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Diagnostic Performance and Interobserver Consistency of the Prostate Imaging Reporting and Data System Version 2: A Study on Six Prostate Radiologists with Different Experiences from Half a Year to 17 Years

Background: One of the main aims of the updated Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2) is to diminish variation in the interpretation and reporting of prostate imaging, especially among readers with varied experience levels. This study aimed to retrospectively analyze diagnostic consistency and accuracy for prostate disease among six radiologists with different experience levels from a single center and to evaluate the diagnostic performance of PI-RADS v2 scores in the detection of clinically significant prostate cancer (PCa). Methods: From December 2014 to March 2016, 84 PCa patients and 99 benign prostatic shyperplasia patients who underwent 3.0T multiparametric magnetic resonance imaging before biopsy were included in our study. All patients received evaluation according to the PI-RADS v2 scale (1–5 scores) from six blinded readers (with 6 months and 2, 3, 4, 5, or 17 years of experience, respectively, the last reader was a reviewer/contributor for the PI-RADS v2). The correlation among the readers' scores and the Gleason score (GS) was determined with the Kendall test. Intra-/inter-observer agreement was evaluated using κ statistics, while receiver operating characteristic curve and area under the curve analyses were performed to evaluate the diagnostic performance of the scores. Results: Based on the PI-RADS v2, the median κ score and standard error among all possible pairs of readers were 0.506 and 0.043, respectively; the average correlation between the six readers' scores and the GS was positive, exhibiting weak-to-moderate strength (r = 0.391, P = 0.006). The AUC values of the six radiologists were 0.883, 0.924, 0.927, 0.932, 0.929, and 0.947, respectively. Conclusion: The inter-reader agreement for the PI-RADS v2 among the six readers with different experience is weak to moderate. Different experience levels affect the interpretation of MRI images.

combining anatomical T2-weighted imaging (T2WI) and functional MRI sequences, such as diffusion-weighted imaging (DWI), apparent-diffusion coefficient (ADC) maps, or dynamic contrast-enhanced (DCE) imaging, [2,3] which has become the preferred imaging method for the prostate and periprostatic structures. This approach provides more accurate localization and high-quality images for the detection of prostate diseases, especially for PCa. [4][5][6][7] Due to differences in magnetic resonance scanners, acquisition parameter settings, and subjective evaluation criteria, the interpretation of mp-MRI findings by radiologists differs from different clinicians. Therefore, how to unify diagnostic systems and bridge the gap between different radiologists is increasingly recognized as an important clinical problem.
To address this issue, the European Society of Urogenital Radiology (ESUR) launched the first version of a global prostate standardization guide called the Prostate Imaging Reporting and Data System (PI-RADS; herein referred to as the PI-RADS v1) in 2012. [8] The PI-RADS v1 was widely distributed, but some limitations in its clinical application caused significant controversy regarding inter-reader reproducibility and the feasibility of the guidelines. [9][10][11][12][13] First, the PIRADS v1 does not include a rating scheme, and no weights for individual parameters were defined. Second, the PI-RADS v1 does not combine all imaging sequences into a comprehensive assessment. [14] Third, the value of DCE in evaluating the transition zone (TZ) is overestimated by the PI-RADS v1 [15] and no value was assigned or recommended for DCE. In addition, DWI in the peripheral zone (PZ) has previously been reported to exhibit superior performance. [12] Considering these issues, in 2014, the updated PI-RADS version 2 (herein referred to as the PI-RADS v2) was released by the International Collaboration of the American College of Radiology, ESUR, and AdMetech Foundation, based on the best available evidence and expert consensus opinion worldwide. [16] Compared with the PI-RADS v1, the PI-RADS v2 has a simplified scoring system and uses only a 5-point scale for comprehensive evaluation of all imaging sequences. In addition, the PI-RADS v2 uses a more differentiated weighting system based on the concept of dominant techniques and does not recommend the magnetic resonance spectroscopic (MRS) imaging for PI-RADS assessment but rather DWI as the dominant sequence in PZ and T2WI as the dominant sequence in TZ. Third, the PI-RADS v2 recommends optimal technical parameters for T2WI, DWI, and DCE sequences and introduces a new size threshold of 15 mm for T2WI, DWI, and ADC to differentiate between PI-RADS scores of 4 and 5. Moreover, the aims of the PI-RADS v2 are to improve the detection of clinically significant cancer and increase the accuracy of risk assessment for patients with suspected PCa, to enhance diagnostic confidence in benign diseases, to establish the most simplified MRI capture process globally and diminish variation in the acquisition and interpretation of prostate images, and to promote communication between clinicians and radiologists. [16,17] Based on these advantages and aims of the PI-RADS v2, investigation of the utility of the PI-RADS among readers is crucial, not only between two readers for a small number of cases, but also among more readers with varying experience levels for a high number of cases. Therefore, the purpose of this study was to retrospectively analyze consistency and accuracy in diagnosing prostate disease among six radiologists with different experience levels and to evaluate the diagnostic performance of the PI-RADS v2 in detecting clinically significant PCa.

