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1. Detection of Acute Respiratory Distress Syndrome by Incorporation of Label Uncertainty and Partially Available Privileged Information*

   https://doi.org/10.1109/EMBC.2019.8857434  

   Sabeti, Elyas ; Drews, Joshua ; Reamaroon, Narathip ; Gryak, Jonathan ; Sjoding, Michael ; Najarian, Kayvan ( July 2019 , 2019 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC))

   When training a machine learning algorithm for a supervised-learning task in some clinical applications, uncertainty in the correct labels of some patients may adversely affect the performance of the algorithm. For example, even clinical experts may have less confidence when assigning a medical diagnosis to some patients because of ambiguity in the patient's case or imperfect reliability of the diagnostic criteria. As a result, some cases used in algorithm training may be mislabeled, adversely affecting the algorithm's performance. However, experts may also be able to quantify their diagnostic uncertainty in these cases. We present a robust method implemented with support vector machines (SVM) to account for such clinical diagnostic uncertainty when training an algorithm to detect patients who develop the acute respiratory distress syndrome (ARDS). ARDS is a syndrome of the critically ill that is diagnosed using clinical criteria known to be imperfect. We represent uncertainty in the diagnosis of ARDS as a graded weight of confidence associated with each training label. We also performed a novel time-series sampling method to address the problem of intercorrelation among the longitudinal clinical data from each patient used in model training to limit overfitting. Preliminary results show that we can achieve meaningful improvement in the performance of algorithm to detect patients with ARDS on a hold-out sample, when we compare our method that accounts for the uncertainty of training labels with a conventional SVM algorithm. 

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2. Accounting for Label Uncertainty in Machine Learning for Detection of Acute Respiratory Distress Syndrome

   https://doi.org/10.1109/JBHI.2018.2810820  

   Reamaroon, Narathip ; Sjoding, Michael W. ; Lin, Kaiwen ; Iwashyna, Theodore J. ; Najarian, Kayvan ( February 2018 , IEEE Journal of Biomedical and Health Informatics)

   When training a machine learning algorithm for a supervised-learning task in some clinical applications, uncertainty in the correct labels of some patients may adversely affect the performance of the algorithm. For example, even clinical experts may have less confidence when assigning a medical diagnosis to some patients because of ambiguity in the patient's case or imperfect reliability of the diagnostic criteria. As a result, some cases used in algorithm training may be mis-labeled, adversely affecting the algorithm's performance. However, experts may also be able to quantify their diagnostic uncertainty in these cases. We present a robust method implemented with Support Vector Machines to account for such clinical diagnostic uncertainty when training an algorithm to detect patients who develop the acute respiratory distress syndrome (ARDS). ARDS is a syndrome of the critically ill that is diagnosed using clinical criteria known to be imperfect. We represent uncertainty in the diagnosis of ARDS as a graded weight of confidence associated with each training label. We also performed a novel time-series sampling method to address the problem of inter-correlation among the longitudinal clinical data from each patient used in model training to limit overfitting. Preliminary results show that we can achieve meaningful improvement in the performance of algorithm to detect patients with ARDS on a hold-out sample, when we compare our method that accounts for the uncertainty of training labels with a conventional SVM algorithm. 

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3. Ensemble Machine Learning for Alzheimer’s disease Classification from Retinal Vasculature

   Lin, Hely ; Fang, Ruogu ( October 2021 , Biomedical Engineering Society Annual Meeting)

   null (Ed.)

   Introduction: Alzheimer’s disease (AD) causes progressive irreversible cognitive decline and is the leading cause of dementia. Therefore, a timely diagnosis is imperative to maximize neurological preservation. However, current treatments are either too costly or limited in availability. In this project, we explored using retinal vasculature as a potential biomarker for early AD diagnosis. This project focuses on stage 3 of a three-stage modular machine learning pipeline which consisted of image quality selection, vessel map generation, and classification [1]. The previous model only used support vector machine (SVM) to classify AD labels which limited its accuracy to 82%. In this project, random forest and gradient boosting were added and, along with SVM, combined into an ensemble classifier, raising the classification accuracy to 89%. Materials and Methods: Subjects classified as AD were those who were diagnosed with dementia in “Dementia Outcome: Alzheimer’s disease” from the UK Biobank Electronic Health Records. Five control groups were chosen with a 5:1 ratio of control to AD patients where the control patients had the same age, gender, and eye side image as the AD patient. In total, 122 vessel images from each group (AD and control) were used. The vessel maps were then segmented from fundus images through U-net. A t-test feature selection was first done on the training folds and the selected features was fed into the classifiers with a p-value threshold of 0.01. Next, 20 repetitions of 5-fold cross validation were performed where the hyperparameters were solely tuned on the training data. An ensemble classifier consisting of SVM, gradient boosting tree, and random forests was built and the final prediction was made through majority voting and evaluated on the test set. Results and Discussion: Through ensemble classification, accuracy increased by 4-12% relative to the individual classifiers, precision by 9-15%, sensitivity by 2-9%, specificity by at least 9-16%, and F1 score by 712%. Conclusions: Overall, a relatively high classification accuracy was achieved using machine learning ensemble classification with SVM, random forest, and gradient boosting. Although the results are very promising, a limitation of this study is that the requirement of needing images of sufficient quality decreased the amount of control parameters that can be implemented. However, through retinal vasculature analysis, this project shows machine learning’s high potential to be an efficient, more cost-effective alternative to diagnosing Alzheimer’s disease. Clinical Application: Using machine learning for AD diagnosis through retinal images will make screening available for a broader population by being more accessible and cost-efficient. Mobile device based screening can also be enabled at primary screening in resource-deprived regions. It can provide a pathway for future understanding of the association between biomarkers in the eye and brain. 

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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. Brain Hematoma Segmentation Using Active Learning and an Active Contour Model

   https://doi.org/10.1007/978-3-030-17935-9_35  

   Yao, Heming ; Williamson, Craig ; Gryak, Jonathan ; Najarian, Kayvan ( April 2019 , Bioinformatics and Biomedical Engineering)

   Traumatic brain injury (TBI) is a massive public health problem worldwide. Accurate and fast automatic brain hematoma segmentation is important for TBI diagnosis, treatment and outcome prediction. In this study, we developed a fully automated system to detect and segment hematoma regions in head Computed Tomography (CT) images of patients with acute TBI. We first over-segmented brain images into superpixels and then extracted statistical and textural features to capture characteristics of superpixels. To overcome the shortage of annotated data, an uncertainty-based active learning strategy was designed to adaptively and iteratively select the most informative unlabeled data to be annotated for training a Support Vector Machine classifier (SVM). Finally, the coarse segmentation from the SVM classifier was incorporated into an active contour model to improve the accuracy of the segmentation. From our experiments, the proposed active learning strategy can achieve a comparable result with 5 times fewer labeled data compared with regular machine learning. Our proposed automatic hematoma segmentation system achieved an average Dice coefficient of 0.60 on our dataset, where patients are from multiple health centers and at multiple levels of injury. Our results show that the proposed method can effectively overcome the challenge of limited and highly varied dataset. 

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