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1.  Diagnosing relapse in children's brain tumors using metabolite profiles 
Neuro-Oncology  2013;16(1):156-164.
Malignant brain tumors in children generally have a very poor prognosis when they relapse and improvements are required in their management. It can be difficult to accurately diagnose abnormalities detected during tumor surveillance, and new techniques are required to aid this process. This study investigates how metabolite profiles measured noninvasively by 1H magnetic resonance spectroscopy (MRS) at relapse reflect those at diagnosis and may be used in this monitoring process.
Single-voxel MRS (1.5 T, point-resolved spectroscopy, echo time 30 ms, repetition time 1500 ms was performed on 19 children with grades II–IV brain tumors during routine MRI scans prior to treatment for a suspected brain tumor and at suspected first relapse. MRS was analyzed using TARQUIN software to provide metabolite concentrations. Paired Student's t-tests were performed between metabolite profiles at diagnosis and at first relapse.
There was no significant difference (P > .05) in the level of any metabolite, lipid, or macromolecule from tumors prior to treatment and at first relapse. This was true for the whole group (n = 19), those with a local relapse (n = 12), and those with a distant relapse (n = 7). Lipids at 1.3 ppm were close to significance when comparing the level at diagnosis with that at distant first relapse (P = .07, 6.5 vs 12.9). In 5 cases the MRS indicative of tumor preceded a formal diagnosis of relapse.
Tumor metabolite profiles, measured by MRS, do not change greatly from diagnosis to first relapse, and this can aid the confirmation of the presence of tumor.
PMCID: PMC3870841  PMID: 24305716
brain tumors; diagnosis; MR spectroscopy; pediatrics; relapse.
2.  Extension of the primary care research object model (PCROM) as clinical research information model (CRIM) for the “learning healthcare system” 
Patient data from general practices is already used for many types of epidemiological research and increasingly, primary care systems to facilitate randomized clinical trials. The EU funded project TRANSFoRm aims to create a “Learning Healthcare System” at a European level that is able to support all types of research using primary care data, to recruit patients and follow patients in clinical studies and to improve diagnosis and therapy. The implementation of such a Learning Healthcare System needs an information model for clinical research (CRIM), as an informational backbone to integrate aspects of primary care with clinical trials and database searches.
Workflow descriptions and corresponding data objects of two clinical use cases (Gastro-Oesophageal Reflux Disease and Type 2 Diabetes) were described in UML activity diagrams. The components of activity diagrams were mapped to information objects of PCROM (Primary Care Research Object Model) and BRIDG (Biomedical Research Integrated Domain Group) and evaluated. The class diagram of PCROM was adapted to comply with workflow descriptions.
The suitability of PCROM, a primary care information model already used for clinical trials, to act as an information model for TRANSFoRm was evaluated and resulted in its extension with 14 new information object types, two extensions of existing objects and the introduction of two new high-ranking concepts (CARE area and ENTRY area). No PCROM component was redundant. Our result illustrates that in primary care based research an important but underestimated portion of research activity takes place in the area of care (e.g. patient consultation, screening, recruitment and response to adverse events). The newly introduced CARE area for care-related research activities accounts for this shift and includes Episode of Care and Encounter as two new basic elements. In the ENTRY area different aspects of data collection were combined, including data semantics for observations, assessment activities, intervention activities and patient reporting to enable case report form (CRF) based data collection combined with decision support.
Research with primary care data needs an extended information model that covers research activities at the care site which are characteristic for primary care based research and the requirements of the complicated data collection processes.
PMCID: PMC4276023  PMID: 25519481
3.  Patients’ online access to their electronic health records and linked online services: a systematic interpretative review 
BMJ Open  2014;4(9):e006021.
To investigate the effect of providing patients online access to their electronic health record (EHR) and linked transactional services on the provision, quality and safety of healthcare. The objectives are also to identify and understand: barriers and facilitators for providing online access to their records and services for primary care workers; and their association with organisational/IT system issues.
Primary care.
A total of 143 studies were included. 17 were experimental in design and subject to risk of bias assessment, which is reported in a separate paper. Detailed inclusion and exclusion criteria have also been published elsewhere in the protocol.
Primary and secondary outcome measures
Our primary outcome measure was change in quality or safety as a result of implementation or utilisation of online records/transactional services.
No studies reported changes in health outcomes; though eight detected medication errors and seven reported improved uptake of preventative care. Professional concerns over privacy were reported in 14 studies. 18 studies reported concern over potential increased workload; with some showing an increase workload in email or online messaging; telephone contact remaining unchanged, and face-to face contact staying the same or falling. Owing to heterogeneity in reporting overall workload change was hard to predict. 10 studies reported how online access offered convenience, primarily for more advantaged patients, who were largely highly satisfied with the process when clinician responses were prompt.
