Application of multiple-finding segmentation utilizing Mask R-CNN-based deep learning in a rat model of drug-induced liver injury.

Drug-induced liver injury (DILI) presents significant diagnostic challenges, and recently artificial intelligence-based deep learning technology has been used to predict various hepatic findings. In this study, we trained a set of Mask R-CNN-based deep algorithms to learn and quantify typical toxicant induced-histopathological lesions, portal area, and connective tissue in Sprague Dawley rats. We compared a set of single-finding models (SFMs) and a combined multiple-finding model (MFM) for their ability to simultaneously detect, classify, and quantify multiple hepatic findings on rat liver slide images. All of the SFMs yielded mean average precision (mAP) values above 85%, suggesting that the models had been successfully established. The MFM showed better performance than the SFMs, with a total mAP value of 92.46%. We compared the model predictions for slide images with ground-truth annotations generated by an accredited pathologist. For the MFM, the overall and individual finding predictions were highly correlated with the annotated areas, with R-squared values of 0.852, 0.952, 0.999, 0.990, and 0.958 being obtained for portal area, infiltration, necrosis, vacuolation, and connective tissue (including fibrosis), respectively. Our results indicate that the proposed MFM could be a useful tool for detecting and predicting multiple hepatic findings in basic non-clinical study settings.

A comparative study on the implementation of deep learning algorithms for detection of hepatic necrosis in toxicity studies.

Deep learning has recently become one of the most popular methods of image analysis. In non-clinical studies, several tissue slides are generated to investigate the toxicity of a test compound. These are converted into digital image data using a slide scanner, which is then studied by researchers to investigate abnormalities, and the deep learning method has been started to adopt in this study. However, comparative studies evaluating different deep learning algorithms for analyzing abnormal lesions are scarce. In this study, we applied three algorithms, SSD, Mask R-CNN, and DeepLabV3+, to detect hepatic necrosis in slide images and determine the best deep learning algorithm for analyzing abnormal lesions. We trained each algorithm on 5750 images and 5835 annotations of hepatic necrosis including validation and test, augmented with 500 image tiles of 448 × 448 pixels. Precision, recall, and accuracy were calculated for each algorithm based on the prediction results of 60 test images of 2688 × 2688 pixels. The two segmentation algorithms, DeepLabV3+ and Mask R-CNN, showed over 90% of accuracy (0.94 and 0.92, respectively), whereas SSD, an object detection algorithm, showed lower accuracy. The trained DeepLabV3+ outperformed all others in recall while also successfully separating hepatic necrosis from other features in the test images. It is important to localize and separate the abnormal lesion of interest from other features to investigate it on a slide level. Therefore, we suggest that segmentation algorithms are more appropriate than object detection algorithms for use in the pathological analysis of images in non-clinical studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00173-5.

Segmentation algorithm can be used for detecting hepatic fibrosis in SD rat.

BACKGROUND: Liver fibrosis is an early stage of liver cirrhosis. As a reversible lesion before cirrhosis, liver failure, and liver cancer, it has been a target for drug discovery. Many antifibrotic candidates have shown promising results in experimental animal models; however, due to adverse clinical reactions, most antifibrotic agents are still preclinical. Therefore, rodent models have been used to examine the histopathological differences between the control and treatment groups to evaluate the efficacy of anti-fibrotic agents in non-clinical research. In addition, with improvements in digital image analysis incorporating artificial intelligence (AI), a few researchers have developed an automated quantification of fibrosis. However, the performance of multiple deep learning algorithms for the optimal quantification of hepatic fibrosis has not been evaluated. Here, we investigated three different localization algorithms, mask R-CNN, DeepLabV3+, and SSD, to detect hepatic fibrosis. RESULTS: 5750 images with 7503 annotations were trained using the three algorithms, and the model performance was evaluated in large-scale images and compared to the training images. The results showed that the precision values were comparable among the algorithms. However, there was a gap in the recall, leading to a difference in model accuracy. The mask R-CNN outperformed the recall value (0.93) and showed the closest prediction results to the annotation for detecting hepatic fibrosis among the algorithms. DeepLabV3+ also showed good performance; however, it had limitations in the misprediction of hepatic fibrosis as inflammatory cells and connective tissue. The trained SSD showed the lowest performance and was limited in predicting hepatic fibrosis compared to the other algorithms because of its low recall value (0.75). CONCLUSIONS: We suggest it would be a more useful tool to apply segmentation algorithms in implementing AI algorithms to predict hepatic fibrosis in non-clinical studies.

Preparing pathological data to develop an artificial intelligence model in the nonclinical study.

Artificial intelligence (AI)-based analysis has recently been adopted in the examination of histological slides via the digitization of glass slides using a digital scanner. In this study, we examined the effect of varying the staining color tone and magnification level of a dataset on the result of AI model prediction in hematoxylin and eosin stained whole slide images (WSIs). The WSIs of liver tissues with fibrosis were used as an example, and three different datasets (N20, B20, and B10) were prepared with different color tones and magnifications. Using these datasets, we built five models trained Mask R-CNN algorithm by a single or mixed dataset of N20, B20, and B10. We evaluated their model performance using the test dataset of three datasets. It was found that the models that were trained with mixed datasets (models B20/N20 and B10/B20), which consist of different color tones or magnifications, performed better than the single dataset trained models. Consequently, superior performance of the mixed models was obtained from the actual prediction results of the test images. We suggest that training the algorithm with various staining color tones and multi-scaled image datasets would be more optimized for consistent remarkable performance in predicting pathological lesions of interest.

Artificial Intelligence-Assisted Image Analysis of Acetaminophen-Induced Acute Hepatic Injury in Sprague-Dawley Rats.

Although drug-induced liver injury (DILI) is a major target of the pharmaceutical industry, we currently lack an efficient model for evaluating liver toxicity in the early stage of its development. Recent progress in artificial intelligence-based deep learning technology promises to improve the accuracy and robustness of current toxicity prediction models. Mask region-based CNN (Mask R-CNN) is a detection-based segmentation model that has been used for developing algorithms. In the present study, we applied a Mask R-CNN algorithm to detect and predict acute hepatic injury lesions induced by acetaminophen (APAP) in Sprague-Dawley rats. To accomplish this, we trained, validated, and tested the model for various hepatic lesions, including necrosis, inflammation, infiltration, and portal triad. We confirmed the model performance at the whole-slide image (WSI) level. The training, validating, and testing processes, which were performed using tile images, yielded an overall model accuracy of 96.44%. For confirmation, we compared the model's predictions for 25 WSIs at 20× magnification with annotated lesion areas determined by an accredited toxicologic pathologist. In individual WSIs, the expert-annotated lesion areas of necrosis, inflammation, and infiltration tended to be comparable with the values predicted by the algorithm. The overall predictions showed a high correlation with the annotated area. The R square values were 0.9953, 0.9610, and 0.9445 for necrosis, inflammation plus infiltration, and portal triad, respectively. The present study shows that the Mask R-CNN algorithm is a useful tool for detecting and predicting hepatic lesions in non-clinical studies. This new algorithm might be widely useful for predicting liver lesions in non-clinical and clinical settings.

Implementation and Practice of Deep Learning-Based Instance Segmentation Algorithm for Quantification of Hepatic Fibrosis at Whole Slide Level in Sprague-Dawley Rats.

Exponential development in artificial intelligence or deep learning technology has resulted in more trials to systematically determine the pathological diagnoses using whole slide images (WSIs) in clinical and nonclinical studies. In this study, we applied Mask Regions with Convolution Neural Network (Mask R-CNN), a deep learning model that uses instance segmentation, to detect hepatic fibrosis induced by N-nitrosodimethylamine (NDMA) in Sprague-Dawley rats. From 51 WSIs, we collected 2011 cropped images with hepatic fibrosis annotations. Training and detection of hepatic fibrosis via artificial intelligence methods was performed using Tensorflow 2.1.0, powered by an NVIDIA 2080 Ti GPU. From the test process using tile images, 95% of model accuracy was verified. In addition, we validated the model to determine whether the predictions by the trained model can reflect the scoring system by the pathologists at the WSI level. The validation was conducted by comparing the model predictions in 18 WSIs at 20× and 10× magnifications with ground truth annotations and board-certified pathologists. Predictions at 20× showed a high correlation with ground truth (R2 = 0.9660) and a good correlation with the average fibrosis rank by pathologists (R2 = 0.8887). Therefore, the Mask R-CNN algorithm is a useful tool for detecting and quantifying pathological findings in nonclinical studies.