Generative models improve fairness of medical classifiers under distribution shifts.

Domain generalization is a ubiquitous challenge for machine learning in healthcare. Model performance in real-world conditions might be lower than expected because of discrepancies between the data encountered during deployment and development. Underrepresentation of some groups or conditions during model development is a common cause of this phenomenon. This challenge is often not readily addressed by targeted data acquisition and 'labeling' by expert clinicians, which can be prohibitively expensive or practically impossible because of the rarity of conditions or the available clinical expertise. We hypothesize that advances in generative artificial intelligence can help mitigate this unmet need in a steerable fashion, enriching our training dataset with synthetic examples that address shortfalls of underrepresented conditions or subgroups. We show that diffusion models can automatically learn realistic augmentations from data in a label-efficient manner. We demonstrate that learned augmentations make models more robust and statistically fair in-distribution and out of distribution. To evaluate the generality of our approach, we studied three distinct medical imaging contexts of varying difficulty: (1) histopathology, (2) chest X-ray and (3) dermatology images. Complementing real samples with synthetic ones improved the robustness of models in all three medical tasks and increased fairness by improving the accuracy of clinical diagnosis within underrepresented groups, especially out of distribution.

An intentional approach to managing bias in general purpose embedding models.

Advances in machine learning for health care have brought concerns about bias from the research community; specifically, the introduction, perpetuation, or exacerbation of care disparities. Reinforcing these concerns is the finding that medical images often reveal signals about sensitive attributes in ways that are hard to pinpoint by both algorithms and people. This finding raises a question about how to best design general purpose pretrained embeddings (GPPEs, defined as embeddings meant to support a broad array of use cases) for building downstream models that are free from particular types of bias. The downstream model should be carefully evaluated for bias, and audited and improved as appropriate. However, in our view, well intentioned attempts to prevent the upstream components-GPPEs-from learning sensitive attributes can have unintended consequences on the downstream models. Despite producing a veneer of technical neutrality, the resultant end-to-end system might still be biased or poorly performing. We present reasons, by building on previously published data, to support the reasoning that GPPEs should ideally contain as much information as the original data contain, and highlight the perils of trying to remove sensitive attributes from a GPPE. We also emphasise that downstream prediction models trained for specific tasks and settings, whether developed using GPPEs or not, should be carefully designed and evaluated to avoid bias that makes models vulnerable to issues such as distributional shift. These evaluations should be done by a diverse team, including social scientists, on a diverse cohort representing the full breadth of the patient population for which the final model is intended.

Large language models encode clinical knowledge.

Large language models (LLMs) have demonstrated impressive capabilities, but the bar for clinical applications is high. Attempts to assess the clinical knowledge of models typically rely on automated evaluations based on limited benchmarks. Here, to address these limitations, we present MultiMedQA, a benchmark combining six existing medical question answering datasets spanning professional medicine, research and consumer queries and a new dataset of medical questions searched online, HealthSearchQA. We propose a human evaluation framework for model answers along multiple axes including factuality, comprehension, reasoning, possible harm and bias. In addition, we evaluate Pathways Language Model1 (PaLM, a 540-billion parameter LLM) and its instruction-tuned variant, Flan-PaLM2 on MultiMedQA. Using a combination of prompting strategies, Flan-PaLM achieves state-of-the-art accuracy on every MultiMedQA multiple-choice dataset (MedQA3, MedMCQA4, PubMedQA5 and Measuring Massive Multitask Language Understanding (MMLU) clinical topics6), including 67.6% accuracy on MedQA (US Medical Licensing Exam-style questions), surpassing the prior state of the art by more than 17%. However, human evaluation reveals key gaps. To resolve this, we introduce instruction prompt tuning, a parameter-efficient approach for aligning LLMs to new domains using a few exemplars. The resulting model, Med-PaLM, performs encouragingly, but remains inferior to clinicians. We show that comprehension, knowledge recall and reasoning improve with model scale and instruction prompt tuning, suggesting the potential utility of LLMs in medicine. Our human evaluations reveal limitations of today's models, reinforcing the importance of both evaluation frameworks and method development in creating safe, helpful LLMs for clinical applications.

Enhancing the reliability and accuracy of AI-enabled diagnosis via complementarity-driven deferral to clinicians.

Predictive artificial intelligence (AI) systems based on deep learning have been shown to achieve expert-level identification of diseases in multiple medical imaging settings, but can make errors in cases accurately diagnosed by clinicians and vice versa. We developed Complementarity-Driven Deferral to Clinical Workflow (CoDoC), a system that can learn to decide between the opinion of a predictive AI model and a clinical workflow. CoDoC enhances accuracy relative to clinician-only or AI-only baselines in clinical workflows that screen for breast cancer or tuberculosis (TB). For breast cancer screening, compared to double reading with arbitration in a screening program in the UK, CoDoC reduced false positives by 25% at the same false-negative rate, while achieving a 66% reduction in clinician workload. For TB triaging, compared to standalone AI and clinical workflows, CoDoC achieved a 5-15% reduction in false positives at the same false-negative rate for three of five commercially available predictive AI systems. To facilitate the deployment of CoDoC in novel futuristic clinical settings, we present results showing that CoDoC's performance gains are sustained across several axes of variation (imaging modality, clinical setting and predictive AI system) and discuss the limitations of our evaluation and where further validation would be needed. We provide an open-source implementation to encourage further research and application.

Robust and data-efficient generalization of self-supervised machine learning for diagnostic imaging.

Machine-learning models for medical tasks can match or surpass the performance of clinical experts. However, in settings differing from those of the training dataset, the performance of a model can deteriorate substantially. Here we report a representation-learning strategy for machine-learning models applied to medical-imaging tasks that mitigates such 'out of distribution' performance problem and that improves model robustness and training efficiency. The strategy, which we named REMEDIS (for 'Robust and Efficient Medical Imaging with Self-supervision'), combines large-scale supervised transfer learning on natural images and intermediate contrastive self-supervised learning on medical images and requires minimal task-specific customization. We show the utility of REMEDIS in a range of diagnostic-imaging tasks covering six imaging domains and 15 test datasets, and by simulating three realistic out-of-distribution scenarios. REMEDIS improved in-distribution diagnostic accuracies up to 11.5% with respect to strong supervised baseline models, and in out-of-distribution settings required only 1-33% of the data for retraining to match the performance of supervised models retrained using all available data. REMEDIS may accelerate the development lifecycle of machine-learning models for medical imaging.

Predicting lymph node metastasis from primary tumor histology and clinicopathologic factors in colorectal cancer using deep learning.

BACKGROUND: Presence of lymph node metastasis (LNM) influences prognosis and clinical decision-making in colorectal cancer. However, detection of LNM is variable and depends on a number of external factors. Deep learning has shown success in computational pathology, but has struggled to boost performance when combined with known predictors. METHODS: Machine-learned features are created by clustering deep learning embeddings of small patches of tumor in colorectal cancer via k-means, and then selecting the top clusters that add predictive value to a logistic regression model when combined with known baseline clinicopathological variables. We then analyze performance of logistic regression models trained with and without these machine-learned features in combination with the baseline variables. RESULTS: The machine-learned extracted features provide independent signal for the presence of LNM (AUROC: 0.638, 95% CI: [0.590, 0.683]). Furthermore, the machine-learned features add predictive value to the set of 6 clinicopathologic variables in an external validation set (likelihood ratio test, p < 0.00032; AUROC: 0.740, 95% CI: [0.701, 0.780]). A model incorporating these features can also further risk-stratify patients with and without identified metastasis (p < 0.001 for both stage II and stage III). CONCLUSION: This work demonstrates an effective approach to combine deep learning with established clinicopathologic factors in order to identify independently informative features associated with LNM. Further work building on these specific results may have important impact in prognostication and therapeutic decision making for LNM. Additionally, this general computational approach may prove useful in other contexts.

When colorectal cancers spread to the lymph nodes, it can indicate a poorer prognosis. However, detecting lymph node metastasis (spread) can be difficult and depends on a number of factors such as how samples are taken and processed. Here, we show that machine learning, which involves computer software learning from patterns in data, can predict lymph node metastasis in patients with colorectal cancer from the microscopic appearance of their primary tumor and the clinical characteristics of the patients. We also show that the same approach can predict patient survival. With further work, our approach may help clinicians to inform patients about their prognosis and decide on appropriate treatments.

Does your dermatology classifier know what it doesn't know? Detecting the long-tail of unseen conditions.

Supervised deep learning models have proven to be highly effective in classification of dermatological conditions. These models rely on the availability of abundant labeled training examples. However, in the real-world, many dermatological conditions are individually too infrequent for per-condition classification with supervised learning. Although individually infrequent, these conditions may collectively be common and therefore are clinically significant in aggregate. To prevent models from generating erroneous outputs on such examples, there remains a considerable unmet need for deep learning systems that can better detect such infrequent conditions. These infrequent 'outlier' conditions are seen very rarely (or not at all) during training. In this paper, we frame this task as an out-of-distribution (OOD) detection problem. We set up a benchmark ensuring that outlier conditions are disjoint between the model training, validation, and test sets. Unlike traditional OOD detection benchmarks where the task is to detect dataset distribution shift, we aim at the more challenging task of detecting subtle differences resulting from a different pathology or condition. We propose a novel hierarchical outlier detection (HOD) loss, which assigns multiple abstention classes corresponding to each training outlier class and jointly performs a coarse classification of inliers vs. outliers, along with fine-grained classification of the individual classes. We demonstrate that the proposed HOD loss based approach outperforms leading methods that leverage outlier data during training. Further, performance is significantly boosted by using recent representation learning methods (BiT, SimCLR, MICLe). Further, we explore ensembling strategies for OOD detection and propose a diverse ensemble selection process for the best result. We also perform a subgroup analysis over conditions of varying risk levels and different skin types to investigate how OOD performance changes over each subgroup and demonstrate the gains of our framework in comparison to baseline. Furthermore, we go beyond traditional performance metrics and introduce a cost matrix for model trust analysis to approximate downstream clinical impact. We use this cost matrix to compare the proposed method against the baseline, thereby making a stronger case for its effectiveness in real-world scenarios.

Deep neural maps for unsupervised visualization of high-grade cancer in prostate biopsies.

Prostate cancer (PCa) is the most frequent noncutaneous cancer in men. Early detection of PCa is essential for clinical decision making, and reducing metastasis and mortality rates. The current approach for PCa diagnosis is histopathologic analysis of core biopsies taken under transrectal ultrasound guidance (TRUS-guided). Both TRUS-guided systematic biopsy and MR-TRUS-guided fusion biopsy have limitations in accurately identifying PCa, intraoperatively. There is a need to augment this process by visualizing highly probable areas of PCa. Temporal enhanced ultrasound (TeUS) has emerged as a promising modality for PCa detection. Prior work focused on supervised classification of PCa verified by gold standard pathology. Pathology labels are noisy, and data from an entire core have a single label even when significantly heterogeneous. Additionally, supervised methods are limited by data from cores with known pathology, and a significant portion of prostate data is discarded without being used. We provide an end-to-end unsupervised solution to map PCa distribution from TeUS data using an innovative representation learning method, deep neural maps. TeUS data are transformed to a topologically arranged hyper-lattice, where similar samples are closer together in the lattice. Therefore, similar regions of malignant and benign tissue in the prostate are clustered together. Our proposed method increases the number of training samples by several orders of magnitude. Data from biopsy cores with known labels are used to associate the clusters with PCa. Cancer probability maps generated using the unsupervised clustering of TeUS data help intuitively visualize the distribution of abnormal tissue for augmenting TRUS-guided biopsies.

Exploring microRNA Regulation of Cancer with Context-Aware Deep Cancer Classifier.

BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNA that regulate gene expression through post-transcriptional silencing. Differential expression observed in miRNAs, combined with advancements in deep learning (DL), have the potential to improve cancer classification by modelling non-linear miRNA-phenotype associations. We propose a novel miRNA-based deep cancer classifier (DCC) incorporating genomic and hierarchical tissue annotation, capable of accurately predicting the presence of cancer in wide range of human tissues. METHODS: miRNA expression profiles were analyzed for 1746 neoplastic and 3871 normal samples, across 26 types of cancer involving six organ sub-structures and 68 cell types. miRNAs were ranked and filtered using a specificity score representing their information content in relation to neoplasticity, incorporating 3 levels of hierarchical biological annotation. A DL architecture composed of stacked autoencoders (AE) and a multi-layer perceptron (MLP) was trained to predict neoplasticity using 497 abundant and informative miRNAs. Additional DCCs were trained using expression of miRNA cistrons and sequence families, and combined as a diagnostic ensemble. Important miRNAs were identified using backpropagation, and analyzed in Cytoscape using iCTNet and BiNGO. RESULTS: Nested four-fold cross-validation was used to assess the performance of the DL model. The model achieved an accuracy, AUC/ROC, sensitivity, and specificity of 94.73%, 98.6%, 95.1%, and 94.3%, respectively. CONCLUSION: Deep autoencoder networks are a powerful tool for modelling complex miRNA-phenotype associations in cancer. The proposed DCC improves classification accuracy by learning from the biological context of both samples and miRNAs, using anatomical and genomic annotation. Analyzing the deep structure of DCCs with backpropagation can also facilitate biological discovery, by performing gene ontology searches on the most highly significant features.

Deep Recurrent Neural Networks for Prostate Cancer Detection: Analysis of Temporal Enhanced Ultrasound.

Temporal enhanced ultrasound (TeUS), comprising the analysis of variations in backscattered signals from a tissue over a sequence of ultrasound frames, has been previously proposed as a new paradigm for tissue characterization. In this paper, we propose to use deep recurrent neural networks (RNN) to explicitly model the temporal information in TeUS. By investigating several RNN models, we demonstrate that long short-term memory (LSTM) networks achieve the highest accuracy in separating cancer from benign tissue in the prostate. We also present algorithms for in-depth analysis of LSTM networks. Our in vivo study includes data from 255 prostate biopsy cores of 157 patients. We achieve area under the curve, sensitivity, specificity, and accuracy of 0.96, 0.76, 0.98, and 0.93, respectively. Our result suggests that temporal modeling of TeUS using RNN can significantly improve cancer detection accuracy over previously presented works.

Toward a real-time system for temporal enhanced ultrasound-guided prostate biopsy.

PURPOSE: We have previously proposed temporal enhanced ultrasound (TeUS) as a new paradigm for tissue characterization. TeUS is based on analyzing a sequence of ultrasound data with deep learning and has been demonstrated to be successful for detection of cancer in ultrasound-guided prostate biopsy. Our aim is to enable the dissemination of this technology to the community for large-scale clinical validation. METHODS: In this paper, we present a unified software framework demonstrating near-real-time analysis of ultrasound data stream using a deep learning solution. The system integrates ultrasound imaging hardware, visualization and a deep learning back-end to build an accessible, flexible and robust platform. A client-server approach is used in order to run computationally expensive algorithms in parallel. We demonstrate the efficacy of the framework using two applications as case studies. First, we show that prostate cancer detection using near-real-time analysis of RF and B-mode TeUS data and deep learning is feasible. Second, we present real-time segmentation of ultrasound prostate data using an integrated deep learning solution. RESULTS: The system is evaluated for cancer detection accuracy on ultrasound data obtained from a large clinical study with 255 biopsy cores from 157 subjects. It is further assessed with an independent dataset with 21 biopsy targets from six subjects. In the first study, we achieve area under the curve, sensitivity, specificity and accuracy of 0.94, 0.77, 0.94 and 0.92, respectively, for the detection of prostate cancer. In the second study, we achieve an AUC of 0.85. CONCLUSION: Our results suggest that TeUS-guided biopsy can be potentially effective for the detection of prostate cancer.

Investigation of Physical Phenomena Underlying Temporal-Enhanced Ultrasound as a New Diagnostic Imaging Technique: Theory and Simulations.

Temporal-enhanced ultrasound (TeUS) is a novel noninvasive imaging paradigm that captures information from a temporal sequence of backscattered US radio frequency data obtained from a fixed tissue location. This technology has been shown to be effective for classification of various in vivo and ex vivo tissue types including prostate cancer from benign tissue. Our previous studies have indicated two primary phenomena that influence TeUS: 1) changes in tissue temperature due to acoustic absorption and 2) micro vibrations of tissue due to physiological vibration. In this paper, first, a theoretical formulation for TeUS is presented. Next, a series of simulations are carried out to investigate micro vibration as a source of tissue characterizing information in TeUS. The simulations include finite element modeling of micro vibration in synthetic phantoms, followed by US image generation during TeUS imaging. The simulations are performed on two media, a sparse array of scatterers and a medium with pathology mimicking scatterers that match nuclei distribution extracted from a prostate digital pathology data set. Statistical analysis of the simulated TeUS data shows its ability to accurately classify tissue types. Our experiments suggest that TeUS can capture the microstructural differences, including scatterer density, in tissues as they react to micro vibrations.

Detection and grading of prostate cancer using temporal enhanced ultrasound: combining deep neural networks and tissue mimicking simulations.

PURPOSE  : Temporal Enhanced Ultrasound (TeUS) has been proposed as a new paradigm for tissue characterization based on a sequence of ultrasound radio frequency (RF) data. We previously used TeUS to successfully address the problem of prostate cancer detection in the fusion biopsies. METHODS  : In this paper, we use TeUS to address the problem of grading prostate cancer in a clinical study of 197 biopsy cores from 132 patients. Our method involves capturing high-level latent features of TeUS with a deep learning approach followed by distribution learning to cluster aggressive cancer in a biopsy core. In this hypothesis-generating study, we utilize deep learning based feature visualization as a means to obtain insight into the physical phenomenon governing the interaction of temporal ultrasound with tissue. RESULTS  : Based on the evidence derived from our feature visualization, and the structure of tissue from digital pathology, we build a simulation framework for studying the physical phenomenon underlying TeUS-based tissue characterization. CONCLUSION  : Results from simulation and feature visualization corroborated with the hypothesis that micro-vibrations of tissue microstructure, captured by low-frequency spectral features of TeUS, can be used for detection of prostate cancer.

Transfer learning from RF to B-mode temporal enhanced ultrasound features for prostate cancer detection.

PURPOSE: We present a method for prostate cancer (PCa) detection using temporal enhanced ultrasound (TeUS) data obtained either from radiofrequency (RF) ultrasound signals or B-mode images. METHODS: For the first time, we demonstrate that by applying domain adaptation and transfer learning methods, a tissue classification model trained on TeUS RF data (source domain) can be deployed for classification using TeUS B-mode data alone (target domain), where both data are obtained on the same ultrasound scanner. This is a critical step for clinical translation of tissue classification techniques that primarily rely on accessing RF data, since this imaging modality is not readily available on all commercial scanners in clinics. Proof of concept is provided for in vivo characterization of PCa using TeUS B-mode data, where different nonlinear processing filters in the pipeline of the RF to B-mode conversion result in a distribution shift between the two domains. RESULTS: Our in vivo study includes data obtained in MRI-guided targeted procedure for prostate biopsy. We achieve comparable area under the curve using TeUS RF and B-mode data for medium to large cancer tumor sizes in biopsy cores (>4 mm). CONCLUSION: Our result suggests that the proposed adaptation technique is successful in reducing the divergence between TeUS RF and B-mode data.

Detection of prostate cancer using temporal sequences of ultrasound data: a large clinical feasibility study.

PURPOSE: This paper presents the results of a large study involving fusion prostate biopsies to demonstrate that temporal ultrasound can be used to accurately classify tissue labels identified in multi-parametric magnetic resonance imaging (mp-MRI) as suspicious for cancer. METHODS: We use deep learning to analyze temporal ultrasound data obtained from 255 cancer foci identified in mp-MRI. Each target is sampled in axial and sagittal planes. A deep belief network is trained to automatically learn the high-level latent features of temporal ultrasound data. A support vector machine classifier is then applied to differentiate cancerous versus benign tissue, verified by histopathology. Data from 32 targets are used for the training, while the remaining 223 targets are used for testing. RESULTS: Our results indicate that the distance between the biopsy target and the prostate boundary, and the agreement between axial and sagittal histopathology of each target impact the classification accuracy. In 84 test cores that are 5 mm or farther to the prostate boundary, and have consistent pathology outcomes in axial and sagittal biopsy planes, we achieve an area under the curve of 0.80. In contrast, all of these targets were labeled as moderately suspicious in mp-MR. CONCLUSION: Using temporal ultrasound data in a fusion prostate biopsy study, we achieved a high classification accuracy specifically for moderately scored mp-MRI targets. These targets are clinically common and contribute to the high false-positive rates associated with mp-MRI for prostate cancer detection. Temporal ultrasound data combined with mp-MRI have the potential to reduce the number of unnecessary biopsies in fusion biopsy settings.