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1. Multi‐scale cascaded networks for synthesis of mammogram to decrease intensity distortion and increase model‐based perceptual similarity

   https://doi.org/10.1002/mp.16007  

   Jiang, Gongfa ; He, Zilong ; Zhou, Yuanpin ; Wei, Jun ; Xu, Yuesheng ; Zeng, Hui ; Wu, Jiefang ; Qin, Genggeng ; Chen, Weiguo ; Lu, Yao ( October 2022 , Medical Physics)

   Synthetic digital mammogram (SDM) is a 2D image generated from digital breast tomosynthesis (DBT) and used as a substitute for a full‐field digital mammogram (FFDM) to reduce the radiation dose for breast cancer screening. The previous deep learning‐based method used FFDM images as the ground truth, and trained a single neural network to directly generate SDM images with similar appearances (e.g., intensity distribution, textures) to the FFDM images. However, the FFDM image has a different texture pattern from DBT. The difference in texture pattern might make the training of the neural network unstable and result in high‐intensity distortion, which makes it hard to decrease intensity distortion and increase perceptual similarity (e.g., generate similar textures) at the same time. Clinically, radiologists want to have a 2D synthesized image that feels like an FFDM image in vision and preserves local structures such as both mass and microcalcifications (MCs) in DBT because radiologists have been trained on reading FFDM images for a long time, while local structures are important for diagnosis. In this study, we proposed to use a deep convolutional neural network to learn the transformation to generate SDM from DBT.

   To decrease intensity distortion and increase perceptual similarity, a multi‐scale cascaded network (MSCN) is proposed to generate low‐frequency structures (e.g., intensity distribution) and high‐frequency structures (e.g., textures) separately. The MSCN consist of two cascaded sub‐networks: the first sub‐network is used to predict the low‐frequency part of the FFDM image; the second sub‐network is used to generate a full SDM image with textures similar to the FFDM image based on the prediction of the first sub‐network. The mean‐squared error (MSE) objective function is used to train the first sub‐network, termed low‐frequency network, to generate a low‐frequency SDM image. The gradient‐guided generative adversarial network's objective function is to train the second sub‐network, termed high‐frequency network, to generate a full SDM image with textures similar to the FFDM image.

   1646 cases with FFDM and DBT were retrospectively collected from the Hologic Selenia system for training and validation dataset, and 145 cases with masses or MC clusters were independently collected from the Hologic Selenia system for testing dataset. For comparison, the baseline network has the same architecture as the high‐frequency network and directly generates a full SDM image. Compared to the baseline method, the proposed MSCN improves the peak‐to‐noise ratio from 25.3 to 27.9 dB and improves the structural similarity from 0.703 to 0.724, and significantly increases the perceptual similarity.

   The proposed method can stabilize the training and generate SDM images with lower intensity distortion and higher perceptual similarity.

    

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2. Robust explanation supervision for false positive reduction in pulmonary nodule detection

   https://doi.org/10.1002/mp.16937  

   Zhao, Qilong ; Chang, Chih‐Wei ; Yang, Xiaofeng ; Zhao, Liang ( January 2024 , Medical Physics)

   Lung cancer is the deadliest and second most common cancer in the United States due to the lack of symptoms for early diagnosis. Pulmonary nodules are small abnormal regions that can be potentially correlated to the occurrence of lung cancer. Early detection of these nodules is critical because it can significantly improve the patient's survival rates. Thoracic thin‐sliced computed tomography (CT) scanning has emerged as a widely used method for diagnosing and prognosis lung abnormalities.

   The standard clinical workflow of detecting pulmonary nodules relies on radiologists to analyze CT images to assess the risk factors of cancerous nodules. However, this approach can be error‐prone due to the various nodule formation causes, such as pollutants and infections. Deep learning (DL) algorithms have recently demonstrated remarkable success in medical image classification and segmentation. As an ever more important assistant to radiologists in nodule detection, it is imperative ensure the DL algorithm and radiologist to better understand the decisions from each other. This study aims to develop a framework integrating explainable AI methods to achieve accurate pulmonary nodule detection.

