Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). METHODS: The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. ETHICS AND DISSEMINATION: The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.

Harmonisation of German Health Care Data Using the OMOP Common Data Model - A Practice Report.

Data harmonization is an important step in large-scale data analysis and for generating evidence on real world data in healthcare. With the OMOP common data model, a relevant instrument for data harmonization is available that is being promoted by different networks and communities. At the Hannover Medical School (MHH) in Germany, an Enterprise Clinical Research Data Warehouse (ECRDW) is established and harmonization of that data source is the focus of this work. We present MHH's first implementation of the OMOP common data model on top of the ECRDW data source and demonstrate the challenges concerning the mapping of German healthcare terminologies to a standardized format.

Research Data Management and Data Sharing for Reproducible Research-Results of a Community Survey of the German National Research Data Infrastructure Initiative Neuroscience.

Science is changing: the volume and complexity of data are increasing, the number of studies is growing and the goal of achieving reproducible results requires new solutions for scientific data management. In the field of neuroscience, the German National Research Data Infrastructure (NFDI-Neuro) initiative aims to develop sustainable solutions for research data management (RDM). To obtain an understanding of the present RDM situation in the neuroscience community, NFDI-Neuro conducted a comprehensive survey among the neuroscience community. Here, we report and analyze the results of the survey. We focused the survey and our analysis on current needs, challenges, and opinions about RDM. The German neuroscience community perceives barriers with respect to RDM and data sharing mainly linked to (1) lack of data and metadata standards, (2) lack of community adopted provenance tracking methods, (3) lack of secure and privacy preserving research infrastructure for sensitive data, (4) lack of RDM literacy, and (5) lack of resources (time, personnel, money) for proper RDM. However, an overwhelming majority of community members (91%) indicated that they would be willing to share their data with other researchers and are interested to increase their RDM skills. Taking advantage of this willingness and overcoming the existing barriers requires the systematic development of standards, tools, and infrastructure, the provision of training, education, and support, as well as additional resources for RDM to the research community and a constant dialogue with relevant stakeholders including policy makers to leverage of a culture change through adapted incentivization and regulation.

Visual Assistance in Development and Validation of Bayesian Networks for Clinical Decision Support.

The development and validation of Clinical Decision Support Models (CDSM) based on Bayesian networks (BN) is commonly done in a collaborative work between medical researchers providing the domain expertise and computer scientists developing the decision support model. Although modern tools provide facilities for data-driven model generation, domain experts are required to validate the accuracy of the learned model and to provide expert knowledge for fine-tuning it while computer scientists are needed to integrate this knowledge in the learned model (hybrid modeling approach). This generally time-expensive procedure hampers CDSM generation and updating. To address this problem, we developed a novel interactive visual approach allowing medical researchers with less knowledge in CDSM to develop and validate BNs based on domain specific data mainly independently and thus, diminishing the need for an additional computer scientist. In this context, we abstracted and simplified the common workflow in BN development as well as adjusted the workflow to medical experts' needs. We demonstrate our visual approach with data of endometrial cancer patients and evaluated it with six medical researchers who are domain experts in the gynecological field.

StRegA: Unsupervised anomaly detection in brain MRIs using a compact context-encoding variational autoencoder.

Expert interpretation of anatomical images of the human brain is the central part of neuroradiology. Several machine learning-based techniques have been proposed to assist in the analysis process. However, the ML models typically need to be trained to perform a specific task, e.g., brain tumour segmentation or classification. Not only do the corresponding training data require laborious manual annotations, but a wide variety of abnormalities can be present in a human brain MRI - even more than one simultaneously, which renders a representation of all possible anomalies very challenging. Hence, a possible solution is an unsupervised anomaly detection (UAD) system that can learn a data distribution from an unlabelled dataset of healthy subjects and then be applied to detect out-of-distribution samples. Such a technique can then be used to detect anomalies - lesions or abnormalities, for example, brain tumours, without explicitly training the model for that specific pathology. Several Variational Autoencoder (VAE) based techniques have been proposed in the past for this task. Even though they perform very well on controlled artificially simulated anomalies, many of them perform poorly while detecting anomalies in clinical data. This research proposes a compact version of the "context-encoding" VAE (ceVAE) model, combined with pre and post-processing steps, creating a UAD pipeline (StRegA), which is more robust on clinical data and shows its applicability in detecting anomalies such as tumours in brain MRIs. The proposed pipeline achieved a Dice score of 0.642 ± 0.101 while detecting tumours in T2w images of the BraTS dataset and 0.859 ± 0.112 while detecting artificially induced anomalies, while the best performing baseline achieved 0.522 ± 0.135 and 0.783 ± 0.111, respectively.

Quantitative evaluation of prospective motion correction in healthy subjects at 7T MRI.

PURPOSE: Quantitative assessment of prospective motion correction (PMC) capability at 7T MRI for compliant healthy subjects to improve high-resolution images in the absence of intentional motion. METHODS: Twenty-one healthy subjects were imaged at 7 T. They were asked not to move, to consider only unintentional motion. An in-bore optical tracking system was used to monitor head motion and consequently update the imaging volume. For all subjects, high-resolution T1 (3D-MPRAGE), T2 (2D turbo spin echo), proton density (2D turbo spin echo), and T2∗ (2D gradient echo) weighted images were acquired with and without PMC. The images were evaluated through subjective and objective analysis. RESULTS: Subjective evaluation overall has shown a statistically significant improvement (5.5%) in terms of image quality with PMC ON. In a separate evaluation of every contrast, three of the four contrasts (T1 , T2 , and proton density) have shown a statistically significant improvement (9.62%, 9.85%, and 9.26%), whereas the fourth one ( T2∗ ) has shown improvement, although not statistically significant. In the evaluation with objective metrics, average edge strength has shown an overall improvement of 6% with PMC ON, which was statistically significant; and gradient entropy has shown an overall improvement of 2%, which did not reach statistical significance. CONCLUSION: Based on subjective assessment, PMC improved image quality in high-resolution images of healthy compliant subjects in the absence of intentional motion for all contrasts except T2∗ , in which no significant differences were observed. Quantitative metrics showed an overall trend for an improvement with PMC, but not all differences were significant.

Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson's disease using neuromelanin-sensitive MRI.

PURPOSE: Development and performance measurement of a fully automated pipeline that localizes and segments the locus coeruleus in so-called neuromelanin-sensitive magnetic resonance imaging data for the derivation of quantitative biomarkers of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. METHODS: We propose a pipeline composed of several 3D-Unet-based convolutional neural networks for iterative multi-scale localization and multi-rater segmentation and non-deep learning-based components for automated biomarker extraction. We trained on the healthy aging cohort and did not carry out any adaption or fine-tuning prior to the application to Parkinson's disease subjects. RESULTS: The localization and segmentation pipeline demonstrated sufficient performance as measured by Euclidean distance (on average around 1.3mm on healthy aging subjects and 2.2mm in Parkinson's disease subjects) and Dice similarity coefficient (overall around [Formula: see text] on healthy aging subjects and [Formula: see text] for subjects with Parkinson's disease) as well as promising agreement with respect to contrast ratios in terms of intraclass correlation coefficient of [Formula: see text] for healthy aging subjects compared to a manual segmentation procedure. Lower values ([Formula: see text]) for Parkinson's disease subjects indicate the need for further investigation and tests before the application to clinical samples. CONCLUSION: These promising results suggest the usability of the proposed algorithm for data of healthy aging subjects and pave the way for further investigations using this approach on different clinical datasets to validate its practical usability more conclusively.

Comprehensive ultrahigh resolution whole brain in vivo MRI dataset as a human phantom.

Here, we present an extension to our previously published structural ultrahigh resolution T1-weighted magnetic resonance imaging (MRI) dataset with an isotropic resolution of 250 µm, consisting of multiple additional ultrahigh resolution contrasts. Included are up to 150 µm Time-of-Flight angiography, an updated 250 µm structural T1-weighted reconstruction, 330 µm quantitative susceptibility mapping, up to 450 µm structural T2-weighted imaging, 700 µm T1-weighted back-to-back scans, 800 µm diffusion tensor imaging, one hour continuous resting-state functional MRI with an isotropic spatial resolution of 1.8 mm as well as more than 120 other structural T1-weighted volumes together with multiple corresponding proton density weighted acquisitions collected over ten years. All data are from the same participant and were acquired on the same 7 T scanner. The repository contains the unprocessed data as well as (pre-)processing results. The data were acquired in multiple studies with individual goals. This is a unique and comprehensive collection comprising a "human phantom" dataset. Therefore, we compiled, processed, and structured the data, making them publicly available for further investigation.

