Abstract
Histopathologic evaluation of muscle biopsy samples is essential for classifying and diagnosing muscle diseases. However, the numbers of experienced specialists and pathologists are limited. Although new technologies such as artificial intelligence are expected to improve medical reach, their use with rare diseases, such as muscle diseases, is challenging because of the limited availability of training datasets. To address this gap, we developed an algorithm based on deep convolutional neural networks (CNNs) and collected 4041 microscopic images of 1400 hematoxylin-and-eosin-stained pathology slides stored in the National Center of Neurology and Psychiatry for training CNNs. Our trained algorithm differentiated idiopathic inflammatory myopathies (mostly treatable) from hereditary muscle diseases (mostly non-treatable) with an area under the curve (AUC) of 0.996 and achieved better sensitivity and specificity than the diagnoses done by nine physicians under limited diseases and conditions. Furthermore, it successfully and accurately classified four subtypes of the idiopathic inflammatory myopathies with an average AUC of 0.958 and classified seven subtypes of hereditary muscle disease with an average AUC of 0.936. We also established a method to validate the similarity between the predictions made by the algorithm and the seven physicians using visualization technology and clarified the validity of the predictions. These results support the reliability of the algorithm and suggest that our algorithm has the potential to be used straightforwardly in a clinical setting.
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Introduction
The diagnosis, management, and further study of rare diseases, such as muscle diseases, carry fundamental challenges that are different from those of common diseases, owing to fewer patients and limited expert facilities and clinicians1. Novel digital tools, such as artificial intelligence (AI), are expected to circumvent these shortcomings by accelerating the processes of diagnosis, specialist referrals, gathering and sharing of data, and clinical research on rare diseases2. Deep learning is a highly reliable AI technology used for specific tasks3; analyzing medical and pathological images using deep learning4,5,6,7,8,9 is comparable to that by human experts4,5,6,7,8. However, thus far, almost all deep learning-based medical image analyses have only dealt with common diseases4,5,6,7,8,9 owing to the limited data available on rare diseases. Previous studies using muscle magnetic resonance imaging and AI scored conditions manually and did not diagnose them using the images directly10,11.
In this study, we aimed to diagnose muscle diseases with histopathology. Evaluating muscle pathology is unique because muscle biopsy specimens require freeze-fixation and a different set of histochemical staining techniques from general pathology. Classifying muscle diseases according to their pathological features remains diagnostically relevant even in today’s era of molecular diagnoses12.
Previous studies required whole-slide pathological images13,14 and important infrastructural investments. However, real-world pathological diagnoses are performed with analog microscopes. Developing a diagnostic tool with a charge-coupled device (CCD) camera that is much cheaper than a whole-slide scanner and can recruit analog microscope images is the key to establishing a practically applicable system, especially in underserved areas worldwide.
To address this issue, we developed a deep learning, convolutional neural network (CNN)-based algorithm that could differentiate between major muscle diseases using a small amount of training data. To train and evaluate the algorithm, we collected microscopic images of hematoxylin and eosin (H&E)-stained pathological slides that were obtained by CCD cameras. The underlying algorithmic architecture for classifying dominant muscular dystrophies with whole-slide images has been previously established15.
Materials and methods
Target muscle diseases
We chose 11 muscular diseases: 4 idiopathic inflammatory myopathies (IIM) [dermatomyositis (DM), inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and antisynthetase syndrome (ASS)] and 7 hereditary muscle diseases [dystrophinopathy (DYST), limb-girdle muscular dystrophy 2A (LGMD2A), limb-girdle muscular dystrophy 2B (LGMD2B), Ullrich congenital muscular dystrophy (UCMD), Fukuyama-type congenital muscular dystrophy (FCMD), congenital myopathy (CM), and GNE myopathy (GNEM)], and neuropathy (Table 1). CM included nemaline myopathy, central core disease, and centronuclear myopathy.
