Unsupervised mutual transformer learning for multi-gigapixel Whole Slide Image classification.

The classification of gigapixel Whole Slide Images (WSIs) is an important task in the emerging area of computational pathology. There has been a surge of interest in deep learning models for WSI classification with clinical applications such as cancer detection or prediction of cellular mutations. Most supervised methods require expensive and labor-intensive manual annotations by expert pathologists. Weakly supervised Multiple Instance Learning (MIL) methods have recently demonstrated excellent performance; however, they still require large-scale slide-level labeled training datasets that require a careful inspection of each slide by an expert pathologist. In this work, we propose a fully unsupervised WSI classification algorithm based on mutual transformer learning. The instances (i.e., patches) from gigapixel WSIs are transformed into a latent space and then inverse-transformed to the original space. Using the transformation loss, pseudo labels are generated and cleaned using a transformer label cleaner. The proposed transformer-based pseudo-label generator and cleaner modules mutually train each other iteratively in an unsupervised manner. A discriminative learning mechanism is introduced to improve normal versus cancerous instance labeling. In addition to the unsupervised learning, we demonstrate the effectiveness of the proposed framework for weakly supervised learning and cancer subtype classification as downstream analysis. Extensive experiments on four publicly available datasets show better performance of the proposed algorithm compared to the existing state-of-the-art methods.

An interpretable dual attention network for diabetic retinopathy grading: IDANet.

Diabetic retinopathy (DR) is the most prevalent cause of visual impairment in adults worldwide. Typically, patients with DR do not show symptoms until later stages, by which time it may be too late to receive effective treatment. DR Grading is challenging because of the small size and variation in lesion patterns. The key to fine-grained DR grading is to discover more discriminating elements such as cotton wool, hard exudates, hemorrhages, microaneurysms etc. Although deep learning models like convolutional neural networks (CNN) seem ideal for the automated detection of abnormalities in advanced clinical imaging, small-size lesions are very hard to distinguish by using traditional networks. This work proposes a bi-directional spatial and channel-wise parallel attention based network to learn discriminative features for diabetic retinopathy grading. The proposed attention block plugged with a backbone network helps to extract features specific to fine-grained DR-grading. This scheme boosts classification performance along with the detection of small-sized lesion parts. Extensive experiments are performed on four widely used benchmark datasets for DR grading, and performance is evaluated on different quality metrics. Also, for model interpretability, activation maps are generated using the LIME method to visualize the predicted lesion parts. In comparison with state-of-the-art methods, the proposed IDANet exhibits better performance for DR grading and lesion detection.

Unsupervised Dual Transformer Learning for 3-D Textured Surface Segmentation.

Analysis of the 3-D texture is indispensable for various tasks, such as retrieval, segmentation, classification, and inspection of sculptures, knit fabrics, and biological tissues. A 3-D texture represents a locally repeated surface variation (SV) that is independent of the overall shape of the surface and can be determined using the local neighborhood and its characteristics. Existing methods mostly employ computer vision techniques that analyze a 3-D mesh globally, derive features, and then utilize them for classification or retrieval tasks. While several traditional and learning-based methods have been proposed in the literature, only a few have addressed 3-D texture analysis, and none have considered unsupervised schemes so far. This article proposes an original framework for the unsupervised segmentation of 3-D texture on the mesh manifold. The problem is approached as a binary surface segmentation task, where the mesh surface is partitioned into textured and nontextured regions without prior annotation. The proposed method comprises a mutual transformer-based system consisting of a label generator (LG) and a label cleaner (LC). Both models take geometric image representations of the surface mesh facets and label them as texture or nontexture using an iterative mutual learning scheme. Extensive experiments on three publicly available datasets with diverse texture patterns demonstrate that the proposed framework outperforms standard and state-of-the-art unsupervised techniques and performs reasonably well compared to supervised methods.

Drone-Person Tracking in Uniform Appearance Crowd: A New Dataset.

Drone-person tracking in uniform appearance crowds poses unique challenges due to the difficulty in distinguishing individuals with similar attire and multi-scale variations. To address this issue and facilitate the development of effective tracking algorithms, we present a novel dataset named D-PTUAC (Drone-Person Tracking in Uniform Appearance Crowd). The dataset comprises 138 sequences comprising over 121 K frames, each manually annotated with bounding boxes and attributes. During dataset creation, we carefully consider 18 challenging attributes encompassing a wide range of viewpoints and scene complexities. These attributes are annotated to facilitate the analysis of performance based on specific attributes. Extensive experiments are conducted using 44 state-of-the-art (SOTA) trackers, and the performance gap between the visual object trackers on existing benchmarks compared to our proposed dataset demonstrate the need for a dedicated end-to-end aerial visual object tracker that accounts the inherent properties of aerial environment.

