AstraZeneca, Macclesfield, 1Department of Medical Physics, Ninewells Hospital, Dundee, 2Rheumatology Research Group, University Hospital Aintree, Liverpool and 3Department of Rheumatology, Southmead Hospital, Bristol, UK.
Correspondence to: S. R. Morgan, Experimental Medicine Group, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. E-mail: shethah.morgan{at}astrazeneca.com
Abstract
Objective. To investigate the variability between different high-field scanners in magnetic resonance imaging (MRI) measurement of knee cartilage volume in healthy female volunteers.
Methods. Five volunteers had both knees scanned using three different MRI scanners. Cartilage volume in each compartment was measured from the images by image segmentation. The data were analysed using analysis of variance models.
Results. The mean total cartilage volume of the 10 knees scanned at three different centres was 16.15, 16.40 and 15.63 ml for the Siemens, GE and Philips scanners respectively. Small systematic differences were seen in the total knee cartilage volume results.
Conclusions. Although there were small systematic differences in knee cartilage volume, the three MRI scanners gave broadly similar results.
KEY WORDS: MRI, Knee cartilage, Multicentre clinical trials.
In osteoarthritis (OA), the current standard technique for measuring structural changes in the joint approved by the US Food and Drug Administration is X-radiography of joint space width [1]. However, this technique lacks precision, particularly in short-term studies: it has been estimated that several hundred patients would have to be studied for 23 yr to have any chance of detecting drug effects on structural changes in OA [2]. Other techniques under investigation include: (i) arthroscopy, an invasive procedure that itself may have an effect on the disease [3]; (ii) biomarkers, the results of which have been limited to date [4]; and (iii) magnetic resonance imaging (MRI), for which techniques have been developed that allow accurate measurement of both the volume and the thickness of cartilage in the knee joint from the analysis of data collected using standardized clinical MRI pulse sequences [57]. Recently, single-centre studies have shown disease progression [8, 9]. However, large clinical trials of investigational disease-modifying agents will need to be performed in a multicentre environment.
There is a broad consensus concerning the use of fat-suppressed spoiled-gradient recalled echo sequences in the MRI assessment of articular cartilage. However, the implementation of this sequence is slightly different among the major MRI scanner manufacturers. Data demonstrating that cartilage volume assessed by machines from different manufacturers is broadly comparable would lend support to the use of multicentre MRI trials of disease-modifying agents in OA. To our knowledge, this is the first study that has been conducted to investigate differences in cartilage volume in subjects scanned with machines from different manufacturers.
Methods
This study was conducted in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki. The local Ethics Committee for each centre approved the protocol before commencement of the study, and all volunteers gave written informed consent.
Volunteers
Twenty healthy female volunteers, aged between 24 and 58 yr, with no history of previous knee injury or knee pain and a normal knee on examination were enrolled into the study.
Study design
Five volunteers were recruited at Macclesfield and had both knees scanned using three different scanners in three cities in the UK to provide data for inter-scanner variability. In addition, 15 volunteers were enrolled at Liverpool, Bristol and Manchester and had one knee scanned using one scanner to provide data for validation of within-segmenter variability. Each volunteer underwent a non-weight-bearing period of at least 30 min prior to scanning.
MRI
Imaging was performed using a 1.5 tesla GE (Milwaukee, WI, USA) Signa scanner at Liverpool, a 1.0 tesla Siemens (Erlangen, Germany) Impact scanner at Bristol, and a 1.5 tesla Philips (Eindhoven, The Netherlands) Gyroscan scanner at Manchester. For each scanner, the gradient calibration was checked regularly during routine maintenance. To allow measurement of cartilage volume, a standardized 3D spoiled-gradient echo sequence with fat suppression was employed. The respective manufacturers' implementations of this sequence are 3D SPGR FATSAT (GE), 3D FATSAT FLASH (Siemens) and 3D-SPIR-FFE (Philips). A repetition/echo time of 58/11 ms was used (flip angle 40°) to generate a series of 60 sagittal slices (each 1.6 mm thick) across the knee, with field of view 160 x 160 mm and displayed matrix 256 x 256, giving an effective pixel resolution of 0.63 x 0.63 mm. The total imaging times were 11 min 52 s, 11 min 08 s and 11 min 11 s for the GE, Siemens and Philips scanners, respectively.