Approach
We employed a two-step approach to distinguish between the diseases: 1) differentiating IIM from other conditions, and 2) subclassifying each category because most IIM conditions are treatable but other hereditary conditions are not (Fig. 1a). In the first step, we combined images of DM, IBM, IMNM, and ASS to create the IIM group, and those of DYST, FCMD, LGMD2A, LGMD2B, UCMD, CM, GNEM, and NP to create the counterpart group. We used a holdout method16 to train and evaluate the CNNs and compare them to human physicians. In the second step, we subclassified four IIM subtypes and seven hereditary muscle diseases. We evaluated the results using five-fold cross-validation16.
We also developed a visualization method using Grad-cam17 to check the prediction accuracy of the CNNs. We used it to create AI-focused images (Fig. 1c and f) that masked the areas that were not evaluated by the CNNs and AI-unfocused images (Fig. 1d and g) that masked the areas to be targeted by the CNNs. We then identified the image group that physicians could use to obtain correct diagnoses and investigated the relationship between the predictions made by the CNNs and the physicians’ diagnoses.
Dataset
We utilized H&E-stained frozen muscle sections on glass slides that were mounted for diagnostic purposes in the National Center of Neurology and Psychiatry between 1981 and 2019. All materials used in the present study were obtained for diagnostic purposes with written informed consent. The Ethics Committee of the National Center of Neurology and Psychiatry approved the study. The samples had already been evaluated by immunostaining, western blot, blood biochemistry, and genetic testing.
Data preparation
Images were taken from slides with CCD cameras (DP72/DP74, Olympus, Tokyo) attached to the microscope. The objective lens magnification was 4×, and the image size was 1024 × 1360 or 1600 × 1200. Three pathological images were taken per slide to maximize the coverage of the sample and minimize overlaps between them. If the sample size was small enough to fit into the finder field, only one image was taken.
By contrast, more than three shots were obtained if the sample size was too large. In total, 4041 images were obtained from 1400 slides, with one slide per patient. When the training and validation sets were created, two image patches (1024 × 1024) were cropped from both the left and right edges of the images for data augmentation. Meanwhile, an image patch (1024 × 1024) was cropped from the image center when the test sets were created.
CNN design
The CNN architecture developed for this study is illustrated in Fig. 1h. The CNNs resized the input images from 1024 × 1024 to 640 × 640, divided an imported image into sixteen 160 × 160 image patches, and generated a feature map per patch. The 16 feature maps were concatenated and used for the prediction of each image; we expected that the CNN could be trained effectively even with a small number of images. All feature maps were concatenated, averaged by global average-pooling, and used to generate the final probability. At the same time, each feature map was used to generate the probability per image patch. In the test phase, only the final probability was used for the prediction. In the training phase, the final probability and probabilities of image patches were used to calculate the loss function (L) as:
where M is the number of classes, T is the number of patches, y is a one-hot vector (true class is 1 and others are 0), \({{{{{\boldsymbol{p}}}}}}^{final}\) is a vector of the probability of final prediction, and \({{{{{\boldsymbol{p}}}}}}^{image\;patch}\) is a vector of the probability of prediction by image patch.
In this study, a densely connected convolutional network18, called DenseNet, was used as a feature generator. DenseNet generally consisted of dense blocks and transition layers, with each dense block having two convolutional layers and a concatenation layer, and each transition layer having a convolutional layer and an average-pooling layer. Our DenseNet had 58 dense blocks and three transition layers, and it was pretrained with ImageNet19, an extensive image database.
Training and testing the algorithm for the IIM differentiation task
For this task, we adopted the holdout method that divides the data into training and test sets. We randomly selected 96 slides as the test set and used the remaining 1304 slides as the training set. In the training phase, the training set was divided into five groups; four were used for training and one to validate the progress of the training set. We conducted the training five times while shifting the evaluation set one by one to train five CNNs (Fig. 1i). In the test phase, we used a model ensemble method20 that averaged the probabilities of images cropped from the same slide to obtain the image probability by one slide and also averaged the output probabilities of the five CNNs. The probability averaging function is:
where n is the number of images per slide, \({{{{{\boldsymbol{p}}}}}}_{slide}\) is a vector of the probability of a slide, and \({{{{{\boldsymbol{p}}}}}}_{image}\) is a vector of the probability of an image. The class with the highest probability was adopted as the final prediction.
