Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Applying Data-driven Imaging Biomarker in Mammography for Breast Cancer Screening: Preliminary Study


We assessed the feasibility of a data-driven imaging biomarker based on weakly supervised learning (DIB; an imaging biomarker derived from large-scale medical image data with deep learning technology) in mammography (DIB-MG). A total of 29,107 digital mammograms from five institutions (4,339 cancer cases and 24,768 normal cases) were included. After matching patients’ age, breast density, and equipment, 1,238 and 1,238 cases were chosen as validation and test sets, respectively, and the remainder were used for training. The core algorithm of DIB-MG is a deep convolutional neural network; a deep learning algorithm specialized for images. Each sample (case) is an exam composed of 4-view images (RCC, RMLO, LCC, and LMLO). For each case in a training set, the cancer probability inferred from DIB-MG is compared with the per-case ground-truth label. Then the model parameters in DIB-MG are updated based on the error between the prediction and the ground-truth. At the operating point (threshold) of 0.5, sensitivity was 75.6% and 76.1% when specificity was 90.2% and 88.5%, and AUC was 0.903 and 0.906 for the validation and test sets, respectively. This research showed the potential of DIB-MG as a screening tool for breast cancer.


Mammography is widely recommended for breast cancer screening, although the starting age and screening interval for its application have been debated1,2,3,4,5. Screening mammography is recommended as it has a sensitivity over 85% and a specificity over 90%6; however, performance varies according to the radiologists’ experience or working area (academic vs nonacademic, general vs specific)7,8,9. Computer-aided detection (CAD) acts as an automated second reader by marking potentially suspicious spots for radiologists to review and several early reports emphasized that this could improve mammographic sensitivity10,11,12,13, with 74% of all screening mammograms in the Medicare population being interpreted with CAD by 200814,15.

Since the wide introduction of CAD into clinics, radiologists using this technology have complained of a high number of false-positive markers and several recent studies reported that CAD does not improve the diagnostic accuracy of mammography16,17. This was somewhat expected. Most learning algorithms including CAD are based on pre-defined hand-crafted features, so they are task-specific, a-priori knowledge based, which causes a large bias towards how humans think the task is performed18. Whereas in new algorithms including deep learning, the research has shifted from rule-based, problem specific solutions to increasingly generic, problem agnostic methods19,20,21. This is possible due to the backup of big data, increased computing power and sophisticated algorithms.

The algorithm developed in this study was named data-driven imaging biomarker (DIB; an imaging biomarker derived from large-scale medical image data by using deep learning technology) in mammography (DIB-MG). The basic learning strategy of DIB-MG is weakly supervised learning. Unlike the conventional CAD designs, DIB-MG learns radiologic features from large scale images without any human annotations. So, the purpose of our study was to assess the feasibility of DIB in mammography (DIB-MG) and to evaluate its potential for the detection of breast cancer.

Materials and Methods

Data collection

Five institutions (all tertiary referral centers) formed a consortium for the imaging database. All study protocols were approved by the institutional review board of Yonsei University Health System (approval number: 1-2016-0001) and the requirement for informed consent was waived. All experiments were conducted in accordance with the Good Clinical Practice guidelines. For algorithm development, digital mammography images were retrospectively obtained from PACS. We included women with four views of digital mammograms. Exclusion criteria were as follows. 1) Women with previous surgery for breast cancer, 2) Women with previous surgery for benign breast disease within 2 years, 3) Women with mammoplastic bag, 4) Women with mammographic clip or marker. All cancer cases were confirmed by pathology and all normal cases were defined as BI-RADS category 1 (negative) without malignancy development during at least 2 years of follow-up. Both screening and diagnostic mammograms were included. This study was solely focused on whether our algorithm could discriminate cancer from normal cases, so presumed benign cases (BI-RADS categories 2, 3, 4, and 5 without cancer) were not included. Accordingly, 29,107 digital mammogram sets were obtained, in which there were 4,339 cancer cases and 24,768 normal cases. All images in the data sets were recorded by radiologists for breast density, cancer type (invasive vs noninvasive), features (mass, mass with microcalcifications, asymmetry or focal asymmetry, distortion, microcalcification only, etc.) and size of the invasive cancer. For cancers showing mass with microcalcifications, both mass and microcalcifications were recorded as features. Breast density was recorded using BI-RADS standard terminology of almost entire fat (A), scattered fibroglandular densities (B), heterogeneous dense (C), and extremely dense (D)6.

Data sets

In 4,339 cancer cases, training, validation and test sets were randomly selected with a ratio of 5:1:1 (3,101/619/619). Each dataset was evenly distributed in terms of patients’ age, breast density, and manufacturer, and cancer type, feature, and size in order to remove selection bias between training, validation and test sets (Table 1). Predominant features of cancer were mass (n = 2,366) or microcalcifications (n = 1,962), so other features (asymmetry for focal asymmetry (n = 463), distortion (n = 100)) were not controlled in the data sets.

Table 1 Demographics in cancer cases.

In 24,768 normal cases, the same number of validation (n = 619) and test (n = 619) cases were randomly selected, and the rest were used for training. For normal cases, each partition of the dataset was evenly distributed in terms of patients’ age, breast density, and manufacturer in order to remove selection bias (Table 2).

Table 2 Demographics in normal cases.

Development of the Algorithm

Deep convolutional neural network (DCNN) is a deep learning algorithm specialized for images22. Each convolutional layer extracts features hierarchically (layer-by-layer) to abstract semantics from the raw input images. DIB-MG is implemented based on a residual network (ResNet)23, the state-of-the-art DCNN model for image recognition. Figure 1 shows the overall architecture of DIB-MG. It consists of two initial blocks (init_block), four residual blocks (residual_block), and an aggregation block (aggregate_block). Each residual block includes four consecutive convolution layers with skip connection as described in the right-bottom of the Fig. 1 (\(\oplus \) is an element-wise addition operator), while the other blocks include a single convolution layer. Each block also includes some auxiliary components such as a batch normalization layer (BN: normalization of activations within a batch)24, a rectified linear unit (ReLU: a simple mathematical function for non-linear activation)22, a max-pooling layer (Pmax: static dimension reduction function for translation-invariant feature abstraction)22, and a global-average-pooling (GPavg: average of the entire 2-dimensional input feature map)23. Details of the components are well described in the original literatures22,23,24.

Figure 1

Overall architecture – 19 convolutions followed by a global-average-pooling (GPavg).

DIB-MG consists of nineteen convolution layers with a two-stage global-average-pooling layer. The former eighteen convolution layers extract hierarchical features for cancer classification, while the last convolution layer (1 × 1 convolution kernel with filter width 2) generates per-view maps (one for cancer, and the other for normal cases) via for final DIB construction (Fig. 2). Figure 3 shows an example of DIB as well as ground-truth lesions. Since we did not use pixel-level lesion annotation in this experiment, each per-view map generated from the last convolution layer (i.e. map generation stage) was converted in a single value to be compared with the ground-truth label (biopsy-proven cancer: 1 or normal: 0). So, the final maps were converted into a vector (each vector element represents its own class) using the global-average-pooling operation. In the training stage, the error between the output vector (y_pred in Fig. 2) and the ground-truth label was propagated backward via back-propagation algorithm25, and the model parameters of the entire network were updated based on the propagated errors.

Figure 2

Hierarchical feature abstraction, DIB map generation, and cancer probability generation.

Figure 3

DIB example with ground-truth lesion. A 44-year-old woman with invasive ductal carcinoma of the right breast. A 22 mm-sized mass was correctly highlighted by DIB. The confidence score for cancer of DIB was 1.0 and 0.026 for the right and left breast.

Training Set-up

All the DICOM files are first converted to PNG files considering window_center and window_width defined in the header of each DICOM, and then the pixel values are normalized to be in the range −1.0 to 1.0. Random perturbation of the pixel intensity in terms of constrast (±10%) and brightness (±10%) is used every training iteration to overcome the difference in vendor-specific contrast/brightness characteristics. All the input images are downscaled to 1600 × 1600, i.e. rescaled to 1600 in terms of the longer side and zero-padded to be 1600 × 1600 (zero-padded on the left side of RCC/RMLO and the right side of LCC/LMLO).

Initial learning rate 0.001 is decayed by a factor of 5 every 10 epochs until the 30 epochs. Stochastic gradient descent (SGD) with momentum 0.9 is used for optimization. Minibatch size is 64 images (16 exams) based on eight graphic processing units (GPUs). Weight decay constant 0.0005 is used for regularization. All the experiment is done with TensorFlow26.

