Search

Background: The aim of this study was to compare three surgical interventions for correction of sagittal synostosis-frontobiparietal remodeling (FBR), extended strip craniotomy (ESC), and spring-Assisted correction (SAC)-based on three-dimensional (3D) photogrammetry and operation characteristics. Methods: Patients who were born between 1991 and 2019 and diagnosed with nonsyndromic sagittal synostosis who underwent FBR, ESC, or SAC and had at least one postoperative 3D photogrammetry image taken during one of six follow-up appointments until age 6 were considered for this study. Operative characteristics, postoperative complications, reinterventions, and presence of intracranial hypertension were collected. To assess cranial growth, orthogonal cranial slices and 3D photocephalometric measurements were extracted automatically and evaluated from 3D photogrammetry images. Results: A total of 322 postoperative 3D images from 218 patients were included. After correcting for age and sex, no significant differences were observed in 3D photocephalometric measurements. Mean cranial shapes suggested that postoperative growth and shape gradually normalized with higher occipitofrontal head circumference and intracranial volume values compared with normal values, regardless of type of surgery. Flattening of the vertex seems to persist after surgical correction. The authors' cranial 3D mesh processing tool has been made publicly available as a part of this study. Conclusions: The findings suggest that until age 6, there are no significant differences among the FBR, ESC, and SAC in their ability to correct sagittal synostosis with regard to 3D photocephalometric measurements. Therefore, efforts should be made to ensure early diagnosis so that minimally invasive surgery is a viable treatment option. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III., ImPhys/Vos group, ImPhys/Computational Imaging

Computer-aided methods have shown added value for diagnosing and predicting brain disorders and can thus support decision making in clinical care and treatment planning. This chapter will provide insight into the type of methods, their working, their input data –such as cognitive tests, imaging, and genetic data– and the types of output they provide. We will focus on specific use cases for diagnosis, i.e., estimating the current “condition” of the patient, such as early detection and diagnosis of dementia, differential diagnosis of brain tumors, and decision making in stroke. Regarding prediction, i.e., estimation of the future “condition” of the patient, we will zoom in on use cases such as predicting the disease course in multiple sclerosis and predicting patient outcomes after treatment in brain cancer. Furthermore, based on these use cases, we will assess the current state-of-the-art methodology and highlight current efforts on benchmarking of these methods and the importance of open science therein. Finally, we assess the current clinical impact of computer-aided methods and discuss the required next steps to increase clinical impact., ImPhys/Vos group, ImPhys/Computational Imaging

STUDY QUESTION: Is there an association between low-to-moderate levels of prenatal alcohol exposure (PAE) and children's facial shape? SUMMARY ANSWER: PAE before and during pregnancy, even at low level (<12 g of alcohol per week), was found associated with the facial shape of children, and these associations were found attenuated as children grow older. WHAT IS KNOWN ALREADY: High levels of PAE during pregnancy can have significant adverse associations with a child's health development resulting in recognizably abnormal facial development. STUDY DESIGN, SIZE, DURATION: This study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. We analyzed children 3-dimensional (3D) facial images taken at ages 9 (n = 3149) and 13 years (n = 2477) together with the data of maternal alcohol consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined six levels of PAE based on the frequency and dose of alcohol consumption and defined three tiers based on the timing of alcohol exposure of the unborn child. For the image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 traits representing facial morphology. These 200 traits were used for statistical analysis to search for associations with PAE. Finally, we generated heatmaps to display the facial phenotypes associated with PAE. MAIN RESULTS AND THE ROLE OF CHANCE: The results of the linear regression in the 9-year-old children survived correction for multiple testing with false discovery rate (FDR). In Tier 1 where we examined PAE only before pregnancy (exposed N = 278, unexposed N = 760), we found three traits survived FDR correction. The lowest FDR-P is 1.7e-05 (beta = 0.021, SE = 0.0040) in Trait #29; In Tier 2b where we examine any PAE during first trimester (exposed N = 756; unexposed N = 760), we found eight traits survived FDR correction. The lowest FDR-P is, ImPhys/Vos group, ImPhys/Computational Imaging

Background: X-ray digital subtraction angiography (DSA) is the imaging modality for peri-procedural guidance and treatment evaluation in (neuro-) vascular interventions. Perfusion image construction from DSA, as a means of quantitatively depicting cerebral hemodynamics, has been shown feasible. However, the quantitative property of perfusion DSA has not been well studied. Purpose: To comparatively study the independence of deconvolution-based perfusion DSA with respect to varying injection protocols, as well as its sensitivity to alterations in brain conditions. Methods: We developed a deconvolution-based algorithm to compute perfusion parametric images from DSA, including cerebral blood volume (CBV (Figure presented.)), cerebral blood flow (CBF (Figure presented.)), time to maximum (Tmax), and mean transit time (MTT (Figure presented.)) and applied it to DSA sequences obtained from two swine models. We also extracted the time intensity curve (TIC)-derived parameters, that is, area under the curve (AUC), peak concentration of the curve, and the time to peak (TTP) from these sequences. Deconvolution-based parameters were quantitatively compared to TIC-derived parameters in terms of consistency upon variations in injection profile and time resolution of DSA, as well as sensitivity to alterations of cerebral condition. Results: Comparing to TIC-derived parameters, the standard deviation (SD) of deconvolution-based parameters (normalized with respect to the mean) are two to five times smaller, indicating that they are more consistent across different injection protocols and time resolutions. Upon ischemic stroke induced in a swine model, the sensitivities of deconvolution-based parameters are equal to, if not higher than, those of TIC-derived parameters. Conclusions: In comparison to TIC-derived parameters, deconvolution-based perfusion imaging in DSA shows significantly higher quantitative reliability against variations in injection protocols across different time r, ImPhys/Vos group, ImPhys/Computational Imaging

Augmented reality (AR) has shown potential in computer-aided surgery. It allows for the visualization of hidden anatomical structures as well as assists in navigating and locating surgical instruments at the surgical site. Various modalities (devices and/or visualizations) have been used in the literature, but few studies investigated the adequacy/superiority of one modality over the other. For instance, the use of optical see-through (OST) HMDs has not always been scientifically justified. Our goal is to compare various visualization modalities for catheter insertion in external ventricular drain and ventricular shunt procedures. We investigate two AR approaches: (1) 2D approaches consisting of a smartphone and a 2D window visualized through an OST (Microsoft HoloLens 2), and (2) 3D approaches consisting of a fully aligned patient model and a model that is adjacent to the patient and is rotationally aligned using an OST. 32 participants joined this study. For each visualization approach, participants were asked to perform five insertions after which they filled NASA-TLX and SUS forms. Moreover, the position and orientation of the needle with respect to the planning during the insertion task were collected. The results show that participants achieved a better insertion performance significantly under 3D visualizations, and the NASA-TLX and SUS forms reflected the preference of participants for these approaches compared to 2D approaches., Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public., ImPhys/Vos group, ImPhys/Computational Imaging

BACKGROUND: Accurate characterization of glioma is crucial for clinical decision making. A delineation of the tumor is also desirable in the initial decision stages but is time-consuming. Previously, deep learning methods have been developed that can either non-invasively predict the genetic or histological features of glioma, or that can automatically delineate the tumor, but not both tasks at the same time. Here, we present our method that can predict the molecular subtype and grade, while simultaneously providing a delineation of the tumor. METHODS: We developed a single multi-task convolutional neural network that uses the full 3D, structural, preoperative MRI scans to predict the IDH mutation status, the 1p/19q co-deletion status, and the grade of a tumor, while simultaneously segmenting the tumor. We trained our method using a patient cohort containing 1508 glioma patients from 16 institutes. We tested our method on an independent dataset of 240 patients from 13 different institutes. RESULTS: In the independent test set, we achieved an IDH-AUC of 0.90, an 1p/19q co-deletion AUC of 0.85, and a grade AUC of 0.81 (grade II/III/IV). For the tumor delineation, we achieved a mean whole tumor Dice score of 0.84. CONCLUSIONS: We developed a method that non-invasively predicts multiple, clinically relevant features of glioma. Evaluation in an independent dataset shows that the method achieves a high performance and that it generalizes well to the broader clinical population. This first-of-its-kind method opens the door to more generalizable, instead of hyper-specialized, AI methods., ImPhys/Vos group, ImPhys/Computational Imaging

Background & Aims: Impaired liver function affects brain health and therefore understanding potential mechanisms for subclinical liver disease is essential. We assessed the liver–brain associations using liver measures with brain imaging markers, and cognitive measures in the general population. Methods: Within the population-based Rotterdam Study, liver serum and imaging measures (ultrasound and transient elastography), metabolic dysfunction-associated fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD) and fibrosis phenotypes, and brain structure were determined in 3493 non-demented and stroke-free participants in 2009–2014. This resulted in subgroups of n = 3493 for MAFLD (mean age 69 ± 9 years, 56% ♀), n = 2938 for NAFLD (mean age 70 ± 9 years, 56% ♀) and n = 2252 for fibrosis (mean age 65 ± 7 years, 54% ♀). Imaging markers of small vessel disease and neurodegeneration, cerebral blood flow (CBF) and brain perfusion (BP) were acquired from brain MRI (1.5-tesla). General cognitive function was assessed by Mini-Mental State Examination and the g-factor. Multiple linear and logistic regression models were used for liver-brain associations and adjusted for age, sex, intracranial volume, cardiovascular risk factors and alcohol use. Results: Higher gamma-glutamyltransferase (GGT) levels were significantly associated with smaller total brain volume (TBV, standardized mean difference (SMD), −0.02, 95% confidence interval (CI) (−0.03 to −0.01); p = 8.4·10−4), grey matter volumes, and lower CBF and BP. Liver serum measures were not related to small vessel disease markers, nor to white matter microstructural integrity or general cognition. Participants with ultrasound-based liver steatosis had a higher fractional anisotropy (FA, SMD 0.11, 95% CI (0.04 to 0.17), p = 1.5·10−3) and lower CBF and BP. MAFLD and NAFLD phenotypes were associated with alterations in white matter microstructural integrity (NAFLD ~ FA, SMD 0.14, 95% CI, ImPhys/Vos group, ImPhys/Computational Imaging

Extracting the cerebral anterior vessel tree of patients with an intracranial large vessel occlusion (LVO) is relevant to investigate potential biomarkers that can contribute to treatment decision making. The purpose of our work is to develop a method that can achieve this from routinely acquired computed tomography angiography (CTA) and computed tomography perfusion (CTP) images. To this end, we regard the anterior vessel tree as a set of bifurcations and connected centerlines. The method consists of a proximal policy optimization (PPO) based deep reinforcement learning (DRL) approach for tracking centerlines, a convolutional neural network based bifurcation detector, and a breadth-first vessel tree construction approach taking the tracking and bifurcation detection results as input. We experimentally determine the added values of various components of the tracker. Both DRL vessel tracking and CNN bifurcation detection were assessed in a cross validation experiment using 115 subjects. The anterior vessel tree formation was evaluated on an independent test set of 25 subjects, and compared to interobserver variation on a small subset of images. The DRL tracking result achieves a median overlapping rate until the first error (1.8 mm off the reference standard) of 100, [46, 100] % on 8032 vessels over 115 subjects. The bifurcation detector reaches an average recall and precision of 76% and 87% respectively during the vessel tree formation process. The final vessel tree formation achieves a median recall of 68% and precision of 70%, which is in line with the interobserver agreement., ImPhys/Vos group, ImPhys/Computational Imaging, Biomechanical Engineering

Identification and detection of thin-cap fibroatheroma (TCFA) from intravascular optical coherence tomography (IVOCT) images is critical for treatment of coronary heart diseases. Recently, deep learning methods have shown promising successes in TCFA identification. However, most methods usually do not effectively utilize multi-view information or incorporate prior domain knowledge. In this paper, we propose a multi-view contour-constrained transformer network (MVCTN) for TCFA identification in IVOCT images. Inspired by the diagnosis process of cardiologists, we use contour constrained self-attention modules (CCSM) to emphasize features corresponding to salient regions (i.e., vessel walls) in an unsupervised manner and enhance the visual interpretability based on class activation mapping (CAM). Moreover, we exploit transformer modules (TM) to build global-range relations between two views (i.e., polar and Cartesian views) to effectively fuse features at multiple feature scales. Experimental results on a semi-public dataset and an in-house dataset demonstrate that the proposed MVCTN outperforms other single-view and multi-view methods. Lastly, the proposed MVCTN can also provide meaningful visualization for cardiologists via CAM., ImPhys/Vos group, ImPhys/Computational Imaging

Purpose: In minimally invasive spring-assisted craniectomy, surgeons plan the surgery by manually locating the cranial sutures. However, this approach is prone to error. Augmented reality (AR) could be used to visualize the cranial sutures and assist in the surgery planning. The purpose of our work is to develop an AR-based system to visualize cranial sutures, and to assess the accuracy and usability of using AR-based navigation for surgical guidance in minimally invasive spring-assisted craniectomy. Methods: An AR system was developed that consists of an electromagnetic tracking system linked with a Microsoft HoloLens. The system was used to conduct a study with two skull phantoms. For each phantom, five sutures were annotated and visualized on the skull surface. Twelve participants assessed the system. For each participant, model alignment using six anatomical landmarks was performed, followed by the participant delineation of the visualized sutures. At the end, the participants filled a system usability scale (SUS) questionnaire. For evaluation, an independent optical tracking system was used and the delineated sutures were digitized and compared to the CT-annotated sutures. Results: For a total of 120 delineated sutures, the distance of the annotated sutures to the planning reference was 2.4 ± 1.2 mm. The average delineation time per suture was 13 ± 5 s. For the system usability questionnaire, an average SUS score of 73 was obtained. Conclusion: The developed AR-system has good accuracy (average 2.4 mm distance) and could be used in the OR. The system can assist in the pre-planning of minimally invasive craniosynostosis surgeries to locate cranial sutures accurately instead of the traditional approach of manual palpation. Although the conducted phantom study was designed to closely reflect the clinical setup in the OR, further clinical validation of the developed system is needed and will be addressed in a future work., ImPhys/Medical Imaging, ImPhys/Computational Imaging, Biomechanical Engineering

The computer-aided analysis of prostate multiparametric MRI (mpMRI) could improve significant-prostate-cancer (PCa) detection. Various deep-learning-and radiomics-based methods for significant-PCa segmentation or classification have been reported in the literature. To be able to assess the generalizability of the performance of these methods, using various external data sets is crucial. While both deep-learning and radiomics approaches have been compared based on the same data set of one center, the comparison of the performances of both approaches on various data sets from different centers and different scanners is lacking. The goal of this study was to compare the performance of a deep-learning model with the performance of a radiomics model for the significant-PCa diagnosis of the cohorts of various patients. We included the data from two consecutive patient cohorts from our own center (n = 371 patients), and two external sets of which one was a publicly available patient cohort (n = 195 patients) and the other contained data from patients from two hospitals (n = 79 patients). Using multiparametric MRI (mpMRI), the radiologist tumor delineations and pathology reports were collected for all patients. During training, one of our patient cohorts (n = 271 patients) was used for both the deep-learning-and radiomics-model development, and the three remaining cohorts (n = 374 patients) were kept as unseen test sets. The performances of the models were assessed in terms of their area under the receiver-operating-characteristic curve (AUC). Whereas the internal cross-validation showed a higher AUC for the deep-learning approach, the radiomics model obtained AUCs of 0.88, 0.91 and 0.65 on the independent test sets compared to AUCs of 0.70, 0.73 and 0.44 for the deep-learning model. Our radiomics model that was based on delineated regions resulted in a more accurate tool for significant-PCa classification in the three unseen test sets when compared to a fully automated, ImPhys/Computational Imaging, ImPhys/Medical Imaging

Intracranial vessel perforation is a peri-procedural complication during endovascular therapy (EVT). Prompt recognition is important as its occurrence is strongly associated with unfavorable treatment outcomes. However, perforations can be hard to detect because they are rare, can be subtle, and the interventionalist is working under time pressure and focused on treatment of vessel occlusions. Automatic detection holds potential to improve rapid identification of intracranial vessel perforation. In this work, we present the first study on automated perforation detection and localization on X-ray digital subtraction angiography (DSA) image series. We adapt several state-of-the-art single-frame detectors and further propose temporal modules to learn the progressive dynamics of contrast extravasation. Application-tailored loss function and post-processing techniques are designed. We train and validate various automated methods using two national multi-center datasets (i.e., MR CLEAN Registry and MR CLEAN-NoIV Trial), and one international multi-trial dataset (i.e., the HERMES collaboration). With ten-fold cross-validation, the proposed methods achieve an area under the curve (AUC) of the receiver operating characteristic of 0.93 in terms of series level perforation classification. Perforation localization precision and recall reach 0.83 and 0.70 respectively. Furthermore, we demonstrate that the proposed automatic solutions perform at similar level as an expert radiologist., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Augmented reality (AR) permits the visualization of pre-operative data in the surgical field of view of the surgeon. This requires the alignment of the AR device’s coordinate system with the used navigation/tracking system. We propose a multimodal marker approach to align an AR device with a tracking system: in our implementation, an electromagnetic tracking system (EMTS). The solution makes use of a calibration method which determines the relationship between a 2D pattern detected by an RGB camera and an electromagnetic sensor of the EMTS. This allowed the projection of a 3D skull model on its physical counterpart. This projection was evaluated using a monocular camera and an optical see-through device (HoloLens 2) (https://www.microsoft.com/en-us/hololens/) achieving an accuracy of less than 2.5 mm in the image plane of the HoloLens 2 (HL2). Additionally, 10 volunteers participated in a user study consisting of an alignment task of a pointer with 25 projections viewed through the HL2. The participants achieved a mean error of 2.7 1.3 mm and 2.9 2.9∘ in positional and orientation error. This study showcases the feasibility of the approach, provides an evaluation of the alignment, and finally, discusses its advantages and limitations., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Optical-based navigation systems are widely used in surgical interventions. However, despite their great utility and accuracy, they are expensive and require time and effort to setup for surgeries. Moreover, traditional navigation systems use 2D screens to display instrument positions causing the surgeons to look away from the operative field. Head mounted displays such as the Microsoft HoloLens may provide an attractive alternative for surgical navigation that also permits augmented reality visualization. The HoloLens is equipped with multiple sensors for tracking and scene understanding. Mono and stereo-vision in the HoloLens have been both reported to be used for marker tracking, but no extensive evaluation on accuracy has been done to compare the two approaches. The objective of our work is to investigate the tracking performance of various camera setups in the HoloLens, and to study the effect of the marker size, marker distance from camera, and camera resolution on marker locating accuracy. We also investigate the speed and stability of marker pose for each camera setup. The tracking approaches are evaluated using ArUco markers. Our results show that mono-vision is more accurate in marker locating than stereo-vision when high resolution is used. However, this comes at the expense of higher frame processing time. Alternatively, we propose a combined low-resolution mono-stereo tracking setup that outperforms each tracking approach individually and is comparable to high resolution mono tracking, with a mean translational error of 1.8 ± 0.6mm for 10cm marker size at 50cm distance. We further discuss our findings and their implications for navigation in surgical interventions., ImPhys/Computational Imaging, ImPhys/Medical Imaging

Optical-based navigation systems are widely used in surgical interventions. However, despite their great utility and accuracy, they are expensive and require time and effort to setup for surgeries. Moreover, traditional navigation systems use 2D screens to display instrument positions causing the surgeons to look away from the operative field. Head mounted displays such as the Microsoft HoloLens may provide an attractive alternative for surgical navigation that also permits augmented reality visualization. The HoloLens is equipped with multiple sensors for tracking and scene understanding. Mono and stereo-vision in the HoloLens have been both reported to be used for marker tracking, but no extensive evaluation on accuracy has been done to compare the two approaches. The objective of our work is to investigate the tracking performance of various camera setups in the HoloLens, and to study the effect of the marker size, marker distance from camera, and camera resolution on marker locating accuracy. We also investigate the speed and stability of marker pose for each camera setup. The tracking approaches are evaluated using ArUco markers. Our results show that mono-vision is more accurate in marker locating than stereo-vision when high resolution is used. However, this comes at the expense of higher frame processing time. Alternatively, we propose a combined low-resolution mono-stereo tracking setup that outperforms each tracking approach individually and is comparable to high resolution mono tracking, with a mean translational error of 1.8 ± 0.6mm for 10cm marker size at 50cm distance. We further discuss our findings and their implications for navigation in surgical interventions., ImPhys/Computational Imaging, ImPhys/Medical Imaging

Purpose: In minimally invasive spring-assisted craniectomy, surgeons plan the surgery by manually locating the cranial sutures. However, this approach is prone to error. Augmented reality (AR) could be used to visualize the cranial sutures and assist in the surgery planning. The purpose of our work is to develop an AR-based system to visualize cranial sutures, and to assess the accuracy and usability of using AR-based navigation for surgical guidance in minimally invasive spring-assisted craniectomy. Methods: An AR system was developed that consists of an electromagnetic tracking system linked with a Microsoft HoloLens. The system was used to conduct a study with two skull phantoms. For each phantom, five sutures were annotated and visualized on the skull surface. Twelve participants assessed the system. For each participant, model alignment using six anatomical landmarks was performed, followed by the participant delineation of the visualized sutures. At the end, the participants filled a system usability scale (SUS) questionnaire. For evaluation, an independent optical tracking system was used and the delineated sutures were digitized and compared to the CT-annotated sutures. Results: For a total of 120 delineated sutures, the distance of the annotated sutures to the planning reference was 2.4 ± 1.2 mm. The average delineation time per suture was 13 ± 5 s. For the system usability questionnaire, an average SUS score of 73 was obtained. Conclusion: The developed AR-system has good accuracy (average 2.4 mm distance) and could be used in the OR. The system can assist in the pre-planning of minimally invasive craniosynostosis surgeries to locate cranial sutures accurately instead of the traditional approach of manual palpation. Although the conducted phantom study was designed to closely reflect the clinical setup in the OR, further clinical validation of the developed system is needed and will be addressed in a future work., ImPhys/Medical Imaging, ImPhys/Computational Imaging, Biomechanical Engineering

Augmented reality (AR) permits the visualization of pre-operative data in the surgical field of view of the surgeon. This requires the alignment of the AR device’s coordinate system with the used navigation/tracking system. We propose a multimodal marker approach to align an AR device with a tracking system: in our implementation, an electromagnetic tracking system (EMTS). The solution makes use of a calibration method which determines the relationship between a 2D pattern detected by an RGB camera and an electromagnetic sensor of the EMTS. This allowed the projection of a 3D skull model on its physical counterpart. This projection was evaluated using a monocular camera and an optical see-through device (HoloLens 2) (https://www.microsoft.com/en-us/hololens/) achieving an accuracy of less than 2.5 mm in the image plane of the HoloLens 2 (HL2). Additionally, 10 volunteers participated in a user study consisting of an alignment task of a pointer with 25 projections viewed through the HL2. The participants achieved a mean error of 2.7 1.3 mm and 2.9 2.9∘ in positional and orientation error. This study showcases the feasibility of the approach, provides an evaluation of the alignment, and finally, discusses its advantages and limitations., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Intracranial vessel perforation is a peri-procedural complication during endovascular therapy (EVT). Prompt recognition is important as its occurrence is strongly associated with unfavorable treatment outcomes. However, perforations can be hard to detect because they are rare, can be subtle, and the interventionalist is working under time pressure and focused on treatment of vessel occlusions. Automatic detection holds potential to improve rapid identification of intracranial vessel perforation. In this work, we present the first study on automated perforation detection and localization on X-ray digital subtraction angiography (DSA) image series. We adapt several state-of-the-art single-frame detectors and further propose temporal modules to learn the progressive dynamics of contrast extravasation. Application-tailored loss function and post-processing techniques are designed. We train and validate various automated methods using two national multi-center datasets (i.e., MR CLEAN Registry and MR CLEAN-NoIV Trial), and one international multi-trial dataset (i.e., the HERMES collaboration). With ten-fold cross-validation, the proposed methods achieve an area under the curve (AUC) of the receiver operating characteristic of 0.93 in terms of series level perforation classification. Perforation localization precision and recall reach 0.83 and 0.70 respectively. Furthermore, we demonstrate that the proposed automatic solutions perform at similar level as an expert radiologist., ImPhys/Medical Imaging, ImPhys/Computational Imaging

The computer-aided analysis of prostate multiparametric MRI (mpMRI) could improve significant-prostate-cancer (PCa) detection. Various deep-learning-and radiomics-based methods for significant-PCa segmentation or classification have been reported in the literature. To be able to assess the generalizability of the performance of these methods, using various external data sets is crucial. While both deep-learning and radiomics approaches have been compared based on the same data set of one center, the comparison of the performances of both approaches on various data sets from different centers and different scanners is lacking. The goal of this study was to compare the performance of a deep-learning model with the performance of a radiomics model for the significant-PCa diagnosis of the cohorts of various patients. We included the data from two consecutive patient cohorts from our own center (n = 371 patients), and two external sets of which one was a publicly available patient cohort (n = 195 patients) and the other contained data from patients from two hospitals (n = 79 patients). Using multiparametric MRI (mpMRI), the radiologist tumor delineations and pathology reports were collected for all patients. During training, one of our patient cohorts (n = 271 patients) was used for both the deep-learning-and radiomics-model development, and the three remaining cohorts (n = 374 patients) were kept as unseen test sets. The performances of the models were assessed in terms of their area under the receiver-operating-characteristic curve (AUC). Whereas the internal cross-validation showed a higher AUC for the deep-learning approach, the radiomics model obtained AUCs of 0.88, 0.91 and 0.65 on the independent test sets compared to AUCs of 0.70, 0.73 and 0.44 for the deep-learning model. Our radiomics model that was based on delineated regions resulted in a more accurate tool for significant-PCa classification in the three unseen test sets when compared to a fully automated, ImPhys/Computational Imaging, ImPhys/Medical Imaging

Treatment planning of gastrointestinal stromal tumors (GISTs) includes distinguishing GISTs from other intra-abdominal tumors and GISTs’ molecular analysis. The aim of this study was to evaluate radiomics for distinguishing GISTs from other intra-abdominal tumors, and in GISTs, predict the c-KIT, PDGFRA, BRAF mutational status, and mitotic index (MI). Patients diagnosed at the Erasmus MC between 2004 and 2017, with GIST or non-GIST intra-abdominal tumors and a contrast-enhanced venous-phase CT, were retrospectively included. Tumors were segmented, from which 564 image features were extracted. Prediction models were constructed using a combination of machine learning approaches. The evaluation was performed in a 100 × random-split cross-validation. Model performance was compared to that of three radiologists. One hundred twenty-five GISTs and 122 non-GISTs were included. The GIST vs. non-GIST radiomics model had a mean area under the curve (AUC) of 0.77. Three radiologists had an AUC of 0.69, 0.76, and 0.84, respectively. The radiomics model had an AUC of 0.52 for c-KIT, 0.56 for c-KIT exon 11, and 0.52 for the MI. The numbers of PDGFRA, BRAF, and other c-KIT mutations were too low for analysis. Our radiomics model was able to distinguish GISTs from non-GISTs with a performance similar to three radiologists, but less observer dependent. Therefore, it may aid in the early diagnosis of GIST, facilitating rapid referral to specialized treatment centers. As the model was not able to predict any genetic or molecular features, it cannot aid in treatment planning yet., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Data-driven disease progression models have provided important insight into the timeline of brain changes in AD phenotypes. However, their utility in predicting the progression of pre-symptomatic AD in a population-based setting has not yet been investigated. In this study, we investigated if the disease timelines constructed in a case-controlled setting, with subjects stratified according to APOE status, are generalizable to a population-based cohort, and if progression along these disease timelines is predictive of AD. Seven volumetric biomarkers derived from structural MRI were considered. We estimated APOE-specific disease timelines of changes in these biomarkers using a recently proposed method called co-initialized discriminative event-based modeling (co-init DEBM). This method can also estimate a disease stage for new subjects by calculating their position along the disease timelines. The model was trained and cross-validated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and tested on the population-based Rotterdam Study (RS) cohort. We compared the diagnostic and prognostic value of the disease stage in the two cohorts. Furthermore, we investigated if the rate of change of disease stage in RS participants with longitudinal MRI data was predictive of AD. In ADNI, the estimated disease timeslines for ϵ4 non-carriers and carriers were found to be significantly different from one another (p<0.001). The estimate disease stage along the respective timelines distinguished AD subjects from controls with an AUC of 0.83 in both APOE ϵ4 non-carriers and carriers. In the RS cohort, we obtained an AUC of 0.83 and 0.85 in ϵ4 non-carriers and carriers, respectively. Progression along the disease timelines as estimated by the rate of change of disease stage showed a significant difference (p<0.005) for subjects with pre-symptomatic AD as compared to the general aging population in RS. It distinguished pre-symptomatic AD subjects with an AUC of, ImPhys/Computational Imaging, ImPhys/Medical Imaging, Biomechanical Engineering

For the segmentation of magnetic resonance brain images into anatomical regions, numerous fully automated methods have been proposed and compared to reference segmentations obtained manually. However, systematic differences might exist between the resulting segmentations, depending on the segmentation method and underlying brain atlas. This potentially results in sensitivity differences to disease and can further complicate the comparison of individual patients to normative data. In this study, we aim to answer two research questions: 1) to what extent are methods interchangeable, as long as the same method is being used for computing normative volume distributions and patient-specific volumes? and 2) can different methods be used for computing normative volume distributions and assessing patient-specific volumes? To answer these questions, we compared volumes of six brain regions calculated by five state-of-the-art segmentation methods: Erasmus MC (EMC), FreeSurfer (FS), geodesic information flows (GIF), multi-atlas label propagation with expectation–maximization (MALP-EM), and model-based brain segmentation (MBS). We applied the methods on 988 non-demented (ND) subjects and computed the correlation (PCC-v) and absolute agreement (ICC-v) on the volumes. For most regions, the PCC-v was good ((Formula presented.)), indicating that volume differences between methods in ND subjects are mainly due to systematic differences. The ICC-v was generally lower, especially for the smaller regions, indicating that it is essential that the same method is used to generate normative and patient data. To evaluate the impact on single-subject analysis, we also applied the methods to 42 patients with Alzheimer’s disease (AD). In the case where the normative distributions and the patient-specific volumes were calculated by the same method, the patient’s distance to the normative distribution was assessed with the z-score. We determined the diagnostic value of this z-score, which sho, ImPhys/Medical Imaging, ImPhys/Computational Imaging

Brain pathology develops at different rates between individuals with similar burden of risk factors, possibly explained by brain resistance. We examined if education contributes to brain resistance by studying its influence on the association between vascular risk factors and brain pathology. In 4111 stroke-free and dementia-free community-dwelling participants (62.9 ± 10.7 years), we explored the association between vascular risk factors (hypertension and the Framingham Stroke Risk Profile [FRSP]) and imaging markers of brain pathology (markers of cerebral small vessel disease and brain volumetry), stratified by educational attainment level. Associations of hypertension and FSRP with markers of brain pathology were not significantly different between levels of educational attainment. Certain associations appeared weaker in those with higher compared to lower educational attainment, particularly for white matter hyperintensities (WMH). Supplementary residual analyses showed significant associations between higher educational attainment and stronger resistance to WMH among others. Our results suggest a role for educational attainment in resistance to vascular brain pathology. Yet, further research is needed to better characterize determinants of brain resistance., ImPhys/Medical Imaging, ImPhys/Computational Imaging

This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924–0.955) and CNN (0.933; 95%CI: 0.918–0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p<0.01 for McNemar's test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855–0.932) and CNN (0.876; 95%CI: 0.836–0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p=0.01). Deep and conventional classifiers performed, ImPhys/Medical Imaging, ImPhys/Computational Imaging, ImPhys/Imaging Physics

Radiomics applied in MRI has shown promising results in classifying prostate cancer lesions. However, many papers describe single-center studies without external validation. The issues of using radiomics models on unseen data have not yet been sufficiently addressed. The aim of this study is to evaluate the generalizability of radiomics models for prostate cancer classification and to compare the performance of these models to the performance of radiologists. Multiparametric MRI, photographs and histology of radical prostatectomy specimens, and pathology reports of 107 patients were obtained from three healthcare centers in the Netherlands. By spatially correlating the MRI with histology, 204 lesions were identified. For each lesion, radiomics features were extracted from the MRI data. Radiomics models for discriminating high-grade (Gleason score ≥ 7) versus low-grade lesions were automatically generated using open-source machine learning software. The performance was tested both in a single-center setting through cross-validation and in a multi-center setting using the two unseen datasets as external validation. For comparison with clinical practice, a multi-center classifier was tested and compared with the Prostate Imaging Reporting and Data System version 2 (PIRADS v2) scoring performed by two expert radiologists. The three single-center models obtained a mean AUC of 0.75, which decreased to 0.54 when the model was applied to the external data, the radiologists obtained a mean AUC of 0.46. In the multi-center setting, the radiomics model obtained a mean AUC of 0.75 while the radiologists obtained a mean AUC of 0.47 on the same subset. While radiomics models have a decent performance when tested on data from the same center(s), they may show a significant drop in performance when applied to external data. On a multi-center dataset our radiomics model outperformed the radiologists, and thus, may represent a more accurate alternative for malignancy prediction., ImPhys/Computational Imaging, ImPhys/Medical Imaging

In this paper, we propose the use of Recurrent Inference Machines (RIMs) to perform T1 and T2 mapping. The RIM is a neural network framework that learns an iterative inference process based on the signal model, similar to conventional statistical methods for quantitative MRI (QMRI), such as the Maximum Likelihood Estimator (MLE). This framework combines the advantages of both data-driven and model-based methods, and, we hypothesize, is a promising tool for QMRI. Previously, RIMs were used to solve linear inverse reconstruction problems. Here, we show that they can also be used to optimize non-linear problems and estimate relaxometry maps with high precision and accuracy. The developed RIM framework is evaluated in terms of accuracy and precision and compared to an MLE method and an implementation of the Residual Neural Network (ResNet). The results show that the RIM improves the quality of estimates compared to the other techniques in Monte Carlo experiments with simulated data, test-retest analysis of a system phantom, and in-vivo scans. Additionally, inference with the RIM is 150 times faster than the MLE, and robustness to (slight) variations of scanning parameters is demonstrated. Hence, the RIM is a promising and flexible method for QMRI. Coupled with an open-source training data generation tool, it presents a compelling alternative to previous methods., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Histopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003–2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician’s and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Thrombus perviousness is strongly associated with functional outcome and intravenous alteplase treatment success in patients with acute ischemic stroke. Accuracy of thrombus attenuation increase (TAI) assessment may be compromised by a heterogeneous thrombus composition and interobserver variations of currently used manual measurements. We hypothesized that TAI is more strongly associated with clinical outcomes when evaluated on the entire thrombus. In 195 patients, five TAI measures were performed: one manual by placing three regions of interest (TAImanual) and four automated ones assessing densities from the entire thrombus. The automated TAI measures were calculated by comparing quartiles; Q1, Q2, and Q3 of the non-contrast and contrast enhanced thrombus density distribution and using the lag of the maximum of the cross correlations (MCC). Associations with functional outcome (mRS at 90 days) were assessed with univariate and multivariable analyses. All entire TAI measures were significantly associated with functional outcome with odd ratios (OR) of 1.63(95 %CI:1.19–2.25, p = 0.003) for Q1, 1.56(95 %CI:1.16–2.10, p = 0.003) for Q2, 1.24(95 %CI:1.00–1.54, p = 0.045) for Q3, and 1.70(95 %CI:1.24–2.34, p = 0.001) for MCC per 10 HU increase in univariate models. TAImanual was not significantly associated with functional outcome (p = 0.055). In the multivariable logistic regression models including age, NIHSS, and recanalization, only TAI measures derived from the entire thrombus were independently associated with favorable outcome; OR of 1.64(95 %CI:1.01–2.66, p = 0.048) for Q2 and 1.82(1.13–2.95, p = 0.014) for MCC per 10 HU increase of thrombus attenuation. The novel perviousness measures of the entire thrombus are more strongly associated with functional outcome than the traditional manual perviousness assessments., ImPhys/Computational Imaging, ImPhys/Medical Imaging

Applying deep learning in population genomics is challenging because of computational issues and lack of interpretable models. Here, we propose GenNet, a novel open-source deep learning framework for predicting phenotypes from genetic variants. In this framework, interpretable and memory-efficient neural network architectures are constructed by embedding biologically knowledge from public databases, resulting in neural networks that contain only biologically plausible connections. We applied the framework to seventeen phenotypes and found well-replicated genes such as HERC2 and OCA2 for hair and eye color, and novel genes such as ZNF773 and PCNT for schizophrenia. Additionally, the framework identified ubiquitin mediated proteolysis, endocrine system and viral infectious diseases as most predictive biological pathways for schizophrenia. GenNet is a freely available, end-to-end deep learning framework that allows researchers to develop and use interpretable neural networks to obtain novel insights into the genetic architecture of complex traits and diseases., ImPhys/Medical Imaging, ImPhys/Computational Imaging, Applied Sciences

Patients with BRAF mutated (BRAF-mt) metastatic melanoma benefit significantly from treatment with BRAF inhibitors. Currently, the BRAF status is determined on archival tumor tissue or on fresh tumor tissue from an invasive biopsy. The aim of this study was to evaluate whether radiomics can predict the BRAF status in a non-invasive manner. Patients with melanoma lung metastases, known BRAF status, and a pretreatment computed tomography scan were included. After semi-automatic annotation of the lung lesions (maximum two per patient), 540 radiomics features were extracted. A chest radiologist scored all segmented lung lesions according to the Lung Image Database Consortium (LIDC) criteria. Univariate analysis was performed to assess the predictive value of each feature for BRAF mutation status. A combination of various machine learning methods was used to develop BRAF decision models based on the radiomics features and LIDC criteria. A total of 169 lung lesions from 103 patients (51 BRAF-mt; 52 BRAF wild type) were included. There were no features with a significant discriminative value in the univariate analysis. Models based on radiomics features and LIDC criteria both performed as poorly as guessing. Hence, the BRAF mutation status in melanoma lung metastases cannot be predicted using radiomics features or visually scored LIDC criteria., ImPhys/Medical Imaging, ImPhys/Computational Imaging

This work presents a single-step deep-learning framework for longitudinal image analysis, coined Segis-Net. To optimally exploit information available in longitudinal data, this method concurrently learns a multi-class segmentation and nonlinear registration. Segmentation and registration are modeled using a convolutional neural network and optimized simultaneously for their mutual benefit. An objective function that optimizes spatial correspondence for the segmented structures across time-points is proposed. We applied Segis-Net to the analysis of white matter tracts from N=8045 longitudinal brain MRI datasets of 3249 elderly individuals. Segis-Net approach showed a significant increase in registration accuracy, spatio-temporal segmentation consistency, and reproducibility compared with two multistage pipelines. This also led to a significant reduction in the sample-size that would be required to achieve the same statistical power in analyzing tract-specific measures. Thus, we expect that Segis-Net can serve as a new reliable tool to support longitudinal imaging studies to investigate macro- and microstructural brain changes over time., ImPhys/Medical Imaging, ImPhys/Computational Imaging, ImPhys/Imaging Physics

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/beta-catenin, TGF-beta; and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging., ImPhys/Vos group

For the segmentation of magnetic resonance brain images into anatomical regions, numerous fully automated methods have been proposed and compared to reference segmentations obtained manually. However, systematic differences might exist between the resulting segmentations, depending on the segmentation method and underlying brain atlas. This potentially results in sensitivity differences to disease and can further complicate the comparison of individual patients to normative data. In this study, we aim to answer two research questions: 1) to what extent are methods interchangeable, as long as the same method is being used for computing normative volume distributions and patient-specific volumes? and 2) can different methods be used for computing normative volume distributions and assessing patient-specific volumes? To answer these questions, we compared volumes of six brain regions calculated by five state-of-the-art segmentation methods: Erasmus MC (EMC), FreeSurfer (FS), geodesic information flows (GIF), multi-atlas label propagation with expectation–maximization (MALP-EM), and model-based brain segmentation (MBS). We applied the methods on 988 non-demented (ND) subjects and computed the correlation (PCC-v) and absolute agreement (ICC-v) on the volumes. For most regions, the PCC-v was good ((Formula presented.)), indicating that volume differences between methods in ND subjects are mainly due to systematic differences. The ICC-v was generally lower, especially for the smaller regions, indicating that it is essential that the same method is used to generate normative and patient data. To evaluate the impact on single-subject analysis, we also applied the methods to 42 patients with Alzheimer’s disease (AD). In the case where the normative distributions and the patient-specific volumes were calculated by the same method, the patient’s distance to the normative distribution was assessed with the z-score. We determined the diagnostic value of this z-score, which sho, ImPhys/Medical Imaging, ImPhys/Computational Imaging

Applying deep learning in population genomics is challenging because of computational issues and lack of interpretable models. Here, we propose GenNet, a novel open-source deep learning framework for predicting phenotypes from genetic variants. In this framework, interpretable and memory-efficient neural network architectures are constructed by embedding biologically knowledge from public databases, resulting in neural networks that contain only biologically plausible connections. We applied the framework to seventeen phenotypes and found well-replicated genes such as HERC2 and OCA2 for hair and eye color, and novel genes such as ZNF773 and PCNT for schizophrenia. Additionally, the framework identified ubiquitin mediated proteolysis, endocrine system and viral infectious diseases as most predictive biological pathways for schizophrenia. GenNet is a freely available, end-to-end deep learning framework that allows researchers to develop and use interpretable neural networks to obtain novel insights into the genetic architecture of complex traits and diseases., ImPhys/Computational Imaging, ImPhys/Medical Imaging

Thrombus perviousness is strongly associated with functional outcome and intravenous alteplase treatment success in patients with acute ischemic stroke. Accuracy of thrombus attenuation increase (TAI) assessment may be compromised by a heterogeneous thrombus composition and interobserver variations of currently used manual measurements. We hypothesized that TAI is more strongly associated with clinical outcomes when evaluated on the entire thrombus. In 195 patients, five TAI measures were performed: one manual by placing three regions of interest (TAImanual) and four automated ones assessing densities from the entire thrombus. The automated TAI measures were calculated by comparing quartiles; Q1, Q2, and Q3 of the non-contrast and contrast enhanced thrombus density distribution and using the lag of the maximum of the cross correlations (MCC). Associations with functional outcome (mRS at 90 days) were assessed with univariate and multivariable analyses. All entire TAI measures were significantly associated with functional outcome with odd ratios (OR) of 1.63(95 %CI:1.19–2.25, p = 0.003) for Q1, 1.56(95 %CI:1.16–2.10, p = 0.003) for Q2, 1.24(95 %CI:1.00–1.54, p = 0.045) for Q3, and 1.70(95 %CI:1.24–2.34, p = 0.001) for MCC per 10 HU increase in univariate models. TAImanual was not significantly associated with functional outcome (p = 0.055). In the multivariable logistic regression models including age, NIHSS, and recanalization, only TAI measures derived from the entire thrombus were independently associated with favorable outcome; OR of 1.64(95 %CI:1.01–2.66, p = 0.048) for Q2 and 1.82(1.13–2.95, p = 0.014) for MCC per 10 HU increase of thrombus attenuation. The novel perviousness measures of the entire thrombus are more strongly associated with functional outcome than the traditional manual perviousness assessments., ImPhys/Computational Imaging, ImPhys/Medical Imaging

Histopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003–2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician’s and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Brain pathology develops at different rates between individuals with similar burden of risk factors, possibly explained by brain resistance. We examined if education contributes to brain resistance by studying its influence on the association between vascular risk factors and brain pathology. In 4111 stroke-free and dementia-free community-dwelling participants (62.9 ± 10.7 years), we explored the association between vascular risk factors (hypertension and the Framingham Stroke Risk Profile [FRSP]) and imaging markers of brain pathology (markers of cerebral small vessel disease and brain volumetry), stratified by educational attainment level. Associations of hypertension and FSRP with markers of brain pathology were not significantly different between levels of educational attainment. Certain associations appeared weaker in those with higher compared to lower educational attainment, particularly for white matter hyperintensities (WMH). Supplementary residual analyses showed significant associations between higher educational attainment and stronger resistance to WMH among others. Our results suggest a role for educational attainment in resistance to vascular brain pathology. Yet, further research is needed to better characterize determinants of brain resistance., ImPhys/Medical Imaging, ImPhys/Computational Imaging

In this paper, we propose the use of Recurrent Inference Machines (RIMs) to perform T1 and T2 mapping. The RIM is a neural network framework that learns an iterative inference process based on the signal model, similar to conventional statistical methods for quantitative MRI (QMRI), such as the Maximum Likelihood Estimator (MLE). This framework combines the advantages of both data-driven and model-based methods, and, we hypothesize, is a promising tool for QMRI. Previously, RIMs were used to solve linear inverse reconstruction problems. Here, we show that they can also be used to optimize non-linear problems and estimate relaxometry maps with high precision and accuracy. The developed RIM framework is evaluated in terms of accuracy and precision and compared to an MLE method and an implementation of the Residual Neural Network (ResNet). The results show that the RIM improves the quality of estimates compared to the other techniques in Monte Carlo experiments with simulated data, test-retest analysis of a system phantom, and in-vivo scans. Additionally, inference with the RIM is 150 times faster than the MLE, and robustness to (slight) variations of scanning parameters is demonstrated. Hence, the RIM is a promising and flexible method for QMRI. Coupled with an open-source training data generation tool, it presents a compelling alternative to previous methods., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Radiomics applied in MRI has shown promising results in classifying prostate cancer lesions. However, many papers describe single-center studies without external validation. The issues of using radiomics models on unseen data have not yet been sufficiently addressed. The aim of this study is to evaluate the generalizability of radiomics models for prostate cancer classification and to compare the performance of these models to the performance of radiologists. Multiparametric MRI, photographs and histology of radical prostatectomy specimens, and pathology reports of 107 patients were obtained from three healthcare centers in the Netherlands. By spatially correlating the MRI with histology, 204 lesions were identified. For each lesion, radiomics features were extracted from the MRI data. Radiomics models for discriminating high-grade (Gleason score ≥ 7) versus low-grade lesions were automatically generated using open-source machine learning software. The performance was tested both in a single-center setting through cross-validation and in a multi-center setting using the two unseen datasets as external validation. For comparison with clinical practice, a multi-center classifier was tested and compared with the Prostate Imaging Reporting and Data System version 2 (PIRADS v2) scoring performed by two expert radiologists. The three single-center models obtained a mean AUC of 0.75, which decreased to 0.54 when the model was applied to the external data, the radiologists obtained a mean AUC of 0.46. In the multi-center setting, the radiomics model obtained a mean AUC of 0.75 while the radiologists obtained a mean AUC of 0.47 on the same subset. While radiomics models have a decent performance when tested on data from the same center(s), they may show a significant drop in performance when applied to external data. On a multi-center dataset our radiomics model outperformed the radiologists, and thus, may represent a more accurate alternative for malignancy prediction., ImPhys/Computational Imaging, ImPhys/Medical Imaging

This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924–0.955) and CNN (0.933; 95%CI: 0.918–0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p<0.01 for McNemar's test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855–0.932) and CNN (0.876; 95%CI: 0.836–0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p=0.01). Deep and conventional classifiers performed, ImPhys/Medical Imaging, ImPhys/Computational Imaging, ImPhys/Imaging Physics

This work presents a single-step deep-learning framework for longitudinal image analysis, coined Segis-Net. To optimally exploit information available in longitudinal data, this method concurrently learns a multi-class segmentation and nonlinear registration. Segmentation and registration are modeled using a convolutional neural network and optimized simultaneously for their mutual benefit. An objective function that optimizes spatial correspondence for the segmented structures across time-points is proposed. We applied Segis-Net to the analysis of white matter tracts from N=8045 longitudinal brain MRI datasets of 3249 elderly individuals. Segis-Net approach showed a significant increase in registration accuracy, spatio-temporal segmentation consistency, and reproducibility compared with two multistage pipelines. This also led to a significant reduction in the sample-size that would be required to achieve the same statistical power in analyzing tract-specific measures. Thus, we expect that Segis-Net can serve as a new reliable tool to support longitudinal imaging studies to investigate macro- and microstructural brain changes over time., ImPhys/Medical Imaging, ImPhys/Computational Imaging, ImPhys/Imaging Physics

Patients with BRAF mutated (BRAF-mt) metastatic melanoma benefit significantly from treatment with BRAF inhibitors. Currently, the BRAF status is determined on archival tumor tissue or on fresh tumor tissue from an invasive biopsy. The aim of this study was to evaluate whether radiomics can predict the BRAF status in a non-invasive manner. Patients with melanoma lung metastases, known BRAF status, and a pretreatment computed tomography scan were included. After semi-automatic annotation of the lung lesions (maximum two per patient), 540 radiomics features were extracted. A chest radiologist scored all segmented lung lesions according to the Lung Image Database Consortium (LIDC) criteria. Univariate analysis was performed to assess the predictive value of each feature for BRAF mutation status. A combination of various machine learning methods was used to develop BRAF decision models based on the radiomics features and LIDC criteria. A total of 169 lung lesions from 103 patients (51 BRAF-mt; 52 BRAF wild type) were included. There were no features with a significant discriminative value in the univariate analysis. Models based on radiomics features and LIDC criteria both performed as poorly as guessing. Hence, the BRAF mutation status in melanoma lung metastases cannot be predicted using radiomics features or visually scored LIDC criteria., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Purpose: Diagnosing desmoid-type fibromatosis (DTF) requires an invasive tissue biopsy with β-catenin staining and CTNNB1 mutational analysis, and is challenging due to its rarity. The aim of this study was to evaluate radiomics for distinguishing DTF from soft tissue sarcomas (STS), and in DTF, for predicting the CTNNB1 mutation types. Methods: Patients with histologically confirmed extremity STS (non-DTF) or DTF and at least a pretreatment T1-weighted (T1w) MRI scan were retrospectively included. Tumors were semi-automatically annotated on the T1w scans, from which 411 features were extracted. Prediction models were created using a combination of various machine learning approaches. Evaluation was performed through a 100x random-split cross-validation. The model for DTF vs. non-DTF was compared to classification by two radiologists on a location matched subset. Results: The data included 203 patients (72 DTF, 131 STS). The T1w radiomics model showed a mean AUC of 0.79 on the full dataset. Addition of T2w or T1w post-contrast scans did not improve the performance. On the location matched cohort, the T1w model had a mean AUC of 0.88 while the radiologists had an AUC of 0.80 and 0.88, respectively. For the prediction of the CTNNB1 mutation types (S45 F, T41A and wild-type), the T1w model showed an AUC of 0.61, 0.56, and 0.74. Conclusions: Our radiomics model was able to distinguish DTF from STS with high accuracy similar to two radiologists, but was not able to predict the CTNNB1 mutation status., ImPhys/Medical Imaging, ImPhys/Computational Imaging, Electrical Engineering, Mathematics and Computer Science

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Subtle changes in white matter (WM) microstructure have been associated with normal aging and neurodegeneration. To study these associations in more detail, it is highly important that the WM tracts can be accurately and reproducibly characterized from brain diffusion MRI. In addition, to enable analysis of WM tracts in large datasets and in clinical practice it is essential to have methodology that is fast and easy to apply. This work therefore presents a new approach for WM tract segmentation: Neuro4Neuro, that is capable of direct extraction of WM tracts from diffusion tensor images using convolutional neural network (CNN). This 3D end-to-end method is trained to segment 25 WM tracts in aging individuals from a large population-based study (N ​= ​9752, 1.5T MRI). The proposed method showed good segmentation performance and high reproducibility, i.e., a high spatial agreement (Cohen's kappa, κ=0.72−0.83) and a low scan-rescan error in tract-specific diffusion measures (e.g., fractional anisotropy: ε=1%−5%). The reproducibility of the proposed method was higher than that of a tractography-based segmentation algorithm, while being orders of magnitude faster (0.5s to segment one tract). In addition, we showed that the method successfully generalizes to diffusion scans from an external dementia dataset (N ​= ​58, 3T MRI). In two proof-of-principle experiments, we associated WM microstructure obtained using the proposed method with age in a normal elderly population, and with disease subtypes in a dementia cohort. In concordance with the literature, results showed a widespread reduction of microstructural organization with aging and substantial group-wise microstructure differences between dementia subtypes. In conclusion, we presented a highly reproducible and fast method for WM tract segmentation that has the potential of being used in large-scale studies and clinical practice., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Background: Identifying persons at risk for cognitive decline may aid in early detection of persons at risk of dementia and to select those that would benefit most from therapeutic or preventive measures for dementia. Objective: In this study we aimed to validate whether cognitive decline in the general population can be predicted with multivariate data using a previously proposed supervised classification method: Disease State Index (DSI). Methods: We included 2,542 participants, non-demented and without mild cognitive impairment at baseline, from the population-based Rotterdam Study (mean age 60.9 ± 9.1 years). Participants with significant global cognitive decline were defined as the 5% of participants with the largest cognitive decline per year. We trained DSI to predict occurrence of significant global cognitive decline using a large variety of baseline features, including magnetic resonance imaging (MRI) features, cardiovascular risk factors, APOE-ε4 allele carriership, gait features, education, and baseline cognitive function as predictors. The prediction performance was assessed as area under the receiver operating characteristic curve (AUC), using 500 repetitions of 2-fold cross-validation experiments, in which (a randomly selected) half of the data was used for training and the other half for testing. Results: A mean AUC (95% confidence interval) for DSI prediction was 0.78 (0.77–0.79) using only age as input feature. When using all available features, a mean AUC of 0.77 (0.75–0.78) was obtained. Without age, and with age-corrected features and feature selection on MRI features, a mean AUC of 0.70 (0.63–0.76) was obtained, showing the potential of other features besides age. Conclusion: The best performance in the prediction of global cognitive decline in the general population by DSI was obtained using only age as input feature. Other features showed potential, but did not improve prediction. Future studies should evaluate whether the performance could, ImPhys/Computational Imaging, Biomechanical Engineering

Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different steps of DEBM into group-aspecific and group-specific parts, where the entire dataset is used to train the group-aspecific parts and only the data from a specific group is used to train the group-specific parts of the DEBM. We performed simulation experiments to benchmark the accuracy of the proposed approaches and to select the optimal approach. Subsequently, the chosen approach was applied to the baseline data of 417 cognitively normal, 235 mild cognitively impaired who convert to AD within 3 years, and 342 AD patients from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset to gain new insights into the effect of APOE carriership on the disease progression timeline of AD. In the ε4 carrier group, the model predicted with high confidence that CSF Amyloidβ42 and the cognitive score of Alzheimer's Disease Assessment Scale (ADAS) are early biomarkers. Hippocampus was the earliest volumetric biomarker to become abnormal, closely followed by the CSF Phosphorylated Tau181 (PTAU) biomarker. In the homozygous ε3 carrier group, the model predicted a similar ordering among CSF biomarkers. However, the volume of the fusiform gyrus was identified as one of the earliest volumetric biomarker. While the findings in the ε4 carrier and the homozygous ε3 carrier groups fit the current understanding of progression of AD, the finding in the ε2 carrier group did n, ImPhys/Medical Imaging, ImPhys/Computational Imaging

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials., Pattern Recognition and Bioinformatics, ImPhys/Medical Imaging, ImPhys/Computational Imaging

Introduction: We examined the role of hemodynamic dysfunction in cognition by relating cerebral blood flow (CBF), measured with arterial spin labeling (ASL), to cognitive functioning, in patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (MRI; ie, possible vascular cognitive impairment [VCI]). Methods: We included 439 participants (124 HF; 75 COD; 127 possible VCI; 113 reference participants) from the Dutch multi-center Heart–Brain Study. We used pseudo-continuous ASL to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and four cognitive domains. Results: CBF values were lowest in COD, followed by VCI and HF, compared to reference participants. This did not explain cognitive impairment, as we did not find an association between CBF and cognitive functioning. Discussion: We found that reduced CBF is not the major explanatory factor underlying cognitive impairment in patients with hemodynamic dysfunction along the heart–brain axis., ImPhys/Medical Imaging, ImPhys/Computational Imaging

Significant prostate carcinoma (sPCa) classification based on MRI using radiomics or deep learning approaches has gained much interest, due to the potential application in assisting in clinical decision-making. Objective: To systematically review the literature (i) to determine which algorithms are most frequently used for sPCa classification, (ii) to investigate whether there exists a relation between the performance and the method or the MRI sequences used, (iii) to assess what study design factors affect the performance on sPCa classification, and (iv) to research whether performance had been evaluated in a clinical setting Methods: The databases Embase and Ovid MEDLINE were searched for studies describing machine learning or deep learning classification methods discriminating between significant and nonsignificant PCa on multiparametric MRI that performed a valid validation procedure. Quality was assessed by the modified radiomics quality score. We computed the median area under the receiver operating curve (AUC) from overall methods and the interquartile range. Results: From 2846 potentially relevant publications, 27 were included. The most frequent algorithms used in the literature for PCa classification are logistic regression (22%) and convolutional neural networks (CNNs) (22%). The median AUC was 0.79 (interquartile range: 0.77–0.87). No significant effect of number of included patients, image sequences, or reference standard on the reported performance was found. Three studies described an external validation and none of the papers described a validation in a prospective clinical trial. Conclusions: To unlock the promising potential of machine and deep learning approaches, validation studies and clinical prospective studies should be performed with an established protocol to assess the added value in decision-making., ImPhys/Medical Imaging, ImPhys/Computational Imaging