Ethical approval
This retrospective, single-center study was approved by the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Institutional Review Board, and written informed consent was provided by all patients before examination.

Study design
Between December 2014 and March 2016, patients with clinically suspected PCa due to elevated prostate-specific antigen (PSA) levels and/or abnormal signal nodules were recruited for this study. Initially, we reviewed 317 patients who underwent 3.0T prostate MRI. However, 134 patients were excluded for the following reasons: (1) the patients had no histopathologically confirmed results (n = 30); (2) the patients underwent prior treatment, including surgical therapies, irradiation, cryosurgery, or hormonotherapy (n = 15); (3) previous biopsies were performed within 6 weeks before the MR examination (n = 2); (4) DCE imaging was not performed in the patient due to renal dysfunction and/or unwillingness to undergo the procedure (n = 84); and (5) the quality of the MRI images was poor due to movement artifacts, catheter artifacts, or the presence of hip implants (n = 3). Finally, the remaining 183 patients were included and a flowchart of the patient selection process is provided in Figure 1.

Magnetic resonance imaging protocol
All examinations were performed with a 3.0T system (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany), using an anterior 18-element body coil combined with a posterior spine coil array. The scan sequences included T2WI, DWI, and DCE, which were performed using the parameters shown in Table 1. In DWI, the b values consisted of 0, 50, 200, 400, 600, 800, 1000, and 1500 s/mm 2 . ADC maps were automatically reconstructed for qualitative and quantitative assessments of DWI. Axial DCE images were obtained before, during, and after rapid injection of gadolinium chelate (35 phases and 8 s for each phase) using a power injector (Medtron, Saarbruecken, Germany), followed by a 20 ml saline flush injected at a rate of 2.5 ml/s. All axial images were copied at the same location.   These six readers were blinded to all identifying information of the patients and their clinicopathologic outcomes. During scoring, the T2WI, DWI, and DCE images of each patient were shown to the readers at the same location on one single screen by an assistant fellow who assigned a scoring region but was not involved in the scoring process, and then the readers independently provided a single score (on a scale from 1 to 5 scores) based on the PI-RADS v2 and their own experience and comprehensive judgment after browsing all sequences. After 2 weeks, reader 3 repeated the scoring process to test intrareader reproducibility.

Pathologic evaluation
After the MRI examination, all patients underwent a 12-core transrectal ultrasound (TRUS)-guided prostate biopsy (within 6 weeks; median: 1 week) to obtain tissue samples for histopathological examination. To match biopsy sextants and MR images, the prostate was divided into 12 regions, and each specimen was individually labeled according to its location and histologically analyzed. The targeted biopsy was performed using an ultrasound system (Hawk 2102, BK Medical, Denmark) equipped with a 5.1-MHz endocavitary probe and a spring-loaded biopsy gun with an 18G core biopsy needle; a single urologist with 20 years of skilled experience performed these biopsies. The samples were assessed by an experienced genitourinary pathologist with more than 10 years of experience, who was blinded to the MRI results. The cases were obtained from standard pathologic reports, and each sample was histologically analyzed as cancerous or noncancerous and then given a respective Gleason score (GS) if the sample was classified as PCa. Finally, we selected the GS matching the scoring region in the MRI images as the final GS. SPSS 19.0 (SPSS, Chicago, IL, USA) and MedCalc version 11.4.2.0 (MedCalc statistical software, Mariakerke, Belgium) were used for the data analysis, and all data were expressed as the mean ± standard deviation (SD). The normality and equality of variances of the parameter value

