Use of Artificial Intelligence in the Prediction of Chiari Malformation Type 1 Recurrence After Posterior Fossa Decompressive Surgery.

Purpose The purpose of this study was to train a deep learning-based method for the prediction of postoperative recurrence of symptoms in Chiari malformation type 1 (CM1) patients undergoing surgery. Studies suggest that certain radiological and clinical features do exist in patients with treatment failure, though these are inconsistent and poorly defined. Methodology This study was a retrospective cohort study of patients who underwent primary surgical intervention for CM1 from January 2010 to May 2020. Only patients who completed pre- and postoperative 12-item short form (SF-12) surveys were included and these were used to classify the recurrence or persistence of symptoms. Forty patients had an improvement in overall symptoms while 17 had recurrence or persistence. After magnetic resonance imaging (MRI) data augmentation, a ResNet50, pre-trained on the ImageNet dataset, was used for feature extraction, and then clustering-constrained attention multiple instance learning (CLAM), a weakly supervised multi-instance learning framework, was trained for prediction of recurrence. Five-fold cross-validation was used for the development of MRI only, clinical features only, and a combined machine learning model. Results This study included 57 patients who underwent CM1 decompression. The recurrence rate was 30%. The combined model incorporating MRI, pre-operative SF-12 physical component scale (PCS), and extent of cerebellar ectopia performed best with an area under the curve (AUC) of 0.71 and an F1 score of 0.74. Conclusion This is the first study to our knowledge to explore the prediction of postoperative recurrence of symptoms in CM1 patients using machine learning methods and represents the first step toward developing a clinically useful prognostication machine learning model. Further studies utilizing a similar deep learning approach with a larger sample size are needed to improve the performance.

Analyzing Eye Paths Using Fractals.

Visual patterns reflect the anatomical and cognitive background underlying process governing how we perceive information, influenced by stimulus characteristics and our own visual perception. These patterns are both spatially complex and display self-similarity seen in fractal geometry at different scales, making them challenging to measure using the traditional topological dimensions used in Euclidean geometry.However, methods for measuring eye gaze patterns using fractals have shown success in quantifying geometric complexity, matchability, and implementation into machine learning methods. This success is due to the inherent capabilities that fractals possess when reducing dimensionality using Hilbert curves, measuring temporal complexity using the Higuchi fractal dimension (HFD), and determining geometric complexity using the Minkowski-Bouligand dimension.Understanding the many applications of fractals when measuring and analyzing eye gaze patterns can extend the current growing body of knowledge by identifying markers tied to neurological pathology. Additionally, in future work, fractals can facilitate defining imaging modalities in eye tracking diagnostics by exploiting their capability to acquire multiscale information, including complementary functions, structures, and dynamics.

A Deep Learning Framework for Skull Stripping in Brain MRI.

Skull-stripping, an important pre-processing step in neuroimage computing, involves the automated removal of non-brain anatomy (such as the skull, eyes, and ears) from brain images to facilitate brain segmentation and analysis. Manual segmentation is still practiced, but it is time-consuming and highly dependent on the expertise of clinicians or image analysts. Prior studies have developed various skull-stripping algorithms that perform well on brains with mild or no structural abnormalities. Nonetheless, they were not able to address the issue for brains with significant morphological changes, such as those caused by brain tumors, particularly when the tumors are located near the skull's border. In such cases, a portion of the normal brain may be stripped, or the reverse may occur during skull stripping. To address this limitation, we propose to use a novel deep learning framework based on nnUNet for skull stripping in brain MRI. Two publicly available datasets were used to evaluate the proposed method, including a normal brain MRI dataset - The Neurofeedback Skull-stripped Repository (NFBS), and a brain tumor MRI dataset - The Cancer Genome Atlas (TCGA). The method proposed in the study performed better than six other current methods, namely BSE, ROBEX, UNet, SC-UNet, MV-UNet, and 3D U-Net. The proposed method achieved an average Dice coefficient of 0.9960, a sensitivity of 0.9999, and a specificity of 0.9996 on the NFBS dataset, and an average Dice coefficient of 0.9296, a sensitivity of 0.9288, a specificity of 0.9866 and an accuracy of 0.9762 on the TCGA brain tumor dataset.

