Jeb Palmer

The NeuroGrid stroke exemplar clinical trial protocol

Rationale Trials of new treatments for neurological disorders like stroke require imaging as part of the patient assessment, but need to be large enough to obtain reliable results if treatment effects are likely to be modest. However, multicentre trials use many different scanners in different hospitals and present complex problems for image data collection, interpretation and analysis and long-term secure archiving. Aims NeuroGrid aims to develop and test grid technologies for collecting, analysing and interpreting, and secure archiving of neuroimaging data for large multicentre trials in common neurological and psychiatric disorders. Design A 3-year multicentre consortium of clinicians, neuroimaging centres and e-scientists are designing a Grid storage network, mechanisms for uploading, curating and retrieving image and metadata, combining image data from different scanners and an analysis tool box. Three clinical exemplars – stroke, dementia and psychosis – provide the data and ‘real-world’ clinical trial applications, and a set of specific and typical problems encountered with image data in multicentre trials for NeuroGrid to address. The stroke exemplar is using image data from two multicentre stroke trials: Third International Stroke Trial and Efficacy of Nitric Oxide in Stroke. Outcomes The final product is intended to appear as an integrated capability consisting of services, both database and analyses, accessed through simple portals. These will include image submission, automated scan quality control, appropriate metadata linkage, streamlined image review and coding tools and long-term secure storage for future multicentre stroke trials.

The Challenges of Developing a Collaborative Data and Compute Grid for Neurosciences

The three-year UK NeuroGrid project aims to develop a grid-based collaborative research environment to support the data and compute needs for a UK Neurosciences community. This paper describes the challenges in developing this architecture and details initial results from the development of its first prototype to support psychosis, dementia and stroke research and the social challenges of such a collaborative research project. The paper discusses approaches being taken to explore the collaborative science process to inform the requirements for follow on prototypes and methods utilized to develop an effective project team

Arterial Obstruction on Computed Tomographic or Magnetic Resonance Angiography and Response to Intravenous Thrombolytics in Ischemic Stroke

Background and Purpose— Computed tomographic angiography and magnetic resonance angiography are used increasingly to assess arterial patency in patients with ischemic stroke. We determined which baseline angiography features predict response to intravenous thrombolytics in ischemic stroke using randomized controlled trial data. Methods— We analyzed angiograms from the IST-3 (Third International Stroke Trial), an international, multicenter, prospective, randomized controlled trial of intravenous alteplase. Readers, masked to clinical, treatment, and outcome data, assessed prerandomization computed tomographic angiography and magnetic resonance angiography for presence, extent, location, and completeness of obstruction and collaterals. We compared angiography findings to 6-month functional outcome (Oxford Handicap Scale) and tested for interactions with alteplase, using ordinal regression in adjusted analyses. We also meta-analyzed all available angiography data from other randomized controlled trials of intravenous thrombolytics. Results— In IST-3, 300 patients had prerandomization angiography (computed tomographic angiography=271 and magnetic resonance angiography=29). On multivariable analysis, more extensive angiographic obstruction and poor collaterals independently predicted poor outcome (P<0.01). We identified no significant interaction between angiography findings and alteplase effect on Oxford Handicap Scale (P≥0.075) in IST-3. In meta-analysis (5 trials of alteplase or desmoteplase, including IST-3, n=591), there was a significantly increased benefit of thrombolytics on outcome (odds ratio>1 indicates benefit) in patients with (odds ratio, 2.07; 95% confidence interval, 1.18–3.64; P=0.011) versus without (odds ratio, 0.88; 95% confidence interval, 0.58–1.35; P=0.566) arterial obstruction (P for interaction 0.017). Conclusions— Intravenous thrombolytics provide benefit to stroke patients with computed tomographic angiography or magnetic resonance angiography evidence of arterial obstruction, but the sample was underpowered to demonstrate significant treatment benefit or harm among patients with apparently patent arteries. Clinical Trial Registration— URL: http://www.isrctn.com. Unique identifier: ISRCTN25765518.