Patient characteristics
One-hundred and eighty-three patients were included in this retrospective, single-center study, including 84 patients who were diagnosed with PCa and 99 patients whose 1188 biopsy specimens were all diagnosed as benign hyperplasia tissue, representing the BPH group in the study. The mean age of our study population was 65.4 ± 8.5 years (range: 46-88 years). The mean PSA level was 134.48 ± 230.97 ng/ml (range: 1.51-1000.00 ng/ml, excluding one patient without a PSA value) in the PCa group and 14.29 ± 19.17 ng/ml (range: 0.26-115.04 ng/ml, excluding six patients without a PSA value) in the BPH group. The biopsy results confirmed clinically significant PCa (GS ≥ 4 + 3 = 7) in 58 (69%) patients and low-risk PCa (GS ≤ 3 + 4 = 7) in 26 (31%) patients. Patient characteristics are shown in Table 2.

Interobserver agreement
The κ statistics of all possible pairs of readers were calculated, and pairwise κ statistics and standard errors are shown in Table 3. In general, the inter-reader agreement was weak to moderate, while the intrareader agreement was good. The median κ statistic and standard error among all possible pairs of readers for the PI-RADS v2 were 0.506 and 0.043, respectively. Figures 2 and 3 show representative lesions for BPH and PCa with inter-reader variability, respectively.

Differences in grouping variables
The data did not conform to the criteria for normality or homogeneity of variance. The Kruskal-Wallis H-test distributions were tested by the Kolmogorov-Smirnov test and Levene's F-test. Differences in reader grouping variables were evaluated by the Kruskal-Wallis H-test and a comparison between all possible pairs of readers was performed using the Nemenyi test. Intra-and inter-reader agreement was evaluated using κ statistics, [18] and κ coefficients were assessed as follows: [19] 0.01-020: slight agreement; 0.21-0.40: fair agreement; 0.41-0.60: moderate agreement; 0.61-0.80: substantial agreement; and 0.81-0.99: almost perfect agreement. The correlation among the readers' scores of PCa and the GS was determined with the Kendall τ correlation coefficient (presented as "r"), which is a nonparametric statistical method used for variables that do not meet normality. The r ranged from −1 to 1, with 1 corresponding to a 100% positive correlation, −1 corresponding to a 100% negative correlation, and 0 corresponding to independence. [18] The Wald test was used to obtain the P value of the final Kendall τ estimate. A receiver operating characteristic curve (ROC) analysis was performed, and the area under the curve (AUC) was obtained to evaluate diagnostic performance. The AUC values from the six readers were compared using the Z-test. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated by dichotomizing the PI-RADS criteria according to cutoff values of 3 and 4, which were used as the threshold to distinguish benign cases from cancer and low-risk cancer (defined as GS ≤ 3 + 4 = 7) from clinically significant cancer (defined as GS ≥ 4 + 3 = 7) [16] in PCa patients. A P < 0.05 was used to identify a statistically significant difference.  0.788 0.036 *κ score of the overall PI-RADS score; † 3a-The first score of reader 3; 3b-The second score of reader 3 (the second score was performed two weeks after the first score). PI-RADS v2: Prostate Imaging Reporting and Data System Version 2.

Correlations of the Prostate Imaging Reporting and Data System with pathologic results
The double-variable data in our study did not meet the requirements for normality, and the correlations between the PI-RADS v2 scores of the readers and the GSs of the pathologic results are shown in Table 4. On the basis of the PI-RADS v2, the average correlation between the six readers' scores and the GS was positive (r = 0.319; P = 0.006), exhibiting significance and weak-to-moderate strength. The scores of reader 3 were most significant in relation to the GS (r = 0.464; P = 0.000), while the correlation between the scores of readers 2, 4, and 6 and the GS was weak.