Domain-Specific Pre-training Improves Confidence in Whole Slide Image Classification.

Whole Slide Images (WSIs) or histopathology images are used in digital pathology. WSIs pose great challenges to deep learning models for clinical diagnosis, owing to their size and lack of pixel-level annotations. With the recent advancements in computational pathology, newer multiple-instance learning-based models have been proposed. Multiple-instance learning for WSIs necessitates creating patches and uses the encoding of these patches for diagnosis. These models use generic pre-trained models (ResNet-50 pre-trained on ImageNet) for patch encoding. The recently proposed KimiaNet, a DenseNet121 model pre-trained on TCGA slides, is a domain-specific pre-trained model. This paper shows the effect of domain-specific pre-training on WSI classification. To investigate the effect of domain-specific pre-training, we considered the current state-of-the-art multiple-instance learning models, 1) CLAM, an attention-based model, and 2) TransMIL, a self-attention-based model, and evaluated the models' confidence and predictive performance in detecting primary brain tumors - gliomas. Domain-specific pre-training improves the confidence of the models and also achieves a new state-of-the-art performance of WSI-based glioma subtype classification, showing a high clinical applicability in assisting glioma diagnosis. We will publicly share our code and experimental results at https://github.com/soham-chitnis10/WSI-domain-specific.

RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.

AIM: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood. METHODS: Whole blood RNA-seq data were generated for 96 Australian sporadic ALS (sALS) cases and 48 healthy controls (NCBI GEO accession GSE234297). Differences in sALS-control gene expression, transcript usage and predicted leukocyte proportions were assessed, with pathway analysis used to predict the activity state of biological processes. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms were applied to search for diagnostic and prognostic gene expression patterns. Unsupervised clustering analysis was employed to determine whether sALS patient subgroups could be detected. RESULTS: Two hundred and forty-five differentially expressed genes were identified in sALS patients relative to controls, with enrichment of immune, metabolic and stress-related pathways. sALS patients also demonstrated switches in transcript usage across a small set of genes. We established a classification model that distinguished sALS patients from controls with an accuracy of 78% (sensitivity: 79%, specificity: 75%) using the expression of 20 genes. Clustering analysis identified four patient subgroups with gene expression signatures and immune cell proportions reflective of distinct peripheral effects. CONCLUSIONS: Our findings suggest that peripheral blood RNA-seq can identify diagnostic biomarkers and distinguish molecular subtypes of sALS patients however, its prognostic value requires further investigation.

Radiomics and Machine Learning in Brain Tumors and Their Habitat: A Systematic Review.

Radiomics is a rapidly evolving field that involves extracting and analysing quantitative features from medical images, such as computed tomography or magnetic resonance images. Radiomics has shown promise in brain tumor diagnosis and patient-prognosis prediction by providing more detailed and objective information about tumors' features than can be obtained from the visual inspection of the images alone. Radiomics data can be analyzed to determine their correlation with a tumor's genetic status and grade, as well as in the assessment of its recurrence vs. therapeutic response, among other features. In consideration of the multi-parametric and high-dimensional space of features extracted by radiomics, machine learning can further improve tumor diagnosis, treatment response, and patients' prognoses. There is a growing recognition that tumors and their microenvironments (habitats) mutually influence each other-tumor cells can alter the microenvironment to increase their growth and survival. At the same time, habitats can also influence the behavior of tumor cells. In this systematic review, we investigate the current limitations and future developments in radiomics and machine learning in analysing brain tumors and their habitats.

Inter-Regional Proteomic Profiling of the Human Brain Using an Optimized Protein Extraction Method from Formalin-Fixed Tissue to Identify Signaling Pathways.

