Sustaining Meaningful Patient Engagement Across the Lifecycle of Medicines: A Roadmap for Action.

BACKGROUND: There is increased recognition that incorporating patients' perspectives and insights into the medicines development process results in better health outcomes and benefits for all involved stakeholders. Despite the increased interest and the existence of frameworks and practical recommendations, patient engagement (PE) is not yet considered standard practice. The objective of this work was to provide a roadmap to support systematic change in all stakeholder organisations involved in medicines development across Europe, patients and patient organisations, medicines developers, academia, regulatory authorities, Health Technology Assessment bodies, payers, policy-makers and public research funders, to sustain PE practices. METHODS: A mixed-methods approach was used by the EU-funded Innovative Medicines Initiative PARADIGM Consortium to co-develop the sustainability roadmap including background work to identify success factors and scenarios for sustainable PE. The roadmap development was based on the Theory of Change concept and populated with findings from (1) interviews with national/ and international institutions with the potential to increase PE uptake by other stakeholders; (2) multi-stakeholder workshops and webinars; and (3) consultations with specific stakeholder groups, Consortium members and a consultative body formed by international PE initiatives. RESULTS: This roadmap sets strategic goals for the PE community to achieve meaningful and systematic PE through changes in the culture, processes and resources of stakeholder organisations. It brings in key PARADIGM outputs to work in a coordinated fashion with existing frameworks and mechanisms to achieve system-wide sustained PE. CONCLUSIONS: The roadmap provides a framework for all stakeholders to take collective action within their organisations and across Europe to implement PE in a sustainable manner.

Solving bottlenecks in data sharing in the life sciences.

The joint Open PHACTS/GEN2PHEN workshop on "Solving Bottlenecks in Data Sharing in the Life Sciences" was held in Volendam, the Netherlands, on September 19 and 20, 2011, and was attended by representatives from academia, industry, publishing, and funding agencies. The aim of the workshop was to explore the issues that influence the extent to which data in the life sciences are shared, and to explore sustainability scenarios that would enable and promote "open" data sharing. Several key challenges were identified and solutions to each of these were proposed.

Genetic structure of the Spanish population.

BACKGROUND: Genetic admixture is a common caveat for genetic association analysis. Therefore, it is important to characterize the genetic structure of the population under study to control for this kind of potential bias. RESULTS: In this study we have sampled over 800 unrelated individuals from the population of Spain, and have genotyped them with a genome-wide coverage. We have carried out linkage disequilibrium, haplotype, population structure and copy-number variation (CNV) analyses, and have compared these estimates of the Spanish population with existing data from similar efforts. CONCLUSIONS: In general, the Spanish population is similar to the Western and Northern Europeans, but has a more diverse haplotypic structure. Moreover, the Spanish population is also largely homogeneous within itself, although patterns of micro-structure may be able to predict locations of origin from distant regions. Finally, we also present the first characterization of a CNV map of the Spanish population. These results and original data are made available to the scientific community.

Training multidisciplinary biomedical informatics students: three years of experience.

OBJECTIVE: The European INFOBIOMED Network of Excellence recognized that a successful education program in biomedical informatics should include not only traditional teaching activities in the basic sciences but also the development of skills for working in multidisciplinary teams. DESIGN: A carefully developed 3-year training program for biomedical informatics students addressed these educational aspects through the following four activities: (1) an internet course database containing an overview of all Medical Informatics and BioInformatics courses, (2) a BioMedical Informatics Summer School, (3) a mobility program based on a 'brokerage service' which published demands and offers, including funding for research exchange projects, and (4) training challenges aimed at the development of multi-disciplinary skills. MEASUREMENTS: This paper focuses on experiences gained in the development of novel educational activities addressing work in multidisciplinary teams. The training challenges described here were evaluated by asking participants to fill out forms with Likert scale based questions. For the mobility program a needs assessment was carried out. RESULTS: The mobility program supported 20 exchanges which fostered new BMI research, resulted in a number of peer-reviewed publications and demonstrated the feasibility of this multidisciplinary BMI approach within the European Union. Students unanimously indicated that the training challenge experience had contributed to their understanding and appreciation of multidisciplinary teamwork. CONCLUSION: The training activities undertaken in INFOBIOMED have contributed to a multi-disciplinary BMI approach. It is our hope that this work might provide an impetus for training efforts in Europe, and yield a new generation of biomedical informaticians.

Sex and body mass index specific regulation of blood pressure by CYP19A1 gene variants.