The following is the function of averaging the probabilities of models:
where m is the number of models, and \({{{{{\boldsymbol{p}}}}}}_{image}^{m,n}\) is a vector of the probability of an image outputted by a model. Furthermore, \({{{{{\boldsymbol{p}}}}}}_{slide}\) is:
The disease with the highest probability was selected as the final prediction.
Setting the training algorithm
The number of trainings (the epoch size) was 60. Loss and accuracy were calculated using the validation set in every training. The CNN with the best accuracy was chosen for the test phase. We used rectified Adam21 as the optimizer because it is more robust against the variance of learning rates than the conventional Adam22 optimizer. The initial learning rate of the optimizer was 0.0001. The CNNs were trained on Nvidia V100 using TensorFlow 1.13.2 (https://github.com/tensorflow/tensorflow) and Keras 2.2.4 software (https://github.com/keras-team/keras).
Transfer learning
Transfer learning23 is a technique employed to improve the performance of deep neural networks when the training data are limited. It uses the parameters of CNNs that are trained in one task and applies them to another task. In this study, the CNNs trained in IIM differentiation were used to classify IIMs and non-myositis muscle diseases. First, the CNNs were trained in IIM differentiation. Second, the final output layer of the trained CNNs was changed from two units to four units because there were two classes in the IIM differentiation task and four in the IIM classification task. Finally, the CNNs were trained in IIM classification. Transfer learning can be implemented in one of two ways: one is by having fixed parameters and excluding the output layer, and the other is by having unfixed parameters. We used the unfixed approach while classifying IIMs and non-myositis muscle diseases and set the number of output units to seven.
Metrics
We evaluated the performance of the algorithm using the following metrics: accuracy, receiver operating characteristic (ROC) curves (true- versus false-positive rate), and AUC (area under the ROC). The accuracy was calculated as follows:
\({{{{{\mathrm{Accuracy}}}}}} = \left( {{{{{{\mathrm{TP}}}}}} + {{{{{\mathrm{TN}}}}}}} \right)/\left( {{{{{{\mathrm{TP}}}}}} + {{{{{\mathrm{TN}}}}}} + {{{{{\mathrm{FP}}}}}} + {{{{{\mathrm{FN}}}}}}} \right),\) where TP is true-positive, TN is true-negative, FP is false-positive, and FN is false-negative. When we used the five-fold cross-validation, we summed all the TP, TN, FP, and FN values in five shots. ROC curves were generated by sweeping the threshold from 0 to 1. In multi-class classifications, one target class was set as a positive class and the other classes as negative.
Visualization
In previous studies, heatmaps were generated to visualize the prediction by deep CNNs17,24,25. In this study, we adopted Grad-cam, which can generate visual explanations from any CNN-based network without requiring architectural changes or retraining. This method uses gradients between confidences and feature maps to identify reactive filters. The gradients are calculated as:
where \(y^c\) is the confidence of class c, and A is a feature map. We used the following function to calculate gradients because the aggregated classifier internally generated feature maps per image patch.
where m is the number of image patches, and \(y_k^c\) is \(y^c\) of image patch k.
The representation ability of Grad-cam depends on the size of the feature map: the larger the feature map, the better the representation. The size of the feature map in this study was 5 × 5, but the aggregated classifier generated 16 (4 × 4) feature maps, which means that, practically, the size of the feature maps was 20 × 20.
Participating physicians
Nine physicians (three adult neurologists, four pediatric neurologists, and two pathologists) who were specially trained in muscle pathology differentiated between IIM and other conditions by studying 96 pathology slides. Their training period for muscle pathology was in the range of 1–23 years (average: 5.5 years). For the visualization test, seven physicians (excluding two adult neurologists from the nine physicians) diagnosed 98 slides by studying AI-focused or AI-unfocused images.
Results
Differentiation of IIM
The deep CNN was able to precisely differentiate IIM from other muscle diseases with an AUC of 0.996 and outperform the nine human specialists (Fig. 2a). Its accuracy was 96.9% if a probability of 0.5 or higher was determined as myositis, whereas the physicians’ highest accuracy was 93.8%. The average and variability of the accuracies of the nine human specialists were 83.4% and 0.004, respectively. The number of misclassifications was similar between IIM and other conditions (Fig. 2b). If a probability of 0.3 or more was determined as IIM, the accuracy decreased to 95.8%, but the number of incorrectly classified IIMs became zero (Fig. 2c). We also confirmed that the model ensemble was efficient in further improving the CNNs’ performance (Fig. 2d). Detailed test conditions and test results are presented in Table 2.
Classification of IIM and classification of hereditary muscle diseases
The CNN successfully classified four subtypes of IIM with AUCs of 0.953 (IMNM), 0.969 (IBM), 0.965 (DM), and 0.944 (ASS) (average = 0.958) (Fig. 2e). We found that the accuracy was 83.9% when the disease with the highest probability was the predicted class; ASS tended to be incorrectly classified as IMNM, and IMNM tended to be erroneously judged as IBM (Fig. 2f). It also classified seven subtypes of hereditary muscle disease with AUCs of 0.942 (CM), 0.949 (LGMD2B), 0.930 (DYST), 0.869 (LGMD2A), 0.985 (FCMD), 0.959 (UCMD), and 0.915 (GNEM) (average = 0.936) (Fig. 2g). We found that the accuracy was 74.5% when the disease with the highest probability was the predicted class; LGMD2A tended to be classified as LGMD2B; and GNEM tended to be misjudged as all other classes (Fig. 2h). Detailed test conditions and test results are presented in Table 2.
Test with visualization
We created masked images to investigate the relationship between the physicians’ predictions and diagnoses. First, we generated heatmap images with Grad-cam from H&E-stained images. Second, we calculated the median for each heatmap image. Finally, we transformed some heatmap images into mask images by masking areas below the median and applying them to H&E-stained images to create AI-focused images (Fig. 1c and f) and created the remaining mask images by using the same method to obtain AI-unfocused images. The number of AI-focused IIM images, AI-unfocused IIM images (Fig. 1d and g), AI-focused non-myositis muscle disease images, and AI-unfocused non-myositis muscle disease images was 25, 25, 24, and 24, respectively.
Seven physicians differentiated the IIM images into four subtypes (ASS, IBM, DM, and IMNM) and the non-myositis images into seven subtypes (DYST, LGMD2A, LGMD2B, CM, FCMD, UCMD, and GNEM). The pathologists were not informed about which images were AI-focused during testing. Each pathologist’s accuracy was calculated and averaged in each group to calculate the significant difference between AI-focused and AI-unfocused images using the paired t-test. The function of the test was:
where \(\mu _d\)and s are the mean and standard deviation of differences between all pairs, and n is the number of samples. We assumed that the results of the pathologists followed a normal distribution.
Result of test with visualization
Red and yellow areas were the most important to visualize the CNN predictions (Fig. 3b and d) because they were interspersed within the specimen (Fig. 3a–d). The average accuracy of the physicians’ diagnosis with AI-focused and AI-unfocused images in myositis was 0.674 and 0.526, respectively (Fig. 3e). The accuracy of DM decreased significantly (Fig. 3f and g). The average accuracies of non-myositis diseases were 0.458 and 0.440, respectively (Fig. 3h). Comparatively, the AI-focused and AI-unfocused images of myositis conditions were significantly different (p = 0.003) but those of non-myositis conditions were not (p = 0.629) (Fig. 3f–g and i–j).
