Lars Ailo Bongo

Masoud Tafavvoghi, Lars Ailo Bongo, Nikita Shvetsov et al.

Advancements in digital pathology and computing resources have made a significant impact in the field of computational pathology for breast cancer diagnosis and treatment. However, access to high-quality labeled histopathological images of breast cancer is a big challenge that limits the development of accurate and robust deep learning models. In this scoping review, we identified the publicly available datasets of breast H&E stained whole-slide images (WSI) that can be used to develop deep learning algorithms. We systematically searched nine scientific literature databases and nine research data repositories and found 17 publicly available datasets containing 10385 H&E WSIs of breast cancer. Moreover, we reported image metadata and characteristics for each dataset to assist researchers in selecting proper datasets for specific tasks in breast cancer computational pathology. In addition, we compiled two lists of breast H&E patches and private datasets as supplementary resources for researchers. Notably, only 28% of the included articles utilized multiple datasets, and only 14% used an external validation set, suggesting that the performance of other developed models may be susceptible to overestimation. The TCGA-BRCA was used in 52% of the selected studies. This dataset has a considerable selection bias that can impact the robustness and generalizability of the trained algorithms. There is also a lack of consistent metadata reporting of breast WSI datasets that can be an issue in developing accurate deep learning models, indicating the necessity of establishing explicit guidelines for documenting breast WSI dataset characteristics and metadata.

Masoud Tafavvoghi, Anders Sildnes, Mehrdad Rakaee et al.

Classifying breast cancer molecular subtypes is crucial for tailoring treatment strategies. While immunohistochemistry (IHC) and gene expression profiling are standard methods for molecular subtyping, IHC can be subjective, and gene profiling is costly and not widely accessible in many regions. Previous approaches have highlighted the potential application of deep learning models on H&E-stained whole slide images (WSI) for molecular subtyping, but these efforts vary in their methods, datasets, and reported performance. In this work, we investigated whether H&E-stained WSIs could be solely leveraged to predict breast cancer molecular subtypes (luminal A, B, HER2-enriched, and Basal). We used 1,433 WSIs of breast cancer in a two-step pipeline: first, classifying tumor and non-tumor tiles to use only the tumor regions for molecular subtyping; and second, employing a One-vs-Rest (OvR) strategy to train four binary OvR classifiers and aggregating their results using an eXtreme Gradient Boosting (XGBoost) model. The pipeline was tested on 221 hold-out WSIs, achieving an overall macro F1 score of 0.95 for tumor detection and 0.73 for molecular subtyping. Our findings suggest that, with further validation, supervised deep learning models could serve as supportive tools for molecular subtyping in breast cancer. Our codes are made available to facilitate ongoing research and development.

Pavitra Chauhan, Mohsen Gamal Saad Askar, Kristian Svendsen et al.

The translation of clinical decision support system (CDSS) tools from research settings into the clinic is often non-existent, partly because the focus tends to be on training machine learning models rather than tool development using the model for inference. To develop a CDSS tool that can be deployed in the clinical workflow, there is a need to integrate, validate, and test the tool on the Electronic Health Record (EHR) systems that store and manage patient data. Not surprisingly, it is rarely possible for researchers to get the necessary access to an EHR system due to legal restrictions pertaining to the protection of data privacy in patient records. We propose an architecture for using synthetic data in EHR systems to make CDSS tool development and testing much easier. In this study, the architecture is implemented in the SyntHIR system. SyntHIR has three noteworthy architectural features enabling (i) integration with synthetic data generators, (ii) data interoperability, and (iii) tool transportability. The translational value of this approach was evaluated through two primary steps. First, a working proof-of-concept of a machine learning-based CDSS tool was developed using data from patient registries in Norway. Second, the transportability of this CDSS tool was demonstrated by successfully deploying it in Norway's largest EHR system vendor (DIPS). These findings showcase the value of the SyntHIR architecture as a useful reference model to accelerate the translation of "bench to bedside" research of CDSS tools.