Arterial obstruction on CT or MR angiography and response to intravenous thrombolytics in ischemic stroke

Background and Purpose— Computed tomographic angiography and magnetic resonance angiography are used increasingly to assess arterial patency in patients with ischemic stroke. We determined which baseline angiography features predict response to intravenous thrombolytics in ischemic stroke using randomized controlled trial data. Methods— We analyzed angiograms from the IST-3 (Third International Stroke Trial), an international, multicenter, prospective, randomized controlled trial of intravenous alteplase. Readers, masked to clinical, treatment, and outcome data, assessed prerandomization computed tomographic angiography and magnetic resonance angiography for presence, extent, location, and completeness of obstruction and collaterals. We compared angiography findings to 6-month functional outcome (Oxford Handicap Scale) and tested for interactions with alteplase, using ordinal regression in adjusted analyses. We also meta-analyzed all available angiography data from other randomized controlled trials of intravenous thrombolytics. Results— In IST-3, 300 patients had prerandomization angiography (computed tomographic angiography=271 and magnetic resonance angiography=29). On multivariable analysis, more extensive angiographic obstruction and poor collaterals independently predicted poor outcome (P<0.01). We identified no significant interaction between angiography findings and alteplase effect on Oxford Handicap Scale (P≥0.075) in IST-3. In meta-analysis (5 trials of alteplase or desmoteplase, including IST-3, n=591), there was a significantly increased benefit of thrombolytics on outcome (odds ratio>1 indicates benefit) in patients with (odds ratio, 2.07; 95% confidence interval, 1.18–3.64; P=0.011) versus without (odds ratio, 0.88; 95% confidence interval, 0.58–1.35; P=0.566) arterial obstruction (P for interaction 0.017). Conclusions— Intravenous thrombolytics provide benefit to stroke patients with computed tomographic angiography or magnetic resonance angiography evidence of arterial obstruction, but the sample was underpowered to demonstrate significant treatment benefit or harm among patients with apparently patent arteries. Clinical Trial Registration— URL: http://www.isrctn.com. Unique identifier: ISRCTN25765518.

Developing an Integrated Image Bank and Metadata for Large-scale Research in Cerebrovascular Disease: Our Experience from the Stroke Image Bank Project

A framework for building an infrastructure that semantically integrates, archives and reuses data for various research purposes in human brain imaging remains critical. In particular, problems of aligning technical, clinical and professional systems in order to facilitate data sharing are a recurring issue in brain imaging. However, large samples of well characterised images with detailed metadata are increasingly needed. This paper outlines the experience of the NeuroGrid Stroke Exemplar and further work in the Brain Research Imaging Centre and Stroke Trials Unit in developing an infrastructure that facilitates the linkage, archiving and reuse of imaging data from stroke patients for large scale clinical and epidemiological studies. We examined data from 12 past stroke projects carried out over the past two decades in our centre and two large trials with 329 centres. We assessed previously published schemas and those developed specifically for large multicentre ischaemic and haemorrhagic stroke treatment trials. We then developed our own harmonised and integrated schema and database with a web-based interface system, aiming to be flexible and adaptable to future trials and observational studies. We then linked image and meta-data from 3079 patients acquired in stroke research in one centre in a 14 year period (1996 – 2010) with prospective central hospital health statistics to obtain long term follow-up. Our integrated database includes 3079 subjects and over 550 federated and searchable data items including imaging details, medical history and examination, stroke and laboratory details, which maps to large multicentre stroke trials with imaging data from over 10,000 patients from 30 countries. The central linkage identified 879 of 3079 patients had died, 525 had recurrent strokes and 291 developed dementia during up to a 19 year period (range=0 -19; median=9.04; IQR=12.17) of follow-up, demonstrating its utility. The core metadata schema, has benefited from extensive development in large clinical trials. Further trials’ data can now be added. It provides an opportunity to crosslink and reuse data for a range of large scale stroke brain imaging clinical and research purposes including developing data analytics models for research into common brain diseases and their consequences.

Developing collaborative technology for neuro-science

Using the NeuroGrid project as a case study, this paper explores the experiences and challenges in collaboratively developing technology and in the use of collaborative technology to enhance the science for the diverse scientific community of neuroscience. It explores methodologies adopted for ensuring continual engagement with a disparate clinical and technical community, the methods used for communication and the perceptions of technology from the perspective of the clinical scientific researchers. It explores the experiences of the multidisciplinary project staff in developing solutions and in the use and potential use of collaborative tools to achieve these goals.