Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer : a Mendelian randomisation analysis

BACKGROUND: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). METHODS: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. RESULTS: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown. CONCLUSIONS: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.Peer reviewe

Can regional resource shares be based only on prevalence data? An empirical investigation of the proportionality assumption

The needs component of the current formulae for allocating resources for hospital services and prescribing in England is based on a utilisation approach. This assumes that expenditure on NHS activity in different geographical areas reflects relative needs and supply conditions, and that these can be disentangled by regression models to yield an estimate of relative need. These assumptions have been challenged on the grounds that the needs of some groups may be systematically 'unmet'. Critics have suggested an alternative based on variations in the prevalence of health conditions, called the 'epidemiological approach'. The epidemiological approach uses direct measures of morbidity to allocate health care resources. It divides the total national budget into disease programmes based on primary diagnosis, computes the proportion of total cases for each programme in each geographical area, and then allocates budgets to geographical areas proportional to their share of total cases. The main obstacle to the epidemiological approach has been seen as its very demanding data requirements. But it also faces methodological challenges. These centre on the assumption of proportionality which, at the area level to which resources will be allocated, requires that the average level of need for 'cases' within each disease programme is the same in every area. We illustrate the epidemiological approach, and test the proportionality assumption underpinning it, using data from the 2002-2004 rounds of the Health Survey for England. We find regional variation in disease severity for major diseases, which suggests that health care needs for some conditions vary by area. Further analysis suggests that the epidemiological approach might systematically underallocate resources to rural areas, areas with younger populations, and deprived areas. Since the proportionality assumption underpinning the epidemiological approach does not hold, its adoption would fail to take account of variations in severity. This casts some doubt on the utility of the approach for resource allocation at the present time.Resource allocation formula Epidemiological approach Utilisation approach Proportionality Health care