinal studies. Therefore, radiation dose is the most important parameter to control in longitudinal CT scan emphysema studies. Second, as our subjects have a significant smoking history it is possible that over the duration of this study actual changes in lung density occurred due to disease improvement or progression and may have obscured or exaggerated the differences we have ascribed to CT scan parameters. However, we think that a change in the extent of emphysema is unlikely considering the short mean time intervals between CT imaging studies (dose study, 0.5 ± 0.2 years; manufacturer study, 1.2 ± 0.4 years). Furthermore, there was no significant change in the pulmonary function of subjects during this time frame, so we think that the difference we observed in the measurements of lung density are due to the CT scan parameters and not to changes in lung structure.

In summary, this study confirms previous data showing that parameters affecting signal-to-noise ratio have to be carefully controlled in order not to introduce a bias into the quantitative CT scan measurements. Furthermore, this study extends the previous studies by describing the effect that decreased radiation dose has on quantitative emphysema measurements. The current data also show that when all the image acquisition parameters are standardized between different CT scanner manufacturers, comparable measurements of lung structure are obtained. These data will assist in the interpretation of longitudinal trials performed in multicenter settings. Finally, the choice of thresholds to identify emphysema is critical because, although the proper validation of these thresholds now has been performed using modern CT scanners and CT protocols,35 these values are only appropriate when using the same scanner acquisition and reconstruction settings (ie, dose and reconstruction kernel) as those in the validation study. However, if these variables are carefully controlled, valuable quantitative data can be obtained from CT scans that will yield important information on pathogenesis and intervention without exposing the subject to potentially high levels of ionizing radiation.

Acknowledgements

The authors wish to acknowledge Dr. Elizabeth Tench for statistical analysis; Anh-Toan Tran and Ida Chan, MD, for technical assistance in developing and supporting the lung analysis application; and Claudine Storness-Bliss, Dianna Louie, and Sukhinder Khattra for logistical assistance.

Footnotes

Abbreviations: %Emphysema = percentage of emphysema; HU = Hounsfield unit

This work was supported by National Cancer Institute grants N01-CN-85188, 1U01-CA-96109 and P01–96964 (to Dr. Lam); a Canadian Institutes of Health Research-Industry Partnership Grant (GlaxoSmithKline) No. DOP#76813 (PDP), and a British Columbia Lung Association/Canadian Institutes of Health Research New Investigator Award (to Dr. Coxson).

Dr. Coxson has received honoraria, consultant fees, and contract service agreements from GlaxoSmithKline for research studiesinvolving quantitative CT scanning and COPD. A percentage of his salary between 2003 and 2006 derived from contract funds provided to a colleague (Dr. Paré) by GlaxoSmithKline for the development of validated methods to measure emphysema and airway disease using CT scanning. There is no financial relationship between any industry and the current study. Dr. Paré is the principal investigator of a project jointly funded by the Canadian Institute of Health Research (CIHR) and GlaxoSmithKline (one third by the CIHR and two thirds by industry). This grant application was funded after peer review by the regular CIHR mechanism, and the funds received from industry are directly related to the operating costs of the study. Dr. Paré is also principal investigator of a Merck Frosst-supported research program to investigate gene expression in the lungs of patients who have COPD. These funds have supported the technical personnel and expendables involved in the project. Dr. Hogg served as a consultant to Altana Pharmaceuticals in 2003, 2004, and 2005, and also served on the Canadian advisory board for GlaxoSmithKline for 1 year in 2003. He has participated as a speaker in scientific meetings and courses organized and financed by various pharmaceutical companies including AstraZeneca, Altana Pharmaceuticals, and GlaxoSmithKline. He serves as the principal investigator on a grant jointly funded by the CIHR and GlaxoSmithKline (one third by the CIHR and two thirds by industry). This grant application was funded after peer review by the regular CIHR mechanism, and the funds received from industry are directly related to the operating costs of the study. Drs. Yuan, Mayo, Lam, and McWilliams have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication September 21, 2006. Accepted for publication April 6, 2007.

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