Proteomics offers vast potential for studying the molecular regulation of the human brain. Formalin fixation is a common method for preserving human tissue; however, it presents challenges for proteomic analysis. In this study, we compared the efficiency of two different protein-extraction buffers on three post-mortem, formalin-fixed human brains. Equal amounts of extracted proteins were subjected to in-gel tryptic digestion and LC-MS/MS. Protein, peptide sequence, and peptide group identifications; protein abundance; and gene ontology pathways were analyzed. Protein extraction was superior using lysis buffer containing tris(hydroxymethyl)aminomethane hydrochloride, sodium dodecyl sulfate, sodium deoxycholate, and Triton X-100 (TrisHCl, SDS, SDC, Triton X-100), which was then used for inter-regional analysis. Pre-frontal, motor, temporal, and occipital cortex tissues were analyzed by label free quantification (LFQ) proteomics, Ingenuity Pathway Analysis and PANTHERdb. Inter-regional analysis revealed differential enrichment of proteins. We found similarly activated cellular signaling pathways in different brain regions, suggesting commonalities in the molecular regulation of neuroanatomically-linked brain functions. Overall, we developed an optimized, robust, and efficient method for protein extraction from formalin-fixed human brain tissue for in-depth LFQ proteomics. We also demonstrate herein that this method is suitable for rapid and routine analysis to uncover molecular signaling pathways in the human brain.

Simultaneous sequencing of genetic and epigenetic bases in DNA.

DNA comprises molecular information stored in genetic and epigenetic bases, both of which are vital to our understanding of biology. Most DNA sequencing approaches address either genetics or epigenetics and thus capture incomplete information. Methods widely used to detect epigenetic DNA bases fail to capture common C-to-T mutations or distinguish 5-methylcytosine from 5-hydroxymethylcytosine. We present a single base-resolution sequencing methodology that sequences complete genetics and the two most common cytosine modifications in a single workflow. DNA is copied and bases are enzymatically converted. Coupled decoding of bases across the original and copy strand provides a phased digital readout. Methods are demonstrated on human genomic DNA and cell-free DNA from a blood sample of a patient with cancer. The approach is accurate, requires low DNA input and has a simple workflow and analysis pipeline. Simultaneous, phased reading of genetic and epigenetic bases provides a more complete picture of the information stored in genomes and has applications throughout biomedicine.

Artificial Intelligence-Assisted Classification of Gliomas Using Whole Slide Images.

CONTEXT.­: Glioma is the most common primary brain tumor in adults. The diagnosis and grading of different pathological subtypes of glioma is essential in treatment planning and prognosis. OBJECTIVE.­: To propose a deep learning-based approach for the automated classification of glioma histopathology images. Two classification methods, the ensemble method based on 2 binary classifiers and the multiclass method using a single multiclass classifier, were implemented to classify glioma images into astrocytoma, oligodendroglioma, and glioblastoma, according to the 5th edition of the World Health Organization classification of central nervous system tumors, published in 2021. DESIGN.­: We tested 2 different deep neural network architectures (VGG19 and ResNet50) and extensively validated the proposed approach based on The Cancer Genome Atlas data set (n = 700). We also studied the effects of stain normalization and data augmentation on the glioma classification task. RESULTS.­: With the binary classifiers, our model could distinguish astrocytoma and oligodendroglioma (combined) from glioblastoma with an accuracy of 0.917 (area under the curve [AUC] = 0.976) and astrocytoma from oligodendroglioma (accuracy = 0.821, AUC = 0.865). The multiclass method (accuracy = 0.861, AUC = 0.961) outperformed the ensemble method (accuracy = 0.847, AUC = 0.933) with the best performance displayed by the ResNet50 architecture. CONCLUSIONS.­: With the high performance of our model (>80%), the proposed method can assist pathologists and physicians to support examination and differential diagnosis of glioma histopathology images, with the aim to expedite personalized medical care.

Evidence synthesis, digital scribes, and translational challenges for artificial intelligence in healthcare.