Integrated Dual Analysis of Quantitative and Qualitative High-Dimensional Data.

The Dual Analysis framework is a powerful enabling technology for the exploration of high dimensional quantitative data by treating data dimensions as first-class objects that can be explored in tandem with data values. In this article, we extend the Dual Analysis framework through the joint treatment of quantitative (numerical) and qualitative (categorical) dimensions. Computing common measures for all dimensions allows us to visualize both quantitative and qualitative dimensions in the same view. This enables a natural joint treatment of mixed data during interactive visual exploration and analysis. Several measures of variation for nominal qualitative data can also be applied to ordinal qualitative and quantitative data. For example, instead of measuring variability from a mean or median, other measures assess inter-data variation or average variation from a mode. In this work, we demonstrate how these measures can be integrated into the Dual Analysis framework to explore and generate hypotheses about high-dimensional mixed data. A medical case study using clinical routine data of patients suffering from Cerebral Small Vessel Disease (CSVD), conducted with a senior neurologist and a medical student, shows that a joint Dual Analysis approach for quantitative and qualitative data can rapidly lead to new insights based on which new hypotheses may be generated.

DimLift: Interactive Hierarchical Data Exploration Through Dimensional Bundling.

The identification of interesting patterns and relationships is essential to exploratory data analysis. This becomes increasingly difficult in high dimensional datasets. While dimensionality reduction techniques can be utilized to reduce the analysis space, these may unintentionally bury key dimensions within a larger grouping and obfuscate meaningful patterns. With this work we introduce DimLift, a novel visual analysis method for creating and interacting with dimensional bundles. Generated through an iterative dimensionality reduction or user-driven approach, dimensional bundles are expressive groups of dimensions that contribute similarly to the variance of a dataset. Interactive exploration and reconstruction methods via a layered parallel coordinates plot allow users to lift interesting and subtle relationships to the surface, even in complex scenarios of missing and mixed data types. We exemplify the power of this technique in an expert case study on clinical cohort data alongside two additional case examples from nutrition and ecology.

Obtaining Patient-Reported Outcomes Electronically With "OncoFunction" in Head and Neck Cancer Patients During Aftercare.

The disease and treatment of patients with head and neck cancer can lead to multiple late and long-term sequelae. Especially pain, psychosocial problems, and voice issues can have a high impact on patients' health-related quality of life. The aim was to show the feasibility of implementing an electronic Patient-Reported Outcome Measure (PROM) in patients with head and neck cancer (HNC). Driven by our department's intention to assess Patient-Reported Outcomes (PRO) based on the International Classification of Functioning during tumor aftercare, the program "OncoFunction" has been implemented and continuously refined in everyday practice. The new version of "OncoFunction" was evaluated by 20 head and neck surgeons and radiation oncologists in an interview. From 7/2013 until 7/2017, 846 patients completed the PROM during 2,833 of 3,610 total visits (78.5%). The latest software version implemented newly developed add-ins and increased the already high approval ratings in the evaluation as the number of errors and the time required decreased (6 vs. 0 errors, 1.35 vs. 0.95 min; p<0.01). Notably, patients had different requests using PRO in homecare use. An additional examination shows that only 59% of HNC patients use the world wide web. Using OncoFunction for online-recording and interpretation of PROM improved data acquisition in daily HNC patients' follow-up. An accessory timeline grants access to former consultations and their visualization supported and simplified structured examinations. This provides an easy-to-use representation of the patient's functional outcome supporting comprehensive aftercare, considering all aspects of the patient's life.

Modeling and processing up-to-dateness of patient information in probabilistic therapy decision support.

