The de novo FAIRification process of a registry for vascular anomalies.

BACKGROUND: Patient data registries that are FAIR-Findable, Accessible, Interoperable, and Reusable for humans and computers-facilitate research across multiple resources. This is particularly relevant to rare diseases, where data often are scarce and scattered. Specific research questions can be asked across FAIR rare disease registries and other FAIR resources without physically combining the data. Further, FAIR implies well-defined, transparent access conditions, which supports making sensitive data as open as possible and as closed as necessary. RESULTS: We successfully developed and implemented a process of making a rare disease registry for vascular anomalies FAIR from its conception-de novo. Here, we describe the five phases of this process in detail: (i) pre-FAIRification, (ii) facilitating FAIRification, (iii) data collection, (iv) generating FAIR data in real-time, and (v) using FAIR data. This includes the creation of an electronic case report form and a semantic data model of the elements to be collected (in this case: the "Set of Common Data Elements for Rare Disease Registration" released by the European Commission), and the technical implementation of automatic, real-time data FAIRification in an Electronic Data Capture system. Further, we describe how we contribute to the four facets of FAIR, and how our FAIRification process can be reused by other registries. CONCLUSIONS: In conclusion, a detailed de novo FAIRification process of a registry for vascular anomalies is described. To a large extent, the process may be reused by other rare disease registries, and we envision this work to be a substantial contribution to an ecosystem of FAIR rare disease resources.

De-novo FAIRification via an Electronic Data Capture system by automated transformation of filled electronic Case Report Forms into machine-readable data.

INTRODUCTION: Existing methods to make data Findable, Accessible, Interoperable, and Reusable (FAIR) are usually carried out in a post hoc manner: after the research project is conducted and data are collected. De-novo FAIRification, on the other hand, incorporates the FAIRification steps in the process of a research project. In medical research, data is often collected and stored via electronic Case Report Forms (eCRFs) in Electronic Data Capture (EDC) systems. By implementing a de novo FAIRification process in such a system, the reusability and, thus, scalability of FAIRification across research projects can be greatly improved. In this study, we developed and implemented a novel method for de novo FAIRification via an EDC system. We evaluated our method by applying it to the Registry of Vascular Anomalies (VASCA). METHODS: Our EDC and research project independent method ensures that eCRF data entered into an EDC system can be transformed into machine-readable, FAIR data using a semantic data model (a canonical representation of the data, based on ontology concepts and semantic web standards) and mappings from the model to questions on the eCRF. The FAIRified data are stored in a triple store and can, together with associated metadata, be accessed and queried through a FAIR Data Point. The method was implemented in Castor EDC, an EDC system, through a data transformation application. The FAIRness of the output of the method, the FAIRified data and metadata, was evaluated using the FAIR Evaluation Services. RESULTS: We successfully applied our FAIRification method to the VASCA registry. Data entered on eCRFs is automatically transformed into machine-readable data and can be accessed and queried using SPARQL queries in the FAIR Data Point. Twenty-one FAIR Evaluator tests pass and one test regarding the metadata persistence policy fails, since this policy is not in place yet. CONCLUSION: In this study, we developed a novel method for de novo FAIRification via an EDC system. Its application in the VASCA registry and the automated FAIR evaluation show that the method can be used to make clinical research data FAIR when they are entered in an eCRF without any intervention from data management and data entry personnel. Due to the generic approach and developed tooling, we believe that our method can be used in other registries and clinical trials as well.

Case-specific non-linear finite element models to predict failure behavior in two functional spinal units.

Current finite element (FE) models predicting failure behavior comprise single vertebrae, thereby neglecting the role of the posterior elements and intervertebral discs. Therefore, this study aimed to develop a more clinically relevant, case-specific non-linear FE model of two functional spinal units able to predict failure behavior in terms of (i) the vertebra predicted to fail; (ii) deformation of the specimens; (iii) stiffness; and (iv) load to failure. For this purpose, we also studied the effect of different bone density-mechanical properties relationships (material models) on the prediction of failure behavior. Twelve two functional spinal units (T6-T8, T9-T11, T12-L2, and L3-L5) with and without artificial metastases were destructively tested in axial compression. These experiments were simulated using CT-based case-specific non-linear FE models. Bone mechanical properties were assigned using four commonly used material models. In 10 of the 11 specimens our FE model was able to correctly indicate which vertebrae failed during the experiments. However, predictions of the three-dimensional deformations of the specimens were less promising. Whereas stiffness of the whole construct could be strongly predicted (R2 = 0.637-0.688, p < 0.01), we obtained weak correlations between FE predicted and experimentally determined load to failure, as defined by the total reaction force exhibiting a drop in force (R2 = 0.219-0.247, p > 0.05). Additionally, we found that the correlation between predicted and experimental fracture loads did not strongly depend on the material model implemented, but the stiffness predictions did. In conclusion, this work showed that, in its current state, our FE models may be used to identify the weakest vertebra, but that substantial improvements are required in order to quantify in vivo failure loads. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodical, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:3208-3218, 2018.

The Dutch national guideline on metastases and hematological malignancies localized within the spine; a multidisciplinary collaboration towards timely and proactive management.