Discussion
It is difficult to diagnose rare diseases such as muscle diseases because very few experienced specialists are available; therefore, there is an urgent need for accurate and cost-effective technological diagnostic systems that can be used in remote regions2. Herein, we reported a novel AI-based, CNN-assisted system to diagnose muscle diseases with pathology using an algorithm trained with limited image data (H&E-stained, CCD-shot slides). Our major finding is that the CNNs outperformed human physicians under limited diseases and conditions, indicating their potential for cost-effective clinical use, especially in underserved areas.
Most IIMs are treatable, but hereditary muscle diseases are untreatable; therefore, accurately differentiating between them is very important but often challenging even for experts (e.g., IMNM clinically and pathologically mimics muscular dystrophy, especially in children26,27). Moreover, each IIM subtype requires specific treatment, further highlighting the need for differentiation. In this study, CNNs successfully differentiated IIMs from other muscle diseases and classified them into its four subtypes (IBM, IMNM, DM, and ASS), suggesting that the system was effective for IIMs. We did not include polymyositis in this analysis because muscle pathologists are increasingly skeptical about its histopathological definitions—a recent conceptual change in IIMs27,28.
The CNNs also classified seven major hereditary muscle diseases, demonstrating that the system is compatible with conventional muscle pathology diagnoses. This also suggests that genetic differences can be computationally predicted based on histological features.
To visualize the accuracy of CNN predictions, Coudray et al. manually highlighted cropped image patches from a whole-slide photo5. In this study, we used Grad-cam17 to automatically identify the critical regions for CNN predictions and create images to help investigate the relationship between the CNN predictions and physicians’ diagnoses.
AI-focused IIM areas were useful for the physicians and CNNs; however, there was no significant difference in the non-myositis images. We speculated that the physicians were not as accurate as CNNs for non-myositis diseases because (1) the CNNs may have considered findings that were unknown to the physicians; (2) the CNNs may have recognized microstructures, such as rimmed vacuoles and nemaline bodies, that are important diagnostic features of hereditary diseases and are usually recognized by physicians only at high magnifications; and (3) physicians are usually trained to observe muscular findings on stains other than H&E. The pathological findings of IIM, such as perifascicular atrophy in DM, are large enough to observe even in low-magnification H&E images, but hereditary muscle diseases are easier to identify with other stains such as the modified Gomori trichrome stain (vacuoles and nemaline bodies) and nicotinamide adenine dinucleotide dehydrogenase (NADH)‐tetrazolium reductase stain (central cores).
In this study, we collected data from one of the world’s largest muscle biopsy collections. The performance of CNNs can be influenced by differences in the image data collection, staining protocols, and cameras at various centers. Therefore, it is necessary to conduct further studies with a larger number of pathological images from several laboratories. We expect that CNNs will be used in prospective studies and will be embedded directly into medical equipment, as has been done in augmented reality microscopes29. We believe that this study provides promising outcomes that support the use of an AI-assisted system for diagnosing neuromuscular disorders.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Funding
This study was supported by AMED under Grant Number 20ek0109348s0503 and Intramural Research Grant (2-5) for Neurological and Psychiatric Disorders of NCNP.
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Contributions
Y.K. designed and conducted the experiments and wrote the manuscript; M.O. reviewed the pathological and genetic data and performed the physicians’ test; H.N. and S.Y. analyzed the data and contributed to writing the manuscript; M.I., M.O., Y.S., J.T., A.I., T.K., YL.C., W.Y., and S.H. performed the physicians’ test; T.I. designed the deep learning algorithm; Y.T. prepared the experimental environment; R.T. and A.T. directed the project; F.M. contributed to obtaining grants and designing the framework of the study; I.N. made the pathological diagnoses for all cases and supervised the study. All authors read and approved the final paper.
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Kabeya, Y., Okubo, M., Yonezawa, S. et al. Deep convolutional neural network-based algorithm for muscle biopsy diagnosis. Lab Invest 102, 220–226 (2022). https://doi.org/10.1038/s41374-021-00647-w
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DOI: https://doi.org/10.1038/s41374-021-00647-w
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