Assessment of scans
Femoral, patellar, medial tibial and lateral tibial cartilage compartments were segmented manually using the image-processing package Tosca (IBM, Winchester, UK). A medical physicist with previous segmentation experience [5] trained a non-expert segmenter to assess the scans centrally. 3D reconstructed volumes were generated for each cartilage compartment, as described previously [5]. In order to set the results from the different scanners in context, the reproducibility of the segmentation method was assessed using a single knee scan from all 20 volunteers recruited. These scans were then segmented twice and the within-scan coefficient of variation was found to be 3.0% for total knee cartilage volume and between 3 and 10% for the other compartments.
Statistical analysis
The articular cartilage volume in each compartment (femoral, patellar, medial tibial and lateral tibial) and the total cartilage volume in the knee joint were analysed statistically using analysis of variance (ANOVA) models.
The primary aim was to assess the effect of different scanners on knee cartilage volume. This analysis included data from both knees of five volunteers recruited at Macclesfield and from three scanners (30 observations in total). Using these values, an ANOVA model was fitted with random-effect terms for volunteer, scanner and volunteer x scanner interaction. Between-volunteer coefficients of variation within and between scanners were calculated from the components of variation estimated from this model.
Results
Demography
Five volunteers provided data for inter-scanner variability. Their median (range) age, height, body weight and body mass index were 30.0 (2437) yr, 170 (152174) cm, 69 (5898) kg and 25 (2036) kg/m2 respectively.
Cartilage volume
Figure 1 shows MRIs for the same volunteer using Siemens, GE and Philips scanners. The statistical analysis of the cartilage volume data for the five volunteers (10 knees) who had assessments repeated using all three scanners showed that there were small systematic differences between the scanners for some endpoints (Table 1). The size of this difference varied but was considered to be small. The mean total knee cartilage volume of the 10 knees scanned at the three centres was 16.15, 16.40 and 15.63 ml for the Siemens, GE and Philips scanners, respectively. The mean results from the Philips scanner were generally lower. Scanner miscalibration may have contributed to this. Even allowing for the small systematic difference between the scanners, the results show that there was little extra between-volunteer variability when scans were taken using different scanners (e.g. for total knee cartilage the coefficient of variation was 9.0%) compared with the variability within a scanner (e.g. for total knee cartilage the coefficient of variation was 8.7%).
|
|
Discussion
The variability of MRI cartilage measurements in a multicentre setting may be influenced by variables such as the type of scanner, pulse sequence, method of scanner calibration, radiographic practice and patient positioning in the scanner.
In our pilot studies (our unpublished data), image quality for 1.0 and 1.5 tesla scanners were comparable. However, the image quality from a 0.5 tesla scanner was found to be inadequate. Therefore, centres providing at least 1.0 tesla magnets were chosen. The imaging time (approximately 11 min for each examination) was considered to be practical for multicentre patient studies.
The three different MRI scanners used in this study, manufactured by GE, Siemens and Philips, enabled a quantitative evaluation of knee volume from scans using a range of scanner models located at different centres. There were small systematic differences in cartilage volume between the scanners for some of the endpoints; however, once these systematic differences between the scanners had been taken into account there was little extra between-volunteer variability observed using the different scanners. The small differences in cartilage measurement suggest that we were unable to control fully for differences between centres in the study.
Within-segmenter variability may be higher in this study compared with published data [6, 7] because of differences in image resolution or segmenter performance. Moreover, it is recognized that greater variability might be seen in patients with OA who have cartilage lesions compared with healthy volunteers.
Whilst the study was small in size, it is reassuring that cartilage volumes assessed by scanners from different manufacturers were broadly comparable. However, in the context of a study of an investigational disease-modifying agent, which may be up to 23 yr in duration, it is essential that in each centre the same scanner is used throughout the trial, as the magnitude of cartilage loss expected over time in such trials is small. In order to minimize variability, a schedule and specification for consistent, regular, documented calibration of dimensions measured using MRI equipment should be agreed prior to study commencement at each centre; standardized imaging protocols should be used as far as possible, and assessment of images should be carried out centrally, ideally by a single segmenter.
Conclusion
Although there were small systematic differences in knee cartilage volume, the three MRI scanners gave broadly similar results.
Acknowledgments
We are grateful to Dr Z. Gao of the University of Manchester for preparing 3D reconstructed cartilage volumes. The clinical collaborators were: Professor A. J. Silman (University of Manchester), and the radiologists Dr B. Eyes (University of Liverpool), Dr I. Watt (University of Bristol), Dr C. Hutchinson and Professor J. Adams (University of Manchester) provided MRI clinical reports.
References