Center-Focused Affinity Loss for Class Imbalance Histology Image Classification.

Early-stage cancer diagnosis potentially improves the chances of survival for many cancer patients worldwide. Manual examination of Whole Slide Images (WSIs) is a time-consuming task for analyzing tumor-microenvironment. To overcome this limitation, the conjunction of deep learning with computational pathology has been proposed to assist pathologists in efficiently prognosing the cancerous spread. Nevertheless, the existing deep learning methods are ill-equipped to handle fine-grained histopathology datasets. This is because these models are constrained via conventional softmax loss function, which cannot expose them to learn distinct representational embeddings of the similarly textured WSIs containing an imbalanced data distribution. To address this problem, we propose a novel center-focused affinity loss (CFAL) function that exhibits 1) constructing uniformly distributed class prototypes in the feature space, 2) penalizing difficult samples, 3) minimizing intra-class variations, and 4) placing greater emphasis on learning minority class features. We evaluated the performance of the proposed CFAL loss function on two publicly available breast and colon cancer datasets having varying levels of imbalanced classes. The proposed CFAL function shows better discrimination abilities as compared to the popular loss functions such as ArcFace, CosFace, and Focal loss. Moreover, it outperforms several SOTA methods for histology image classification across both datasets.

Neural Graph Refinement for Robust Recognition of Nuclei Communities in Histopathological Landscape.

Accurate classification of nuclei communities is an important step towards timely treating the cancer spread. Graph theory provides an elegant way to represent and analyze nuclei communities within the histopathological landscape in order to perform tissue phenotyping and tumor profiling tasks. Many researchers have worked on recognizing nuclei regions within the histology images in order to grade cancerous progression. However, due to the high structural similarities between nuclei communities, defining a model that can accurately differentiate between nuclei pathological patterns still needs to be solved. To surmount this challenge, we present a novel approach, dubbed neural graph refinement, that enhances the capabilities of existing models to perform nuclei recognition tasks by employing graph representational learning and broadcasting processes. Based on the physical interaction of the nuclei, we first construct a fully connected graph in which nodes represent nuclei and adjacent nodes are connected to each other via an undirected edge. For each edge and node pair, appearance and geometric features are computed and are then utilized for generating the neural graph embeddings. These embeddings are used for diffusing contextual information to the neighboring nodes, all along a path traversing the whole graph to infer global information over an entire nuclei network and predict pathologically meaningful communities. Through rigorous evaluation of the proposed scheme across four public datasets, we showcase that learning such communities through neural graph refinement produces better results that outperform state-of-the-art methods.

Tomato maturity recognition with convolutional transformers.

Tomatoes are a major crop worldwide, and accurately classifying their maturity is important for many agricultural applications, such as harvesting, grading, and quality control. In this paper, the authors propose a novel method for tomato maturity classification using a convolutional transformer. The convolutional transformer is a hybrid architecture that combines the strengths of convolutional neural networks (CNNs) and transformers. Additionally, this study introduces a new tomato dataset named KUTomaData, explicitly designed to train deep-learning models for tomato segmentation and classification. KUTomaData is a compilation of images sourced from a greenhouse in the UAE, with approximately 700 images available for training and testing. The dataset is prepared under various lighting conditions and viewing perspectives and employs different mobile camera sensors, distinguishing it from existing datasets. The contributions of this paper are threefold: firstly, the authors propose a novel method for tomato maturity classification using a modular convolutional transformer. Secondly, the authors introduce a new tomato image dataset that contains images of tomatoes at different maturity levels. Lastly, the authors show that the convolutional transformer outperforms state-of-the-art methods for tomato maturity classification. The effectiveness of the proposed framework in handling cluttered and occluded tomato instances was evaluated using two additional public datasets, Laboro Tomato and Rob2Pheno Annotated Tomato, as benchmarks. The evaluation results across these three datasets demonstrate the exceptional performance of our proposed framework, surpassing the state-of-the-art by 58.14%, 65.42%, and 66.39% in terms of mean average precision scores for KUTomaData, Laboro Tomato, and Rob2Pheno Annotated Tomato, respectively. This work can potentially improve the efficiency and accuracy of tomato harvesting, grading, and quality control processes.