   A robust and explainable detection (RXD) framework is proposed, focusing on reducing false positives in pulmonary nodule detection. Its implementation is based on an explanation supervision method, which uses nodule contours of radiologists as supervision signals to force the model to learn nodule morphologies, enabling improved learning ability on small dataset, and enable small dataset learning ability. In addition, two imputation methods are applied to the nodule region annotations to reduce the noise within human annotations and allow the model to have robust attributions that meet human expectations. The 480, 265, and 265 CT image sets from the public Lung Image Database Consortium and Image Database Resource Initiative (LIDC‐IDRI) dataset are used for training, validation, and testing.

   Using only 10, 30, 50, and 100 training samples sequentially, our method constantly improves the classification performance and explanation quality of baseline in terms of Area Under the Curve (AUC) and Intersection over Union (IoU). In particular, our framework with a learnable imputation kernel improves IoU from baseline by 24.0% to 80.0%. A pre‐defined Gaussian imputation kernel achieves an even greater improvement, from 38.4% to 118.8% from baseline. Compared to the baseline trained on 100 samples, our method shows less drop in AUC when trained on fewer samples. A comprehensive comparison of interpretability shows that our method aligns better with expert opinions.

   A pulmonary nodule detection framework was demonstrated using public thoracic CT image datasets. The framework integrates the robust explanation supervision (RES) technique to ensure the performance of nodule classification and morphology. The method can reduce the workload of radiologists and enable them to focus on the diagnosis and prognosis of the potential cancerous pulmonary nodules at the early stage to improve the outcomes for lung cancer patients.

    

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3. Generating Explanations for Chest Medical Scan Pneumonia Predictions

   Samson Qian ( May 2021 , COVID Information Commons)

   With the spread of COVID-19, significantly more patients have required medical diagnosis to determine whether they are a carrier of the virus. COVID-19 can lead to the development of pneumonia in the lungs, which can be captured in X-Ray and CT scans of the patient's chest. The abundance of X-Ray and CT image data available can be used to develop a high-performing computer vision model able to identify and classify instances of pneumonia present in medical scans. Predictions made by these deep learning models can increase the confidence of diagnoses made by analyzing minute features present in scans exhibiting COVID-19 pneumonia, often unnoticeable to the human eye. Furthermore, rather than teaching clinicians about the mathematics behind deep learning and heat maps, we introduce novel methods of explainable artificial intelligence (XAI) with the goal to annotate instances of pneumonia in medical scans exactly as radiologists do to inform other radiologists, clinicians, and interns about patterns and findings. This project explores methods to train and optimize state-of-the-art deep learning models on COVID-19 pneumonia medical scans and apply explainability algorithms to generate annotated explanations of model predictions that are useful to clinicians and radiologists in analyzing these images. 

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4. The Temple University Digital Pathology Corpus: The Breast Tissue Subset

   https://doi.org/10.1109/SPMB52430.2021.9672275  

   Wevodau, Z. ; Doshna, B. ; Jhala, N. ; Akhtar, I. ; Obeid, I. ; Picone, J. ( December 2021 , Proceedings of the IEEE Signal Processing in Medicine and Biology Symposium (SPMB))

   Obeid, I. (Ed.)

