Goals per work package

Work package 1

 The overall objective of WP1 is to create and maintain the conditions needed to achieve the objectives and deliverables of the CARING Project. Specific objectives are to:
• establish and maintain the governance structure of CARING
• develop the global CARING Management Plan and implement the overall strategy of the project
• issue progress reports and budget reviews
• do the day-to-day administrative and financial management of the programme

Work package 2

Objectives are to:
• conduct a systematic review on the risk of cancer and different cancer types associated with diabetes mellitus, in order to estimate the background risk of cancer in the patient population using insulins
• conduct a systematic review of clinical trials and epidemiological studies on the risk of cancer associated with the use of insulin and insulin analogues
• identify methodological issues and research gaps of available clinical trials and epidemiological studies
• conduct a systematic review of the published pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues

Work package 3

The overall aims are to:
• determine the advantages/disadvantages of multi-database studies over a single database study (of similar size)
• determine the statistically best design for multi-database studies

More specific aims are to:
• review statistical techniques that can be used in multi-database studies
• perform simulation studies that will evaluate the performance of different statistical techniques to deal with inter-database variability in the completeness of data, data quality and variability in exposure and outcomes
• analyze and combine the data from the different sources using different approaches for confounder control and aggregation levels
• explore heterogeneity between countries, characteristics of databases and healthcare systems

Work package 4

The objectives are to:
• study the influence of potential confounders on the association between insulin (type, dose, duration) and cancer risk in observational studies in the literature
• identify potential confounders available in the databases and quantify the strength of their association with insulin use and cancer risk, individually and combined
 quantify the influence of the available confounders on the association between insulin use and cancer risk in the databases, individually and combined
 develop methods for external adjustment for unmeasured confounders in databases with missing information on certain confounders
 do sensitivity analyses of risk estimates using external adjustment for confounders of single country/single database studies

Work package 5

The aims are to:
 determine whether diabetic breast cancer patients have a specific breast cancer subtype defined by clinically used immunohistochemical tumour markers
 study whether diabetic breast cancer patients have a specific tumour profile (or tumour subtype) compared to non-diabetic breast cancer patients, and whether this may be related to specific pathways (e.g. IGF), using CGH profiling
 study whether the use of insulin and insulin analogues are related to specific pathways in breast tumours of diabetic patients

Work package 6

Objectives are to:
 determine associations between new insulin and insulin analogues use and risk of cancer and different cancer types. Exposure effects of daily dosage, time and/or intensity of insulin treatment on the likelihood of developing cancer will be studied
 study the hazard patterns of cancer risk associated with the use of insulin and insulin analogues
 develop a clinical risk score for the prediction of cancer in users of insulin and insulin analogues

Work package 7

The aims are to:
 raise awareness of the project among key stakeholders and influencers
 communicate the findings of the project to the scientific community, regulators, policymakers and to the healthcare sector across Europe
 interact with related national, European and international projects for mutual benefit concerning exchange of research expertise and dissemination of results