Receiver operating characteristic curves and diagnostic performance
Supplementary Table 2 shows that in all cases, readers 2 and 6 showed the highest accuracy (90.2%), reader 4 showed the highest sensitivity (96.4%), and reader 1 showed the highest specificity (91.9%). For PCa detection, reader 6 showed the lowest accuracy (70.2%), reader 3 showed the highest accuracy (79.8%), and reader 5 showed the highest sensitivity (96.6%). Figure 4 shows the ROC curves of the six readers with different experience levels. The comparison of the AUC values is shown in Supplementary Table 3. In addition to readers 1 and 6 (Z = 2.341; P = 0.019), no significant differences were found in the overall AUC values  , and (c) an axial early DCE image, and the results were confirmed by (d) a pathology image (hematoxylin and eosin staining, ×200). Five of the six readers did not note the right peripheral zone lesion; only reader 6 noticed it. The DCE image showed that the lesion presented slight early enhancement, but the other five readers considered the prostate as a whole to be negative for DCE. Finally, the overall PI-RADS v2 scores assigned by the six readers were 2, 2, 2, 2, 2, and 4, respectively.  among the readers. However, readers 2 and 3, readers 3 and 4, readers 3 and 6, readers 1 and 6, and readers 5 and 6 showed significant differences in AUC values for the PCa group.

