Modified look-locker inversion recovery T1 mapping indices: assessment of accuracy and reproducibility between magnetic resonance scanners

Phantom

Eight phantoms total, or a set of four phantoms for each 1.5T and 3T, were made from a NiCl₂-DTPA/agarose solution to evaluate a range of pre- and post-contrast myocardium and blood pool T1 values [15]. The concentrations of reagents were adjusted to mimic the T1 and T2 values of the normal myocardium and blood pool [9, 16, 17].

CMR parameters

Reference T1 times on each scanner were determined using standard inversion recovery prepared spin echo sequences at 10 different TIs from 22 to 5,000 ms (TR=10,000 ms, TE=9 ms), with the same FOV, matrix size, and slice thickness as the MOLLI experiment. For precision/reproducibility measurements, the phantoms were taken out of the magnet after the MOLLI and IR-SE images were acquired. Phantoms were then repositioned into the magnet 10–15 minutes later and a second set of MOLLI images acquired using the exact same parameters. The total average delay between two MOLLI scans was 8 hours. Our method of testing the true reproducibility measurements by leaving a long time span between the scans and repositioning the phantom resembles those of clinical reproducibility studies [19, 20], allowing these results to be more directly transferrable for in-vivo assessment.

Image analysis

Accuracy assessment

Smaller error numbers represent better accuracy.

Precision assessment (test-retest reproducibility)

Statistical analysis

Statistical analyses were performed using SAS 9.1 (Cary, North Carolina, USA) and MedCalc 12.2 (MedCalc Software, Mariakerke, Belgium). Statistical significance was defined as p<0.05. In order to statistically compare the T1/partition coefficient accuracy and reproducibility across field strengths, scanners, and protocols, a general linear mixed model was used. The scanners, field strengths, and MOLLI protocols were included as a fixed effect. Results were reported as least squared means ± standard error. Bland-Altman plots were used to describe the difference between scan repetitions for both native T1 and partition coefficient values.

Comparison of T1 and partition coefficient

Accuracy assessment

The mean percent error of MOLLI T1 values are displayed in Figure 1 and comparison of field strengths and protocols are summarized in Table 4. The MOLLI T1 errors were 6-14% across various MR scanners, while the errors for partition coefficient were less (6-10%) between MR scanners (Figure 1). There was no statistical significance in MOLLI T1 accuracy between the 17HB protocol and 11HB protocol (8.3% vs. 8.8%, p=0.18), so these values were combined for subsequent analyses. Mean percentage T1 errors were 6.7 ± 0.5%, 6.0 ± 0.4%, 8.0 ± 0.4%, 13.9 ± 0.4%, and 10.6 ± 0.4% for scanners 1 thru 5, respectively (least square means ± standard error).

1.5T scanners had smaller percent error, and hence better T1 accuracy, than 3T scanners (6.3 ± 0.3% for 1.5T vs. 10.8 ± 0.2% for 3T, p<0.0001). T1 accuracy for individual vials was also compared to look at subtleties as shown in Figure 2. The two post-contrast vials with lower T1 times had better accuracy (6.4 ± 0.4% and 7.2 ± 0.4%) than the two pre-contrast vials with longer T1 values (11.0 ± 0.4% and 15.9 ± 0.4%). The partition coefficient accuracy lies in the middle of pre and post-contrast vials (9.4 ± 0.3%).

The reference partition coefficient values estimated from IR-SE were 43.7% for 1.5T and 46.0% for 3T, corresponding to ECV values of 26.2% and 27.6%, respectively, if an average hematocrit of 0.4 is assumed. These values were similar to normal in-vivo ECV values from literature, 25.4% at 1.5T [17] and 26.7% at 3T [8]. Partition coefficient accuracy varied significantly between different scanners (p<0.0001). Average percentage partition coefficient errors were 7.9 ± 1.0%, 9.7 ± 0.9%, 8.9 ± 0.9%, 8.6 ± 0.9%, and 6.7 ± 0.9% for scanners 1 thru 5, respectively (least square means ± standard error, Figure 1). Field strength did not significantly affect partition coefficient accuracy (8.8 ± 0.6% for 1.5T vs. 8.0 ± 0.5% for 3T, p=0.109). In addition, different MOLLI protocols did not significantly affect partition coefficient accuracy (8.3 ± 0.6% for 17HB vs. 8.5 ± 0.6% for 11HB, p=0.574). Both T1 (p<0.001) and partition coefficient (p=0.001) accuracy vary significantly across heart rate.