Sexual dimorphism in blood pressure (BP) regulation has been observed both in humans and experimental animals, and estrogens have been shown to contribute to this epidemiological observation. A key enzyme in determining estrogen levels is aromatase cytochrome P450. The aim of this study was to evaluate the role of the gene encoding aromatase, CYP19A1, as an independent risk factor for hypertension and its relationship with systolic and diastolic BP measures. We genotyped 2 polymorphisms within the CYP19A1 gene, IVS4 rs11575899 and 3'UTR rs10046, in 3448 individuals. In quantitative analysis, we observed significant associations between the 2 polymorphisms and BP values in women, being these associations dependent on BMI and independent of menopause status. The case-control analysis revealed that the most prominent associations were found for nonobese women in diastolic hypertension (DHT): the IVS4_22 and 3'UTR_11 are risk genotypes (OR=1.61, P=0.027 and OR=1.59, P=0.012, respectively), whereas IVS4_11 and 3'UTR_22 genotypes have a protective effect against DHT (OR=0.63, P=0.009, and OR=0.61, P=0.020, respectively). Haplotype analysis confirmed the above associations: among nonobese women the haplotype 21 is overrepresented in hypertensive women (OR=1.33, P=0.004, for DHT and OR=1.25, P=0.026, for systolic hypertension, SHT) and, conversely, the haplotype 12 protects against hypertension (OR=0.78, P=0.015 for DHT and OR=0.82, P=0.04 for SHT). Our study has shown that the CYP19A1 gene may be involved in the genetic regulation of BP in women. This effect is dependent on BMI and independent of menopause status, suggesting that this action is mainly driven by aromatase activity in fat tissue.

Education and research in INFOBIOMED, the European Network of Excellence in Biomedical Informatics.

During the last three years several initiatives have been deployed within INFOBIOMED, the European Network of Excellence (NoE) in Biomedical Informatics, for promoting research and education. In the context of genomic medicine, four research pilots were designed. To address the informational complexities of such research problems, new educational approaches are needed.

Genetic analysis of caveolin-1 and eNOS genes in colorectal cancer.

Caveolae are involved in physical compartmentalization between different groups of signaling events. Its main component, CAV1, modulates different pathways in cellular physiology. The emerging evidence pointing to the role of CAV1 in cancer led us to study whether different alleles of this gene are associated with colorectal cancer (CRC). Since one of the most characterized enzymes regulated by CAV1 is eNOS, we decided to include both genes in this study. We analyzed five SNPs in 360 unrelated CRC patients and 550 controls from the general population. Two of these SNPs were located within eNOS and three within the CAV1 gene. Although haplotype distribution was not associated with CRC, haplotype TiA (CAV1) was associated with familiar forms of CRC (p<0.05). This was especially evident in CRC antecedents and nuclear forms of CRC. If both CG (eNOS) and TiA (CAV1) haplotypes were taken together, this association increased in significance. Thus, we propose that CAV1, either alone or together with eNOS alleles, might modify CRC heritability.

Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis.

Osteoporosis is a common disease with multiple environmental and genetic risk factors involved. Using a marker-by-marker approach, the role of different estrogen-related genes has been analyzed in different populations, but most of these studies ignore the complex multigenic nature of human osteoporosis. Looking for markers related to osteoporosis, we have analyzed five single nucleotide polymorphisms located in genes related to the estrogen pathway, Follicle Stimulating Hormone Receptor (FSHR) gene, the CYP19 aromatase (CYP19A1) gene, the Estrogen Receptor alpha (ESR1) gene, the Estrogen Receptor beta (ESR2) gene and the Nuclear Receptor Interacting Protein 1 (NRIP1) gene in 265 unrelated postmenopausal women. We have obtained nominal P values for the NRIP1 Gly75Gly and ESR2 *39A>G markers (P=0.013 and P=0.02 respectively), but no gene seems to be associated after multiple test corrections. Reanalysis of this study using 437 postmenopausal women confirmed our results and only detect marginal effects for ESR2 marker (P=0.045). By contrast, multilocus analysis predicted epistatic interactions between ESR1, ESR2 and NRIP1 loci and its involvement in postmenopausal osteoporosis (P=0.003). We detected two digenic genotypes involving ESR2-NRIP1 and ESR2-ESR1 genes strongly associated with osteoporosis (P=0.007). Replication of multilocus studies using 437 patients confirmed the detected interactions (P<0.01). We proposed a non-additive non-multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis. Our results reaffirm the polygenic nature and the genetic complexity of osteoporosis trait adding a new candidate gene (NRIP1) for association studies of bone-related traits.