Here, we describe the development of a Dutch national guideline on metastases and hematological malignancies localized within the spine. The aim was to create a comprehensive guideline focusing on proactive management of these diseases, enabling healthcare professionals to weigh patient perspectives, life expectancy, and expected outcomes to make informed treatment recommendations. A national multidisciplinary panel consisting of clinicians, a nurse, a patient advocate, an epidemiologist, and a methodologist drafted the guideline. The important role of patients in the realization of the guideline enabled us to identify and address perceived shortcomings in patient care. The guideline covers not only metastatic epidural spinal cord compression, but also the treatment of uncomplicated metastases and hematological malignancies localized within the spine. The guideline is applicable in daily practice and provides an up-to-date and concise overview of the diagnostic and treatment possibilities for patients suffering from a disease that can have a serious impact on their quality of life. Suggestions for the practical implementation of patient care in hospitals are also provided, including approaches for pursuing proactive management. The crucial role of the patient in decision making is emphasized in this guideline.

Inducing targeted failure in cadaveric testing of 3-segment spinal units with and without simulated metastases.

We propose an experimental setup and protocol able to induce targeted failure of the middle vertebra in 3-segment spinal units and to capture the specimens' deformation in their post-failure state. Sixteen 3-segment spinal units with and without artificial metastases were destructively tested in axial compression using one of two failure criteria; either: (A) A clear drop in force (>10-15% of peak force) (n = 4); or (B) A minimum displacement of 5 mm (n = 12). Subsequently, the specimens were fully fixated in polymethylmethacrylate (PMMA), thereby preserving their post-failure state. Pre- and post-experiment computed tomography (CT) scans were acquired to determine the occurrence of failure in one of the vertebral bodies. All specimens were successfully fixated in their post-failure state. When applying failure criterion A, two specimens showed signs of failure. When applying failure criterion B, all specimens showed signs of failure; in 9 out of 12 specimens this occurred in the middle vertebrae only. In conclusion, this research provides an experimental setup and protocol able to induce targeted failure of 3-segment spinal units and to capture the specimens' deformation in their post-failure state. Furthermore, this study illustrates the importance of an adequate failure criterion for successful simulation of vertebral fractures in an experimental setup.

Twente spine model: A complete and coherent dataset for musculo-skeletal modeling of the thoracic and cervical regions of the human spine.

Musculo-skeletal modeling could play a key role in advancing our understanding of the healthy and pathological spine, but the credibility of such models are strictly dependent on the accuracy of the anatomical data incorporated. In this study, we present a complete and coherent musculo-skeletal dataset for the thoracic and cervical regions of the human spine, obtained through detailed dissection of an embalmed male cadaver. We divided the muscles into a number of muscle-tendon elements, digitized their attachments at the bones, and measured morphological muscle parameters. In total, 225 muscle elements were measured over 39 muscles. For every muscle element, we provide the coordinates of its attachments, fiber length, tendon length, sarcomere length, optimal fiber length, pennation angle, mass, and physiological cross-sectional area together with the skeletal geometry of the cadaver. Results were consistent with similar anatomical studies. Furthermore, we report new data for several muscles such as rotatores, multifidus, levatores costarum, spinalis, semispinalis, subcostales, transversus thoracis, and intercostales muscles. This dataset complements our previous study where we presented a consistent dataset for the lumbar region of the spine (Bayoglu et al., 2017). Therefore, when used together, these datasets enable a complete and coherent dataset for the entire spine. The complete dataset will be used to develop a musculo-skeletal model for the entire human spine to study clinical and ergonomic applications.

Twente spine model: A complete and coherent dataset for musculo-skeletal modeling of the lumbar region of the human spine.

Musculo-skeletal modeling can greatly help in understanding normal and pathological functioning of the spine. For such models to produce reliable muscle and joint force estimations, an adequate set of musculo-skeletal data is necessary. In this study, we present a complete and coherent dataset for the lumbar spine, based on medical images and dissection measurements from one embalmed human cadaver. We divided muscles into muscle-tendon elements, digitized their attachments at the bones and measured morphological parameters. In total, we measured 11 muscles from one body side, using 96 elements. For every muscle element, we measured three-dimensional coordinates of its attachments, fiber length, tendon length, sarcomere length, optimal fiber length, pennation angle, mass, and physiological cross-sectional area together with the geometry of the lumbar spine. Results were consistent with other anatomical studies and included new data for the serratus posterior inferior muscle. The dataset presented in this paper enables a complete and coherent musculo-skeletal model for the lumbar spine and will improve the current state-of-the art in predicting spinal loading.

The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review.

PURPOSE: The role of radiotherapy in stabilizing metastatic bones is unclear. This systematic review assessed the effects of (1) radiotherapy, (2) radiotherapy combined with bisphosphonates, and (3) radiotherapy combined with RANK ligand (RANKL) inhibitors on bone quality and bone strength in bone metastases originating from solid tumors. METHODS: Pubmed, EMBASE and the Cochrane Library were searched. Any type of study design and type and dose of radiotherapy, bisphosphonates and RANKL inhibitors were allowed. RESULTS: 39 articles were identified. Animal studies showed that radiotherapy had similar effects on bone quality and strength as receiving no treatment, whereas adding bisphosphonates to radiotherapy restored bone quality and strength. In patient studies, bone density increased after radiotherapy and radiotherapy combined with bisphosphonates. However, due to the often non-optimal study design and study quality, it was unclear whether this increase could be attributed to these treatments. There was insufficient evidence to assess the additional effect of bisphosphonates or RANKL inhibitors. CONCLUSION: Despite the clinical experience that radiotherapy is an effective treatment for bone metastases, there was no sufficient evidence for a positive effect on bone quality and fracture risk. Animal studies showed that adding bisphosphonates to radiotherapy restored bone quality and strength, whereas this was not proven in patients. There were no studies addressing the adjunct effect of RANKL inhibitors to radiotherapy. Although associated with several methodological, practical and ethical challenges, randomized controlled trials are needed.