Automated Total Kidney Volume Measurements in Pre-clinical Magnetic Resonance Imaging For Resourcing Imaging Data, Annotations, And Source Code

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Marie E.Edwards， Sigapriya Periyanan， Deema Anaam²， Adriana V. Gregory and Timothy L. Kline 'Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; and 2Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA

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The objective of this study was to validate a fully automated total kidney volume measurement method for pre-clinical rodent trials that is fast, accurate, reproducible, and to provide these resources to the research community. Rodent studies that involve imaging are crucial for monitoring treatment efficacy in diseases such as polycystic kidney disease. Previous studies utilize manual or semi-automated segmentation, which is time-consuming and potentially biased. To develop our automated system, a total of 150 axial magnetic resonance images(MRI) from a variety of mouse models were manually segmented and used to train/validate an automated algorithm. To test the longitudinal application of the model, four mutant and four wild-type mice were imaged sequentially over three to twelve weeks via MRI. Segmentations of the kidneys (excluding the renal pelvis)were generated by the automated method and two different readers, with one reader repeating the

measurements. Similarity metrics and longitudinal analysis were calculated to assess the performance of the automated compared to the manual methods. The automated approach required no user input, besides a final visual quality control step. Similarity metrics of the automated method versus the manual segmentations were on par with inter-and intra-reader comparisons. Thus, our fully automated approach described here can be safely used in longitudinal, pre-clinical trials that involve the segmentation of rodent kidneys in T2-weighted MRIs.

Translational Statement

This study developed a fully automated method for measuring total kidney volume for preclinical imaging in a mutant mouse model of polycystic kidney disease as well as wild-type mice. This study also established both interreader and intrareader variabilities in the measurement of total kidney volume for preclinical imaging. Similar studies and algorithmic approaches can be used to establish methods for clinical imaging data and are needed for accurate disease prognosis and clinical decision-making. We are providing the imaging data, annotations, and source code to the research community.

The measurement of organ volume has been shown to correlate with clinical manifestations and morbidity of diseases such as total kidney volume (TKV) in autosomal dominant polycystic kidney disease (PKD)l,2 and is used to ascertain the effectiveness of treatment interventions. Research, clinical trials, and increasingly clinical nephrology use these measurements to monitor disease progression in both animal models and patients, evaluate the effectiveness of therapies," and predict outcomes.

Currently, preclinical studies are occurring at an unprecedented rate to look for new treatments to slow the progression of PKD. A key advantage of magnetic resonance imaging (MRI) in animal models of PKD is the ability to use in vivo imaging, which allows for longitudinal volumetric studies that use the same animal. Numerous studies that involve 2semiautomated,'3,14and registration-based manual,9-12 automated segmentations56 of mouse kidneys have been performed previously.

Many of the methods deemed as automated still require user input. A majority of these preclinical studies use manual segmentations, which are time-consuming and costly as well as introduce observer bias. Therefore, our laboratory has assessed the variability in the measurement of TKV and developed an automated analysis program to measure TKV in magnetic resonance scans of murine models of the disease.

RESULTS

Intra-and interobserver variability of manual kidney segmentations

Figure 1 shows the results of the Bland-Altman analysis of TKV as measured manually by 2 readers(interobserver variance) and repeat measurements by reader 2 (intraobserver variance). When reader 1 was compared with reader 2, there was a mean percentage difference of 7.7% and a 95% confidence interval of ±4.5%. When reader 2 performed repeat measurements of the same image, there was a mean percentage difference of -0.5% and a 95% confidence interval of ±3.9%. Regression analysis indicated that there is a high agreement in TKV among all methods， with an R² value of ≥0.99.

Validation of the automated segmentation algorithm The automated method compared with each reader in relation to the percentage difference of TKV was similar to that of the inter-and intraobserver variance as suggested by the Bland-Altman plots in Figure 1. When reader 1 was compared with the automated method, there was a mean percentage difference of 5.2% and a 95% confidence interval of ±5.8%When reader 2 was compared with the automated method, there was a mean percentage difference of -2.5% and a 95%confidence interval of ±6.5%.

The distinction between wild-type and mutant mice

The mean and SD TKVs were plotted at each time point for each method and separated by genotype (mutant vs. wild-type). As seen in Figure 2, the mean TKV is always smaller in wild-type mice at each time point than in mutant mice. All 3 methods(automated, reader 1, and reader 2) demonstrate a significant separation of mouse type at 9 and 12 weeks of age.

DISCUSSION

The analysis of kidney volume in PKD is one of the most important metrics currently used for characterizing disease status. Before our work, there was no alternative to manually tracing kidneys in model systems of PKD. Because of the time taken to trace these structures, as well as the time required to train a person to perform these measurements, and the potential for inter-operator variability, in this study we developed and validated a fully automated segmentation method for TKV. Automated segmentations are computed in a matter of minutes(depending on computing power), whereas manual segmentations take 20 to 40 minutes. Unlike manual or even semiautomated segmentation methods, this automated method will produce the same exact results each time it is applied to the same image.

Preclinical trials often comprise both a control group and treatment group(s); therefore, it is essential that the auto-mated method is sensitive enough to detect volume differences between groups appropriately.7 Figure 2 shows that manual segmentation and automated segmentation both show a significant separation in the wild-type and mutant groups at 9 weeks of age. Although the overall agreement was excellent, visual comparisons suggested minor disagreement on whether to include or exclude the renal pelvis in a small subset of slices. Although it is common practice to exclude the

Figure 1|Bland-Altman and regression analysis of (a,e) interobserver and (b,f) intraobserver total kidney volume (TKV)

measurements (measured in millimeters) in addition to the automated (Auto) method compared with (c,g) reader 1 and (d,h) reader 2. Bland-Altman plots show the mean difference (solid line) and 95% confidence interval (dotted lines). Regression analysis shows the correlation between the compared methods.