OBJECTIVES: Probabilistic modeling of a patient's situation with the goal of providing calculated therapy recommendations can improve the decision making of interdisciplinary teams. Relevant information entities and direct causal dependencies, as well as uncertainty, must be formally described. Possible therapy options, tailored to the patient, can be inferred from the clinical data using these descriptions. However, there are several avoidable factors of uncertainty influencing the accuracy of the inference. For instance, inaccuracy may emerge from outdated information. In general, probabilistic models, e.g. Bayesian Networks can depict the causality and relations of individual information entities, but in general cannot evaluate individual entities concerning their up-to-dateness. The goal of the work at hand is to model diagnostic up-to-dateness, which can reasonably adjust the influence of outdated diagnostic information to improve the inference results of clinical decision models. METHODS AND MATERIALS: We analyzed 68 laryngeal cancer cases and modeled the state of up-to-dateness of different diagnostic modalities. All cases were used for cross-validation. 55 cases were used to train the model, 13 for testing. Each diagnostic procedure involved in the decision making process of these cases was associated with a specific threshold for the time the information is considered up-to-date, i.e. reliable. Based on this threshold, outdated findings could be identified and their impact on probabilistic calculations could be reduced. We applied the model for reducing the weight of outdated patient data in the computation of TNM stagings for the 13 test cases and compared the results to the manually derived TNM stagings in the patient files. RESULTS: With the implementation of these weights in the laryngeal cancer model, we increased the accuracy of the TNM calculation from 0.61 (8 out of 13 cases correct) to 0.76 (10 out of 13 cases correct). CONCLUSION: Decision delay may cause specific patient data to be outdated. This can cause contradictory or false information and impair calculations for clinical decision support. Our approach demonstrates that the accuracy of Bayesian Network models can be improved when pre-processing the patient-specific data and evaluating their up-to-dateness with reduced weights on outdated information.

Hippocampal vascularization patterns: A high-resolution 7 Tesla time-of-flight magnetic resonance angiography study.

Considerable evidence suggests a close relationship between vascular and degenerative pathology in the human hippocampus. Due to the intrinsic fragility of its vascular network, the hippocampus appears less able to cope with hypoperfusion and anoxia than other cortical areas. Although hippocampal blood supply is generally provided by the collateral branches of the posterior cerebral artery (PCA) and the anterior choroidal artery (AChA), different vascularization patterns have been detected postmortem. To date, a methodology that enables the classification of individual hippocampal vascularization patterns in vivo has not been established. In this study, using high-resolution 7 Tesla time-of-flight angiography data (0.3 mm isotropic resolution) in young adults, we classified individual variability in hippocampal vascularization patterns involved in medial temporal lobe blood supply in vivo. A strong concordance between our classification and previous autopsy findings was found, along with interesting anatomical observations, such as the variable contribution of the AChA to hippocampal supply, the relationships between hippocampal and PCA patterns, and the different distribution patterns of the right and left hemispheres. The approach presented here for determining hippocampal vascularization patterns in vivo may provide new insights into not only the vulnerability of the hippocampus to vascular and neurodegenerative diseases but also hippocampal vascular plasticity after exercise training.

Classification of Blood Flow Patterns in Cerebral Aneurysms.

We present a Cerebral Aneurysm Vortex Classification (CAVOCLA) that allows to classify blood flow in cerebral aneurysms. Medical studies assume a strong relation between the progression and rupture of aneurysms and flow patterns. To understand how flow patterns impact the vessel morphology, they are manually classified according to predefined classes. However, manual classifications are time-consuming and exhibit a high inter-observer variability. In contrast, our approach is more objective and faster than manual methods. The classification of integral lines, representing steady or unsteady blood flow, is based on a mapping of the aneurysm surface to a hemisphere by calculating polar-based coordinates. The lines are clustered and for each cluster a representative is calculated. Then, the polar-based coordinates are transformed to the representative as basis for the classification. Classes are based on the flow complexity. The classification results are presented by a detail-on-demand approach using a visual transition from the representative over an enclosing surface to the associated lines. Based on seven representative datasets, we conduct an informal interview with five domain experts to evaluate the system. They confirmed that CAVOCLA allows for a robust classification of intra-aneurysmal flow patterns. The detail-on-demand visualization enables an efficient exploration and interpretation of flow patterns.

Modular Architecture for Integrated Model-Based Decision Support.

Model-based decision support systems promise to be a valuable addition to oncological treatments and the implementation of personalized therapies. For the integration and sharing of decision models, the involved systems must be able to communicate with each other. In this paper, we propose a modularized architecture of dedicated systems for the integration of probabilistic decision models into existing hospital environments. These systems interconnect via web services and provide model sharing and processing capabilities for clinical information systems. Along the lines of IHE integration profiles from other disciplines and the meaningful reuse of routinely recorded patient data, our approach aims for the seamless integration of decision models into hospital infrastructure and the physicians' daily work.