Patient online access and services offer increased convenience and satisfaction. However, professionals were concerned about impact on workload and risk to privacy. Studies correcting medication errors may improve patient safety. There may need to be a redesign of the business process to engage health professionals in online access and of the EHR to make it friendlier and provide equity of access to a wider group of patients.
A1. Systematic review registration number
PROSPERO CRD42012003091.
PMCID: PMC4158217  PMID: 25200561
4.  Clinical protocols for 31P MRS of the brain and their use in evaluating optic pathway gliomas in children 
European Journal of Radiology  2014;83(2):e106-e112.
In vivo 31P Magnetic Resonance Spectroscopy (MRS) measures phosphorus-containing metabolites that play an essential role in many disease processes. An advantage over 1H MRS is that total choline can be separated into phosphocholine and glycerophosphocholine which have opposite associations with tumour grade. We demonstrate 31P MRS can provide robust metabolic information on an acceptable timescale to yield information of clinical importance.
All MRI examinations were carried out on a 3T whole body scanner with all 31P MRS scans conducted using a dual-tuned 1H/31P head coil. Once optimised on phantoms, the protocol was tested in six healthy volunteers (four male and two female, mean age: 25 ± 2.7). 31P MRS was then implemented on three children with optic pathway gliomas.
31P MRS on volunteers showed that a number of metabolite ratios varied significantly (p < 0.05 ANOVA) across different structures of the brain, whereas PC/GPC did not. Standard imaging showed the optic pathway gliomas were enhancing on T1-weighted imaging after contrast injection and have high tCho on 1H MRS, both of which are associated with high grade lesions. 31P MRS showed the phosphocholine/glycerophosphocholine ratio to be low (<0.6) which suggests low grade tumours in keeping with their clinical behaviour and the histology of most biopsied optic pathway gliomas.
31P MRS can be implemented in the brain as part of a clinical protocol to provide robust measurement of important metabolites, in particular providing a greater understanding of cases where tCho is raised on 1H MRS.
PMCID: PMC4029084  PMID: 24331847
MR spectroscopy; Chemical shift imaging; MRI; Functional
5.  A unified structural/terminological interoperability framework based on LexEVS: application to TRANSFoRm 
Biomedical research increasingly relies on the integration of information from multiple heterogeneous data sources. Despite the fact that structural and terminological aspects of interoperability are interdependent and rely on a common set of requirements, current efforts typically address them in isolation. We propose a unified ontology-based knowledge framework to facilitate interoperability between heterogeneous sources, and investigate if using the LexEVS terminology server is a viable implementation method.
Materials and methods
We developed a framework based on an ontology, the general information model (GIM), to unify structural models and terminologies, together with relevant mapping sets. This allowed a uniform access to these resources within LexEVS to facilitate interoperability by various components and data sources from implementing architectures.
Our unified framework has been tested in the context of the EU Framework Program 7 TRANSFoRm project, where it was used to achieve data integration in a retrospective diabetes cohort study. The GIM was successfully instantiated in TRANSFoRm as the clinical data integration model, and necessary mappings were created to support effective information retrieval for software tools in the project.
We present a novel, unifying approach to address interoperability challenges in heterogeneous data sources, by representing structural and semantic models in one framework. Systems using this architecture can rely solely on the GIM that abstracts over both the structure and coding. Information models, terminologies and mappings are all stored in LexEVS and can be accessed in a uniform manner (implementing the HL7 CTS2 service functional model). The system is flexible and should reduce the effort needed from data sources personnel for implementing and managing the integration.
PMCID: PMC3756256  PMID: 23571850
Translational Medical Research; Interoperability; Semantics; Terminology; Ontology; LexEVS
6.  Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours 
European Journal of Cancer  2013;49(2):457-464.
Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. 1H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients.
Patients and methods
Short echo time (30 ms) single voxel 1H MRS was performed on children attending Birmingham Children’s Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power.
Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p < 0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p < 5e–5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules.
MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy.
PMCID: PMC3560036  PMID: 23036848
MRS; Metabolism; 1H; Proton; Lipids; Glutamine; LCModel; Grade; Non-invasive; Childhood
7.  Increased unsaturation of lipids in cytoplasmic lipid droplets in DAOY cancer cells in response to cisplatin treatment 
Metabolomics  2012;9(3):722-729.
Increases in 1H nuclear magnetic resonance spectroscopy (NMR) visible lipids are a well-documented sign of treatment response in cancers. Lipids in cytoplasmic lipid droplets (LDs) are the main contributors to the NMR lipid signals. Two human primitive neuroectodermal tumour cell lines with different sensitivities to cisplatin treatment were studied. Increases in NMR visible saturated and unsaturated lipids in cisplatin treated DAOY cells were associated with the accumulation of LDs prior to DNA fragmentation due to apoptosis. An increase in unsaturated fatty acids (UFAs) was detected in isolated LDs from DAOY cells, in contrast to a slight decrease in UFAs in lipid extracts from whole cells. Oleic acid and linoleic acid were identified as the accumulating UFAs in LDs by heteronuclear single quantum coherence spectroscopy (HSQC). 1H NMR lipids in non-responding PFSK-1 cells were unchanged by exposure to 10 μM cisplatin. These findings support the potential of NMR detectable UFAs to serve as a non-invasive marker of tumour cell response to treatment.
PMCID: PMC3651531  PMID: 23678346
Lipid droplets; 1H NMR; Isolation; Cisplatin
8.  Cohort Identification for Clinical Research: Querying Federated Electronic Healthcare Records Using Controlled Vocabularies and Semantic Types 
In the United Kingdom (UK), local initiatives have started to federate electronic healthcare records from different primary care clinical systems, mainly for the purposes of ensuring that health care services effectively meet the needs of the population. The use of such information is being investigated for clinical research, notably in patient cohort identification and recruitment. To achieve these aims, it is essential that the information from different systems can be searched from a single interface. While interoperability is a widely researched topic, interoperable methods and data sources in primary care are largely missing. This paper describes our approach to enabling primary care data in England to be searchable on a platform developed for performing large national collaborative primary care research studies throughout the United States.
PMCID: PMC3392063  PMID: 22779039
9.  How are "teaching the teachers" courses in evidence based medicine evaluated? A systematic review 
BMC Medical Education  2010;10:64.
Teaching of evidence-based medicine (EBM) has become widespread in medical education. Teaching the teachers (TTT) courses address the increased teaching demand and the need to improve effectiveness of EBM teaching. We conducted a systematic review of assessment tools for EBM TTT courses. To summarise and appraise existing assessment methods for teaching the teachers courses in EBM by a systematic review.
We searched PubMed, BioMed, EmBase, Cochrane and Eric databases without language restrictions and included articles that assessed its participants. Study selection and data extraction were conducted independently by two reviewers.
Of 1230 potentially relevant studies, five papers met the selection criteria. There were no specific assessment tools for evaluating effectiveness of EBM TTT courses. Some of the material available might be useful in initiating the development of such an assessment tool.
There is a need for the development of educationally sound assessment tools for teaching the teachers courses in EBM, without which it would be impossible to ascertain if such courses have the desired effect.
PMCID: PMC2958160  PMID: 20920240
10.  Effectiveness of an e-learning course in evidence-based medicine for foundation (internship) training 
To evaluate the educational effectiveness of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduate medical trainees compared to a traditional lecture-based course of equivalent content.
We conducted a cluster randomized controlled trial to compare a clinically integrated e-learning EBM course (intervention) to a lecture-based course (control) among postgraduate trainees at foundation or internship level in seven teaching hospitals in the UK West Midlands region. Knowledge gain among participants was measured with a validated instrument using multiple choice questions. Change in knowledge was compared between groups taking into account the cluster design and adjusted for covariates at baseline using generalized estimating equations (GEE) model.
There were seven clusters involving teaching of 237 trainees (122 in the intervention and 115 in the control group). The total number of postgraduate trainees who completed the course was 88 in the intervention group and 72 in the control group. After adjusting for baseline knowledge, there was no difference in the amount of improvement in knowledge of EBM between the two groups. The adjusted post course difference between the intervention group and the control group was only 0.1 scoring points (95% CI −1.2–1.4).
An e-learning course in EBM was as effective in improving knowledge as a standard lecture-based course. The benefits of an e-learning approach need to be considered when planning EBM curricula as it allows standardization of teaching materials and is a potential cost-effective alternative to standard lecture-based teaching.
PMCID: PMC2895523  PMID: 20522698
11.  Teaching trainers to incorporate evidence-based medicine (EBM) teaching in clinical practice: the EU-EBM project 
Evidence based medicine (EBM) is considered an integral part of medical training, but integration of teaching various EBM steps in everyday clinical practice is uncommon. Currently EBM is predominantly taught through theoretical courses, workshops and e-learning. However, clinical teachers lack confidence in teaching EBM in workplace and are often unsure of the existing opportunities for teaching EBM in the clinical setting. There is a need for continuing professional development (CPD) courses that train clinical trainers to teach EBM through on-the-job training by demonstration of applied EBM real time in clinical practice. We developed such a course to encourage clinically relevant teaching of EBM in post-graduate education in various clinical environments.
We devised an e-learning course targeting trainers with EBM knowledge to impart educational methods needed to teach application of EBM teaching in commonly used clinical settings. The curriculum development group comprised experienced EBM teachers, clinical epidemiologists, clinicians and educationalists from institutions in seven European countries. The e-learning sessions were designed to allow participants (teachers) to undertake the course in the workplace during short breaks within clinical activities. An independent European steering committee provided input into the process.
The curriculum defined specific learning objectives for teaching EBM by exploiting educational opportunities in six different clinical settings. The e-modules incorporated video clips that demonstrate practical and effective methods of EBM teaching in everyday clinical practice. The course encouraged focussed teaching activities embedded within a trainer's personal learning plan and documentation in a CPD portfolio for reflection.
This curriculum will help senior clinicians to identify and make the best use of available opportunities in everyday practice in clinical situations to teach various steps of EBM and demonstrate their applicability to clinical practice. Once fully implemented, the ultimate outcome of this pilot project will be a European qualification in teaching EBM, which will be used by doctors, hospitals, professional bodies responsible for postgraduate qualifications and continuing medical education.
PMCID: PMC2753626  PMID: 19744327
12.  The effectiveness of a clinically integrated e-learning course in evidence-based medicine: A cluster randomised controlled trial 
To evaluate the educational effects of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduates compared to a traditional lecture-based course of equivalent content.
We conducted a cluster randomised controlled trial in the Netherlands and the UK involving postgraduate trainees in six obstetrics and gynaecology departments. Outcomes (knowledge gain and change in attitude towards EBM) were compared between the clinically integrated e-learning course (intervention) and the traditional lecture based course (control). We measured change from pre- to post-intervention scores using a validated questionnaire assessing knowledge (primary outcome) and attitudes (secondary outcome).
There were six clusters involving teaching of 61 postgraduate trainees (28 in the intervention and 33 in the control group). The intervention group achieved slightly higher scores for knowledge gain compared to the control, but these results were not statistically significant (difference in knowledge gain: 3.5 points, 95% CI -2.7 to 9.8, p = 0.27). The attitudinal changes were similar for both groups.
A clinically integrated e-learning course was at least as effective as a traditional lecture based course and was well accepted. Being less costly than traditional teaching and allowing for more independent learning through materials that can be easily updated, there is a place for incorporating e-learning into postgraduate EBM curricula that offer on-the-job training for just-in-time learning.
Trial registration
Trial registration number: ACTRN12609000022268.
PMCID: PMC2688004  PMID: 19435520
13.  The Primary Care Research Object Model (PCROM): A Computable Information Model for Practice-based Primary Care Research 
Chronic disease prevalence and burden is growing, as is the need for applicable large community-based clinical trials of potential interventions. To support the development of clinical trial management systems for such trials, a community-based primary care research information model is needed. We analyzed the requirements of trials in this environment, and constructed an information model to drive development of systems supporting trial design, execution, and analysis. We anticipate that this model will contribute to a deeper understanding of all the dimensions of clinical research and that it will be integrated with other clinical research modeling efforts, such as the Biomedical Research Integrated Domain Group (BRIDG) model, to complement and expand on current domain models.
We used unified modeling language modeling to develop use cases, activity diagrams, and a class (object) model to capture components of research in this setting. The initial primary care research object model (PCROM) scope was the performance of a randomized clinical trial (RCT). It was validated by domain experts worldwide, and underwent a detailed comparison with the BRIDG clinical research reference model.
We present a class diagram and associated definitions that capture the components of a primary care RCT. Forty-five percent of PCROM objects were mapped to BRIDG, 37% differed in class and/or subclass assignment, and 18% did not map.
The PCROM represents an important link between existing research reference models and the real-world design and implementation of systems for managing practice-based primary care clinical trials. Although the high degree of correspondence between PCROM and existing research reference models provides evidence for validity and comprehensiveness, existing models require object extensions and modifications to serve primary care research.
PMCID: PMC2528032  PMID: 18579829
14.  Harmonising Evidence-based medicine teaching: a study of the outcomes of e-learning in five European countries 
We developed and evaluated the outcomes of an e-learning course for evidence based medicine (EBM) training in postgraduate medical education in different languages and settings across five European countries.
We measured changes in knowledge and attitudes with well-developed assessment tools before and after administration of the course. The course consisted of five e-learning modules covering acquisition (formulating a question and search of the literature), appraisal, application and implementation of findings from systematic reviews of therapeutic interventions, each with interactive audio-visual learning materials of 15 to 20 minutes duration. The modules were prepared in English, Spanish, German and Hungarian. The course was delivered to 101 students from different specialties in Germany (psychiatrists), Hungary (mixture of specialties), Spain (general medical practitioners), Switzerland (obstetricians-gynaecologists) and the UK (obstetricians-gynaecologists). We analysed changes in scores across modules and countries.
On average across all countries, knowledge scores significantly improved from pre- to post-course for all five modules (p < 0.001). The improvements in scores were on average 1.87 points (14% of total score) for module 1, 1.81 points (26% of total score) for module 2, 1.9 points (11% of total score) for module 3, 1.9 points (12% of total score) for module 4 and 1.14 points (14% of total score) for module 5. In the country specific analysis, knowledge gain was not significant for module 4 in Spain, Switzerland and the UK, for module 3 in Spain and Switzerland and for module 2 in Spain. Compared to pre-course assessment, after completing the course participants felt more confident that they can assess research evidence and that the healthcare system in their country should have its own programme of research about clinical effectiveness.
E-learning in EBM can be harmonised for effective teaching and learning in different languages, educational settings and clinical specialties, paving the way for development of an international e-EBM course.
PMCID: PMC2386125  PMID: 18442424
15.  A clinically integrated curriculum in Evidence-based Medicine for just-in-time learning through on-the-job training: The EU-EBM project 
Over the last years key stake holders in the healthcare sector have increasingly recognised evidence based medicine (EBM) as a means to improving the quality of healthcare. However, there is considerable uncertainty about the best way to disseminate basic knowledge of EBM. As a result, huge variation in EBM educational provision, setting, duration, intensity, content, and teaching methodology exists across Europe and worldwide. Most courses for health care professionals are delivered outside the work context ('stand alone') and lack adaptation to the specific needs for EBM at the learners' workplace. Courses with modern 'adaptive' EBM teaching that employ principles of effective continuing education might fill that gap. We aimed to develop a course for post-graduate education which is clinically integrated and allows maximum flexibility for teachers and learners.
A group of experienced EBM teachers, clinical epidemiologists, clinicians and educationalists from institutions from eight European countries participated. We used an established methodology of curriculum development to design a clinically integrated EBM course with substantial components of e-learning. An independent European steering committee provided input into the process.
We defined explicit learning objectives about knowledge, skills, attitudes and behaviour for the five steps of EBM. A handbook guides facilitator and learner through five modules with clinical and e-learning components. Focussed activities and targeted assignments round off the learning process, after which each module is formally assessed.
The course is learner-centred, problem-based, integrated with activities in the workplace and flexible. When successfully implemented, the course is designed to provide just-in-time learning through on-the-job-training, with the potential for teaching and learning to directly impact on practice.
PMCID: PMC2228282  PMID: 18042271
16.  Generating prior probabilities for classifiers of brain tumours using belief networks 
Numerous methods for classifying brain tumours based on magnetic resonance spectra and imaging have been presented in the last 15 years. Generally, these methods use supervised machine learning to develop a classifier from a database of cases for which the diagnosis is already known. However, little has been published on developing classifiers based on mixed modalities, e.g. combining imaging information with spectroscopy. In this work a method of generating probabilities of tumour class from anatomical location is presented.
The method of "belief networks" is introduced as a means of generating probabilities that a tumour is any given type. The belief networks are constructed using a database of paediatric tumour cases consisting of data collected over five decades; the problems associated with using this data are discussed. To verify the usefulness of the networks, an application of the method is presented in which prior probabilities were generated and combined with a classification of tumours based solely on MRS data.
Belief networks were constructed from a database of over 1300 cases. These can be used to generate a probability that a tumour is any given type. Networks are presented for astrocytoma grades I and II, astrocytoma grades III and IV, ependymoma, pineoblastoma, primitive neuroectodermal tumour (PNET), germinoma, medulloblastoma, craniopharyngioma and a group representing rare tumours, "other". Using the network to generate prior probabilities for classification improves the accuracy when compared with generating prior probabilities based on class prevalence.
Bayesian belief networks are a simple way of using discrete clinical information to generate probabilities usable in classification. The belief network method can be robust to incomplete datasets. Inclusion of a priori knowledge is an effective way of improving classification of brain tumours by non-invasive methods.
PMCID: PMC2040142  PMID: 17877822

Results 1-17 (17)