BBMRI-ERIC: the novel gateway to biobanks. From humans to humans.

BBMRI-ERIC, the Biobanking and BioMolecular Resources Research Infrastructure-European Research Infrastructure Consortium, is a new form of umbrella organization for biobanking in Europe. For rare and common diseases alike, it aims at providing fair access to quality-controlled human biological samples and associated biomedical and biomolecular data. Such access enables basic mechanisms underlying diseases to be studied, which is indispensable for the development of new biomarkers and drugs. In the context of the European Research Area (ERA), biobanks, which were identified as a particular European strength, contribute to Europe's cohesion policy through capacity-building in the BBMRI-ERIC member countries.

Estimating physical activity using a cell phone questionnaire sent by means of short message service (SMS): a randomized population-based study.

An investigation in a randomized population-based Swedish study with 564 participants aged 18-80 years showed that mean physical activity levels obtained using short message service (SMS) by means of cell phones (n = 171) were equal to corresponding levels obtained when sending identical questions by web (n = 182) or paper (n = 211). The response rates were similar for the SMS, web and paper groups.

App-based COVID-19 syndromic surveillance and prediction of hospital admissions in COVID Symptom Study Sweden.

The app-based COVID Symptom Study was launched in Sweden in April 2020 to contribute to real-time COVID-19 surveillance. We enrolled 143,531 study participants (≥18 years) who contributed 10.6 million daily symptom reports between April 29, 2020 and February 10, 2021. Here, we include data from 19,161 self-reported PCR tests to create a symptom-based model to estimate the individual probability of symptomatic COVID-19, with an AUC of 0.78 (95% CI 0.74-0.83) in an external dataset. These individual probabilities are employed to estimate daily regional COVID-19 prevalence, which are in turn used together with current hospital data to predict next week COVID-19 hospital admissions. We show that this hospital prediction model demonstrates a lower median absolute percentage error (MdAPE: 25.9%) across the five most populated regions in Sweden during the first pandemic wave than a model based on case notifications (MdAPE: 30.3%). During the second wave, the error rates are similar. When we apply the same model to an English dataset, not including local COVID-19 test data, we observe MdAPEs of 22.3% and 19.0% during the first and second pandemic waves, respectively, highlighting the transferability of the prediction model.

Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model.

The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, and its secondary metabolite, 6α-p-3'-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6α-p-3'-dihydroxypaclitaxel. Clearance of 6α-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6α-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

LifeGene--a large prospective population-based study of global relevance.

Studying gene-environment interactions requires that the amount and quality of the lifestyle data is comparable to what is available for the corresponding genomic data. Sweden has several crucial prerequisites for comprehensive longitudinal biomedical research, such as the personal identity number, the universally available national health care system, continuously updated population and health registries and a scientifically motivated population. LifeGene builds on these strengths to bridge the gap between basic research and clinical applications with particular attention to populations, through a unique design in a research-friendly setting. LifeGene is designed both as a prospective cohort study and an infrastructure with repeated contacts of study participants approximately every 5 years. Index persons aged 18-45 years old will be recruited and invited to include their household members (partner and any children). A comprehensive questionnaire addressing cutting-edge research questions will be administered through the web with short follow-ups annually. Biosamples and physical measurements will also be collected at baseline, and re-administered every 5 years thereafter. Event-based sampling will be a key feature of LifeGene. The household-based design will give the opportunity to involve young couples prior to and during pregnancy, allowing for the first study of children born into cohort with complete pre-and perinatal data from both the mother and father. Questions and sampling schemes will be tailored to the participants' age and life events. The target of LifeGene is to enroll 500,000 Swedes and follow them longitudinally for at least 20 years.

Estimation of physical activity levels using cell phone questionnaires: a comparison with accelerometry for evaluation of between-subject and within-subject variations.

