Jan-Eric Litton

Imaging of [11C]-labelled RO 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography

The benzodiazepine antagonist Ro 15-1788 was labelled with [11C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [11C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [11C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [11C]. The in vivo binding of [11C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [11C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [11C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [11C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [11C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [11C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.

New times, new needs; e-epidemiology

The successful and systematic collection of demographic and lifestyle data is central in the process of any epidemiological study. The traditionally used methods such as face-to-face and telephone interviews as well as paper-questionnaires are increasingly failing to produce good qualitative results within financially feasible limits. Tools that are better suited for the present dynamic populations are needed and the Internet presents a powerful alternative for the collection of data with several intrinsic features still unexplored.

A Minimum Data Set for Sharing Biobank Samples, Information, and Data: MIABIS

Numerous successful scientific results have emerged from projects using shared biobanked samples and data. In order to facilitate the discovery of underutilized biobank samples, it would be helpful if a global biobank register containing descriptive information about the samples existed. But first, for shared data to be comparable, it needs to be harmonized. In compliance with the aim of BBMRI (Biobanking and Biomolecular Resources Research Infrastructure), to harmonize biobanking across Europe, and the conclusion that the move towards a universal information infrastructure for biobanking is directly connected to the issues of semantic interoperability through standardized message formats and controlled terminologies, we have developed an updated version of the minimum data set for biobanks and studies using human biospecimens. The data set called MIABIS (Minimum Information About BIobank data Sharing) consists of 52 attributes describing a biobanks content. The aim is to facilitate data discovery through harmonization of data elements describing a biobank at the aggregate level. As many biobanks across Europe possess a tremendous amount of samples that are underutilized, this would help pave the way for biobank networking on a national and international level, resulting in time and cost savings and faster emergence of new scientific results.

PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls

Benzodiazepine (BZ) receptor binding in the brain was determined in five chronic alcohol-dependent men and in five healthy male control subjects using [11C]flumazenil (Ro 15-1788) and positron emission tomography (PET). Magnetic resonance imaging was used to evaluate brain anatomy and pathology, and to define regions of interest in the brain. [11C]Flumazenil binding was quantified by applying a saturation procedure with two PET experiments, the first with high (400-3400 Ci/mmol) and the second with low (approximately 1 Ci/mmol) specific radioactivity. Radioactivity in the pons was taken as an estimate of free and nonspecifically bound radioligand. Equilibrium was defined to prevail when the derivative of specific binding (dCb(t)/dt) was equal to zero. The values were used in a Scatchard analysis for determination of the maximum density of binding sites (Bmax) and the equilibrium binding constant (Kd). The mean values of Bmax and Kd were about the same in the two groups, but the Bmax variance for the alcoholics was significantly greater for all regions of interest as compared with the healthy volunteers. The results may indicate that chronic alcohol consumption has multiple effects on the BZ receptor complex.

Measures of Physical Activity Using Cell Phones: Validation Using Criterion Methods

Background Physical activity is associated with reduced risks of many chronic diseases. Data collected on physical activity in large epidemiological studies is often based on paper questionnaires. The validity of these questionnaires is debated, and more effective methods are needed. Objective This study evaluates repeated measures of physical activity level (PAL) and the feasibility of using a Java-based questionnaire downloaded onto cell phones for collection of such data. The data obtained were compared with reference estimates based on the doubly labeled water method and indirect calorimetry (PALref). Method Using a Java-based cell phone application, 22 women reported their physical activity based on two short questions answered daily over a 14-day period (PALcell). Results were compared with reference data obtained from the doubly labeled water method and indirect calorimetry (PALref). Results were also compared against physical activity levels assessed by two regular paper questionnaires completed by women at the end of the 14-day period (PALquest1 and PALquest2). PALcell, PALquest1, and PALquest2 were compared with PALref using the Bland and Altman procedure. Results The mean difference between PALcell and PALref was small (0.014) with narrow limits of agreement (2SD = 0.30). Compared with PALref, the mean difference was also small for PALquest1 and PALquest2 (0.004 and 0.07, respectively); however, the limits of agreement were wider (PALquest1, 2SD = 0.50 and PALquest2, 2SD = 0.90). The test for trend was statistically significant for PALquest1 (slope of regression line = 0.79, P = .04) as well as for PALquest2 (slope of regression line = 1.58, P < .001) when compared with PALref. Conclusion A Java-based physical activity questionnaire administered daily using cell phones produced PAL estimates that agreed well with PAL reference values. Furthermore, the limits of agreement between PAL obtained using cell phones, and reference values were narrower than for corresponding estimates obtained using paper questionnaires. Java-based questionnaires downloaded onto cell phones may be a feasible and cost-effective method of data collection for large-scale prospective studies of physical activity.

Optimizing the design of web-based questionnaires - experience from a population-based study among 50,000 women

BackgroundWeb-questionnaires are an important tool for future epidemiological research because these allow for rapid and cost-efficient assembly of self-reported information on risk factors and health outcomes. However, to achieve high response rates it is essential to accommodate factors that prevent drop out and so insure validity of future studies. We aim to study how socio-demographic variables as well as design issues such as the ordering and level of difficulty (Easy-to-hard vs. Hard-to-easy) of questions in a web-questionnaire affects the probability of drop out and non-response.MethodIn 2003 we invited 47,859 women participating in an ongoing prospective study to a follow-up using a web-based mode. Two versions of the questionnaire existed, varying in level of difficulty (Easy-to-hard vs. Hard-to-easy). We report drop out (proportion non-completers) between groups defined by level of difficulty and estimated adjusted risk differences.ResultsThe drop out differs significantly depending on the order of the questions in the web-questionnaire. The socio-demographic pattern among lurkers (participants that enter, start responding to, but do not complete a web-questionnaire) differs from that among completers of web-questionnaires.ConclusionsAn additional 6% units of completers – persons initiating and completing the questionnaire – can be obtained by considering the ordering of questions. A group uniquely identified in web-surveys,␣as lurkers are potentially easier to persuade to complete an already started web-questionnaire compared to a non-responder. Lurkers thus constitute a unique opportunity of decreasing the drop out rate and therefore merit future research.

SMS versus telephone interviews for epidemiological data collection: feasibility study estimating influenza vaccination coverage in the Swedish population

This study compared the use of Short Message Service (SMS) on mobile phones and the use of telephone interviews in collecting self-reported data about influenza vaccination. Through random selection from the Swedish population registry, 2,400 individuals were assigned to be contacted through SMS (SMS-group), and 2,150 were assigned to undergo personal telephone interviews (TI-group). Both groups were asked three questions about influenza and influenza vaccination. Mobile phone numbers were found for 1,055 persons in the SMS-group of whom 154 (6% of the original sample; 15% of all who had a listed mobile phone number) responded. Landline or mobile phone numbers were found for 1,636 persons in the TI-group and 1,009 (47% of the original TI sample; 62% of those where a telephone number was found) responded. The vaccination data collected via SMS was not statistically significantly different from data collected through telephone interviews, and adjustment for different background factors did not change this. Compared to the original sample, there was an under representation of elderly and less educated individuals among the participants in the SMS-group, and under representation of less educated in the TI-group. Though the participation rate was low, SMS is a feasible method for collection of information on vaccination status data among the Swedish population compared to telephone interviews.

The federated database--a basis for biobank-based post-genome studies, integrating phenome and genome data from 600,000 twin pairs in Europe.

Integration of complex data and data management represent major challenges in large-scale biobank-based post-genome era research projects like GenomEUtwin (an international collaboration between eight Twin Registries) with extensive amounts of genotype and phenotype data combined from different data sources located in different countries. The challenge lies not only in data harmonization and constant update of clinical details in various locations, but also in the heterogeneity of data storage and confidentiality of sensitive health-related and genetic data. Solid infrastructure must be built to provide secure, but easily accessible and standardized, data exchange also facilitating statistical analyses of the stored data. Data collection sites desire to have full control of the accumulation of data, and at the same time the integration should facilitate effortless slicing and dicing of the data for different types of data pooling and study designs. Here we describe how we constructed a federated database infrastructure for genotype and phenotype information collected in seven European countries and Australia and connected this database setting via a network called TwinNET to guarantee effortless data exchange and pooled analyses. This federated database system offers a powerful facility for combining different types of information from multiple data sources. The system is transparent to end users and application developers, since it makes the set of federated data sources look like a single system. The user need not be aware of the format or site where the data are stored, the language or programming interface of the data source, how the data are physically stored, whether they are partitioned and/or replicated or what networking protocols are used. The user sees a single standardized interface with the desired data elements for pooled analyses.

BBMRI-ERIC as a resource for pharmaceutical and life science industries: the development of biobank-based Expert Centres.

Biological resources (cells, tissues, bodily fluids or biomolecules) are considered essential raw material for the advancement of health-related biotechnology, for research and development in life sciences, and for ultimately improving human health. Stored in local biobanks, access to the human biological samples and related medical data for transnational research is often limited, in particular for the international life science industry. The recently established pan-European Biobanking and BioMolecular resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC) aims to improve accessibility and interoperability between academic and industrial parties to benefit personalized medicine, disease prevention to promote development of new diagnostics, devices and medicines. BBMRI-ERIC is developing the concept of Expert Centre as public–private partnerships in the precompetitive, not-for-profit field to provide a new structure to perform research projects that would face difficulties under currently established models of academic–industry collaboration. By definition, Expert Centres are key intermediaries between public and private sectors performing the analysis of biological samples under internationally standardized conditions. This paper presents the rationale behind the Expert Centres and illustrates the novel concept with model examples.

[11C]Ro 15-4513, a ligand for visualization of benzodiazepine receptor binding. Preparation autoradiography and positron emission tomography

Ro 15-4513, a partial inverse agonist at the benzodiazepine (BZ) receptor site was labelled with11C and used for in vitro autoradiography on human post mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. The total radiochemical yield of [11C]Ro 15-4513 was 30–40% with an overall synthesis time of 40 min. The specific radioactivity was about 1000 Ci/mmol at end of synthesis. In vitro autoradiography showed that [11C]Ro 15-4513 bound specifically predominately in the neocortex of the human brain. Specific binding was also demonstrated in the basal ganglia and the cerebellar cortex. Flumazenil (Ro 15-1788) and clonazepam inhibited the binding in cerebral regions, but a significant proportion in the cerebellum was not inhibited by these agents. This proportion may represent α6-containing BZ receptors. PET examination of [11C]Ro 15-4513 binding in Cynomolgus monkeys demonstrated high uptake of radioactivity in neocortex. The uptake of radioactivity was markedly displaced by high doses of Ro 15-4513 or clonazepam. [11C]Ro 15-4513 should be a useful ligand to examine BZ receptor characteristics in the living human brain by PET.