Healthcare has well-known challenges with safety, quality, and effectiveness, and many see artificial intelligence (AI) as essential to any solution. Emerging applications include the automated synthesis of best-practice research evidence including systematic reviews, which would ultimately see all clinical trial data published in a computational form for immediate synthesis. Digital scribes embed themselves in the process of care to detect, record, and summarize events and conversations for the electronic record. However, three persistent translational challenges must be addressed before AI is widely deployed. First, little effort is spent replicating AI trials, exposing patients to risks of methodological error and biases. Next, there is little reporting of patient harms from trials. Finally, AI built using machine learning may perform less effectively in different clinical settings.

Medical Image Classification Based on Semi-Supervised Generative Adversarial Network and Pseudo-Labelling.

Deep learning has substantially improved the state-of-the-art in object detection and image classification. Deep learning usually requires large-scale labelled datasets to train the models; however, due to the restrictions in medical data sharing and accessibility and the expensive labelling cost, the application of deep learning in medical image classification has been dramatically hindered. In this study, we propose a novel method that leverages semi-supervised adversarial learning and pseudo-labelling to incorporate the unlabelled images in model learning. We validate the proposed method on two public databases, including ChestX-ray14 for lung disease classification and BreakHis for breast cancer histopathological image diagnosis. The results show that our method achieved highly effective performance with an accuracy of 93.15% while using only 30% of the labelled samples, which is comparable to the state-of-the-art accuracy for chest X-ray classification; it also outperformed the current methods in multi-class breast cancer histopathological image classification with a high accuracy of 96.87%.

SoftMatch: Comparing Scanpaths Using Combinatorial Spatio-Temporal Sequences with Fractal Curves.

Recent studies matching eye gaze patterns with those of others contain research that is heavily reliant on string editing methods borrowed from early work in bioinformatics. Previous studies have shown string editing methods to be susceptible to false negative results when matching mutated genes or unordered regions of interest in scanpaths. Even as new methods have emerged for matching amino acids using novel combinatorial techniques, scanpath matching is still limited by a traditional collinear approach. This approach reduces the ability to discriminate between free viewing scanpaths of two people looking at the same stimulus due to the heavy weight placed on linearity. To overcome this limitation, we here introduce a new method called SoftMatch to compare pairs of scanpaths. SoftMatch diverges from traditional scanpath matching in two different ways: firstly, by preserving locality using fractal curves to reduce dimensionality from 2D Cartesian (x,y) coordinates into 1D (h) Hilbert distances, and secondly by taking a combinatorial approach to fixation matching using discrete Fréchet distance measurements between segments of scanpath fixation sequences. These matching "sequences of fixations over time" are a loose acronym for SoftMatch. Results indicate high degrees of statistical and substantive significance when scoring matches between scanpaths made during free-form viewing of unfamiliar stimuli. Applications of this method can be used to better understand bottom up perceptual processes extending to scanpath outlier detection, expertise analysis, pathological screening, and salience prediction.

Colour adaptive generative networks for stain normalisation of histopathology images.

Deep learning has shown its effectiveness in histopathology image analysis, such as pathology detection and classification. However, stain colour variation in Hematoxylin and Eosin (H&E) stained histopathology images poses challenges in effectively training deep learning-based algorithms. To alleviate this problem, stain normalisation methods have been proposed, with most of the recent methods utilising generative adversarial networks (GAN). However, these methods are either trained fully with paired images from the target domain (supervised) or with unpaired images (unsupervised), suffering from either large discrepancy between domains or risks of undertrained/overfitted models when only the target domain images are used for training. In this paper, we introduce a colour adaptive generative network (CAGAN) for stain normalisation which combines both supervised learning from target domain and unsupervised learning from source domain. Specifically, we propose a dual-decoder generator and force consistency between their outputs thus introducing extra supervision which benefits from extra training with source domain images. Moreover, our model is immutable to stain colour variations due to the use of stain colour augmentation. We further implement histogram loss to ensure the processed images are coloured with the target domain colours regardless of their content differences. Extensive experiments on four public histopathology image datasets including TCGA-IDH, CAMELYON16, CAMELYON17 and BreakHis demonstrate that our proposed method produces high quality stain normalised images which improve the performance of benchmark algorithms by 5% to 10% compared to baselines not using normalisation.