   The Neural Engineering Data Consortium (NEDC) is developing the Temple University Digital Pathology Corpus (TUDP), an open source database of high-resolution images from scanned pathology samples [1], as part of its National Science Foundation-funded Major Research Instrumentation grant titled “MRI: High Performance Digital Pathology Using Big Data and Machine Learning” [2]. The long-term goal of this project is to release one million images. We have currently scanned over 100,000 images and are in the process of annotating breast tissue data for our first official corpus release, v1.0.0. This release contains 3,505 annotated images of breast tissue including 74 patients with cancerous diagnoses (out of a total of 296 patients). In this poster, we will present an analysis of this corpus and discuss the challenges we have faced in efficiently producing high quality annotations of breast tissue. It is well known that state of the art algorithms in machine learning require vast amounts of data. Fields such as speech recognition [3], image recognition [4] and text processing [5] are able to deliver impressive performance with complex deep learning models because they have developed large corpora to support training of extremely high-dimensional models (e.g., billions of parameters). Other fields that do not have access to such data resources must rely on techniques in which existing models can be adapted to new datasets [6]. A preliminary version of this breast corpus release was tested in a pilot study using a baseline machine learning system, ResNet18 [7], that leverages several open-source Python tools. The pilot corpus was divided into three sets: train, development, and evaluation. Portions of these slides were manually annotated [1] using the nine labels in Table 1 [8] to identify five to ten examples of pathological features on each slide. Not every pathological feature is annotated, meaning excluded areas can include focuses particular to these labels that are not used for training. A summary of the number of patches within each label is given in Table 2. To maintain a balanced training set, 1,000 patches of each label were used to train the machine learning model. Throughout all sets, only annotated patches were involved in model development. The performance of this model in identifying all the patches in the evaluation set can be seen in the confusion matrix of classification accuracy in Table 3. The highest performing labels were background, 97% correct identification, and artifact, 76% correct identification. A correlation exists between labels with more than 6,000 development patches and accurate performance on the evaluation set. Additionally, these results indicated a need to further refine the annotation of invasive ductal carcinoma (“indc”), inflammation (“infl”), nonneoplastic features (“nneo”), normal (“norm”) and suspicious (“susp”). This pilot experiment motivated changes to the corpus that will be discussed in detail in this poster presentation. To increase the accuracy of the machine learning model, we modified how we addressed underperforming labels. One common source of error arose with how non-background labels were converted into patches. Large areas of background within other labels were isolated within a patch resulting in connective tissue misrepresenting a non-background label. In response, the annotation overlay margins were revised to exclude benign connective tissue in non-background labels. Corresponding patient reports and supporting immunohistochemical stains further guided annotation reviews. The microscopic diagnoses given by the primary pathologist in these reports detail the pathological findings within each tissue site, but not within each specific slide. The microscopic diagnoses informed revisions specifically targeting annotated regions classified as cancerous, ensuring that the labels “indc” and “dcis” were used only in situations where a micropathologist diagnosed it as such. Further differentiation of cancerous and precancerous labels, as well as the location of their focus on a slide, could be accomplished with supplemental immunohistochemically (IHC) stained slides. When distinguishing whether a focus is a nonneoplastic feature versus a cancerous growth, pathologists employ antigen targeting stains to the tissue in question to confirm the diagnosis. For example, a nonneoplastic feature of usual ductal hyperplasia will display diffuse staining for cytokeratin 5 (CK5) and no diffuse staining for estrogen receptor (ER), while a cancerous growth of ductal carcinoma in situ will have negative or focally positive staining for CK5 and diffuse staining for ER [9]. Many tissue samples contain cancerous and non-cancerous features with morphological overlaps that cause variability between annotators. The informative fields IHC slides provide could play an integral role in machine model pathology diagnostics. Following the revisions made on all the annotations, a second experiment was run using ResNet18. Compared to the pilot study, an increase of model prediction accuracy was seen for the labels indc, infl, nneo, norm, and null. This increase is correlated with an increase in annotated area and annotation accuracy. Model performance in identifying the suspicious label decreased by 25% due to the decrease of 57% in the total annotated area described by this label. A summary of the model performance is given in Table 4, which shows the new prediction accuracy and the absolute change in error rate compared to Table 3. The breast tissue subset we are developing includes 3,505 annotated breast pathology slides from 296 patients. The average size of a scanned SVS file is 363 MB. The annotations are stored in an XML format. A