BACKGROUND: Physical activity promotes health and longevity. Further elaboration of the role of physical activity for human health in epidemiological studies on large samples requires accurate methods that are easy to use, cheap, and possible to repeat. The use of telecommunication technologies such as cell phones is highly interesting in this respect. In an earlier report, we showed that physical activity level (PAL) assessed using a cell phone procedure agreed well with corresponding estimates obtained using the doubly labeled water method. However, our earlier study indicated high within-subject variation in relation to between-subject variations in PAL using cell phones, but we could not assess if this was a true variation of PAL or an artifact of the cell phone technique. OBJECTIVE: Our objective was to compare within- and between-subject variations in PAL by means of cell phones with corresponding estimates using an accelerometer. In addition, we compared the agreement of daily PAL values obtained using the cell phone questionnaire with corresponding data obtained using an accelerometer. METHODS: PAL was measured both with the cell phone questionnaire and with a triaxial accelerometer daily during a 2-week study period in 21 healthy Swedish women (20 to 45 years of age and BMI from 17.7 kg/m² to 33.6 kg/m²). The results were evaluated by fitting linear mixed effect models and descriptive statistics and graphs. RESULTS: With the accelerometer, 57% (95% confidence interval [CI] 40%-66%) of the variation was within subjects, while with the cell phone, within-subject variation was 76% (95% CI 59%-83%). The day-to-day variations in PAL observed using the cell phone questions agreed well with the corresponding accelerometer results. CONCLUSIONS: Both the cell phone questionnaire and the accelerometer showed high within-subject variations. Furthermore, day-to-day variations in PAL within subjects assessed using the cell phone agreed well with corresponding accelerometer values. Consequently, our cell phone questionnaire is a promising tool for assessing levels of physical activity. The tool may be useful for large-scale prospective studies.

Biobanking for Europe.

Biobanks are well-organized resources comprising biological samples and associated information that are accessible to scientific investigation. Across Europe, millions of samples with related data are held in different types of collections. While individual collections can be well organized and accessible, the resources are subject to fragmentation, insecurity of funding and incompleteness. To address these issues, a Biobanking and BioMolecular Resources Infrastructure (BBMRI) is to be developed across Europe, thereby implementing a European 'roadmap' for research infrastructures that was developed by a forum of EU member states and that has been received by the European Commission. In this review, we describe the work involved in preparing for the construction of BBMRI in a European and global context.

Interactive voice response and web-based questionnaires for population-based infectious disease reporting.

The authors aimed to evaluate the web and an Interactive Voice Response (IVR) phone service as vehicles in population-based infectious disease surveillance. Fourteen thousand subjects were randomly selected from the Swedish population register and asked to prospectively report all respiratory tract infections, including Influenza-like Illness (ILI-clinical symptoms indicative of influenza but no laboratory confirmation), immediately as they occurred during a 36-week period starting October 2007. Participants were classified as belonging to the web or IVR group based on their choice of technology for initial registration. In all, 1,297 individuals registered via IVR while 2,044 chose the web. The latter were more often young and well-educated than those registered via IVR. Overall, 52% of the participants reported at least one infection episode. The risk of an infectious disease report was 14% (95% CI: 6, 22%) higher in the web group than in the IVR group. For ILI the excess was 27% (95% CI: 11, 47%). After adjustments for socio-demographic factors, statistically non-significant excesses of 1 and 8% remained, indicating trivial differences potentially attributable to the two reporting techniques. With attention to confounding, it should be possible to combine the web and IVR for simple reporting of infectious disease symptoms.

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 (PAL(ref)). 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 (PAL(cell)). Results were compared with reference data obtained from the doubly labeled water method and indirect calorimetry (PAL(ref)). 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 (PAL(quest1) and PAL(quest2)). PAL(cell), PAL(quest1), and PAL(quest2) were compared with PAL(ref) using the Bland and Altman procedure. RESULTS: The mean difference between PAL(cell) and PAL(ref) was small (0.014) with narrow limits of agreement (2SD = 0.30). Compared with PAL(ref), the mean difference was also small for PAL(quest1) and PAL(quest2) (0.004 and 0.07, respectively); however, the limits of agreement were wider (PAL(quest1), 2SD = 0.50 and PAL(quest2), 2SD = 0.90). The test for trend was statistically significant for PAL(quest1) (slope of regression line = 0.79, P = .04) as well as for PAL(quest2) (slope of regression line = 1.58, P < .001) when compared with PAL(ref). 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.

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.

Unleashing genotypes in epidemiology - A novel method for managing high throughput information.

The large amounts of data generated when high-throughput genotyping methods are used in large-scale epidemiological studies (>10,000 participants) present an enormous challenge to researchers in terms of structured data management. In order to face these challenges, a system has been designed and implemented where genotype data can be efficiently stored. Focus has been on enabling researchers to collaborate by sharing genotype data with each other in a secure and controlled way. Genotype data is available where individuals can be selected using phenotype information and access to specific SNPs can be controlled using user-defined filters. Further value has been added to the basic genotypic information by including extensive metadata. Performance testing of the system was carried out using both artificial and real-world genotype data and shows that the implementation handles large datasets with a linear increase in extraction time and that the retrieval performance is more than sufficient for near-future genotyping research.

Evaluation of an internet-based hearing test--comparison with established methods for detection of hearing loss.

BACKGROUND: Hearing impairment is most accurately measured by a clinical pure-tone audiogram. This method is not suitable for large-scale, population-based epidemiological studies as it requires that study participants visit a clinic with trained personnel. An alternative approach to measuring hearing ability is self-estimation through questionnaires, but the correlation to clinical audiometric tests varies. OBJECTIVE: To evaluate an Internet-based hearing test pilot compared to a question about self-estimated hearing and the feasibility of using an Internet-based hearing test and an Internet-based questionnaire in a population of 560 members of the Swedish Hunters' Association in the age group 20-60 years. METHODS: An invitation was mailed to the participants in March 2007 together with the URL to the study Web site, a personal username, and a password. The Web site included the questionnaire, the hearing test, and instructions for participating in the study. The hearing test resembles a clinical audiogram presenting 6 tones between 500 and 8000 Hz. Tones are presented between 0 and 60 dB, and the participant responds to the tones by pressing the space bar. The hearing test requires headphones and is based on JAVA programming. Before the participant can start the hearing test, it has to be calibrated against a reference person with good hearing between 15 and 35 years of age. RESULTS: After 5 months, 162 out of 560 (29%) had answered the questionnaire, out of which 88 (16%) had completed the hearing test. Those who actively declined participation numbered 230 out of 560 (41%). After removing duplicates and hearing tests calibrated by unreliable reference data, 61 hearing tests remained for analysis. The prevalence of hearing impairment from the Internet-based hearing test was 20% (12 out of 61), compared to 52% (32 out of 61) from the self-estimated question. Those who completed the hearing test were older than the non-participants, and more had headphones (P = .003) and the correct version of the JAVA program (P = .007) than those who only answered the questionnaire. CONCLUSIONS: Though an Internet-based hearing test cannot replace a clinical pure-tone audiogram conducted by a trained audiologist, it is a valid and useful screening tool for hearing ability in a large population carried out at a low cost.

Launch of an Infrastructure for Health Research: BBMRI-ERIC.

Biobanking and BioMolecular resources Research Infrastructure (BBMRI)- European Research Infrastructure Consortium (ERIC) is the largest infrastructure launched in Europe in health research. By nature it is a distributed infrastructure, in which biological samples and data are hosted by the European Member States biobanks. As of today, BBMRI-ERIC consists of 19 European Member States and 1 international organization, the International Agency for Research on Cancer. This means that BBMRI-ERIC has a population of >500 million individuals in Europe. BBMRI-ERIC is a truly Pan-European Research Infrastructure for health research. Given that BBMRI-ERIC is set up to become a key source for users in both academic and scientific institutions as well as in the pharmaceutical and life science industries, it contributes directly to the Innovation Union concept. It is pan-European because BBMRI-ERIC already shows an excellent geographic and regional coverage all over Europe involving countries from South, East, West, North, and Central Europe. BBMRI-ERIC is a service-driven infrastructure for the European Member States, driven by science. The BBMRI-ERIC Directory consists of 100 million samples and a roadmap for better-defined quality in European biobanks for improving reproducibility and reliability of the biological sample and data.

Enhancing Reuse of Data and Biological Material in Medical Research: From FAIR to FAIR-Health.

The known challenge of underutilization of data and biological material from biorepositories as potential resources for medical research has been the focus of discussion for over a decade. Recently developed guidelines for improved data availability and reusability-entitled FAIR Principles (Findability, Accessibility, Interoperability, and Reusability)-are likely to address only parts of the problem. In this article, we argue that biological material and data should be viewed as a unified resource. This approach would facilitate access to complete provenance information, which is a prerequisite for reproducibility and meaningful integration of the data. A unified view also allows for optimization of long-term storage strategies, as demonstrated in the case of biobanks. We propose an extension of the FAIR Principles to include the following additional components: (1) quality aspects related to research reproducibility and meaningful reuse of the data, (2) incentives to stimulate effective enrichment of data sets and biological material collections and its reuse on all levels, and (3) privacy-respecting approaches for working with the human material and data. These FAIR-Health principles should then be applied to both the biological material and data. We also propose the development of common guidelines for cloud architectures, due to the unprecedented growth of volume and breadth of medical data generation, as well as the associated need to process the data efficiently.

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.

E-Science technologies in a workflow for personalized medicine using cancer screening as a case study.

OBJECTIVE: We provide an e-Science perspective on the workflow from risk factor discovery and classification of disease to evaluation of personalized intervention programs. As case studies, we use personalized prostate and breast cancer screenings. MATERIALS AND METHODS: We describe an e-Science initiative in Sweden, e-Science for Cancer Prevention and Control (eCPC), which supports biomarker discovery and offers decision support for personalized intervention strategies. The generic eCPC contribution is a workflow with 4 nodes applied iteratively, and the concept of e-Science signifies systematic use of tools from the mathematical, statistical, data, and computer sciences. RESULTS: The eCPC workflow is illustrated through 2 case studies. For prostate cancer, an in-house personalized screening tool, the Stockholm-3 model (S3M), is presented as an alternative to prostate-specific antigen testing alone. S3M is evaluated in a trial setting and plans for rollout in the population are discussed. For breast cancer, new biomarkers based on breast density and molecular profiles are developed and the US multicenter Women Informed to Screen Depending on Measures (WISDOM) trial is referred to for evaluation. While current eCPC data management uses a traditional data warehouse model, we discuss eCPC-developed features of a coherent data integration platform. DISCUSSION AND CONCLUSION: E-Science tools are a key part of an evidence-based process for personalized medicine. This paper provides a structured workflow from data and models to evaluation of new personalized intervention strategies. The importance of multidisciplinary collaboration is emphasized. Importantly, the generic concepts of the suggested eCPC workflow are transferrable to other disease domains, although each disease will require tailored solutions.

Toward Global Biobank Integration by Implementation of the Minimum Information About BIobank Data Sharing (MIABIS 2.0 Core).

Biobanks are the biological back end of data-driven medicine, but lack standards and generic solutions for interoperability and information harmonization. The move toward a global information infrastructure for biobanking demands semantic interoperability through harmonized services and common ontologies. To tackle this issue, the Minimum Information About BIobank data Sharing (MIABIS) was developed in 2012 by the Biobanking and BioMolecular Resources Research Infrastructure of Sweden (BBMRI.se). The wide acceptance of the first version of MIABIS encouraged evolving it to a more structured and descriptive standard. In 2013 a working group was formed under the largest infrastructure for health in Europe, Biobanking and BioMolecular Resources Research Infrastructure (BBMRI-ERIC), with the remit to continue the development of MIABIS (version 2.0) through a multicountry governance process. MIABIS 2.0 Core has been developed with 22 attributes describing Biobanks, Sample Collections, and Studies according to a modular structure that makes it easier to adhere to and to extend the standard. This integration standard will make a great contribution to the discovery and exploitation of biobank resources and lead to a wider and more efficient use of valuable bioresources, thereby speeding up the research on human diseases. Many within the European Union have accepted MIABIS 2.0 Core as the "de facto" biobank information standard.