Precision/reproducibility assessment

T1 reproducibility varied significantly between different scanners (p=0.007). Average T1 differences were 5.2 ± 0.4%, 5.5 ± 0.3%, 4.7 ± 0.3%, 3.8 ± 0.3%, and 3.1 ± 0.3% for scanners 1 thru 5, respectively (least square means ± standard error, Figure 3). T1 reproducibility did not vary significantly across heart rates (p=0.375). However, field strength did significantly affect T1 precision with 3T showing smaller percent error, or better scan/re-scan reproducibility, than 1.5T (5.3 ± 0.3% for 1.5T vs. 3.9 ± 0.2% for 3T, p<0.0001, Table 4).

Partition coefficient precision/reproducibility varied significantly between different scanners (p<0.0001). Average partition coefficient differences were 1.3 ± 0.6%, 6.4 ± 0.4%, 3.8 ± 0.4%, 3.3 ± 0.4%, and 1.3 ± 0.4% for scanners 1 thru 5, respectively (least square means ± standard error, Figure 3). Partition coefficient precision did not vary significantly across heart rates (p=0.24). However, field strength did significantly affect partition coefficient precision with 3T showing higher precision than 1.5T (3.8 ± 0.3% for 1.5T vs. 2.8 ± 0.2% for 3T, p=0.021, Table 4).

When compared individually, partition coefficient had significantly better precision (scan/re-scan reproducibility) than three of the four T1 vials with the “post-contrast blood” vial being the only exception (p=.096 for “post-contrast blood” vial vs. p<0.05 for all other vials). There was no statistical difference of precision when comparing individual T1 vials with each other. Precision was 3.6% for partition coefficient compared to 4.3%, 4.8%, 4.5%, and 4.5% for the four different T1 vials (Figure 4). Bland-Altman analysis in Figure 5 revealed tighter 95% confidence interval (CI) limits of agreement for partition coefficient over MOLLI T1 for both 1.5T and 3T (1.5T: -9.0% to 12.2% for T1 vs. -11.0% to 2.2% for partition coefficient; 3T: -8.0% to 10.3% for T1 vs. -1.8% to 6.8% for partition coefficient).

Accuracy

Accuracy was defined as the closeness of a MOLLI measurement to a reference IR-SE value, which was represented by percent error between MOLLI and IR-SE in this study. High T1/ECV accuracy will be particularly important for low to moderate extracellular matrix expansion diseases such as aging [25], diabetes [26], and hypertension; compared to diseases with substantial expansion like cardiac amyloidosis [27]. Different accuracy levels due to system differences will increase the inter-site variability and decrease the power of statistical comparison. Our data shows that IR-SE T1 values were different across scanners within the same field strength, validating our method of using scanner-specific IR-SE values to calculate accuracies. 17HB or 11HB protocol did not significantly affect either MOLLI T1 or partition coefficient values (p=0.177 for T1 vs. p=0.574 for partition coefficient). These results are consistent with previous reports on 1.5 and 3T scanners [8, 28]. Unlike MOLLI T1, partition coefficient accuracy was not dependent on field strength (p<0.0001 for T1 vs. p=0.109 for partition coefficient). Within the same field strength, MOLLI T1 values were significantly different across scanners (p<0.0001 for both 1.5T and 3T). However, partition coefficient had no significant difference among 1.5T scanners (p=0.13) and only had a very small difference among 3T scanners (49.2% vs. 49.8% vs. 50.0%, p=0.016).

