CUP RFA: DEVELOPMENT OFSYSTEMATIC REVIEWMETHODOLOGY FOR MECHANISTICSTUDIES
Aim• The aim of this project is to draw on the expertise(in systematic reviews of epidemiological studiesand in experimental studies of cancer) in our groupin order to develop and publish a template forcarrying out rigorous systematic reviews ofmechanistic studies.
Why is this important?Systematic reviews are the most rigorous way to synthesise studieswhich address a common question.Methods for conducting and reporting rigorous systematic reviewsremain lacking for mechanistic studies.But there is a huge amount of published information on themechanisms between dietary factors and different types of cancerfrom animal and cell line studies.This will enable more systematic reviews of mechanistic studies, thusallowing researchers to determine the strength of evidence for aparticular nutrients and cancer risk and also to identify gaps in theresearch.
The TeamUniversity of Bristol• PI- Dr Sarah Lewis –Genetic epidemiology/systematic reviews of genetic studies• Co-PI- Prof Richard Martin –Epidemiology/systematic reviews• Dr Mona Jeffreys- Cancer Epidemiology/systematic reviews• Dr Mike Gardner – Animal biology/systematic reviews• Prof Jeff Holly- Molecular biology – IGF and cancer• Dr Tom Gaunt – Genetic epidemiology/bioinformatics• Prof Jonathan Sterne- Meta-analysis and systematic review methodology• Professor Julian Higgins – Meta-analysis and systematic review methodology• Prof George Davey Smith – Epidemiology• Prof Christos Paraskeva –Molecular biology• Prof Steve Thomas –Epidemiology of head and neck cancer.• Dr Pauline Emmett - Nutritional epidemiology• Dr Kate Northstone – Nutritional Epidemiology• Cath Borwick – Librarian/ Search strategiesUniversity of Cambridge WCRFDr Suzanne Turner- Animal models Prof Martin WisemanDr Pangiota MitrouInternational Agency for Research on Cancer Dr Rachel ThompsonDr Sabina Rinaldi- Hormones and cancer Faye Butler
Study objectivesThe key objectives which will be addressed in this project are:• To design a comprehensive search strategy to identify the diverse studytypes of relevance.• To determine which types of study should be included and determine ahierarchy of evidence.• To develop quality control criteria and produce a data extraction form tocapture this information.• To develop methods to identify and quantify publication bias.• To test our draft methodology (1 to 4 above) in a feasibility study, in whichwe will review the evidence on mechanisms underlying associationsbetween milk and prostate cancer.
Hypothesis to be explored:High milk consumption is a risk factor for prostatecancer• Milk consumption has been implicated as a risk factor for prostate cancer• But milk consumption is measured semi-quantitatively in some studies, with largedifferences between individuals in the same group and therefore subject toattenuation by errors. In addition, milk intake is susceptible to confounding byother diet and lifestyle factors.• Systematic reviews of observational studies remain inconclusive (WCRF SecondExpert Report 2007 showed limited/suggestive evidence for milk as a risk factor forprostate cancer)• Experimental studies have been carried-out but not taken into account in mostsystematic reviews
3 possible mechanisms• High calcium intake in milk may suppress the conversion of 25(OH) vitaminD to 1,25(OH)2 vitamin D, which has antiproliferative and differentialeffects on human prostate cancer cells.• Milk is a rich source of estrogens. Animal models have shown thatestrogen and testosterone act in synergy to initiate prostate cancer.• Insulin-like growth factor I (IGF-I) level is positively associated withprostate cancer risk. Milk has been shown to increase IGF levels.• We plan to investigate the evidence for the 3 mechanisms above (and alsoto identify other potential mechanisms) using our devised protocol forsystematic reviews of mechanistic studies of diet and cancer.
Analytical approach• A series of 4 workshops to call on experts within our group –using a mixture of presentations with discussion, small groupexercises, round table discussions.• On going searches, and development of methods, feedback tomembers of the team• Regular meetings between PIs and research associate
At the end of this workshop we will produce:• A list of study types to be included in the mechanistic review• A hierarchy dependent on relevance and strength of evidence which canbe drawn from the studies• A search strategy.Workshop 1 – 23rd April
Workshop 2At this workshop we will :• Present the search strategy and results for our chosen hypothesis on milk andprostate cancer (see below) for discussion• Produce a list of quality control criteria, by study type and draft inclusion/exclusioncriteria• Agree on a list of variables which will be collected to assess between-studyheterogeneity, and which will be used to design the data extraction form• Determine limits to apply to the search strategy, using the hierarchy of studies andthe quality control criteria, and possibly date of publication to ensure that thesearch yields a manageable number of publications
Workshop 3At this workshop we will:• Present a draft data extraction form, inclusion/exclusion criteria, effect of applyinglimits, quality control and summary data, along with the results of statistical testsfor publication bias for the review of milk and prostate cancer• Consider how to analyse and display results. For the most part we envisage thatstudies will be too heterogeneous to meta-analyse but where possible we will dothis in order to summarise the data• Consider the overall potential for publication bias in mechanistic studies and howto deal with this
Workshop 4• We present the results of our systematic review of mechanistic studies ofmilk and cancer, we will discuss any issues arising during this systematicreview and use these to agree on any amendments to the final template.
Search strategy• Epidemiological review – search strategy developed fornutrients + cancer (WCRF, 2007).• We will adopt this strategy, but will have an additional step inour search, as many mechanistic studies will not have canceras an outcome but may still be relevant.• We will develop a search strategy to find studies on“Nutrient” + “Mechanistic target”“Nutrient” + “Cancer”
Verifying the search strategy• We will test our search against any thoroughsystematic reviews of animal or other mechanisticstudies relating to diet and cancer, to determinewhether we find the same papers.• We will check reference lists of retrieved papers• We will run searches on a selection of authorsworking in this field and cross check their papersagainst our own search.
Types of study found so farMilk + exp DNA damage (NOT Lactation, also excludedCross-Sectional Studies, Cohort Studies and Case-ControlStudies as MESH terms) = 52 studiesBreakdown of study type11 human2 human cross-over15 animal (rats and mice)20 human cells4 animal cells
different mechanistic targets will yield differentamounts and types of data- Searches to date on Milkand Mechanistic target give the following numbers ofstudies:• Genomic Instability 4• DNA Damage 52• DNA Repair 7• Mutation 480• Somatomedins (Insulin-Like Growth Factor I, Insulin-Like Growth Factor II) 238• Growth Hormone 376• Cell Proliferation 577
Timetable• Recruit research associate to work on the project – Jan 2013 - Dr Mike Gardnerrecruited and currently working on the project.• RA will start work on initial exploratory searches – Mar/April 2013• Organise and hold first workshop – April 2013• Second workshop – Sept 2013• Third workshop –Jan 2014• Fourth workshop –June 2014• In between workshops we will refine the protocol, carry-out searches, investigateQC criteria, determine study inclusion/exclusion etc.
Challenges• Developing a one size fits all template –although we expect that when the template is developed research groups will choose to search formechanistic targets relevant to their own question• Finding the relevant studies –this relies on having a good search strategy and validating this• Determining study quality –some QC criteria could be adopted from epidemiology• Determining the strength of evidence for different study typesthis will be arrived at by discussions within the team, tapping into to our multidisciplinary team• Determining the relevance to humansAgain we will arrive at a consensus following examination of the studies and discusses within the team• PUBLICATION BIASWe will use recognised methods to quantify the extent to which this is likely to have occurred• Collating the evidence
Acknowledgements• WCRF• Team members• Mechanisms Protocol Development Group