John C, Reeve NF, Free RC, Williams AT, Farmaki AE, Bethea J, Barton LM, Shrine N, Batini C, Packer R, Terry S, Hargadon B, Wang Q, Melbourne CA, Adams EL, Bee CE, Harrington K, Miola J, Brunskill NJ, Brightling CE, Barwell J, Wallace SE, Hsu R, Shepherd DJ, Hollox EJ, Wain LV, Tobin MD

International Journal of Epidemiology (2019) 48(3):678–679

EXCEED aims to develop understanding of the genetic, environmental and lifestyle-related causes of health and disease. Cohorts like EXCEED, with broad consent to study multiple phenotypes related to onset and progression of disease and drug response, have a role to play in medicines development, by providing genetic evidence that can identify, support or refute putative drug efficacy or identify possible adverse effects. Furthermore, such cohorts are well suited to the study of multimorbidity.

Multimorbidity describes the presence of multiple diseases or conditions in one patient, though definitions in the literature vary widely. It demands a holistic approach to optimize care and avoid iatrogenic complications, such as drug interactions. In the context of increasing specialisation of many health care systems and high health care use among people with multimorbidity, providing such care poses a complex challenge. In high-income countries, multimorbidity is particularly common among more deprived socioeconomic groups and may even be considered as the norm amongst older people and an ageing global population and a growing burden of non-communicable diseases in low- and middle-income countries compound its global importance. An expert working group convened by the UK Academy of Medical Sciences recently highlighted the lack of available evidence relating to the burden, determinants, prevention and treatment of multimorbidity, and recommended the prioritisation of research on multimorbidity spanning the translational pathway from understanding of its biological mechanisms to health services research.

Studies designed to investigate multimorbidity, rather than considering individual conditions in relative isolation, are therefore vital. Linkage to electronic health records (EHR) has enabled information on a broad range of diseases and risk factors to be studied in EXCEED and places multimorbidity at the study’s heart. The EHR linkage also facilitates longitudinal follow-up over an extended period, enabling, for example, the investigation of lifestyle factors and other exposures on healthy ageing and outcomes in later life.

Combining wide-ranging data from EHR with genome-wide genotyping is also central to EXCEED’s purpose. In recent years, our understanding of which genes are associated with both rare and common diseases has advanced rapidly as available sample sizes for genome-wide association studies (GWAS) have grown rapidly. For example, there are now 279 genetic variants associated with lung function and chronic obstructive pulmonary disease (COPD). However in many cases, our understanding of the mechanisms through which these variants influence disease risk—and which could therefore be therapeutic targets—is relatively limited. An efficient design to inform this understanding is to stratify participants based on available study data on their health status (phenotype) or genetic risk factors (genotype), to thus recall them for further detailed investigations which would be impracticable across a whole cohort. EXCEED was purposely designed as a resource for recall-by-genotype sub-studies, and all participants have consented to be recalled on this basis.

The study is led by the University of Leicester, in partnership with University Hospitals of Leicester NHS Trust and in collaboration with Leicestershire Partnership NHS Trust, local general practices and smoking cessation services.