Weak label based Bayesian U-Net for optic disc segmentation in fundus images.

Fundus images have been widely used in routine examinations of ophthalmic diseases. For some diseases, the pathological changes mainly occur around the optic disc area; therefore, detection and segmentation of the optic disc are critical pre-processing steps in fundus image analysis. Current machine learning based optic disc segmentation methods typically require manual segmentation of the optic disc for the supervised training. However, it is time consuming to annotate pixel-level optic disc masks and inevitably induces inter-subject variance. To address these limitations, we propose a weak label based Bayesian U-Net exploiting Hough transform based annotations to segment optic discs in fundus images. To achieve this, we build a probabilistic graphical model and explore a Bayesian approach with the state-of-the-art U-Net framework. To optimize the model, the expectation-maximization algorithm is used to estimate the optic disc mask and update the weights of the Bayesian U-Net, alternately. Our evaluation demonstrates strong performance of the proposed method compared to both fully- and weakly-supervised baselines.

Artificial Intelligence for Survival Prediction in Brain Tumors on Neuroimaging.

Survival prediction of patients affected by brain tumors provides essential information to guide surgical planning, adjuvant treatment selection, and patient counseling. Current reliance on clinical factors, such as Karnofsky Performance Status Scale, and simplistic radiological characteristics are, however, inadequate for survival prediction in tumors such as glioma that demonstrate molecular and clinical heterogeneity with variable survival outcomes. Advances in the domain of artificial intelligence have afforded powerful tools to capture a large number of hidden high-dimensional imaging features that reflect abundant information about tumor structure and physiology. Here, we provide an overview of current literature that apply computational analysis tools such as radiomics and machine learning methods to the pipeline of image preprocessing, tumor segmentation, feature extraction, and construction of classifiers to establish survival prediction models based on neuroimaging. We also discuss challenges relating to the development and evaluation of such models and explore ethical issues surrounding the future use of machine learning predictions.

Use of deep learning in the MRI diagnosis of Chiari malformation type I.

PURPOSE: To train deep learning convolutional neural network (CNN) models for classification of clinically significant Chiari malformation type I (CM1) on MRI to assist clinicians in diagnosis and decision making. METHODS: A retrospective MRI dataset of patients diagnosed with CM1 and healthy individuals with normal brain MRIs from the period January 2010 to May 2020 was used to train ResNet50 and VGG19 CNN models to automatically classify images as CM1 or normal. A total of 101 patients diagnosed with CM1 requiring surgery and 111 patients with normal brain MRIs were included (median age 30 with an interquartile range of 23-43; 81 women with CM1). Isotropic volume transformation, image cropping, skull stripping, and data augmentation were employed to optimize model accuracy. K-fold cross validation was used to calculate sensitivity, specificity, and the area under receiver operating characteristic curve (AUC) for model evaluation. RESULTS: The VGG19 model with data augmentation achieved a sensitivity of 97.1% and a specificity of 97.4% with an AUC of 0.99. The ResNet50 model achieved a sensitivity of 94.0% and a specificity of 94.4% with an AUC of 0.98. CONCLUSIONS: VGG19 and ResNet50 CNN models can be trained to automatically detect clinically significant CM1 on MRI with a high sensitivity and specificity. These models have the potential to be developed into clinical support tools in diagnosing CM1.

Foundations of Multiparametric Brain Tumour Imaging Characterisation Using Machine Learning.

The heterogeneity of brain tumours at the molecular, metabolic and structural levels poses significant challenge for accurate tissue characterisation. Artificial intelligence and radiomics have emerged as valuable tools to analyse quantitative features extracted from medical images which capture the complex microenvironment of brain tumours. In particular, a number of computational tools including machine learning algorithms have been proposed for image preprocessing, tumour segmentation, feature extraction, classification, and prognostic stratifications as well. In this chapter, we explore the fundamentals of multiparametric brain tumour characterisation, as an understanding of the strengths, limitations and applications of these tools allows clinicians to better develop and evaluate models with improved diagnostic and prognostic value in brain tumour patients.

Spherical coordinates transformation pre-processing in Deep Convolution Neural Networks for brain tumor segmentation in MRI.

Magnetic Resonance Imaging (MRI) is used in everyday clinical practice to assess brain tumors. Deep Convolutional Neural Networks (DCNN) have recently shown very promising results in brain tumor segmentation tasks; however, DCNN models fail the task when applied to volumes that are different from the training dataset. One of the reasons is due to the lack of data standardization to adjust for different models and MR machines. In this work, a 3D spherical coordinates transform during the pre-processing phase has been hypothesized to improve DCNN models' accuracy and to allow more generalizable results even when the model is trained on small and heterogeneous datasets and translated into different domains. Indeed, the spherical coordinate system avoids several standardization issues since it works independently of resolution and imaging settings. The model trained on spherical transform pre-processed inputs resulted in superior performance over the Cartesian-input trained model on predicting gliomas' segmentation on Tumor Core and Enhancing Tumor classes, achieving a further improvement in accuracy by merging the two models together. The proposed model is not resolution-dependent, thus improving segmentation accuracy and theoretically solving some transfer learning problems related to the domain shifting, at least in terms of image resolution in the datasets.

Generative Adversarial Networks in Digital Pathology and Histopathological Image Processing: A Review.

Digital pathology is gaining prominence among the researchers with developments in advanced imaging modalities and new technologies. Generative adversarial networks (GANs) are a recent development in the field of artificial intelligence and since their inception, have boosted considerable interest in digital pathology. GANs and their extensions have opened several ways to tackle many challenging histopathological image processing problems such as color normalization, virtual staining, ink removal, image enhancement, automatic feature extraction, segmentation of nuclei, domain adaptation and data augmentation. This paper reviews recent advances in histopathological image processing using GANs with special emphasis on the future perspectives related to the use of such a technique. The papers included in this review were retrieved by conducting a keyword search on Google Scholar and manually selecting the papers on the subject of H&E stained digital pathology images for histopathological image processing. In the first part, we describe recent literature that use GANs in various image preprocessing tasks such as stain normalization, virtual staining, image enhancement, ink removal, and data augmentation. In the second part, we describe literature that use GANs for image analysis, such as nuclei detection, segmentation, and feature extraction. This review illustrates the role of GANs in digital pathology with the objective to trigger new research on the application of generative models in future research in digital pathology informatics.

Prediction of anxiety disorders using a feature ensemble based bayesian neural network.

Anxiety disorders are common among youth, posing risks to physical and mental health development. Early screening can help identify such disorders and pave the way for preventative treatment. To this end, the Youth Online Diagnostic Assessment (YODA) tool was developed and deployed to predict youth disorders using online screening questionnaires filled by parents. YODA facilitated collection of several novel unique datasets of self-reported anxiety disorder symptoms. Since the data is self-reported and often noisy, feature selection needs to be performed on the raw data to improve accuracy. However, a single set of selected features may not be informative enough. Consequently, in this work we propose and evaluate a novel feature ensemble based Bayesian Neural Network (FE-BNN) that exploits an ensemble of features for improving the accuracy of disorder predictions. We evaluate the performance of FE-BNN on three disorder-specific datasets collected by YODA. Our method achieved the AUC of 0.8683, 0.8769, 0.9091 for the predictions of Separation Anxiety Disorder, Generalized Anxiety Disorder and Social Anxiety Disorder, respectively. These results provide initial evidence that our method outperforms the original diagnostic scoring function of YODA and several other baseline methods for three anxiety disorders, which can practically help prioritizing diagnostic interviews. Our promising results call for investigation of interpretable methods maintaining high predictive accuracy.