Transformers for autonomous recognition of psychiatric dysfunction via raw and imbalanced EEG signals.

Early identification of mental disorders, based on subjective interviews, is extremely challenging in the clinical setting. There is a growing interest in developing automated screening tools for potential mental health problems based on biological markers. Here, we demonstrate the feasibility of an AI-powered diagnosis of different mental disorders using EEG data. Specifically, this work aims to classify different mental disorders in the following ecological context accurately: (1) using raw EEG data, (2) collected during rest, (3) during both eye open, and eye closed conditions, (4) at short 2-min duration, (5) on participants with different psychiatric conditions, (6) with some overlapping symptoms, and (7) with strongly imbalanced classes. To tackle this challenge, we designed and optimized a transformer-based architecture, where class imbalance is addressed through focal loss and class weight balancing. Using the recently released TDBRAIN dataset (n= 1274 participants), our method classifies each participant as either a neurotypical or suffering from major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), subjective memory complaints (SMC), or obsessive-compulsive disorder (OCD). We evaluate the performance of the proposed architecture on both the window-level and the patient-level. The classification of the 2-min raw EEG data into five classes achieved a window-level accuracy of 63.2% and 65.8% for open and closed eye conditions, respectively. When the classification is limited to three main classes (MDD, ADHD, SMC), window level accuracy improved to 75.1% and 69.9% for eye open and eye closed conditions, respectively. Our work paves the way for developing novel AI-based methods for accurately diagnosing mental disorders using raw resting-state EEG data.

An appraisal of the performance of AI tools for chronic stroke lesion segmentation.

Automated demarcation of stoke lesions from monospectral magnetic resonance imaging scans is extremely useful for diverse research and clinical applications, including lesion-symptom mapping to explain deficits and predict recovery. There is a significant surge of interest in the development of supervised artificial intelligence (AI) methods for that purpose, including deep learning, with a performance comparable to trained experts. Such AI-based methods, however, require copious amounts of data. Thanks to the availability of large datasets, the development of AI-based methods for lesion segmentation has immensely accelerated in the last decade. One of these datasets is the Anatomical Tracings of Lesions After Stroke (ATLAS) dataset which includes T1-weighted images from hundreds of chronic stroke survivors with their manually traced lesions. This systematic review offers an appraisal of the impact of the ATLAS dataset in promoting the development of AI-based segmentation of stroke lesions. An examination of all published studies, that used the ATLAS dataset to both train and test their methods, highlighted an overall moderate performance (median Dice index = 59.40%) and a huge variability across studies in terms of data preprocessing, data augmentation, AI architecture, and the mode of operation (two-dimensional versus three-dimensional methods). Perhaps most importantly, almost all AI tools were borrowed from existing AI architectures in computer vision, as 90% of all selected studies relied on conventional convolutional neural network-based architectures. Overall, current research has not led to the development of robust AI architectures than can handle spatially heterogenous lesion patterns. This review also highlights the difficulty of gauging the performance of AI tools in the presence of uncertainties in the definition of the ground truth.

Knowledge Distillation in Histology Landscape by Multi-Layer Features Supervision.

Automatic tissue classification is a fundamental task in computational pathology for profiling tumor micro-environments. Deep learning has advanced tissue classification performance at the cost of significant computational power. Shallow networks have also been end-to-end trained using direct supervision however their performance degrades because of the lack of capturing robust tissue heterogeneity. Knowledge distillation has recently been employed to improve the performance of the shallow networks used as student networks by using additional supervision from deep neural networks used as teacher networks. In the current work, we propose a novel knowledge distillation algorithm to improve the performance of shallow networks for tissue phenotyping in histology images. For this purpose, we propose multi-layer feature distillation such that a single layer in the student network gets supervision from multiple teacher layers. In the proposed algorithm, the size of the feature map of two layers is matched by using a learnable multi-layer perceptron. The distance between the feature maps of the two layers is then minimized during the training of the student network. The overall objective function is computed by summation of the loss over multiple layers combination weighted with a learnable attention-based parameter. The proposed algorithm is named as Knowledge Distillation for Tissue Phenotyping (KDTP). Experiments are performed on five different publicly available histology image classification datasets using several teacher-student network combinations within the KDTP algorithm. Our results demonstrate a significant performance increase in the student networks by using the proposed KDTP algorithm compared to direct supervision-based training methods.

DeepBLS: Deep Feature-Based Broad Learning System for Tissue Phenotyping in Colorectal Cancer WSIs.

Tissue phenotyping is a fundamental step in computational pathology for the analysis of tumor micro-environment in whole slide images (WSIs). Automatic tissue phenotyping in whole slide images (WSIs) of colorectal cancer (CRC) assists pathologists in better cancer grading and prognostication. In this paper, we propose a novel algorithm for the identification of distinct tissue components in colon cancer histology images by blending a comprehensive learning system with deep features extraction in the current work. Firstly, we extracted the features from the pre-trained VGG19 network which are then transformed into mapped features space for nodes enhancement generation. Utilizing both mapped features and enhancement nodes, the proposed algorithm classifies seven distinct tissue components including stroma, tumor, complex stroma, necrotic, normal benign, lymphocytes, and smooth muscle. To validate our proposed model, the experiments are performed on two publicly available colorectal cancer histology datasets. We showcase that our approach achieves a remarkable performance boost surpassing existing state-of-the-art methods by (1.3% AvTP, 2% F1) and (7% AvTP, 6% F1) on CRCD-1, and CRCD-2, respectively.

Advancement in Human Face Prediction Using DNA.

The rapid improvements in identifying the genetic factors contributing to facial morphology have enabled the early identification of craniofacial syndromes. Similarly, this technology can be vital in forensic cases involving human identification from biological traces or human remains, especially when reference samples are not available in the deoxyribose nucleic acid (DNA) database. This review summarizes the currently used methods for predicting human phenotypes such as age, ancestry, pigmentation, and facial features based on genetic variations. To identify the facial features affected by DNA, various two-dimensional (2D)- and three-dimensional (3D)-scanning techniques and analysis tools are reviewed. A comparison between the scanning technologies is also presented in this review. Face-landmarking techniques and face-phenotyping algorithms are discussed in chronological order. Then, the latest approaches in genetic to 3D face shape analysis are emphasized. A systematic review of the current markers that passed the threshold of a genome-wide association (GWAS) of single nucleotide polymorphism (SNP)-face traits from the GWAS Catalog is also provided using the preferred reporting items for systematic reviews and meta-analyses (PRISMA), approach. Finally, the current challenges in forensic DNA phenotyping are analyzed and discussed.

Knowledge distillation driven instance segmentation for grading prostate cancer.

Prostate cancer (PCa) is one of the deadliest cancers in men, and identifying cancerous tissue patterns at an early stage can assist clinicians in timely treating the PCa spread. Many researchers have developed deep learning systems for mass-screening PCa. These systems, however, are commonly trained with well-annotated datasets in order to produce accurate results. Obtaining such data for training is often time and resource-demanding in clinical settings and can result in compromised screening performance. To address these limitations, we present a novel knowledge distillation-based instance segmentation scheme that allows conventional semantic segmentation models to perform instance-aware segmentation to extract stroma, benign, and the cancerous prostate tissues from the whole slide images (WSI) with incremental few-shot training. The extracted tissues are then used to compute majority and minority Gleason scores, which, afterward, are used in grading the PCa as per the clinical standards. The proposed scheme has been thoroughly tested on two datasets, containing around 10,516 and 11,000 WSI scans, respectively. Across both datasets, the proposed scheme outperforms state-of-the-art methods by 2.01% and 4.45%, respectively, in terms of the mean IoU score for identifying prostate tissues, and 10.73% and 11.42% in terms of F1 score for grading PCa according to the clinical standards. Furthermore, the applicability of the proposed scheme is tested under a blind experiment with a panel of expert pathologists, where it achieved a statistically significant Pearson correlation of 0.9192 and 0.8984 with the clinicians' grading.

Nucleus classification in histology images using message passing network.

Identification of nuclear components in the histology landscape is an important step towards developing computational pathology tools for the profiling of tumor micro-environment. Most existing methods for the identification of such components are limited in scope due to heterogeneous nature of the nuclei. Graph-based methods offer a natural way to formulate the nucleus classification problem to incorporate both appearance and geometric locations of the nuclei. The main challenge is to define models that can handle such an unstructured domain. Current approaches focus on learning better features and then employ well-known classifiers for identifying distinct nuclear phenotypes. In contrast, we propose a message passing network that is a fully learnable framework build on classical network flow formulation. Based on physical interaction of the nuclei, a nearest neighbor graph is constructed such that the nodes represent the nuclei centroids. For each edge and node, appearance and geometric features are computed which are then used for the construction of messages utilized for diffusing contextual information to the neighboring nodes. Such an algorithm can infer global information over an entire network and predict biologically meaningful nuclear communities. We show that learning such communities improves the performance of nucleus classification task in histology images. The proposed algorithm can be used as a component in existing state-of-the-art methods resulting in improved nucleus classification performance across four different publicly available datasets.