Bjørn-Richard Pedersen, Rigmor Katrine Johansen, Einar Holsbø et al.

Machine learning methods have proven useful in transcribing historical data. However, results from even highly accurate methods require manual verification and correction. Such manual review can be time-consuming and expensive, therefore the objective of this paper was to make it more efficient. Previously, we used machine learning to transcribe 2.3 million handwritten occupation codes from the Norwegian 1950 census with high accuracy (97%). We manually reviewed the 90,000 (3%) codes with the lowest model confidence. We allocated those 90,000 codes to human reviewers, who used our annotation tool to review the codes. To assess reviewer agreement, some codes were assigned to multiple reviewers. We then analyzed the review results to understand the relationship between accuracy improvements and effort. Additionally, we interviewed the reviewers to improve the workflow. The reviewers corrected 62.8% of the labels and agreed with the model label in 31.9% of cases. About 0.2% of the images could not be assigned a label, while for 5.1% the reviewers were uncertain, or they assigned an invalid label. 9,000 images were independently reviewed by multiple reviewers, resulting in an agreement of 86.43% and disagreement of 8.96%. We learned that our automatic transcription is biased towards the most frequent codes, with a higher degree of misclassification for the lowest frequency codes. Our interview findings show that the reviewers did internal quality control and found our custom tool well-suited. So, only one reviewer is needed, but they should report uncertainty.

Nikita Shvetsov, Thomas K. Kilvaer, Masoud Tafavvoghi et al.

Developing clinically useful cell-level analysis tools in digital pathology remains challenging due to limitations in dataset granularity, inconsistent annotations, high computational demands, and difficulties integrating new technologies into workflows. To address these issues, we propose a solution that enhances data quality, model performance, and usability by creating a lightweight, extensible cell segmentation and classification model. First, we update data labels through cross-relabeling to refine annotations of PanNuke and MoNuSAC, producing a unified dataset with seven distinct cell types. Second, we leverage the H-Optimus foundation model as a fixed encoder to improve feature representation for simultaneous segmentation and classification tasks. Third, to address foundation models' computational demands, we distill knowledge to reduce model size and complexity while maintaining comparable performance. Finally, we integrate the distilled model into QuPath, a widely used open-source digital pathology platform. Results demonstrate improved segmentation and classification performance using the H-Optimus-based model compared to a CNN-based model. Specifically, average $R^2$ improved from 0.575 to 0.871, and average $PQ$ score improved from 0.450 to 0.492, indicating better alignment with actual cell counts and enhanced segmentation quality. The distilled model maintains comparable performance while reducing parameter count by a factor of 48. By reducing computational complexity and integrating into workflows, this approach may significantly impact diagnostics, reduce pathologist workload, and improve outcomes. Although the method shows promise, extensive validation is necessary prior to clinical deployment.

Anders Sildnes, Nikita Shvetsov, Masoud Tafavvoghi et al.

Even foundational models that are trained on datasets with billions of data samples may develop shortcuts that lead to overfitting and bias. Shortcuts are non-relevant patterns in data, such as the background color or color intensity. So, to ensure the robustness of deep learning applications, there is a need for methods to detect and remove such shortcuts. Today's model debugging methods are time consuming since they often require customization to fit for a given model architecture in a specific domain. We propose a generalized, model-agnostic framework to debug deep learning models. We focus on the domain of histopathology, which has very large images that require large models - and therefore large computation resources. It can be run on a workstation with a commodity GPU. We demonstrate that our framework can replicate non-image shortcuts that have been found in previous work for self-supervised learning models, and we also identify possible shortcuts in a foundation model. Our easy to use tests contribute to the development of more reliable, accurate, and generalizable models for WSI analysis. Our framework is available as an open-source tool available on github.

Nikita Shvetsov, Morten Grønnesby, Edvard Pedersen et al.

Increased levels of tumor infiltrating lymphocytes (TILs) in cancer tissue indicate favourable outcomes in many types of cancer. Manual quantification of immune cells is inaccurate and time consuming for pathologists. Our aim is to leverage a computational solution to automatically quantify TILs in whole slide images (WSIs) of standard diagnostic haematoxylin and eosin stained sections (H&E slides) from lung cancer patients. Our approach is to transfer an open source machine learning method for segmentation and classification of nuclei in H&E slides trained on public data to TIL quantification without manual labeling of our data. Our results show that additional augmentation improves model transferability when training on few samples/limited tissue types. Models trained with sufficient samples/tissue types do not benefit from our additional augmentation policy. Further, the resulting TIL quantification correlates to patient prognosis and compares favorably to the current state-of-the-art method for immune cell detection in non-small lung cancer (current standard CD8 cells in DAB stained TMAs HR 0.34 95% CI 0.17-0.68 vs TILs in HE WSIs: HoVer-Net PanNuke Aug Model HR 0.30 95% CI 0.15-0.60, HoVer-Net MoNuSAC Aug model HR 0.27 95% CI 0.14-0.53). Moreover, we implemented a cloud based system to train, deploy and visually inspect machine learning based annotation for H&E slides. Our pragmatic approach bridges the gap between machine learning research, translational clinical research and clinical implementation. However, validation in prospective studies is needed to assert that the method works in a clinical setting.

Álvaro Martínez Fernández, Lars Ailo Bongo, Edvard Pedersen

Visualizations are an essential part of biomedical analysis result interpretation. Often, interactive networks are used to visualize the data. However, the high interconnectivity, and high dimensionality of the data often results in information overload, making it hard to interpret the results. To address the information overload problem, existing solutions typically either use data reduction, reduced interactivity, or expensive hardware. We propose using the affordable Oculus Quest Virtual Reality (VR) headset for interactive visualization of large-scale biological networks. We present the design and implementation of our solution, GeneNet VR, and we evaluate its scalability and usability using large gene-to-gene interaction networks. We achieve the 72 FPS required by the Oculus performance guidelines for the largest of our networks (2693 genes) using both a GPU and the Oculus Quest standalone. We found from our interviews with biomedical researchers that GeneNet VR is innovative, interesting, and easy to use for novice VR users. We believe affordable hardware like the Oculus Quest has a big potential for biological data analysis. However, additional work is required to evaluate its benefits to improve knowledge discovery for real data analysis use cases. GeneNet VR is open-sourced: https://github.com/kolibrid/GeneNet-VR. A video demonstrating GeneNet VR used to explore large biological networks: https://youtu.be/N4QDZiZqVNY.

Bjørn-Richard Pedersen, Einar Holsbø, Trygve Andersen et al.

Machine learning approaches achieve high accuracy for text recognition and are therefore increasingly used for the transcription of handwritten historical sources. However, using machine learning in production requires a streamlined end-to-end pipeline that scales to the dataset size and a model that achieves high accuracy with few manual transcriptions. The correctness of the model results must also be verified. This paper describes our lessons learned developing, tuning and using the Occode end-to-end machine learning pipeline for transcribing 2.3 million handwritten occupation codes from the Norwegian 1950 population census. We achieve an accuracy of 97% for the automatically transcribed codes, and we send 3% of the codes for manual verification. We verify that the occupation code distribution found in our results matches the distribution found in our training data, which should be representative for the census as a whole. We believe our approach and lessons learned may be useful for other transcription projects that plan to use machine learning in production. The source code is available at: https://github.com/uit-hdl/rhd-codes

Tengel Ekrem Skar, Einar Holsbø, Kristian Svendsen et al.

Population-scale drug prescription data linked with adverse drug reaction (ADR) data supports the fitting of models large enough to detect drug use and ADR patterns that are not detectable using traditional methods on smaller datasets. However, detecting ADR patterns in large datasets requires tools for scalable data processing, machine learning for data analysis, and interactive visualization. To our knowledge no existing pharmacoepidemiology tool supports all three requirements. We have therefore created a tool for interactive exploration of patterns in prescription datasets with millions of samples. We use Spark to preprocess the data for machine learning and for analyses using SQL queries. We have implemented models in Keras and the scikit-learn framework. The model results are visualized and interpreted using live Python coding in Jupyter. We apply our tool to explore a 384 million prescription data set from the Norwegian Prescription Database combined with a 62 million prescriptions for elders that were hospitalized. We preprocess the data in two minutes, train models in seconds, and plot the results in milliseconds. Our results show the power of combining computational power, short computation times, and ease of use for analysis of population scale pharmacoepidemiology datasets. The code is open source and available at: https://github.com/uit-hdl/norpd_prescription_analyses

Mike Voets, Kajsa Møllersen, Lars Ailo Bongo

Replication studies are essential for validation of new methods, and are crucial to maintain the high standards of scientific publications, and to use the results in practice. We have attempted to replicate the main method in 'Development and validation of a deep learning algorithm for detection of diabetic retinopathy in retinal fundus photographs' published in JAMA 2016; 316(22). We re-implemented the method since the source code is not available, and we used publicly available data sets. The original study used non-public fundus images from EyePACS and three hospitals in India for training. We used a different EyePACS data set from Kaggle. The original study used the benchmark data set Messidor-2 to evaluate the algorithm's performance. We used the same data set. In the original study, ophthalmologists re-graded all images for diabetic retinopathy, macular edema, and image gradability. There was one diabetic retinopathy grade per image for our data sets, and we assessed image gradability ourselves. Hyper-parameter settings were not described in the original study. But some of these were later published. We were not able to replicate the original study. Our algorithm's area under the receiver operating curve (AUC) of 0.94 on the Kaggle EyePACS test set and 0.80 on Messidor-2 did not come close to the reported AUC of 0.99 in the original study. This may be caused by the use of a single grade per image, different data, or different not described hyper-parameter settings. This study shows the challenges of replicating deep learning, and the need for more replication studies to validate deep learning methods, especially for medical image analysis. Our source code and instructions are available at: https://github.com/mikevoets/jama16-retina-replication

Bjørn Pedersen, Maisha Islam, Doris Tove Kristoffersen et al.

This paper investigates the feasibility of using pre-trained generative Large Language Models (LLMs) to automate the assignment of ICD-10 codes to historical causes of death. Due to the complex narratives often found in historical causes of death, this task has traditionally been manually performed by coding experts. We evaluate the ability of GPT-3.5, GPT-4, and Llama 2 LLMs to accurately assign ICD-10 codes on the HiCaD dataset that contains causes of death recorded in the civil death register entries of 19,361 individuals from Ipswich, Kilmarnock, and the Isle of Skye from the UK between 1861-1901. Our findings show that GPT-3.5, GPT-4, and Llama 2 assign the correct code for 69%, 83%, and 40% of causes, respectively. However, we achieve a maximum accuracy of 89% by standard machine learning techniques. All LLMs performed better for causes of death that contained terms still in use today, compared to archaic terms. Also they perform better for short causes (1-2 words) compared to longer causes. LLMs therefore do not currently perform well enough for historical ICD-10 code assignment tasks. We suggest further fine-tuning or alternative frameworks to achieve adequate performance.

Nikita Shvetsov, Anders Sildnes, Masoud Tafavvoghi et al.

Addressing the critical need for accurate prognostic biomarkers in cancer treatment, quantifying tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC) presents considerable challenges. Manual TIL quantification in whole slide images (WSIs) is laborious and subject to variability, potentially undermining patient outcomes. Our study introduces an automated pipeline that utilizes semi-stochastic patch sampling, patch classification to retain prognostically relevant patches, and cell quantification using the HoVer-Net model to streamline the TIL evaluation process. This pipeline efficiently excludes approximately 70% of areas not relevant for prognosis and requires only 5% of the remaining patches to maintain prognostic accuracy (c-index = 0.65). The computational efficiency achieved does not sacrifice prognostic accuracy, as demonstrated by the TILs score's strong association with patient survival, which outperforms traditional CD8 IHC scoring methods. While the pipeline demonstrates potential for enhancing NSCLC prognostication and personalization of treatment, comprehensive clinical validation is still required. Future research should focus on verifying its broader clinical utility and investigating additional biomarkers to improve NSCLC prognosis.

Masoud Tafavvoghi, Lars Ailo Bongo, André Berli Delgado et al.

In this study, we built an end-to-end tumor-infiltrating lymphocytes (TILs) assessment pipeline within QuPath, demonstrating the potential of easily accessible tools to perform complex tasks in a fully automatic fashion. First, we trained a pixel classifier to segment tumor, tumor-associated stroma, and other tissue compartments in breast cancer H&E-stained whole-slide images (WSI) to isolate tumor-associated stroma for subsequent analysis. Next, we applied a pre-trained StarDist deep learning model in QuPath for cell detection and used the extracted cell features to train a binary classifier distinguishing TILs from other cells. To evaluate our TILs assessment pipeline, we calculated the TIL density in each WSI and categorized them as low, medium, or high TIL levels. Our pipeline was evaluated against pathologist-assigned TIL scores, achieving a Cohen's kappa of 0.71 on the external test set, corroborating previous research findings. These results confirm that existing software can offer a practical solution for the assessment of TILs in H&E-stained WSIs of breast cancer.

Cristina Jácome, Johan Ravn, Einar Holsbø et al.

We applied deep learning to create an algorithm for breathing phase detection in lung sound recordings, and we compared the breathing phases detected by the algorithm and manually annotated by two experienced lung sound researchers. Our algorithm uses a convolutional neural network with spectrograms as the features, removing the need to specify features explicitly. We trained and evaluated the algorithm using three subsets that are larger than previously seen in the literature. We evaluated the performance of the method using two methods. First, discrete count of agreed breathing phases (using 50% overlap between a pair of boxes), shows a mean agreement with lung sound experts of 97% for inspiration and 87% for expiration. Second, the fraction of time of agreement (in seconds) gives higher pseudo-kappa values for inspiration (0.73-0.88) than expiration (0.63-0.84), showing an average sensitivity of 97% and an average specificity of 84%. With both evaluation methods, the agreement between the annotators and the algorithm shows human level performance for the algorithm. The developed algorithm is valid for detecting breathing phases in lung sound recordings.

Morten Grønnesby, Juan Carlos Aviles Solis, Einar Holsbø et al.

In recent years, many innovative solutions for recording and viewing sounds from a stethoscope have become available. However, to fully utilize such devices, there is a need for an automated approach for detecting abnormal lung sounds, which is better than the existing methods that typically have been developed and evaluated using a small and non-diverse dataset. We propose a machine learning based approach for detecting crackles in lung sounds recorded using a stethoscope in a large health survey. Our method is trained and evaluated using 209 files with crackles classified by expert listeners. Our analysis pipeline is based on features extracted from small windows in audio files. We evaluated several feature extraction methods and classifiers. We evaluated the pipeline using a training set of 175 crackle windows and 208 normal windows. We did 100 cycles of cross validation where we shuffled training sets between cycles. For all the division between training and evaluation was 70%-30%. We found and evaluated a 5-dimenstional vector with four features from the time domain and one from the spectrum domain. We evaluated several classifiers and found SVM with a Radial Basis Function Kernel to perform best. Our approach had a precision of 86% and recall of 84% for classifying a crackle in a window, which is more accurate than found in studies of health personnel. The low-dimensional feature vector makes the SVM very fast. The model can be trained on a regular computer in 1.44 seconds, and 319 crackles can be classified in 1.08 seconds. Our approach detects and visualizes individual crackles in recorded audio files. It is accurate, fast, and has low resource requirements. It can be used to train health personnel or as part of a smartphone application for Bluetooth stethoscopes.