While optical microscopy inspection of blood films and bone marrow aspirates by a hematologist is a crucial step in establishing diagnosis of acute leukemia, especially in low-resource settings where other diagnostic modalities might not be available, the task remains time-consuming and prone to human inconsistencies. This has an impact especially in cases of Acute Promyelocytic Leukemia (APL) that require urgent treatment. Integration of automated computational hematopathology into clinical workflows can improve the throughput of these services and reduce cognitive human error. However, a major bottleneck in deploying such systems is a lack of sufficient cell morphological object-labels annotations to train deep learning models. We overcome this by leveraging patient diagnostic labels to train weakly-supervised models that detect different types of acute leukemia. We introduce a deep learning approach, Multiple Instance Learning for Leukocyte Identification (MILLIE), able to perform automated reliable analysis of blood films with minimal supervision. Without being trained to classify individual cells, MILLIE differentiates between acute lymphoblastic and myeloblastic leukemia in blood films. More importantly, MILLIE detects APL in blood films (AUC 0.94+/-0.04) and in bone marrow aspirates (AUC 0.99+/-0.01). MILLIE is a viable solution to augment the throughput of clinical pathways that require assessment of blood film microscopy.
Point-based object localization (POL), which pursues high-performance object sensing under low-cost data annotation, has attracted increased attention. However, the point annotation mode inevitably introduces semantic variance for the inconsistency of annotated points. Existing POL methods heavily reply on accurate key-point annotations which are difficult to define. In this study, we propose a POL method using coarse point annotations, relaxing the supervision signals from accurate key points to freely spotted points. To this end, we propose a coarse point refinement (CPR) approach, which to our best knowledge is the first attempt to alleviate semantic variance from the perspective of algorithm. CPR constructs point bags, selects semantic-correlated points, and produces semantic center points through multiple instance learning (MIL). In this way, CPR defines a weakly supervised evolution procedure, which ensures training high-performance object localizer under coarse point supervision. Experimental results on COCO, DOTA and our proposed SeaPerson dataset validate the effectiveness of the CPR approach. The dataset and code will be available at https://github.com/ucas-vg/PointTinyBenchmark/.
This study investigates weakly supervised image segmentation using loose bounding box supervision. It presents a multiple instance learning strategy based on polar transformation to assist image segmentation when loose bounding boxes are employed as supervision. In this strategy, weighted smooth maximum approximation is introduced to incorporate the observation that pixels closer to the origin of the polar transformation are more likely to belong to the object in the bounding box. The proposed approach was evaluated on a public medical dataset using Dice coefficient. The results demonstrate its superior performance. The codes are available at \url{https://github.com/wangjuan313/wsis-polartransform}.
Cancer stage is a large determinant of patient prognosis and management in many cancer types, and is often assessed using medical imaging modalities, such as CT and MRI. These medical images contain rich information that can be explored to stratify patients within each stage group to further improve prognostic algorithms. Although the majority of cancer deaths result from metastatic and multifocal disease, building imaging biomarkers for patients with multiple tumors has been a challenging task due to the lack of annotated datasets and standard study framework. In this paper, we process two public datasets to set up a benchmark cohort of 341 patient in total for studying outcome prediction of multifocal metastatic cancer. We identify the lack of expressiveness in common multiple instance classification networks and propose two injective multiple instance pooling functions that are better suited to outcome prediction. Our results show that multiple instance learning with injective pooling functions can achieve state-of-the-art performance in the non-small-cell lung cancer CT and head and neck CT outcome prediction benchmarking tasks. We will release the processed multifocal datasets, our code and the intermediate files i.e. extracted radiomic features to support further transparent and reproducible research.
The detection of induced pluripotent stem cell (iPSC) colonies often needs the precise extraction of the colony features. However, existing computerized systems relied on segmentation of contours by preprocessing for classifying the colony conditions were task-extensive. To maximize the efficiency in categorizing colony conditions, we propose a multiple instance learning (MIL) in weakly supervised settings. It is designed in a single model to produce weak segmentation and classification of colonies without using finely labeled samples. As a single model, we employ a U-net-like convolution neural network (CNN) to train on binary image-level labels for MIL colonies classification. Furthermore, to specify the object of interest we used a simple post-processing method. The proposed approach is compared over conventional methods using five-fold cross-validation and receiver operating characteristic (ROC) curve. The maximum accuracy of the MIL-net is 95%, which is 15 % higher than the conventional methods. Furthermore, the ability to interpret the location of the iPSC colonies based on the image level label without using a pixel-wise ground truth image is more appealing and cost-effective in colony condition recognition.
Being able to learn on weakly labeled data, and provide interpretability, are two of the main reasons why attention-based deep multiple instance learning (ABMIL) methods have become particularly popular for classification of histopathological images. Such image data usually come in the form of gigapixel-sized whole-slide-images (WSI) that are cropped into smaller patches (instances). However, the sheer size of the data makes training of ABMIL models challenging. All the instances from one WSI cannot be processed at once by conventional GPUs. Existing solutions compromise training by relying on pre-trained models, strategic sampling or selection of instances, or self-supervised learning. We propose a training strategy based on gradient accumulation that enables direct end-to-end training of ABMIL models without being limited by GPU memory. We conduct experiments on both QMNIST and Imagenette to investigate the performance and training time, and compare with the conventional memory-expensive baseline and a recent sampled-based approach. This memory-efficient approach, although slower, reaches performance indistinguishable from the memory-expensive baseline.
Multi-instance learning (MIL) deals with objects represented as bags of instances and can predict instance labels from bag-level supervision. However, significant performance gaps exist between instance-level MIL algorithms and supervised learners since the instance labels are unavailable in MIL. Most existing MIL algorithms tackle the problem by treating multi-instance bags as harmful ambiguities and predicting instance labels by reducing the supervision inexactness. This work studies MIL from a new perspective by considering bags as auxiliary information, and utilize it to identify instance-level causal representations from bag-level weak supervision. We propose the CausalMIL algorithm, which not only excels at instance label prediction but also provides robustness to distribution change by synergistically integrating MIL with identifiable variational autoencoder. Our approach is based on a practical and general assumption: the prior distribution over the instance latent representations belongs to the non-factorized exponential family conditioning on the multi-instance bags. Experiments on synthetic and real-world datasets demonstrate that our approach significantly outperforms various baselines on instance label prediction and out-of-distribution generalization tasks.
Multiple Instance Learning (MIL) is a weakly supervised learning problem where the aim is to assign labels to sets or bags of instances, as opposed to traditional supervised learning where each instance is assumed to be independent and identically distributed (IID) and is to be labeled individually. Recent work has shown promising results for neural network models in the MIL setting. Instead of focusing on each instance, these models are trained in an end-to-end fashion to learn effective bag-level representations by suitably combining permutation invariant pooling techniques with neural architectures. In this paper, we consider modelling the interactions between bags using a graph and employ Graph Neural Networks (GNNs) to facilitate end-to-end learning. Since a meaningful graph representing dependencies between bags is rarely available, we propose to use a Bayesian GNN framework that can generate a likely graph structure for scenarios where there is uncertainty in the graph or when no graph is available. Empirical results demonstrate the efficacy of the proposed technique for several MIL benchmark tasks and a distribution regression task.
Determining early-stage prognostic markers and stratifying patients for effective treatment are two key challenges for improving outcomes for melanoma patients. Previous studies have used tumour transcriptome data to stratify patients into immune subgroups, which were associated with differential melanoma specific survival and potential treatment strategies. However, acquiring transcriptome data is a time-consuming and costly process. Moreover, it is not routinely used in the current clinical workflow. Here we attempt to overcome this by developing deep learning models to classify gigapixel H&E stained pathology slides, which are well established in clinical workflows, into these immune subgroups. Previous subtyping approaches have employed supervised learning which requires fully annotated data, or have only examined single genetic mutations in melanoma patients. We leverage a multiple-instance learning approach, which only requires slide-level labels and uses an attention mechanism to highlight regions of high importance to the classification. Moreover, we show that pathology-specific self-supervised models generate better representations compared to pathology-agnostic models for improving our model performance, achieving a mean AUC of 0.76 for classifying histopathology images as high or low immune subgroups. We anticipate that this method may allow us to find new biomarkers of high importance and could act as a tool for clinicians to infer the immune landscape of tumours and stratify patients, without needing to carry out additional expensive genetic tests.
Progress in digital pathology is hindered by high-resolution images and the prohibitive cost of exhaustive localized annotations. The commonly used paradigm to categorize pathology images is patch-based processing, which often incorporates multiple instance learning (MIL) to aggregate local patch-level representations yielding image-level prediction. Nonetheless, diagnostically relevant regions may only take a small fraction of the whole tissue, and current MIL-based approaches often process images uniformly, discarding the inter-patches interactions. To alleviate these issues, we propose ScoreNet, a new efficient transformer that exploits a differentiable recommendation stage to extract discriminative image regions and dedicate computational resources accordingly. The proposed transformer leverages the local and global attention of a few dynamically recommended high-resolution regions at an efficient computational cost. We further introduce a novel mixing data-augmentation, namely ScoreMix, by leveraging the image's semantic distribution to guide the data mixing and produce coherent sample-label pairs. ScoreMix is embarrassingly simple and mitigates the pitfalls of previous augmentations, which assume a uniform semantic distribution and risk mislabeling the samples. Thorough experiments and ablation studies on three breast cancer histology datasets of Haematoxylin & Eosin (H&E) have validated the superiority of our approach over prior arts, including transformer-based models on tumour regions-of-interest (TRoIs) classification. ScoreNet equipped with proposed ScoreMix augmentation demonstrates better generalization capabilities and achieves new state-of-the-art (SOTA) results with only 50% of the data compared to other mixing augmentation variants. Finally, ScoreNet yields high efficacy and outperforms SOTA efficient transformers, namely TransPath and SwinTransformer.
Image-based brain cancer prediction models, based on radiomics, quantify the radiologic phenotype from magnetic resonance imaging (MRI). However, these features are difficult to reproduce because of variability in acquisition and preprocessing pipelines. Despite evidence of intra-tumor phenotypic heterogeneity, the spatial diversity between different slices within an MRI scan has been relatively unexplored using such methods. In this work, we propose a deep anchor attention aggregation strategy with a Vision Transformer to predict survival risk for brain cancer patients. A Deep Anchor Attention Learning (DAAL) algorithm is proposed to assign different weights to slice-level representations with trainable distance measurements. We evaluated our method on N = 326 MRIs. Our results outperformed attention multiple instance learning-based techniques. DAAL highlights the importance of critical slices and corroborates the clinical intuition that inter-slice spatial diversity can reflect disease severity and is implicated in outcome.
The current medical standard for setting an oral cancer (OC) diagnosis is histological examination of a tissue sample from the oral cavity. This process is time consuming and more invasive than an alternative approach of acquiring a brush sample followed by cytological analysis. Skilled cytotechnologists are able to detect changes due to malignancy, however, to introduce this approach into clinical routine is associated with challenges such as a lack of experts and labour-intensive work. To design a trustworthy OC detection system that would assist cytotechnologists, we are interested in AI-based methods that reliably can detect cancer given only per-patient labels (minimizing annotation bias), and also provide information on which cells are most relevant for the diagnosis (enabling supervision and understanding). We, therefore, perform a comparison of a conventional single instance learning (SIL) approach and a modern multiple instance learning (MIL) method suitable for OC detection and interpretation, utilizing three different neural network architectures. To facilitate systematic evaluation of the considered approaches, we introduce a synthetic PAP-QMNIST dataset, that serves as a model of OC data, while offering access to per-instance ground truth. Our study indicates that on PAP-QMNIST, the SIL performs better, on average, than the MIL approach. Performance at the bag level on real-world cytological data is similar for both methods, yet the single instance approach performs better on average. Visual examination by cytotechnologist indicates that the methods manage to identify cells which deviate from normality, including malignant cells as well as those suspicious for dysplasia. We share the code as open source at https://github.com/MIDA-group/OralCancerMILvsSIL
In Multiple Instance Learning (MIL), models are trained using bags of instances, where only a single label is provided for each bag. A bag label is often only determined by a handful of key instances within a bag, making it difficult to interpret what information a classifier is using to make decisions. In this work, we establish the key requirements for interpreting MIL models. We then go on to develop several model-agnostic approaches that meet these requirements. Our methods are compared against existing inherently interpretable MIL models on several datasets, and achieve an increase in interpretability accuracy of up to 30%. We also examine the ability of the methods to identify interactions between instances and scale to larger datasets, improving their applicability to real-world problems.
In response to pathogens, the adaptive immune system generates specific antibodies that bind and neutralize foreign antigens. Understanding the composition of an individual's immune repertoire can provide insights into this process and reveal potential therapeutic antibodies. In this work, we explore the application of antibody-specific language models to aid understanding of immune repertoires. We introduce AntiBERTy, a language model trained on 558M natural antibody sequences. We find that within repertoires, our model clusters antibodies into trajectories resembling affinity maturation. Importantly, we show that models trained to predict highly redundant sequences under a multiple instance learning framework identify key binding residues in the process. With further development, the methods presented here will provide new insights into antigen binding from repertoire sequences alone.
We propose a simple and efficient image classification architecture based on deep multiple instance learning, and apply it to the challenging task of caries detection in dental radiographs. Technically, our approach contributes in two ways: First, it outputs a heatmap of local patch classification probabilities despite being trained with weak image-level labels. Second, it is amenable to learning from segmentation labels to guide training. In contrast to existing methods, the human user can faithfully interpret predictions and interact with the model to decide which regions to attend to. Experiments are conducted on a large clinical dataset of $\sim$38k bitewings ($\sim$316k teeth), where we achieve competitive performance compared to various baselines. When guided by an external caries segmentation model, a significant improvement in classification and localization performance is observed.
We apply deep learning (DL) on Magnetic resonance spectroscopy (MRS) data for the task of brain tumor detection. Medical applications often suffer from data scarcity and corruption by noise. Both of these problems are prominent in our data set. Furthermore, a varying number of spectra are available for the different patients. We address these issues by considering the task as a multiple instance learning (MIL) problem. Specifically, we aggregate multiple spectra from the same patient into a "bag" for classification and apply data augmentation techniques. To achieve the permutation invariance during the process of bagging, we proposed two approaches: (1) to apply min-, max-, and average-pooling on the features of all samples in one bag and (2) to apply an attention mechanism. We tested these two approaches on multiple neural network architectures. We demonstrate that classification performance is significantly improved when training on multiple instances rather than single spectra. We propose a simple oversampling data augmentation method and show that it could further improve the performance. Finally, we demonstrate that our proposed model outperforms manual classification by neuroradiologists according to most performance metrics.
A new multi-attention based method for solving the MIL problem (MAMIL), which takes into account the neighboring patches or instances of each analyzed patch in a bag, is proposed. In the method, one of the attention modules takes into account adjacent patches or instances, several attention modules are used to get a diverse feature representation of patches, and one attention module is used to unite different feature representations to provide an accurate classification of each patch (instance) and the whole bag. Due to MAMIL, a combined representation of patches and their neighbors in the form of embeddings of a small dimensionality for simple classification is realized. Moreover, different types of patches are efficiently processed, and a diverse feature representation of patches in a bag by using several attention modules is implemented. A simple approach for explaining the classification predictions of patches is proposed. Numerical experiments with various datasets illustrate the proposed method.
Objectives: To develop and validate a deep learning (DL)-based primary tumor biopsy signature for predicting axillary lymph node (ALN) metastasis preoperatively in early breast cancer (EBC) patients with clinically negative ALN. Methods: A total of 1,058 EBC patients with pathologically confirmed ALN status were enrolled from May 2010 to August 2020. A DL core-needle biopsy (DL-CNB) model was built on the attention-based multiple instance-learning (AMIL) framework to predict ALN status utilizing the DL features, which were extracted from the cancer areas of digitized whole-slide images (WSIs) of breast CNB specimens annotated by two pathologists. Accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curves, and areas under the ROC curve (AUCs) were analyzed to evaluate our model. Results: The best-performing DL-CNB model with VGG16_BN as the feature extractor achieved an AUC of 0.816 (95% confidence interval (CI): 0.758, 0.865) in predicting positive ALN metastasis in the independent test cohort. Furthermore, our model incorporating the clinical data, which was called DL-CNB+C, yielded the best accuracy of 0.831 (95%CI: 0.775, 0.878), especially for patients younger than 50 years (AUC: 0.918, 95%CI: 0.825, 0.971). The interpretation of DL-CNB model showed that the top signatures most predictive of ALN metastasis were characterized by the nucleus features including density ($p$ = 0.015), circumference ($p$ = 0.009), circularity ($p$ = 0.010), and orientation ($p$ = 0.012). Conclusion: Our study provides a novel DL-based biomarker on primary tumor CNB slides to predict the metastatic status of ALN preoperatively for patients with EBC. The codes and dataset are available at https://github.com/bupt-ai-cz/BALNMP
Clinical decision support for histopathology image data mainly focuses on strongly supervised annotations, which offers intuitive interpretability, but is bound by expert performance. Here, we propose an explainable cancer relapse prediction network (eCaReNet) and show that end-to-end learning without strong annotations offers state-of-the-art performance while interpretability can be included through an attention mechanism. On the use case of prostate cancer survival prediction, using 14,479 images and only relapse times as annotations, we reach a cumulative dynamic AUC of 0.78 on a validation set, being on par with an expert pathologist (and an AUC of 0.77 on a separate test set). Our model is well-calibrated and outputs survival curves as well as a risk score and group per patient. Making use of the attention weights of a multiple instance learning layer, we show that malignant patches have a higher influence on the prediction than benign patches, thus offering an intuitive interpretation of the prediction. Our code is available at www.github.com/imsb-uke/ecarenet.
Understanding model predictions is critical in healthcare, to facilitate rapid verification of model correctness and to guard against use of models that exploit confounding variables. We introduce the challenging new task of explainable multiple abnormality classification in volumetric medical images, in which a model must indicate the regions used to predict each abnormality. To solve this task, we propose a multiple instance learning convolutional neural network, AxialNet, that allows identification of top slices for each abnormality. Next we incorporate HiResCAM, an attention mechanism, to identify sub-slice regions. We prove that for AxialNet, HiResCAM explanations are guaranteed to reflect the locations the model used, unlike Grad-CAM which sometimes highlights irrelevant locations. Armed with a model that produces faithful explanations, we then aim to improve the model's learning through a novel mask loss that leverages HiResCAM and 3D allowed regions to encourage the model to predict abnormalities based only on the organs in which those abnormalities appear. The 3D allowed regions are obtained automatically through a new approach, PARTITION, that combines location information extracted from radiology reports with organ segmentation maps obtained through morphological image processing. Overall, we propose the first model for explainable multi-abnormality prediction in volumetric medical images, and then use the mask loss to achieve a 33% improvement in organ localization of multiple abnormalities in the RAD-ChestCT data set of 36,316 scans, representing the state of the art. This work advances the clinical applicability of multiple abnormality modeling in chest CT volumes.