Continual Learning Objective for Analyzing Complex Knowledge Representations.

Human beings tend to incrementally learn from the rapidly changing environment without comprising or forgetting the already learned representations. Although deep learning also has the potential to mimic such human behaviors to some extent, it suffers from catastrophic forgetting due to which its performance on already learned tasks drastically decreases while learning about newer knowledge. Many researchers have proposed promising solutions to eliminate such catastrophic forgetting during the knowledge distillation process. However, to our best knowledge, there is no literature available to date that exploits the complex relationships between these solutions and utilizes them for the effective learning that spans over multiple datasets and even multiple domains. In this paper, we propose a continual learning objective that encompasses mutual distillation loss to understand such complex relationships and allows deep learning models to effectively retain the prior knowledge while adapting to the new classes, new datasets, and even new applications. The proposed objective was rigorously tested on nine publicly available, multi-vendor, and multimodal datasets that span over three applications, and it achieved the top-1 accuracy of 0.9863% and an F1-score of 0.9930.

Multi-level feature fusion for nucleus detection in histology images using correlation filters.

Nucleus detection is an important step for the analysis of histology images in the field of computational pathology. Pathologists use quantitative nuclear morphology for better cancer grading and prognostication. The nucleus detection becomes very challenging because of the large morphological variations across different types of nuclei, nuclei clutter, and heterogeneity. To address these challenges, we aim to improve the nucleus detection using multi-level feature fusion based on discriminative correlation filters. The proposed algorithm employs multiple features pool, based on varying features combinations. Early fusion is employed to integrate multi-feature information within a pool and inter-pool fusion is proposed to fuse information across multiple pools. Inter-pool consistency is proposed to find the pools which are consistent and complement each other to improve performance. For this purpose, the relative standard deviation is used as an inter-pool consistency measure. Pool robustness to noise is also estimated using relative standard deviation as a robustness measure. High-level pool fusion is proposed using inter-pool consistency and pool-robustness scores. The proposed algorithm facilitates a robust and reliable appearance model for nucleus detection. The proposed algorithm is evaluated on three publicly available datasets and compared with several existing state-of-the-art methods. Our proposed algorithm has consistently outperformed existing methods on a wide range of experiments.

The Classification Power of Classical and Intra-voxel Incoherent Motion (IVIM) Fitting Models of Diffusion-weighted Magnetic Resonance Images: An Experimental Study.

This study aims at investigating the classification power of different b-values of the diffusion-weighted magnetic resonance images (DWI) as indicator of prostate cancer. This paper investigates several techniques for analyzing data from DWI acquired at a range of b-values for the purpose of detecting prostate cancer. In the first phase of experiments, we analyze the available data by producing two main parametric maps using two common models, namely: the intra-voxel incoherent motion (IVIM) model and the mono-exponential ADC model. Accordingly, we evaluated the benign/malignant tissue classification potential of several parametric maps produced using different combinations of b-values and fitting models. In the second phase, we utilized the maps that performed best in the first phase of experiments to design a machine learning-based computer-assisted diagnosis system for the detection of early stage prostate cancer. The system performance was cross-validated using data from 20 patients. On a fivefold cross-validation scheme, a maximum accuracy and an area under the receiver operating characteristic (AUC) of 90% and 0.978, respectively, was achieved by a system that uses ADC maps fitted using the mono-exponential model at 11 different b-values. The results suggest that the proposed machine learning-based diagnosis system is potentially powerful in differentiating between malignant and benign prostate tissues when combined with carefully generated ADC maps.

Hierarchical Spatiotemporal Graph Regularized Discriminative Correlation Filter for Visual Object Tracking.

