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Title: Vitamin D exposure and cancer incidence and mortality, all-cause mortality, and cause-specific mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Author: Murphy, Neil
ISNI:       0000 0005 0731 9847
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Despite extensive epidemiological research and plausible biological mechanisms being elucidated, it is unclear whether vitamin D reduces risks of cancer incidence and mortality. Only for colorectal cancer does the observational evidence seem persuasive, whereas for other cancer types an anti-carcinogenic role has not been established convincingly, with rarer cancers seldom investigated. Similarly, whether vitamin D has a beneficial role on other chronic disease end-points and all-cause mortality remains uncertain, despite extensive research. Prospective studies which directly measure actual circulating 25-hydroxyvitamin D (25(OH)D) are viewed as the 'gold standard' approach to assess vitamin D-disease associations. However, these studies are expensive to carry out (as circulating 25(OH)D usually has to be measured in all participants) and a single measurement of circulating 25(OH)D may not reflect long-term exposures (due to within-person variability). An alternative approach, not yet used in European populations, is to create predictor scores of circulating 25(OH)D levels. This cost effective approach provides the opportunity to examine associations between predicted 25(OH)D and multiple outcomes (including less common diseases). Sex-specific predictor scores were derived in 4,089 participants from the European Investigation into Cancer and Nutrition (EPIC) study by quantifying the relationships between correlates/determinants of circulating 25(OH)D levels (using multivariable linear regression models). The predictor scores were validated in 2,029 participants with measured circulating 25(OH)D levels. In summary, the predictor scores provided poor estimates of absolute circulating 25(OH)D levels but were more successful at ranking individuals similarly by their actual and predicted levels. The predictor scores were also able to replicate results from previous EPIC colorectal cancer incidence and prostate cancer incidence nested case-control studies which used actual circulating 25(OH)D measurements. Overall, this evidence suggests that the predictor scores may have utility for epidemiological research but not in a clinical setting. The predictor scores were then applied to the full EPIC cohort to assess the associations between predicted 25(OH)D levels with risks of cancer incidence and mortality, all-cause mortality, and cause-specific mortality. In summary, significant inverse predicted 25(OH)D score associations were observed for: overall cancer incidence and mortality; colorectal cancer incidence; lung cancer incidence and mortality; kidney cancer incidence; stomach and oesophageal cancer incidence; pancreatic cancer incidence and mortality; thyroid cancer incidence; prostate cancer mortality; all-cause mortality; circulatory disease mortality; respiratory disease mortality; and digestive disease mortality. However, due to the methodological limitations specific to 25(OH)D predictor scores - such as providing poor estimates of absolute levels - and observational epidemiology in general, it is important to acknowledge that alternative explanations may explain some or all of these observed relationships.
Supervisor: Michaud, Dominique; Vineis, Paolo Sponsor: Economic and Social Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral