Choice of knee cartilage thickness change metric for different treatment goals in efficacy studies.

INTRODUCTION: In knee osteoarthritis, local increase and decrease in cartilage thickness has been observed over short time intervals. Hence, averaging cartilage change across large regions may not capture the complexity of structural alterations in disease progression. This study aims to examine the relative performance of different metrics of cartilage thickness change for different clinical studies scenarios. MATERIALS AND METHODS: Metrics for assessing cartilage thickness change were characterized by conventional measures of change versus absolute values (the magnitude) of change, and by different methods of summarizing change over (sub-) regions. Sample sizes for these metrics were derived for 6-24-month observation periods, and for different treatment efficacies. Treatment effects were derived from an observational trial with 6-, 12-, and 24-month follow-up, ranging from slowing cartilage loss to stimulating cartilage growth. RESULTS: Projected sample sizes ranged from 10 to >10,000 patients/arm (median = 164), depending on metric choice, treatment efficacy, and observation period. The smallest sample sizes for metrics using magnitude of change typically were half the size of those using conventional measures of change. Extreme values, e.g., minimum change or average of last four-ordered values of absolute change, required smaller sample sizes than metrics averaging over one or more regions. CONCLUSIONS: Metrics using extreme magnitudes of change were most efficient in detecting differences between treatment and placebo, i.e., involved the smallest sample sizes across different DMOAD study lengths and treatment efficacies. Ancillary metrics can be used to clarify whether differences between treatment and placebo indicate structural benefit when needed.

Femorotibial Cartilage Thickness Change Distributions for Subjects without Signs, Symptoms, or Risk Factors of Knee Osteoarthritis.

OBJECTIVE: To describe the distribution of longitudinal femorotibial cartilage thickness annualized rate of change (ΔThCtAB) from quasi-population-based studies, and to construct a reference distribution for men and women without signs, symptoms, or risk factors of knee osteoarthritis (OA). METHODS: Segmented baseline and 1-year follow-up MRI from 43 men and 69 women of the Osteoarthritis Initiative (OAI) asymptomatic control cohort without risk factors and also baseline and 2-year follow-up data from 77 asymptomatic women of the Pfizer A9001140 study were included. The mean, standard deviation (SD), and correlation of ΔThCtAB in medial and lateral femorotibial subregions were estimated; distributions were tested for normality and for differences between cohorts and gender. RESULTS: Distributions of femorotibial ΔThCtAB rates were consistent between cohorts and were normally distributed, with rates <0.7%/y. Subregion ΔThCtAB SDs were correlated with mean baseline cartilage thickness (ratio = 3%-5%). However, ΔThCtAB SD did not increase with baseline thickness when estimated for different tertiles of any given subregion, indicating the relationship may rather be due to spatial location than to baseline thickness. CONCLUSIONS: Distributions of (subregional) longitudinal cartilage thickness rates of change appear to be normally distributed, not significantly different from zero, and similar for different cohorts of asymptomatic subjects. Given the spatial heterogeneity of subregional cartilage change observed in OA knees, the proposed reference distribution of subregional, ΔThCtAB may be used to describe and identify structural progression (i.e., cartilage loss) in individual OA knees with greater accuracy and sensitivity than conventional approaches, such as minimal detectable difference.

An efficient subset of morphological measures for articular cartilage in the healthy and diseased human knee.

The relationship between three-dimensional, MRI-based morphologic measurements commonly taken of knee cartilage was examined to determine whether a subset of variables fully reflects differences observed in cartilage in cross-sectional and longitudinal studies. The benefits of a subset of measures include increased statistical power due to reduced multiple comparisons, improved understanding of relationships between the morphologic measures of articular knee cartilage, and greater efficiency in reporting results. One hundred fifty-two women (77 healthy and 75 with knee osteoarthritis) had coronal 3-T MR images of the knee acquired at baseline and at 24 months. Measures of femorotibial cartilage morphology (surface area, thickness, volume, etc.) were determined in the medial and lateral tibia and femur. Cartilage thickness (mean cartilage thickness over the total area of the [subchondral] bone), total subchondral bone area, and percentage of denuded area of the subchondral bone were found to explain over 90% of the cross-sectional and longitudinal variation observed in other measures of cartilage morphology commonly reported in knee osteoarthritis. Hence, these three measures of cartilage morphology explain nearly all variation in a larger set of common cartilage morphology measures both cross-sectionally and longitudinally, both in healthy and in osteoarthritic knees. These variables hence define an efficient subset for describing structural status and change in osteoarthritic cartilage.

Does the use of ordered values of subregional change in cartilage thickness improve the detection of disease progression in longitudinal studies of osteoarthritis?

OBJECTIVE: To propose a novel strategy for more efficiently measuring changes in cartilage thickness in osteoarthritis (OA) using magnetic resonance imaging, and to hypothesize that determining the magnitude of thickness change independent of the anatomic location provides improved discrimination between healthy subjects and OA participants longitudinally. METHODS: A total of 148 women were imaged; 90 were Kellgren/Lawrence (K/L) grade 0, 30 were K/L grade 2, and 28 were K/L grade 3. Magnetic resonance images (3T) were acquired at baseline and at 24 months. Changes in femorotibial cartilage thickness were determined in 5 tibial and 3 femoral medial and lateral subregions, respectively (conventional approach). The new strategy provided ordered values of subregional change in each compartment, ranked according to the direction and magnitude of change. RESULTS: Using the new ordered values approach, the minimal P value for the differences in 2-year change in medial cartilage thickness of K/L grade 3 and K/L grade 0 participants was 0.001 (Wilcoxon test), with 4 ordered medial subregions differing significantly between both groups. With the conventional approach, only 1 medial subregion differed significantly between K/L grade 3 and K/L grade 0 (P = 0.037). Cartilage thickening was significantly greater in K/L grade 2 versus K/L grade 0 participants in 1 medial subregion using the conventional approach (P = 0.016), and in 2 medial subregions (minimal P = 0.007) using the ordered values approach. CONCLUSION: The novel ordered values approach is more sensitive in detecting cartilage thinning in K/L grade 3 and cartilage thickening in K/L grade 2 versus K/L grade 0 participants. The new method may be particularly useful in the context of other comparisons, e.g., a group treated with a disease-modifying OA drug versus one treated with a placebo.

Longitudinal quantitative MR imaging of cartilage morphology in the presence of gadopentetate dimeglumine (Gd-DTPA).

MRI-based cartilage morphometry can monitor cartilage loss in osteoarthritis. Intravenous Gd-DTPA injection is needed for compositional (proteoglycan) cartilage imaging with delayed gadolinium enhanced MRI (dGEMRIC). However, longitudinal changes of cartilage morphology have not been compared in the presence and absence of Gd-DTPA. Baseline and 2-year follow-up images were acquired in 41 female participants with definite medial radiographic osteoarthritis, both before and 2 h after Gd-DTPA injection, and cartilage thickness was measured. In the absence of Gd-DTPA, a 2.6% reduction in cartilage thickness was observed between baseline and follow-up in the central subregion of the medial femorotibial compartment (standardized response mean [SRM]= -0.33; P<0.05), but only a 0.7% reduction (SRM= -0.10; P=0.51) in the presence of Gd-DTPA. The findings suggest that morphometric cartilage measurement in the presence of Gd-DTPA needs to undergo further validation, before one can recommend longitudinal dGEMRIC and morphological cartilage imaging to be performed in a single session.

Quantitative imaging of cartilage morphology at 3.0 Tesla in the presence of gadopentate dimeglumine (Gd-DTPA).

MRI-based cartilage morphometry was previously validated in the absence of gadopentate dimeglumine (Gd-DTPA). However, Gd-DTPA is required for compositional (proteoglycan) imaging using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). Therefore, the effect of Gd-DTPA on cartilage morphometry was studied. A total of 165 female participants (67 with and 98 without osteoarthritis [OA]) were imaged at 3.0 Tesla before and 2 hr after intravenous Gd-DTPA injection. Flip angles in post-Gd-DTPA scans varied between 12 degrees and 35 degrees . Cartilage volume and thickness of post- vs. pre-Gd-DTPA scans showed intraclass correlation coefficients (ICCs) of 0.85 > or = r > or = 0.95, mean differences between -2.1% and +1.1%, and standard deviations (SDs) of differences between 4.7% and 9.2%. Mixed-effect models found no consistent impact of flip angle and OA status on post- vs. pre-Gd-DTPA differences. Accurate morphological measurements of cartilage can be obtained after Gd-DTPA injection, allowing compositional and morphological imaging to be combined into one session.

Reader and platform reproducibility for quantitative assessment of carotid atherosclerotic plaque using 1.5T Siemens, Philips, and General Electric scanners.

PURPOSE: To evaluate the platform and reader reproducibility of quantitative carotid plaque measurements. MATERIALS AND METHODS: A total of 32 individuals with >or=15% carotid stenosis by duplex ultrasound were each imaged once by a 1.5T General Electric (GE) whole body scanner and twice by either a 1.5T Philips scanner or a 1.5T Siemens scanner. A standardized multisequence protocol and identical phased-array carotid coils were used. Expert readers, blinded to subject information, scanner type, and time point, measured the lumen, wall, and total vessel areas and determined the modified American Heart Association lesion type (AHA-LT) on the cross-sectional images. RESULTS: AHA-LT was consistently identified across the same (kappa = 0.75) and different scan platforms (kappa = 0.75). Furthermore, scan-rescan coefficients of variation (CV) of wall area measurements on Siemens and Philips scanners ranged from 6.3% to 7.5%. However, wall area measurements differed between Philips and GE (P = 0.003) and between Siemens and GE (P = 0.05). In general, intrareader reproducibility was higher than interreader reproducibility for AHA-LT identification as well as for quantitative measurements. CONCLUSION: All three scanners produced images that allowed AHA-LT to be consistently identified. Reproducibility of quantitative measurements by Siemens and Philips scanners were comparable to previous studies using 1.5T GE scanners. However, bias was introduced with each scanner and the use of different readers substantially increased variability. We therefore recommend using the same platform and the same reader for scans of individual subjects undergoing serial assessment of carotid atherosclerosis.

Accuracy and precision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) of articular cartilage represents a powerful tool in osteoarthritis (OA) research, but has so far been confined to a field strength of 1.5T. The aim of this study was to evaluate the precision of quantitative MRI assessments of human cartilage morphology at 3.0T and to correlate the measurements at 3.0T with validated measurements at 1.5T. METHODS: MR images of the knee of 15 participants with OA and 15 healthy control subjects were acquired using Siemens 1.5T and 3.0T scanners. Double oblique coronal scans were obtained at 1.5T with a 1.5-mm partition thickness, at 3.0T with a 1.5-mm partition thickness, and at 3.0T with a 1.0-mm partition thickness. Cartilage volume, thickness, and surface area of the femorotibial cartilage plates were quantified using proprietary software. RESULTS: For 1.5-mm partition thickness at 1.5T, the precision error was 3.0% and 2.6% for cartilage volume and cartilage thickness, respectively. The error was smaller for a 1.5-mm partition thickness at 3.0T (2.6% and 2.5%) and still smaller for a 1.0-mm partition thickness at 3.0T (2.1% and 2.0%). Correlation coefficients between values obtained at 3.0T and 1.5T were high (r > or = 0.96), with no significant deviation between the two field strengths. CONCLUSION: Quantitative MRI measurement of cartilage morphology at 3.0T (partition thickness 1 mm) was found to be accurate and tended to be more reproducible than at 1.5T (partition thickness 1.5 mm). Imaging at 3.0T may therefore provide superior ability to detect changes in cartilage status over time and to determine responses to treatment with structure-modifying drugs.