Newer T1 mapping techniques, such as shortened modified look-locker inversion recovery (shMOLLI) [29] and saturation recovery sequences [30, 31], which are insensitive to heart rate variation were not available to us at the time of the study. ShMOLLI reduces acquisition time by using sequential inversion recovery measurements in a 5a+1a+1a sampling scheme each separated by only one R-R interval, which does not allow for full recovery of the magnetization for the three inversion pulses. Post-processing of images helps to correct for this problem by excluding data samples that fall outside accurate threshold. Saturation recovery sequences has demonstrated to have less T2 dependence and good agreement with IR-SE, as well as improved acquisition efficiency. As pre- and post-contrast T1 values are inherently different, an adaptive protocol (conditional sampling scheme) that optimizes for specific T1 ranges should improve accuracy. Preliminary data has shown subtle improvements of one such adaptive scheme over the standard MOLLI [32] with less variation at higher heart rates for 1.5T [9, 33]. In addition, latest MOLLI sequence has offered the flexibility of a fixed time pause in seconds instead of the traditional heartbeats between inversion recovery blocks. This improvement is important for proper magnetization recovery in subjects with fast heart rates, especially at 3T where the pre contrast T1 value is longer.

It is well know that considerable spatial variation in transmit field (B1) exists even at 1.5T and adiabatic pulses are used to reduce the sensitivity to B1 field inhomogeneity. Kellman and et al. demonstrated that a shorter tangent/hyperbolic pulse outperforms the traditional hyperbolic secant pulse with an improved inversion factor of 0.96 [34]. This improved inversion efficiency translates directly into higher MOLLI T1 accuracy and meet the specific absorption rate requirement of both 1.5T and 3T. Future research should explore new T1 acquisition techniques to more accurately assess myocardial and blood pool T1.

Precision/reproducibility

Reproducibility or precision is defined as the degree of closeness to which repeated measurements show similar results, which was measured by relative mean percent error between MOLLI scan repetitions. High reproducibility/precision leads to greater reliability of observed changes for a given parameter and significant reduction in sample size needed, as sample size varies with the square of the reproducibility.

Liu et al. reported good ECV and partition coefficient reproducibility for a single center; however, a lack of ECV and partition coefficient reproducibility/precision data exists for multicenter studies [20]. In this study, we demonstrated that although both MOLLI T1 and partition coefficient reproducibility were different across scanners and affected by field strength, they were not affected by heart rate (p=0.432 for T1 vs. p=0.375 for partition coefficient). When comparing partition coefficient to T1 values individually, partition coefficient had better precision than T1 for all vials, with only the “post-contrast blood” vial not showing a significant difference (p=.096 for “post-contrast blood” vial vs. p<0.05 for all others). Tighter limits of agreement for partition coefficient over MOLLI T1 for both 1.5T and 3T via Bland-Altman analysis further demonstrated better reproducibility of partition coefficient over T1 values. Thus, relative measures, such as partition coefficient, displayed its superiority to direct T1 quantification for reproducibility. This will translate directly to better power and smaller sample size requirement for ECV over T1 in multi-center studies [20].

Limitations

Several limitations in this study existed. First, no in vivo human data was used for the study. As the purpose of this study was to validate the accuracy and reproducibility of the acquisition technique itself, phantoms provided the most reproducible tools to examine and optimize the various parameters. To test the accuracy and precision across multiple scanners in-vivo, serial contrast-enhanced CMR studies need to be performed on the same subjects within a short time interval on different scanners. Such testing is unlikely due to the risks associated with multiple injections of MR contrast agents within a short time frame. Measurement errors are expected to be higher in patients compared with phantoms because of increased errors associated with physiological variations in-vivo. Additionally, ECV, rather than partition coefficient, is appearing to be more useful in the detection of subtle abnormalities present in diffuse myocardial fibrosis due to the large variability in patient hematocrit data [17]. As the only difference between partition coefficient and ECV is the hematocrit factor of roughly 0.4, the results in this study are easily translatable. Furthermore, only one time point post-contrast was chosen exemplarily. This coincides with most clinical protocols. Lastly, it is well known that T1 values could be affected by many factors, such as, room temperature [35]. Relative, and not absolute, accuracy and reproducibility measurements were reported in this study. Accuracy measures were standardized with IR-SE T1 and precision measures compared two MOLLIs with one another under same technical condition. This approach negates the potential influence of temperature and many other factors that might affect the results of comparison across different scanners.