CSV version of the annotation file is also available which provides a flat, or simple, annotation that is easy for machine learning researchers to access and interface to their systems. Each patient is identified by an anonymized medical reference number. Within each patient’s directory, one or more sessions are identified, also anonymized to the first of the month in which the sample was taken. These sessions are broken into groupings of tissue taken on that date (in this case, breast tissue). A deidentified patient report stored as a flat text file is also available. Within these slides there are a total of 16,971 total annotated regions with an average of 4.84 annotations per slide. Among those annotations, 8,035 are non-cancerous (normal, background, null, and artifact,) 6,222 are carcinogenic signs (inflammation, nonneoplastic and suspicious,) and 2,714 are cancerous labels (ductal carcinoma in situ and invasive ductal carcinoma in situ.) The individual patients are split up into three sets: train, development, and evaluation. Of the 74 cancerous patients, 20 were allotted for both the development and evaluation sets, while the remain 34 were allotted for train. The remaining 222 patients were split up to preserve the overall distribution of labels within the corpus. This was done in hope of creating control sets for comparable studies. Overall, the development and evaluation sets each have 80 patients, while the training set has 136 patients. In a related component of this project, slides from the Fox Chase Cancer Center (FCCC) Biosample Repository (https://www.foxchase.org/research/facilities/genetic-research-facilities/biosample-repository -facility) are being digitized in addition to slides provided by Temple University Hospital. This data includes 18 different types of tissue including approximately 38.5% urinary tissue and 16.5% gynecological tissue. These slides and the metadata provided with them are already anonymized and include diagnoses in a spreadsheet with sample and patient ID. We plan to release over 13,000 unannotated slides from the FCCC Corpus simultaneously with v1.0.0 of TUDP. Details of this release will also be discussed in this poster. Few digitally annotated databases of pathology samples like TUDP exist due to the extensive data collection and processing required. The breast corpus subset should be released by November 2021. By December 2021 we should also release the unannotated FCCC data. We are currently annotating urinary tract data as well. We expect to release about 5,600 processed TUH slides in this subset. We have an additional 53,000 unprocessed TUH slides digitized. Corpora of this size will stimulate the development of a new generation of deep learning technology. In clinical settings where resources are limited, an assistive diagnoses model could support pathologists’ workload and even help prioritize suspected cancerous cases. ACKNOWLEDGMENTS This material is supported by the National Science Foundation under grants nos. CNS-1726188 and 1925494. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. REFERENCES [1] N. Shawki et al., “The Temple University Digital Pathology Corpus,” in Signal Processing in Medicine and Biology: Emerging Trends in Research and Applications, 1st ed., I. Obeid, I. Selesnick, and J. Picone, Eds. New York City, New York, USA: Springer, 2020, pp. 67 104. https://www.springer.com/gp/book/9783030368432. [2] J. Picone, T. Farkas, I. Obeid, and Y. Persidsky, “MRI: High Performance Digital Pathology Using Big Data and Machine Learning.” Major Research Instrumentation (MRI), Division of Computer and Network Systems, Award No. 1726188, January 1, 2018 – December 31, 2021. https://www. isip.piconepress.com/projects/nsf_dpath/. [3] A. Gulati et al., “Conformer: Convolution-augmented Transformer for Speech Recognition,” in Proceedings of the Annual Conference of the International Speech Communication Association (INTERSPEECH), 2020, pp. 5036-5040. https://doi.org/10.21437/interspeech.2020-3015. [4] C.-J. Wu et al., “Machine Learning at Facebook: Understanding Inference at the Edge,” in Proceedings of the IEEE International Symposium on High Performance Computer Architecture (HPCA), 2019, pp. 331–344. https://ieeexplore.ieee.org/document/8675201. [5] I. Caswell and B. Liang, “Recent Advances in Google Translate,” Google AI Blog: The latest from Google Research, 2020. [Online]. Available: https://ai.googleblog.com/2020/06/recent-advances-in-google-translate.html. [Accessed: 01-Aug-2021]. [6] V. Khalkhali, N. Shawki, V. Shah, M. Golmohammadi, I. Obeid, and J. Picone, “Low Latency Real-Time Seizure Detection Using Transfer Deep Learning,” in Proceedings of the IEEE Signal Processing in Medicine and Biology Symposium (SPMB), 2021, pp. 1 7. https://www.isip. piconepress.com/publications/conference_proceedings/2021/ieee_spmb/eeg_transfer_learning/. [7] J. Picone, T. Farkas, I. Obeid, and Y. Persidsky, “MRI: High Performance Digital Pathology Using Big Data and Machine Learning,” Philadelphia, Pennsylvania, USA, 2020. https://www.isip.piconepress.com/publications/reports/2020/nsf/mri_dpath/. [8] I. Hunt, S. Husain, J. Simons, I. Obeid, and J. Picone, “Recent Advances in the Temple University Digital Pathology Corpus,” in Proceedings of the IEEE Signal Processing in Medicine and Biology Symposium (SPMB), 2019, pp. 1–4. https://ieeexplore.ieee.org/document/9037859. [9] A. P. Martinez, C. Cohen, K. Z. Hanley, and X. (Bill) Li, “Estrogen Receptor and Cytokeratin 5 Are Reliable Markers to Separate Usual Ductal Hyperplasia From Atypical Ductal Hyperplasia and Low-Grade Ductal Carcinoma In Situ,” Arch. Pathol. Lab. Med., vol. 140, no. 7, pp. 686–689, Apr. 2016. https://doi.org/10.5858/arpa.2015-0238-OA. 

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5. Murine Models for Staphylococcal Infection

   https://doi.org/10.1002/cpz1.52  

   Klopfenstein, Nathan ; Cassat, James E. ; Monteith, Andrew ; Miller, Anderson ; Drury, Sydney ; Skaar, Eric ; Serezani, C. Henrique ( March 2021 , Current Protocols)

   Staphylococcus aureusis a Gram‐positive bacterium that colonizes almost every organ in humans and mice and is a leading cause of diseases worldwide.S. aureusinfections can be challenging to treat due to widespread antibiotic resistance and their ability to cause tissue damage. The primary modes of transmission ofS. aureusare via direct contact with a colonized or infected individual or invasive spread from a colonization niche in the same individual.S. aureuscan cause a myriad of diseases, including skin and soft tissue infections (SSTIs), osteomyelitis, pneumonia, endocarditis, and sepsis.S. aureusinfection is characterized by the formation of purulent lesions known as abscesses, which are rich in live and dead neutrophils, macrophages, and surrounded by a capsule containing fibrin and collagen. Different strains ofS. aureusproduce varying amounts of toxins that evade and/or elicit immune responses. Therefore, animal models ofS. aureusinfection provide a unique opportunity to understand the dynamics of organ‐specific immune responses and modifications in the pathogen that could favor the establishment of the pathogen. With advances in in vivo imaging of fluorescent transgenic mice, combined with fluorescent/bioluminescent bacteria, we can use mouse models to better understand the immune response to these types of infections. By understanding the host and bacterial dynamics within various organ systems, we can develop therapeutics to eliminate these pathogens. This module describes in vivo mouse models of both local and systemicS. aureusinfection. © 2021 Wiley Periodicals LLC.

   This article was corrected on 20 July 2022. See the end of the full text for details.

   Basic Protocol 1: Murine model ofStaphylococcus aureussubcutaneous infection

   Alternate Protocol: Murine tape stripping skin infection model

   Basic Protocol 2: Sample collection to determine skin structure, production of inflammatory mediators, and bacterial load

   Basic Protocol 3: Murine model of post‐traumaticStaphylococcus aureusosteomyelitis

   Basic Protocol 4: Intravenous infection of the retro‐orbital sinus

   Support Protocol: Preparation of the bacterial inoculum

    

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