Computational modelling for decision-making: where, why, what, who and how.

In order to deal with an increasingly complex world, we need ever more sophisticated computational models that can help us make decisions wisely and understand the potential consequences of choices. But creating a model requires far more than just raw data and technical skills: it requires a close collaboration between model commissioners, developers, users and reviewers. Good modelling requires its users and commissioners to understand more about the whole process, including the different kinds of purpose a model can have and the different technical bases. This paper offers a guide to the process of commissioning, developing and deploying models across a wide range of domains from public policy to science and engineering. It provides two checklists to help potential modellers, commissioners and users ensure they have considered the most significant factors that will determine success. We conclude there is a need to reinforce modelling as a discipline, so that misconstruction is less likely; to increase understanding of modelling in all domains, so that the misuse of models is reduced; and to bring commissioners closer to modelling, so that the results are more useful.

Accelerating the development of a safe and effective HIV vaccine: HIV vaccine case study for the Decade of Vaccines.

Human immunodeficiency virus (HIV), the etiologic agent that causes AIDS, is the fourth largest killer in the world today. Despite the remarkable achievements in development of anti-retroviral therapies against HIV, and the recent advances in new prevention technologies, the rate of new HIV infections continue to outpace efforts on HIV prevention and control. Thus, the development of a safe and effective vaccine for prevention and control of AIDS remains a global public health priority and the greatest opportunity to eventually end the AIDS pandemic. Currently, there is a renaissance in HIV vaccine development, due in large part to the first demonstration of vaccine induced protection, albeit modest, in human efficacy trials, a generation of improved vaccine candidates advancing in the clinical pipeline, and newly defined targets on HIV for broadly neutralizing antibodies. The main barriers to HIV vaccine development include the global variability of HIV, lack of a validated animal model, lack of correlates of protective immunity, lack of natural protective immune responses against HIV, and the reservoir of infected cells conferred by integration of HIV's genome into the host. Some of these barriers are not unique to HIV, but generic to other variable viral pathogens such as hepatitis C and pandemic influenza. Recommendations to overcome these barriers are presented in this document, including but not limited to expansion of efforts to design immunogens capable of eliciting broadly neutralizing antibodies against HIV, expansion of clinical research capabilities to assess multiple immunogens concurrently with comprehensive immune monitoring, increased support for translational vaccine research, and engaging industry as full partners in vaccine discovery and development.

New models for large prospective studies: is there a better way?

Large prospective cohort studies are critical for identifying etiologic factors for disease, but they require substantial long-term research investment. Such studies can be conducted as multisite consortia of academic medical centers, combinations of smaller ongoing studies, or a single large site such as a dominant regional health-care provider. Still another strategy relies upon centralized conduct of most or all aspects, recruiting through multiple temporary assessment centers. This is the approach used by a large-scale national resource in the United Kingdom known as the "UK Biobank," which completed recruitment/examination of 503,000 participants between 2007 and 2010 within budget and ahead of schedule. A key lesson from UK Biobank and similar studies is that large studies are not simply small studies made large but, rather, require fundamentally different approaches in which "process" expertise is as important as scientific rigor. Embedding recruitment in a structure that facilitates outcome determination, utilizing comprehensive and flexible information technology, automating biospecimen processing, ensuring broad consent, and establishing essentially autonomous leadership with appropriate oversight are all critical to success. Whether and how these approaches may be transportable to the United States remain to be explored, but their success in studies such as UK Biobank makes a compelling case for such explorations to begin.

Identification and characterization of a lupus suppressor 129 locus on chromosome 3.

The 129-derived Sle16 is a susceptibility locus for systemic autoimmunity when present on the C57BL/6 (B6) background. Genetic analysis of a (129xB6)F2 cross identified a region from the B6 chromosome 3 (Sle18) with positive linkage to antinuclear Abs. In this study, we have generated a B6 congenic strain harboring the 129 allele of Sle18 and intercrossed this line with the lupus-prone B6.129-Sle16 strain. The presence of the 129-Sle18 allele in the B6.129-Sle16Sle18 double congenic mice suppressed the development of Sle16-mediated autoantibody production and ameliorated the renal pathology. The 129-Sle18 locus rectified the B cell abnormalities detected in the B6.129-Sle16 mice, such as the reduction in the percentage of marginal zone B and B1a cells and the increased number of germinal centers. The B6.129-Sle16Sle18 spleens still displayed an increased percentage of activated T and B cells. However, in the B6.129-Sle16Sle18 strain the percentage of naive T cells was equivalent to that in B6.129-Sle18 and B6 mice and these cells showed a reduced proliferative response to anti-CD3 stimulation compared with B6.129-Sle16 T cells. There was a significant increase in the percentage of CD4(+)FoxP3(+)regulatory T cells in all congenic strains. These cells had normal regulatory function when tested in vitro. Thus, 129-Sle18 represents a novel, non-MHC lupus-suppressor locus probably operating as a functional modifier of B cells that, in combination with other factors, leads to lupus resistance. Further characterization of this locus will help to uncover the immune mechanism(s) conferring protection against lupus.

Funding scientific discovery: an interview with Sir Mark Walport. Interviewed by Kristin H. Kain.

Sir Mark Walport was appointed as Director of the Wellcome Trust in 2003. Before joining the trust, he was Head of the Division of Medicine at Imperial College London.

Looking for landmarks: the role of expert review and bibliometric analysis in evaluating scientific publication outputs.

OBJECTIVE: To compare expert assessment with bibliometric indicators as tools to assess the quality and importance of scientific research papers. METHODS AND MATERIALS: Shortly after their publication in 2005, the quality and importance of a cohort of nearly 700 Wellcome Trust (WT) associated research papers were assessed by expert reviewers; each paper was reviewed by two WT expert reviewers. After 3 years, we compared this initial assessment with other measures of paper impact. RESULTS: Shortly after publication, 62 (9%) of the 687 research papers were determined to describe at least a 'major addition to knowledge' -6 were thought to be 'landmark' papers. At an aggregate level, after 3 years, there was a strong positive association between expert assessment and impact as measured by number of citations and F1000 rating. However, there were some important exceptions indicating that bibliometric measures may not be sufficient in isolation as measures of research quality and importance, and especially not for assessing single papers or small groups of research publications. CONCLUSION: When attempting to assess the quality and importance of research papers, we found that sole reliance on bibliometric indicators would have led us to miss papers containing important results as judged by expert review. In particular, some papers that were highly rated by experts were not highly cited during the first three years after publication. Tools that link expert peer reviews of research paper quality and importance to more quantitative indicators, such as citation analysis would be valuable additions to the field of research assessment and evaluation.