Evaluation of the Algorithm

Training proceeds to minimize the prediction error of the entire training set, and the final DIB-MG performed best on the validation set is chosen for evaluation on the test set. In an inference stage, the final output value of the trained model (y_pred ranging from 0.0 to 1.0) is used to decide whether the input case is cancer or not. More specifically, y_pred represents the confidence level of malignancy. This value is not exactly equal to the probability of cancer, as cancer cannot be specified as a probability. But it is correlated with the cancer probability in real exams. The constructed DIB (class number of per-view maps generated from the last convolution layer) includes information on spatial discriminativity. As mentioned before, each map represents the corresponding class and shows the most discriminative part in terms of the final classification result; e.g., if y_pred is 0.9 (cancer probability), then the region with the highest value on the cancer map is the most discriminative part in terms of its cancer decision.

Statistical Analysis and Performance Comparison

Chi-square tests were used to see whether there was any difference in categorical variables between training, validation and test sets. With validation and test sets, diagnostic performances were measured. Sensitivity, specificity, and accuracy were compared according to various demographics using the chi-square test. For features, logistic regression with the generalized estimating equation (GEE) method was applied to take into account that some patients had mass with microcalcifications. The AUC were compared between the validation and test sets using chi-square statistics. All analyses were conducted by a statistician using SAS statistical software (version 9.4; SAS Institute Inc., Cary, NC, USA) and R version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria).


At the operating point (threshold) of 0.5, sensitivity was 75.6% and 76.1% when specificity was 90.2% and 88.5%, and AUC was 0.903 and 0.906 for the validation and test sets, respectively, with no statistical difference (Table 3). Sensitivity and specificity were not statistically significant between age 50 and <50, but they were significantly different according to the manufacturer (Table 3). In regards to breast density, sensitivity was not affected, however, specificity and accuracy decreased as breast density increased (Table 4).

Table 3 Diagnostic Performances according to age and manufacturer.
Table 4 Diagnostic Performances according to breast density.

In the malignant group (Table 5), sensitivity was better in mass than in calcifications (84.1–86.1% vs 77.5–77.9%), better in invasive cancer than in non-invasive cancer (77.0–77.9% vs 54.2–59.7%), and better in mass 20 mm than <20 mm (88.5–88.6%, 68.4–71.0%).

Table 5 Diagnostic Performances according to malignant characteristics.


This is the first study that applies deep learning algorithms in mammography without pixel-level supervision. Our results showed that the AUC values for diagnosing breast cancer using the DIB-MG algorithm were 0.903–0.906, which demonstrates that DIB-MG algorithms can be trained with large-scale data sets without pre-defined mammographic features.

Deep learning algorithm in mammography have been previously studied by several researchers. Wang et al. reported that breast cancers presenting microcalcifications could be discriminated by deep learning27. They used a previously reported computerized segmentation algorithm in order to extract the clustered microcalcifications from mammograms28. In their approach, pre-defined microcalcification features obtained from lesion-annotated mammograms were used as an input for the unsupervised deep learning model (stacked autoencoder)29. Kooi et al. compared state-of-the art mammography CAD systems, relying on manually designed features as well as data-driven features using DCNN18. Especially in a deep learning approach, image patches extracted from lesion-annotated mammograms were used for training. Becker et al. evaluated the diagnostic performance of their deep neural network model for breast cancer detection30. A total 143 histology-proven cancers and 1,003 normal cases were used for this study, where all the cancer cases of the training dataset were manually annotated pixel-wise by radiologists according to descriptions in the radiology report. Compared to the aforementioned approaches, we used pure data-driven features from raw mammograms without any lesion annotations, which is scalable and practical for future CAD systems.

In previous reports with CAD, sensitivity was higher in microcalcifications than mass31,32,33,34, however, in this study, sensitivity was better in mass than calcifications. That is due to the difference in data sets. In our data set, both screening and diagnostic mammograms were included, in which 45.7% (1721/3762) of invasive carcinomas were equal or larger than 2 cm, whereas other studies with CAD included only screening mammograms31,32,33,34. Further studies using the DIB-MG algorithm on screening data sets should follow.

Our data showed that sensitivity for breast cancer detection was similar for non-dense breasts and dense breasts. However, specificity decreased as breast density increased. Eventually, low specificity was directly related with increasing false-positives, so we need to develop algorithms increasing specificity in the future.