dIscussIon
In the current study, we invited six radiologists with varying experience levels to read prostate MRI images and assign scores using the PI-RADS v2. Our study revealed a moderate level of interobserver agreement among these readers, indicating that different experience levels may affect the interpretation of images, even under the guidance of the PI-RADS v2. A similar level of interobserver agreement was reported by Muller et al., [18] who showed that the interobserver reproducibility for the overall suspicion score of the PI-RADS v2 was moderate (κ statistic score: 0.46; standard error: 0.03) as scored by five independent readers with varying experience levels (12 years, 7 years, 1 year for two readers, and 6 months). However, the readers in their study showed a narrow range of experience, while our study involved six readers with a broad range of experience (2, 3, 4, 5, and 17 years, and 6 months). In another study, Rosenkrantz et al. [20] found that the interobserver agreement was 0.593 for the PZ and 0.509 for the TZ based on a PI-RADS v2 score of 4 or greater; their analysis included six experienced radiologists from six separate institutions, consisted of two sessions, and included an intersession training period with discussion. However, no substantial difference in interobserver agreement was observed between the two sessions, and a training session was neither required nor provided an added benefit.
Significant differences were identified among the scores of the six readers in our study. Therefore, radiologist experience is a crucial factor when evaluating MR images. However, differences were not noted between each pair of readers, and most of the differences were associated with reader 1 who had only 6 months of experience, suggesting that lack of experience has an impact on MRI interpretation, even though according to the PI-RADS v2 which is based on expert consensus opinion worldwide, lack of experience may correspond to a lack of understanding. Our results also indicated that the average correlation between the scores of the six readers for the 84 PCa patients and the GS was positive and moderate according to the PI-RADS v2. NiMhurchu et al. [21] showed that the correlation between a positive targeted biopsy and both the T2WI and overall PI-RADS scores was also significant (P < 0.001), while the correlation between a targeted biopsy and the DWI score was significant only for PZ tumors. However, this study was based on the PI-RADS v1, and whether the PI-RADS v2 would have led to the same result is difficult to determine.
In distinguishing between benign and malignant lesions, the most experienced reader (reader 6) in our study achieved the highest accuracy and AUC when the cutoff value was set at 3; however, this reader showed neither the highest nor the lowest percentage in terms of sensitivity, specificity, PPV, and NPV. Meanwhile, the least experienced reader (reader 1) achieved the lowest AUC, sensitivity, NPV, and accuracy and the highest specificity and PPV among the readers, which may be due to the different experience levels of the readers. In the study of Baldisserotto et al., [22] a PI-RADS score of 3 was applied as an indicator of the absence of cancer, and the accuracy, sensitivity, specificity,  PPV, and NPV of reader 1 (10 years of experience) were 77.8%, 73.5%, 85.0%, 89.3%, and 65.4%, respectively, and these values for reader 2 (4 years of experience) were 77.8%, 76.5%, 80.0%, 86.7%, and 66.7%, respectively. These values are lower than those of our study, which also demonstrates that the differences among readers may have been caused by varying experience levels. Previous studies without the PI-RADS criteria, such as that by Garcia-Reyes et al., [23] have also shown that readers' experience influences the accuracy of mp-MRI regarding the diagnosis of PCa. Nevertheless, from the results of the distinction between low-risk cancer and clinically significant cancer, reader 1 achieved the highest PPV and specificity, while reader 6 showed the lowest specificity, PPV, and accuracy, which can be interpreted as the reader with more experience showing more conservative tendencies. A study in 2016 by Zhao et al. [24] revealed a significant correlation between a higher PI-RADS v2 score and the presence of clinically significant PCa (P < 0.001), and a PI-RADS score of 3 was identified as the best cutoff point with a sensitivity and specificity greater than 80%. Our results showed a similar average specificity and sensitivity using the same cutoff. In recent years, most studies have concluded that the PI-RADS v2 exhibits better diagnostic performance than the PI-RADS v1. [25,26] Another study by Wang et al. [27] that evaluated the PI-RADS v1 score with respect to the PCa detection rate in patients with PSA levels <20 ng/ml showed a good correlation between an increased PI-RADS score and an increased cancer detection rate, and the summed score of T2WI + DWI showed the highest accuracy for PCa detection. However, a few studies have produced different results, showing that although the PI-RADS v2 uses a simplified approach, this system can lead to a higher rate of false-negative results and lower diagnostic accuracy due to the risk of missing low PI-RADS-scored tumors. In a study by Auer et al., [28] the authors included fifty PCa patients who underwent mp-MRI, and all the images were evaluated according to the PI-RADS v1 and PI-RADS v2 by two radiologists with a similar level of expertise. Their results showed that the PI-RADS v1 had a significantly larger discriminative ability for tumor detection regardless of whether the lesion was in the PZ or the TZ (PI-RADS v1 AUC: 0.96; PI-RADS v2 AUC: 0.90).
Several limitations existed in our study. The primary limitation is that the mean PSA level for the PCa population was slightly higher, and 70% of the PCa cases were locally advanced (stage T3/T4; 23% of the tumors were T4), which may have biased the study because larger, more aggressive tumors will be found by most radiologists; therefore, the agreement will be high and the diagnostic accuracy will be good. This phenomenon has also been observed in other studies. [29] However, PSA screening is not common in China, so our patients usually visit a doctor when they have obvious clinical symptoms, which often reflect an advanced disease stage. Therefore, we hope to improve this aspect in future research. Second, our readers provided only one final score for each case, and the results were not separately analyzed according to the PZ, TZ, T2WI, T1WI, or DWI. The aim of the PI-RADS v2 is to conduct a comprehensive evaluation of prostate lesions according to all major sequences rather than just one sequence. Therefore, providing a fast, accurate, and comprehensive judgment according to the PI-RADS v2 is important, which is why we conducted a comprehensive evaluation to adapt to these new conditions. Another potential limitation is that our reader and patient data all came from the same center, and although the readers were blinded to all identifying patient information, the readers may have been familiar with the cases in our database, which may have increased the inter-reader agreement or accuracy. Therefore, a larger dataset from a multicentric study is needed in the future. In addition, we selected a GS ≥4 + 3 as the definition of clinically significant PCa. However, no universally accepted consensus exists regarding the definition of clinically significant PCa. Finally, the reference standard that we used was TRUS-guided prostate biopsy, which may be less accurate than prostatectomy. [30] However, the primary goal of our study was to explore diagnostic performance and interobserver consistency among readers with different experience levels according to the latest PI-RADS version. Therefore, the impact of this limitation was very small, and we aim to enroll more patients with prostatectomy in the future to support the results of this study.
In conclusion, six prostate radiologists with different experience levels achieved weak-to-moderate inter-reader agreement using the PI-RADS v2 lexicon, and varying levels of experience have an impact on the interpretation of MR images. However, the PI-RADS v2 showed excellent diagnostic performance for different readers; therefore, our data suggested that as a living document, the PI-RADS will evolve and change in response to clinical needs and technical improvements in the future.

Financial support and sponsorship
This work was supported by grants from the National Natural Science Foundation of China (NSFC; No. 81671656 and No. 81171307).

Conflicts of interest
There are no conflicts of interest.