Data and population characteristics
Digital mammograms were collected from nine previously performed multi-reader multi-case (MRMC) observer studies [19,20,21,22,23,24,25,26]. The review board at each institution waived local ethical approval and informed consent or approved the use of the anonymized patient data for retrospective research.
All the datasets of the MRMC studies were enriched with exams with cancer. The ground truth, in terms of cancer present, benign lesion present, or absence of abnormalities, of each DM exam, was confirmed by histopathology and/or at least 1 year of follow-up. During each MRMC study, each DM exam was evaluated by multiple breast radiologists who provided malignancy scores for each exam (BI-RADS and/or level of suspicion).
In total, 2654 exams (653 with cancer, 768 with benign lesions, 1233 normal) and readings by 101 radiologists (52% from the USA and 48% from Europe) were gathered (yielding 28,296 independent exam interpretations). Approximately, half the exams were from screening and half from clinical practice. Detailed information about the tumor histology was not available. The DM images were acquired with devices from four different vendors (Siemens Healthineers; Hologic Inc.; General Electric Healthcare; Sectra Mamea) across seven different countries. Further details of these nine studies have previously been reported elsewhere .
Artificial intelligence system
For this study, we used an AI system dedicated to breast cancer detection in DM and digital breast tomosynthesis (Transpara 1.4.0, Screenpoint Medical BV). The system uses deep learning convolutional neural networks, feature classifiers, and image analysis algorithms to detect calcifications and soft tissue lesions in two different modules . Based on these detected lesions and overall exam appearance, the AI system assigns an exam-based integer score denoting the likelihood that cancer is present in the exam (hereafter AI score, also known as Transpara Score). This AI score ranges between 1 and 10 (10 means high likelihood that a cancer is present in the exam). The AI score is calibrated so that approximately the same number of normal exams (10% of the total) is assigned to each AI score category. In a population with low prevalence of cancer (where most exams are normal), such as a screening population, it may therefore be expected that approximately 10% of the total exams are in each category. In a screening population, the 10% of exams scored 1 are predicted to have the lowest risk of harboring cancer (because category 1 has the lowest incidence of exams with cancer), while the 10% of exams scored 10 have the highest risk of harboring cancer (because category 10 contains the largest fraction of exams with cancer). Since the calibration of the AI score is performed only with screening mammograms without abnormalities, the AI score is independent to the composition of the datasets. However, the fact that all datasets used for this study were enriched with cancers implies that the found distribution of AI scores in our study is skewed towards higher numbers, since it should be expected that cancer cases are not evenly distributed over AI categories.
The AI system was trained, validated, and tested using an external database representative of screening containing over 9000 mammograms with cancer (one-third of which are presented as lesions with calcifications) and 180,000 mammograms without abnormalities. The AI score was also calibrated with this external database, using only the normal mammograms. The mammograms used in this study have never been used to train, validate, or test the algorithms. The mammograms originate from devices from four different vendors (Hologic; Siemens; General Electric; Philips) and institutions across Europe, USA, and Asia.
Automated pre-selection of cases
For this study, the distribution of the normal exams and those containing benign or malignant lesions according to the ground truth was computed as a function of the AI score. To divide the exams into two groups (excluded and pre-selected for evaluation), we varied the threshold dividing these two groups across all possible AI scores, i.e., from 1 to 9. Consequently, the pre-selection scenarios included exams-to-be-evaluated as those with scores greater than 1, 2, 3, 4, 5, 6, 7, 8, or greater than 9 (equivalent to only pre-selected category 10). For each threshold, the characteristics of the exams in both groups were analyzed.
Under the pre-selection scenarios, we assumed that readers would only evaluate exams in the pre-selected group (high likelihood of cancer present), whereas exams in the low-likelihood group would automatically be assigned a “normal” classification. Workload reduction throughout the text is therefore expressed in terms of the number of exams that have to be read by the screening radiologists. Given the calibration of the AI system, a pre-selection threshold of 5, for instance, means that half of the exams in a screening program would be excluded from human reading. An estimation of how radiologists’ performance would change after pre-selection was calculated by a posteriori modification of the original radiologists’ scores: for the exams in the excluded group, all the radiologists’ scores were automatically modified to the lowest possible value (e.g., 1). This implies that we assumed invariance in human behavior for the pre-selected mammograms that were above the threshold and therefore should be evaluated.
The breast cancer detection accuracy of radiologists in the original scenario was compared with the simulated pre-selection scenario with a non-inferiority null hypothesis [27,28,29,30,31] based on the differences in the average area under the receiver operating characteristic curve (AUC). The non-inferiority margin was set at 0.05 in this study. Non-inferiority was concluded when the AUC difference “pre-selection scenario” – “original reading” was greater than 0 and the lower limit of the 95% confidence interval (CI) of the difference was greater than the non-inferiority margin. Confidence intervals were Bonferroni-corrected for multiple comparisons.
To obtain the average AUC across all our data, we used the public-domain iMRMC software for analysis (version 4.0.0, Division of Imaging, Diagnostics, and Software Reliability, OSEL/CDRH/FDA, Silver Spring, MD) [29, 30], which can handle not fully crossed study designs, such as the split-plot design resulting when pooling the nine datasets from this study [32, 33]. The reader-averaged ROC curves were created by averaging the reader-specific non-parametric (trapezoidal) curves along lines perpendicular to the chance line . This average is area-preserving; its AUC is equal to the reader-averaged non-parametric AUCs. The analysis was not done per dataset, given the homogeneous performance of the AI system across datasets seen in Rodriguez-Ruiz et al . We therefore assumed that no differences per dataset would be present in this study.