In our study, diagnostic performance was different according to the manufacturer; sensitivity is the highest (88.8%) and specificity is the lowest (61.7%) in Siemens. In each data set (training, validation and test sets), the three manufacturers were evenly distributed (roughly 4:3:3 in cancer cases, 5:4:1 in normal cases). However, cancer cases were occupied with 27.2–29.2%, compared to 7.6–8.6% in normal cases in Siemens machine. This indicates that the number of cases trained with a certain type of machine can influence the diagnostic performance of mammography. This kind of selection bias should be considered in a future study regarding deep learning.

We acknowledge several limitations of our study. First, in this study we included only normal and cancer cases, so benign cases need to be included. Also, the dataset should be more expanded. Second, our model does not use any pixel-level annotations for training, so there might be errors in predicting the lesion location in examples predicted as cancer. It is necessary to confirm whether the lesion location is accurately predicted, and retrain the model based on those examples to improve localization performance.

In conclusion, this research showed the potential of DIB-MG as a screening tool for breast cancer. Further studies using a large number of high-quality data including benign cases are needed to further investigate its feasibility as a screening tool.


  1. 1.

    Hendrick, R. E., Smith, R. A., Rutledge, J. H., III & Smart, C. R. Benefit of screening mammography in women aged 40–49: a new meta-analysis of randomized controlled trials. Journal of the National Cancer Institute. Monographs 87–92 (1997).

  2. 2.

    Tabar, L. et al. Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality. Cancer 91, 1724–1731 (2001).

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Oeffinger, K. C. et al. Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society. Jama 314, 1599–1614, (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Nelson, H. D. et al. Effectiveness of Breast Cancer Screening: Systematic Review and Meta-analysis to Update the 2009 U.S. Preventive Services Task Force Recommendation. Annals of internal medicine 164, 244–255, (2016).

    Article  PubMed  Google Scholar 

  5. 5.

    Siu, A. L. & Force, U. S. P. S. T. Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Annals of internal medicine 164, 279–296, (2016).

    Article  PubMed  Google Scholar 

  6. 6.

    D’Orsi, C. J., Sickles, E. A., Mendelson, E. B., Morris, E. A. ACR BI-RADS atlas, breast imaging reporting and data system, 5th. (Reston, VA: American College of Radiology, 2013).

  7. 7.

    Beam, C. & Sullivan, D. Variability in mammogram interpretation. Adm Radiol J 15, 47, 49–50, 52 (1996).

  8. 8.

    Breast Cancer Surveillance Consortium. Smoothed plots of sensitivity (among radiologists finding 30 or more cancers), 2004–2008—based on BCSC data through 2009. National Cancer Institute; website. 10.html. Last modified July 9, 2014.

  9. 9.

    Leung, J. W. et al. Performance parameters for screening and diagnostic mammography in a community practice: are there differences between specialists and general radiologists? AJR Am J Roentgenol 188, 236–241, (2007).

    Article  PubMed  Google Scholar 

  10. 10.

    Freer, T. W. & Ulissey, M. J. Screening mammography with computer-aided detection: prospective study of 12,860 patients in a community breast center. Radiology 220, 781–786, (2001).

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Petrick, N. et al. Breast cancer detection: evaluation of a mass-detection algorithm for computer-aided diagnosis–experience in 263 patients. Radiology 224, 217–224, (2002).

    Article  PubMed  Google Scholar 

  12. 12.

    Birdwell, R. L., Bandodkar, P. & Ikeda, D. M. Computer-aided detection with screening mammography in a university hospital setting. Radiology 236, 451–457, (2005).

    Article  PubMed  Google Scholar 

  13. 13.

    Morton, M. J., Whaley, D. H., Brandt, K. R. & Amrami, K. K. Screening mammograms: interpretation with computer-aided detection–prospective evaluation. Radiology 239, 375–383, (2006).

    Article  PubMed  Google Scholar 

  14. 14.

    Fenton, J. J. et al. Short-term outcomes of screening mammography using computer-aided detection: a population-based study of medicare enrollees. Annals of internal medicine 158, 580–587, (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Rao, V. M. et al. How widely is computer-aided detection used in screening and diagnostic mammography? J Am Coll Radiol 7, 802–805, (2010).

    Article  PubMed  Google Scholar 

  16. 16.

    Cole, E. B. et al. Impact of computer-aided detection systems on radiologist accuracy with digital mammography. AJR Am J Roentgenol 203, 909–916, (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Lehman, C. D. et al. Diagnostic Accuracy of Digital Screening Mammography With and Without Computer-Aided Detection. JAMA Intern Med 175, 1828–1837, (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kooi, T. et al. Large scale deep learning for computer aided detection of mammographic lesions. Med Image Anal 35, 303–312, (2017).

