Multivariate brain-based dimensions of child psychiatric problems: degrees of generalizability.

Multivariate machine learning techniques are a promising set of tools for identifying complex brain-behavior associations. However, failure to replicate results from these methods across samples has hampered their clinical relevance. This study aimed to delineate dimensions of brain functional connectivity that are associated with child psychiatric symptoms in two large and independent cohorts: the Adolescent Brain Cognitive Development (ABCD) Study and the Generation R Study (total n =8,605). Using sparse canonical correlations analysis, we identified three brain-behavior dimensions in ABCD: attention problems, aggression and rule-breaking behaviors, and withdrawn behaviors. Importantly, out-of-sample generalizability of these dimensions was consistently observed in ABCD, suggesting robust multivariate brain-behavior associations. Despite this, out-of-study generalizability in Generation R was limited. These results highlight that the degree of generalizability can vary depending on the external validation methods employed as well as the datasets used, emphasizing that biomarkers will remain elusive until models generalize better in true external settings.

DS6, Deformation-Aware Semi-Supervised Learning: Application to Small Vessel Segmentation with Noisy Training Data.

Blood vessels of the brain provide the human brain with the required nutrients and oxygen. As a vulnerable part of the cerebral blood supply, pathology of small vessels can cause serious problems such as Cerebral Small Vessel Diseases (CSVD). It has also been shown that CSVD is related to neurodegeneration, such as Alzheimer's disease. With the advancement of 7 Tesla MRI systems, higher spatial image resolution can be achieved, enabling the depiction of very small vessels in the brain. Non-Deep Learning-based approaches for vessel segmentation, e.g., Frangi's vessel enhancement with subsequent thresholding, are capable of segmenting medium to large vessels but often fail to segment small vessels. The sensitivity of these methods to small vessels can be increased by extensive parameter tuning or by manual corrections, albeit making them time-consuming, laborious, and not feasible for larger datasets. This paper proposes a deep learning architecture to automatically segment small vessels in 7 Tesla 3D Time-of-Flight (ToF) Magnetic Resonance Angiography (MRA) data. The algorithm was trained and evaluated on a small imperfect semi-automatically segmented dataset of only 11 subjects; using six for training, two for validation, and three for testing. The deep learning model based on U-Net Multi-Scale Supervision was trained using the training subset and was made equivariant to elastic deformations in a self-supervised manner using deformation-aware learning to improve the generalisation performance. The proposed technique was evaluated quantitatively and qualitatively against the test set and achieved a Dice score of 80.44 ± 0.83. Furthermore, the result of the proposed method was compared against a selected manually segmented region (62.07 resultant Dice) and has shown a considerable improvement (18.98%) with deformation-aware learning.

Automated Segmentation and Volume Measurement of Intracranial Internal Carotid Artery Calcification at Noncontrast CT.

PURPOSE: To develop and evaluate a fully-automated deep learning-based method for assessment of intracranial internal carotid artery calcification (ICAC). MATERIALS AND METHODS: This was a secondary analysis of prospectively collected data from the Rotterdam study (2003-2006) to develop and validate a deep learning-based method for automated ICAC delineation and volume measurement. Two observers manually delineated ICAC on noncontrast CT scans of 2319 participants (mean age, 69 years ± 7 [standard deviation]; 1154 women [53.2%]), and a deep learning model was trained to segment ICAC and quantify its volume. Model performance was assessed by comparing manual and automated segmentations and volume measurements to those produced by an independent observer (available on 47 scans), comparing the segmentation accuracy in a blinded qualitative visual comparison by an expert observer, and comparing the association with first stroke incidence from the scan date until 2016. All method performance metrics were computed using 10-fold cross-validation. RESULTS: The automated delineation of ICAC reached a sensitivity of 83.8% and positive predictive value (PPV) of 88%. The intraclass correlation between automatic and manual ICAC volume measures was 0.98 (95% CI: 0.97, 0.98; computed in the entire dataset). Measured between the assessments of independent observers, sensitivity was 73.9%, PPV was 89.5%, and intraclass correlation coefficient was 0.91 (95% CI: 0.84, 0.95; computed in the 47-scan subset). In the blinded visual comparisons of 294 regions, automated delineations were judged as more accurate than manual delineations in 131 regions, less accurate in 94 regions, and equally accurate in the rest of the regions (131 of 225, 58.2%; P = .01). The association of ICAC volume with incident stroke was similarly strong for both automated (hazard ratio, 1.38 [95% CI: 1.12, 1.75]) and manually measured volumes (hazard ratio, 1.48 [95% CI: 1.20, 1.87]). CONCLUSION: The developed model was capable of automated segmentation and volume quantification of ICAC with accuracy comparable to human experts.Keywords CT, Neural Networks, Carotid Arteries, Calcifications/Calculi, Arteriosclerosis, Segmentation, Vision Application Domain, Stroke Supplemental material is available for this article. © RSNA, 2021.

Adversarial attack vulnerability of medical image analysis systems: Unexplored factors.

Adversarial attacks are considered a potentially serious security threat for machine learning systems. Medical image analysis (MedIA) systems have recently been argued to be vulnerable to adversarial attacks due to strong financial incentives and the associated technological infrastructure. In this paper, we study previously unexplored factors affecting adversarial attack vulnerability of deep learning MedIA systems in three medical domains: ophthalmology, radiology, and pathology. We focus on adversarial black-box settings, in which the attacker does not have full access to the target model and usually uses another model, commonly referred to as surrogate model, to craft adversarial examples that are then transferred to the target model. We consider this to be the most realistic scenario for MedIA systems. Firstly, we study the effect of weight initialization (pre-training on ImageNet or random initialization) on the transferability of adversarial attacks from the surrogate model to the target model, i.e., how effective attacks crafted using the surrogate model are on the target model. Secondly, we study the influence of differences in development (training and validation) data between target and surrogate models. We further study the interaction of weight initialization and data differences with differences in model architecture. All experiments were done with a perturbation degree tuned to ensure maximal transferability at minimal visual perceptibility of the attacks. Our experiments show that pre-training may dramatically increase the transferability of adversarial examples, even when the target and surrogate's architectures are different: the larger the performance gain using pre-training, the larger the transferability. Differences in the development data between target and surrogate models considerably decrease the performance of the attack; this decrease is further amplified by difference in the model architecture. We believe these factors should be considered when developing security-critical MedIA systems planned to be deployed in clinical practice. We recommend avoiding using only standard components, such as pre-trained architectures and publicly available datasets, as well as disclosure of design specifications, in addition to using adversarial defense methods. When evaluating the vulnerability of MedIA systems to adversarial attacks, various attack scenarios and target-surrogate differences should be simulated to achieve realistic robustness estimates. The code and all trained models used in our experiments are publicly available.3.

Weakly supervised object detection with 2D and 3D regression neural networks.

Finding automatically multiple lesions in large images is a common problem in medical image analysis. Solving this problem can be challenging if, during optimization, the automated method cannot access information about the location of the lesions nor is given single examples of the lesions. We propose a new weakly supervised detection method using neural networks, that computes attention maps revealing the locations of brain lesions. These attention maps are computed using the last feature maps of a segmentation network optimized only with global image-level labels. The proposed method can generate attention maps at full input resolution without need for interpolation during preprocessing, which allows small lesions to appear in attention maps. For comparison, we modify state-of-the-art methods to compute attention maps for weakly supervised object detection, by using a global regression objective instead of the more conventional classification objective. This regression objective optimizes the number of occurrences of the target object in an image, e.g. the number of brain lesions in a scan, or the number of digits in an image. We study the behavior of the proposed method in MNIST-based detection datasets, and evaluate it for the challenging detection of enlarged perivascular spaces - a type of brain lesion - in a dataset of 2202 3D scans with point-wise annotations in the center of all lesions in four brain regions. In MNIST-based datasets, the proposed method outperforms the other methods. In the brain dataset, the weakly supervised detection methods come close to the human intrarater agreement in each region. The proposed method reaches the best area under the curve in two out of four regions, and has the lowest number of false positive detections in all regions, while its average sensitivity over all regions is similar to that of the other best methods. The proposed method can facilitate epidemiological and clinical studies of enlarged perivascular spaces and help advance research in the etiology of enlarged perivascular spaces and in their relationship with cerebrovascular diseases.

Classification of Volumetric Images Using Multi-Instance Learning and Extreme Value Theorem.

Volumetric imaging is an essential diagnostic tool for medical practitioners. The use of popular techniques such as convolutional neural networks (CNN) for analysis of volumetric images is constrained by the availability of detailed (with local annotations) training data and GPU memory. In this paper, the volumetric image classification problem is posed as a multi-instance classification problem and a novel method is proposed to adaptively select positive instances from positive bags during the training phase. This method uses the extreme value theory to model the feature distribution of the images without a pathology and use it to identify positive instances of an imaged pathology. The experimental results, on three separate image classification tasks (i.e. classify retinal OCT images according to the presence or absence of fluid build-ups, emphysema detection in pulmonary 3D-CT images and detection of cancerous regions in 2D histopathology images) show that the proposed method produces classifiers that have similar performance to fully supervised methods and achieves the state of the art performance in all examined test cases.

3D regression neural network for the quantification of enlarged perivascular spaces in brain MRI.

Enlarged perivascular spaces (EPVS) in the brain are an emerging imaging marker for cerebral small vessel disease, and have been shown to be related to increased risk of various neurological diseases, including stroke and dementia. Automated quantification of EPVS would greatly help to advance research into its etiology and its potential as a risk indicator of disease. We propose a convolutional network regression method to quantify the extent of EPVS in the basal ganglia from 3D brain MRI. We first segment the basal ganglia and subsequently apply a 3D convolutional regression network designed for small object detection within this region of interest. The network takes an image as input, and outputs a quantification score of EPVS. The network has significantly more convolution operations than pooling ones and no final activation, allowing it to span the space of real numbers. We validated our approach using a dataset of 2000 brain MRI scans scored visually. Experiments with varying sizes of training and test sets showed that a good performance can be achieved with a training set of only 200 scans. With a training set of 1000 scans, the intraclass correlation coefficient (ICC) between our scoring method and the expert's visual score was 0.74. Our method outperforms by a large margin - more than 0.10 - four more conventional automated approaches based on intensities, scale-invariant feature transform, and random forest. We show that the network learns the structures of interest and investigate the influence of hyper-parameters on the performance. We also evaluate the reproducibility of our network using a set of 60 subjects scanned twice (scan-rescan reproducibility). On this set our network achieves an ICC of 0.93, while the intrarater agreement reaches 0.80. Furthermore, the automated EPVS scoring correlates similarly to age as visual scoring.

Enlarged perivascular spaces in brain MRI: Automated quantification in four regions.

Enlarged perivascular spaces (PVS) are structural brain changes visible in MRI, are common in aging, and are considered a reflection of cerebral small vessel disease. As such, assessing the burden of PVS has promise as a brain imaging marker. Visual and manual scoring of PVS is a tedious and observer-dependent task. Automated methods would advance research into the etiology of PVS, could aid to assess what a "normal" burden is in aging, and could evaluate the potential of PVS as a biomarker of cerebral small vessel disease. In this work, we propose and evaluate an automated method to quantify PVS in the midbrain, hippocampi, basal ganglia and centrum semiovale. We also compare associations between (earlier established) determinants of PVS and visual PVS scores versus the automated PVS scores, to verify whether automated PVS scores could replace visual scoring of PVS in epidemiological and clinical studies. Our approach is a deep learning algorithm based on convolutional neural network regression, and is contingent on successful brain structure segmentation. In our work we used FreeSurfer segmentations. We trained and validated our method on T2-contrast MR images acquired from 2115 subjects participating in a population-based study. These scans were visually scored by an expert rater, who counted the number of PVS in each brain region. Agreement between visual and automated scores was found to be excellent for all four regions, with intraclass correlation coefficients (ICCs) between 0.75 and 0.88. These values were higher than the inter-observer agreement of visual scoring (ICCs between 0.62 and 0.80). Scan-rescan reproducibility was high (ICCs between 0.82 and 0.93). The association between 20 determinants of PVS, including aging, and the automated scores were similar to those between the same 20 determinants of PVS and visual scores. We conclude that this method may replace visual scoring and facilitate large epidemiological and clinical studies of PVS.