Information architecture for a patient-specific dashboard in head and neck tumor boards.

PURPOSE: Overcoming the flaws of current data management conditions in head and neck oncology could enable integrated information systems specifically tailored to the needs of medical experts in a tumor board meeting. Clinical dashboards are a promising method to assist various aspects of the decision-making process in such cognitively demanding scenarios. However, in order to provide extensive and intuitive assistance to the participating physicians, the design and development of such a system have to be user-centric. To accomplish this task, conceptual methods need to be performed prior to the technical development and integration stages. METHODS: We have conducted a qualitative survey including eight clinical experts with different levels of expertise in the field of head and neck oncology. According to the principles of information architecture, the survey focused on the identification and causal interconnection of necessary metrics for information assessment in the tumor board. RESULTS: Based on the feedback by the clinical experts, we have constructed a detailed map of the required information items for a tumor board dashboard in head and neck oncology. Furthermore, we have identified three distinct groups of metrics (patient, disease and therapy metrics) as well as specific recommendations for their structural and graphical implementation. CONCLUSION: By using the information architecture, we were able to gather valuable feedback about the requirements and cognitive processes of the tumor board members. Those insights have helped us to develop a dashboard application that closely adapts to the specified needs and characteristics, and thus is primarily user-centric.

Considering Information Up-to-Dateness to Increase the Accuracy of Therapy Decision Support Systems.

During the diagnostic process a lot of information is generated. All this information is assessed when making a final diagnosis and planning the therapy. While some patient information is stable, e.g., gender, others may become outdated, e.g., tumor size derived from CT data. Quantifying this information up-to-dateness and deriving consequences are difficult. Especially for the implementation in clinical decision support systems, this has not been studied. When information entities tend to become outdated, in practice, clinicians intuitively reduce their impact when making decisions. Therefore, in a system's calculations their impact should be reduced as well. We propose a method of decreasing the certainty of information entities based on their up-to-dateness. The method is tested in a decision support system for TNM staging based on Bayesian networks. We compared the actual N-state in records of 39 patients to the N-state calculated with and without decreasing data certainty. The results under decreased certainty correlated better with the actual states (r=0.958, p=0.008). We conclude that the up-to-dateness must be considered when processing clinical information to enhance decision making and ensure more patient safety.

A functional imaging study of germinating oilseed rape seed.

Germination, the process whereby a dry, quiescent seed springs to life, has been a focus of plant biologist for many years, yet the early events following water uptake, during which metabolism of the embryo is restarted, remain enigmatic. Here, the nature of the cues required for this restarting in oilseed rape (Brassica napus) seed has been investigated. A holistic in vivo approach was designed to display the link between the entry and allocation of water, metabolic events and structural changes occurring during germination. For this, we combined functional magnetic resonance imaging with Fourier transform infrared microscopy, fluorescence-based respiration mapping, computer-aided seed modeling and biochemical tools. We uncovered an endospermal lipid gap, which channels water to the radicle tip, from whence it is distributed via embryonic vasculature toward cotyledon tissues. The resumption of respiration is initiated first in the endosperm, only later spreading to the embryo. Sugar metabolism and lipid utilization are linked to the spatiotemporal sequence of tissue rehydration. Together, this imaging study provides insights into the spatial aspects of key events in oilseed rape seeds leading to germination. It demonstrates how seed architecture predetermines the pattern of water intake, which sets the stage for the orchestrated restart of life.

Towards the Consideration of Diagnostic Delay in Model-Based Clinical Decision Support.

Diagnostic delay involves the peril of information becoming outdated. It is a challenging task to quantify the up-to-dateness of clinical information and the consequences of diagnostic delay with the goal of considering them in clinical decision support. We propose an approach to integrating the up-to-dateness of clinical information in a model-based therapy decision support system.

A Guide for Constructing Bayesian Network Graphs of Cancer Treatment Decisions.

In complex cancer cases, Bayesian networks can support clinical experts in finding the best patient-specific therapeutic decisions. However, the development of decision networks requires teamwork of at least one domain expert and one knowledge engineer making the process expensive, time-consuming, and prone to misunderstandings. We present a novel method for guided modeling. This method enables domain experts to model collaboratively without the need of knowledge engineers, increasing both the development speed and model quality.