    Article  PubMed  Google Scholar 

  19. 19.

    Bengio, Y., Courville, A. & Vincent, P. Representation learning: a review and new perspectives. IEEE Trans Pattern Anal Mach Intell 35, 1798–1828, (2013).

    Article  PubMed  Google Scholar 

  20. 20.

    LeCun, Y., Bengio, Y. & Hinton, G. Deep learning. Nature 521, 436–444, (2015).

    ADS  CAS  Article  PubMed  Google Scholar 

  21. 21.

    Schmidhuber, J. Deep learning in neural networks: an overview. Neural Netw 61, 85–117, (2015).

    Article  PubMed  Google Scholar 

  22. 22.

    Krizhevsky A, S. I. & Hinton, G. E. ImageNet Classification with Deep ConvolutionalNeural Networks. Neural Information Processing Systems (NIPS) (2012).

  23. 23.

    He, K., Zhang, X., Ren, S. & Sun, J. Deep residual learning for image recognition. In Conference on Computer Vision and Pattern Recognition (CVPR) (2016).

  24. 24.

    Ioffe, S. & Szegedy, C. Batch normalization: Accelerating deep network training by reducing internal covariate shift. In International Conference on Machine Learning (ICML) (2015).

  25. 25.

    Hornik, K., Halbert, S. M. & Multilayer, W. feedforward networks are universal approximators. Neural networks Neural networks 2, 359–366 (1989).

    Article  Google Scholar 

  26. 26.

    Abadi, M. et al. TensorFlow: Large-scale machine learning on heterogeneous systems. Software available from (2015).

  27. 27.

    Wang, J. et al. Discrimination of Breast Cancer with Microcalcifications on Mammography by Deep Learning. Sci Rep 6, 27327, (2016).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Shao, Y. Z. et al. Characterizing the clustered microcalcifications on mammograms to predict the pathological classification and grading: a mathematical modeling approach. J Digit Imaging 24, 764–771, (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Vincent, P., Larochelle, H., Lajoie, I., Bengio, Y. & Manzagol, P. A. Stacked Denoising Autoencoders: Learning Useful Representations in a Deep Network with a Local Denoising Criterion. J Mach Learn Res 11, 3371–3408 (2010).

    MathSciNet  MATH  Google Scholar 

  30. 30.

    Becker, A. S. et al. Deep Learning in Mammography: Diagnostic Accuracy of a Multipurpose Image Analysis Software in the Detection of Breast Cancer. Investigative radiology (2017).

  31. 31.

    Sadaf, A., Crystal, P., Scaranelo, A. & Helbich, T. Performance of computer-aided detection applied to full-field digital mammography in detection of breast cancers. Eur J Radiol 77, 457–461, (2011).

    Article  PubMed  Google Scholar 

  32. 32.

    Kim, S. J. et al. Computer-aided detection in digital mammography: comparison of craniocaudal, mediolateral oblique, and mediolateral views. Radiology 241, 695–701, (2006).

    Article  PubMed  Google Scholar 

  33. 33.

    Murakami, R. et al. Detection of breast cancer with a computer-aided detection applied to full-field digital mammography. J Digit Imaging 26, 768–773, (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Yang, S. K. et al. Screening mammography-detected cancers: sensitivity of a computer-aided detection system applied to full-field digital mammograms. Radiology 244, 104–111, (2007).

    Article  PubMed  Google Scholar 

Download references


This work was partly supported by Institute for Information & Communications Technology Promotion(IITP) grant funded by the Korea government(MSIP) (Title: Diagnosis Support System with Hospital-Scale Medical Data and Deep Learning), and partly supported by the research project funded by Lunit Inc. (Title: Study of Verification and Validation of Deep Learning Based Breast Image Diagnosis Support Algorithm).

Author information




All authors were responsible for the study concept. E.-K.K. and H.-E.K. contributed to the study design. E.-K.K. B.J.K., Y.-M.S., O.H.W., C.W.L. contributed to the data collection and wrote the first draft of the manuscript. H.-E.K., E.-K.K. and K.H. contributed to the statistical analysis. All authors reviewed and approved the final draft of the manuscript.

Corresponding author

Correspondence to Eun-Kyung Kim.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, EK., Kim, HE., Han, K. et al. Applying Data-driven Imaging Biomarker in Mammography for Breast Cancer Screening: Preliminary Study. Sci Rep 8, 2762 (2018).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing