Same same but different: a web-based deep learning application for the histopathologic distinction of cortical malformations

We trained a convolutional neural network (CNN) to classify H.E. stained microscopic images of focal cortical dysplasia type IIb (FCD IIb) and cortical tuber of tuberous sclerosis complex (TSC). Both entities are distinct subtypes of human malformations of cortical development that share histopathological features consisting of neuronal dyslamination with dysmorphic neurons and balloon cells. The microscopic review of routine stainings of such surgical specimens remains challenging. A digital processing pipeline was developed for a series of 56 FCD IIb and TSC cases to obtain 4000 regions of interest and 200.000 sub-samples with different zoom and rotation angles to train a CNN. Our best performing network achieved 91% accuracy and 0.88 AUCROC (area under the receiver operating characteristic curve) on a hold-out test-set. Guided gradient-weighted class activation maps visualized morphological features used by the CNN to distinguish both entities. We then developed a web application, which combined the visualization of whole slide images (WSI) with the possibility for classification between FCD IIb and TSC on demand by our pretrained and build-in CNN classifier. This approach might help to introduce deep learning applications for the histopathologic diagnosis of rare and difficult-to-classify brain lesions.

[1]  Abhishek Das,et al.  Grad-CAM: Why did you say that? , 2016, ArXiv.

[2]  Charles B. Mikell,et al.  Tuberous sclerosis: A primary pathology of astrocytes? , 2008, Epilepsia.

[3]  Daisuke Komura,et al.  Machine Learning Methods for Histopathological Image Analysis , 2017, Computational and structural biotechnology journal.

[4]  Lawrence D. Jackel,et al.  Handwritten Digit Recognition with a Back-Propagation Network , 1989, NIPS.

[5]  J Helen Cross,et al.  Defining the spectrum of international practice in pediatric epilepsy surgery patients , 2008, Epilepsia.

[6]  N. Razavian,et al.  Classification and mutation prediction from non–small cell lung cancer histopathology images using deep learning , 2018, Nature Medicine.

[7]  Todd H. Stokes,et al.  Removing Batch Effects From Histopathological Images for Enhanced Cancer Diagnosis , 2014, IEEE Journal of Biomedical and Health Informatics.

[8]  Sergey Ioffe,et al.  Batch Normalization: Accelerating Deep Network Training by Reducing Internal Covariate Shift , 2015, ICML.

[9]  Kilian Q. Weinberger,et al.  Densely Connected Convolutional Networks , 2016, 2017 IEEE Conference on Computer Vision and Pattern Recognition (CVPR).

[10]  George Lee,et al.  Image analysis and machine learning in digital pathology: Challenges and opportunities , 2016, Medical Image Anal..

[11]  Sameer Antani,et al.  Visual Interpretation of Convolutional Neural Network Predictions in Classifying Medical Image Modalities , 2019, Diagnostics.

[12]  Anne E Carpenter,et al.  Opportunities and obstacles for deep learning in biology and medicine , 2017, bioRxiv.

[13]  Leslie N. Smith,et al.  Cyclical Learning Rates for Training Neural Networks , 2015, 2017 IEEE Winter Conference on Applications of Computer Vision (WACV).

[14]  Michael J. Keiser,et al.  Interpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline , 2018, Nature Communications.

[15]  Andrew Janowczyk,et al.  Deep learning for digital pathology image analysis: A comprehensive tutorial with selected use cases , 2016, Journal of pathology informatics.

[16]  T. Hermanns,et al.  Automated Gleason grading of prostate cancer tissue microarrays via deep learning , 2018, Scientific Reports.

[17]  R. Ekong,et al.  Functional Assessment of TSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex , 2013, Human mutation.

[18]  Hanry Yu,et al.  Deep learning enables automated scoring of liver fibrosis stages , 2018, Scientific Reports.

[19]  Guigang Zhang,et al.  Deep Learning , 2016, Int. J. Semantic Comput..

[20]  Charles DeCarli,et al.  Interpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline , 2018 .

[21]  Michael Wong,et al.  Tuberous sclerosis and epilepsy: Role of astrocytes , 2012, Glia.

[22]  Jimmy Ba,et al.  Adam: A Method for Stochastic Optimization , 2014, ICLR.

[23]  Eleonora Aronica,et al.  A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors , 2014, Acta Neuropathologica.

[24]  Li Fei-Fei,et al.  ImageNet: A large-scale hierarchical image database , 2009, CVPR.

[25]  Shengen Yan,et al.  Deep Image: Scaling up Image Recognition , 2015, ArXiv.

[26]  Tae-Yeong Kwak,et al.  Artificial Intelligence in Pathology , 2018, Journal of pathology and translational medicine.

[27]  Maria Thom,et al.  The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission 1 , 2011, Epilepsia.

[28]  François Chollet,et al.  Xception: Deep Learning with Depthwise Separable Convolutions , 2016, 2017 IEEE Conference on Computer Vision and Pattern Recognition (CVPR).

[29]  Andrew Janowczyk,et al.  A deep-learning classifier identifies patients with clinical heart failure using whole-slide images of H&E tissue , 2018, PloS one.

[30]  Mark D. McDonnell,et al.  Understanding Data Augmentation for Classification: When to Warp? , 2016, 2016 International Conference on Digital Image Computing: Techniques and Applications (DICTA).

[31]  Hope Northrup,et al.  Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. , 2013, Pediatric neurology.

[32]  R. Ekong,et al.  Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex , 2012, Human mutation.

[33]  Yuan Yu,et al.  TensorFlow: A system for large-scale machine learning , 2016, OSDI.

[34]  H. García,et al.  Epilepsy in poor regions of the world , 2012, The Lancet.

[35]  Bolei Zhou,et al.  Learning Deep Features for Discriminative Localization , 2015, 2016 IEEE Conference on Computer Vision and Pattern Recognition (CVPR).

[36]  Fares Alahdab,et al.  Global, regional, and national burden of epilepsy, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 , 2019, The Lancet Neurology.

[37]  Vijay Vasudevan,et al.  Learning Transferable Architectures for Scalable Image Recognition , 2017, 2018 IEEE/CVF Conference on Computer Vision and Pattern Recognition.

[38]  Zhiguo Jiang,et al.  Adaptive color deconvolution for histological WSI normalization , 2019, Comput. Methods Programs Biomed..

[39]  Maarten De Vos,et al.  Visualising convolutional neural network decisions in automated sleep scoring , 2018, AIH@IJCAI.

[40]  Masashi Kameyama,et al.  Deep learning-based imaging classification identified cingulate island sign in dementia with Lewy bodies , 2019 .

[41]  Andrew Zisserman,et al.  Very Deep Convolutional Networks for Large-Scale Image Recognition , 2014, ICLR.

[42]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[43]  Maria Thom,et al.  Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery , 2017, The New England journal of medicine.

[44]  Alan D. Lopez,et al.  The Global Burden of Disease Study , 2003 .

[45]  Jian Sun,et al.  Deep Residual Learning for Image Recognition , 2015, 2016 IEEE Conference on Computer Vision and Pattern Recognition (CVPR).

[46]  Peter Bankhead,et al.  QuPath: Open source software for digital pathology image analysis , 2017, Scientific Reports.

[47]  Andrew H. Beck,et al.  Diagnostic Assessment of Deep Learning Algorithms for Detection of Lymph Node Metastases in Women With Breast Cancer , 2017, JAMA.