Visual object tracking is a fundamental and challenging task in many high-level vision and robotics applications. It is typically formulated by estimating the target appearance model between consecutive frames. Discriminative correlation filters (DCFs) and their variants have achieved promising speed and accuracy for visual tracking in many challenging scenarios. However, because of the unwanted boundary effects and lack of geometric constraints, these methods suffer from performance degradation. In the current work, we propose hierarchical spatiotemporal graph-regularized correlation filters for robust object tracking. The target sample is decomposed into a large number of deep channels, which are then used to construct a spatial graph such that each graph node corresponds to a particular target location across all channels. Such a graph effectively captures the spatial structure of the target object. In order to capture the temporal structure of the target object, the information in the deep channels obtained from a temporal window is compressed using the principal component analysis, and then, a temporal graph is constructed such that each graph node corresponds to a particular target location in the temporal dimension. Both spatial and temporal graphs span different subspaces such that the target and the background become linearly separable. The learned correlation filter is constrained to act as an eigenvector of the Laplacian of these spatiotemporal graphs. We propose a novel objective function that incorporates these spatiotemporal constraints into the DCFs framework. We solve the objective function using alternating direction methods of multipliers such that each subproblem has a closed-form solution. We evaluate our proposed algorithm on six challenging benchmark datasets and compare it with 33 existing state-of-the art trackers. Our results demonstrate an excellent performance of the proposed algorithm compared to the existing trackers.

Deep learning based joint segmentation and characterization of multi-class retinal fluid lesions on OCT scans for clinical use in anti-VEGF therapy.

BACKGROUND: In anti-vascular endothelial growth factor (anti-VEGF) therapy, an accurate estimation of multi-class retinal fluid (MRF) is required for the activity prescription and intravitreal dose. This study proposes an end-to-end deep learning-based retinal fluids segmentation network (RFS-Net) to segment and recognize three MRF lesion manifestations, namely, intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED), from multi-vendor optical coherence tomography (OCT) imagery. The proposed image analysis tool will optimize anti-VEGF therapy and contribute to reducing the inter- and intra-observer variability. METHOD: The proposed RFS-Net architecture integrates the atrous spatial pyramid pooling (ASPP), residual, and inception modules in the encoder path to learn better features and conserve more global information for precise segmentation and characterization of MRF lesions. The RFS-Net model is trained and validated using OCT scans from multiple vendors (Topcon, Cirrus, Spectralis), collected from three publicly available datasets. The first dataset consisted of OCT volumes obtained from 112 subjects (a total of 11,334 B-scans) is used for both training and evaluation purposes. Moreover, the remaining two datasets are only used for evaluation purposes to check the trained RFS-Net's generalizability on unseen OCT scans. The two evaluation datasets contain a total of 1572 OCT B-scans from 1255 subjects. The performance of the proposed RFS-Net model is assessed through various evaluation metrics. RESULTS: The proposed RFS-Net model achieved the mean F1 scores of 0.762, 0.796, and 0.805 for segmenting IRF, SRF, and PED. Moreover, with the automated segmentation of the three retinal manifestations, the RFS-Net brings a considerable gain in efficiency compared to the tedious and demanding manual segmentation procedure of the MRF. CONCLUSIONS: Our proposed RFS-Net is a potential diagnostic tool for the automatic segmentation of MRF (IRF, SRF, and PED) lesions. It is expected to strengthen the inter-observer agreement, and standardization of dosimetry is envisaged as a result.

Spatially Constrained Context-Aware Hierarchical Deep Correlation Filters for Nucleus Detection in Histology Images.

Nucleus detection in histology images is a fundamental step for cellular-level analysis in computational pathology. In clinical practice, quantitative nuclear morphology can be used for diagnostic decision making, prognostic stratification, and treatment outcome prediction. Nucleus detection is a challenging task because of large variations in the shape of different types of nucleus such as nuclear clutter, heterogeneous chromatin distribution, and irregular and fuzzy boundaries. To address these challenges, we aim to accurately detect nuclei using spatially constrained context-aware correlation filters using hierarchical deep features extracted from multiple layers of a pre-trained network. During training, we extract contextual patches around each nucleus which are used as negative examples while the actual nucleus patch is used as a positive example. In order to spatially constrain the correlation filters, we propose to construct a spatial structural graph across different nucleus components encoding pairwise similarities. The correlation filters are constrained to act as eigenvectors of the Laplacian of the spatial graphs enforcing these to capture the nucleus structure. A novel objective function is proposed by embedding graph-based structural information as well as the contextual information within the discriminative correlation filter framework. The learned filters are constrained to be orthogonal to both the contextual patches and the spatial graph-Laplacian basis to improve the localization and discriminative performance. The proposed objective function trains a hierarchy of correlation filters on different deep feature layers to capture the heterogeneity in nuclear shape and texture. The proposed algorithm is evaluated on three publicly available datasets and compared with 15 current state-of-the-art methods demonstrating competitive performance in terms of accuracy, speed, and generalization.