In medical research, a lack of reproducibility of research results has caused alarm, raising concerns about the reliability of scientific findings and the wasted resources, both human and financial. Key contributing factors include the explosion in the amount of data available to researchers, who often have inadequate statistical training, and a lack of statistical methods and software to produce robust evidence-based results. My Fellowship will develop methodology to enable non-specialist data analysts to simultaneously assess the sensitivity of their results to four key sources of bias in health research: non-random selection into the study, unmeasured confounding, measurement error, and non-ignorable missing data. Whilst some data analysts provide a qualitative discussion of the effect of such biases on their results, few provide a quantitative assessment; thereby, leading to over-confidence in their scientific findings. Along with the developed methodology, I will provide guidelines for non-specialist data analysts (disseminated via tutorial style papers and training courses) and in collaboration with the UK Reproducibility Network I will engage with stakeholders to ensure that sensitivity analyses become a routine part of study conduct and reporting. My proposed research will make a major contribution to addressing the reproducibility problem, leading to improved public confidence in health-science. Lack of reproducibility of research results (i.e., the inability to obtain the same results on repeating the same study) has caused alarm, raising concerns about the reliability of scientific findings and the wasted resources, both human and financial. Key contributing factors include the explosion in the amount of data available to researchers, inadequate statistical training, and a lack of statistical methods and software to produce reliable results. My Fellowship will develop user-friendly methods and software, with accompanying guidelines, such that non-specialist data analysts can assess the sensitivity of their results to four key sources of bias in health research. Whilst some data analysts provide a qualitative discussion of the effect of such biases on their results, few provide a quantitative assessment; thereby, leading to over-confidence in their scientific findings. My proposed research will make a major contribution to addressing this reproducibility problem, leading to improved public confidence in health-science.

Human genomics is rapidly identifying those gene mutations and perturbed levels of gene expression that lie at the heart of complex diseases. However, simply identifying these genes is, by itself, insufficient to understand the disease process. One needs to understand gene function in a cellular and tissue/organism context. Only then can one validate new protein targets for which rational drug design may help reduce aspects of the disease pathology. Thus, our understanding and treatment of human disease increasingly relies upon cell biology and cell biologists. There is a real need, therefore, to train the next generation of cell biologists in an environment of scientific excellence where they learn how to study fundamental, applied and translational cell biology in the context of specific diseases. In the following, we describe a Wellcome Trust PhD Programme entitled "Dynamic Cell Biology" that aims to achieve this by bringing together the skills and expertise of 31 internationally recognised cell biologists from the School of Medical Sciences - all well funded (13 currently hold Programme Grants) and regularly publishing in high quality journals (over 50% of the PIs have an average impact factor of > 10 for their four most significant publications since 2001; see Appendix). We have selected a balance of established, experienced PIs and young "stars", and the programme will offer training in the broadest range of cell biology topics and techniques from ultrastructural and dynamic studies of intracellular trafficking through to examining cell migration in tissues and whole organisms, and from the purest studies of fundamental cell biology through to those with direct and translational application to human disease. The core research areas are: Dynamic organisation, regulation and re-modelling of the cytoskeleton; Molecular complexes involved in membrane traffic; Dynamic regulation of signalling complexes; Interface between cell signalling and membrane trafficking; Cell organisation, morphogenesis and tissue function. With our human health areas being: Diabetes and obesity, cancer, learning and memory, infection and immunity, hearing/deafness, cardiovascular biology, and channelopathies.

Background Drugs such as statins reduce blood cholesterol, but they may also lower the risk of getting certain cancers, however the evidence surrounding head and neck cancer is inconclusive. In addition, the mechanisms by which these drugs might prevent head and neck cancer requires further evaluation. Statins and similar drugs modify circulating blood factors such as cholesterol, hormones and metabolites which result in the exposure of cells to an environment that may alter the chances of a cancer developing. We want to determine whether such changes to the body’s metabolic environment also influences the likelihood of developing and dying from head and neck cancer. Research approach 1) Analyse large datasets of people with head and neck cancer, to determine if statins and similar drugs causally protect against cancer development and progression. 2) Explore how changes in cholesterol, hormones and metabolite levels might mechanistically prevent head and neck cancer using laboratory studies. 3) Identify potential drug targets for prevention or therapy in head and neck cancer. Impact This project will investigate the link between changes to the body’s cholesterol, hormones and metabolite levels and head and neck cancer. This could help inform targeted cancer screening, prevention and intervention for these patients.

The proposal is for a meeting titled "Metals in neurodegenerative disease: the role of metallospectroscopy" to be held in Queen Mary College, London in January 2003. The Inorganic Biochemistry Discussion Group based in the University of Leicester provides an excellent forum for discussion of current research in neurodegenerative disease, whilst at the same time providing an emphasis on the inorganic biochemistry involved in these diseases. There are two themes of the meeting: (1) Introduction to Metallo Spectroscopy, and (2) Metals in Neurodegeneration.