Application of biomarker-based assessment of dietary patterns to nutritional epidemiology: observational and interventional investigations with a focus on the Mediterranean diet and type 2 diabetes
Existing evidence on healthy dietary patterns suggests that they are modestly inversely associated with incidence of common non-communicable diseases, and in particular cardiometabolic diseases. Trials are rarely feasible to assess causality of these relationships which motivates leveraging observational data with improved methodological approaches. In this PhD thesis, I attempted to address the common limitation in nutritional epidemiology of subjective assessment of adherence to dietary patterns. Chapter 2: I conducted a systematic review of the effects of Mediterranean diet interventions on nutritional biomarkers. I identified 29 trials reporting on 25 biomarkers eligible for meta-analysis (5-18 studies available per biomarker). Circulating carotenoids, vitamin C and fatty acids emerged as candidate biomarkers of compliance. Effect sizes were mostly small which likely reflected the multifaceted nature of whole diet interventions and insufficient validity of single analytes as biomarkers of adherence to the Mediterranean dietary pattern. Chapter 3: I used the EPIC-InterAct case-cohort study which measured nutritional biomarkers at scale (~13,000 subcohort participants and ~9,000 incident type 2 diabetes cases) to evaluate the utility of combining them into biomarker scores predictive of adherence to dietary patterns, and to test their associations with incidence of type 2 diabetes. The available biomarkers included circulating carotenoids, vitamins C and 25(OH)D, fatty acid profiles, iron status biomarkers and cations. The dietary patterns of interest were the Mediterranean diet, alternative Healthy Eating Index-2010 and the Dietary Approaches to Stop Hypertension. The analyses showed modest correlations of the biomarker scores with their respective dietary patterns (r ~0.3) and statistically significant inverse associations with disease risk (hazard ratios ~0.8 per standard deviations of the scores). Chapter 4: I established a collaboration with one of the randomised trials identified in Chapter 2, the MedLey trial, to address the limitations of internal derivation and validation of the biomarker scores. It compared the effects of a partial-feeding Mediterranean diet intervention with continuation of habitual diet in Australia on circulating carotenoids and fatty acids, 29 of which overlapped with those available in EPIC-InterAct. Using end-of-trial biomarker concentrations as predictors of the randomised assignment (n = 128), I developed a biomarker score which discriminated well between the trial arms (C-statistic = 0.88). It was robustly inversely associated with incidence of type 2 diabetes in EPIC-InterAct (hazard ratio 0.71 per standard deviation; 95% confidence and prediction intervals: 0.65-0.77 and 0.55-0.91). Chapter 5: I additionally used the combined InterAct-MedLey data to test generalisability of biomarker scores of the Mediterranean diet. I derived a series of biomarker scores predictive of self-reported adherence to the Mediterranean diet in EPIC-InterAct countries, the MedLey trial baseline sample, and non-InterAct participants of the EPIC-Norfolk cohort (~5,000 with relevant biomarkers). Controlling for multiple testing, values of 8/13 biomarker scores were higher in the Mediterranean diet intervention than the control group of the MedLey trial, and 10/13 scores were inversely associated with incidence of type 2 diabetes in EPIC-InterAct. Chapter 6: In the EPIC-Norfolk study, I investigated the impact of expanding a base set of predictors from circulating carotenoids and fatty acids with additional groups of nutritional biomarkers (urinary sodium, potassium and sugars, urinary and serum phytoestrogens, circulating vitamin C, iron status biomarkers, cations and stable isotopes) or using metabolomics on (i.) the correlations between self-reported Mediterranean diet and its biomarker scores and (ii.) the associations between the biomarker scores and incident cardiovascular disease, cancer, type 2 diabetes and mortality (n range ~500-11,000). The base set biomarker score had a moderate cross-validated correlation with self-report (r = 0.40) and the performance was similar or decreased with inclusion of additional nutritional biomarkers (r range: 0.30-0.41) and modestly improved with metabolomics (r = 0.46). Biomarker scores were inversely associated with disease and mortality outcomes, and use of different sets of biomarkers modified the strength of association for few diet-disease associations. Inverse associations were notably stronger for type 2 diabetes (hazard ratio ~0.80 per standard deviation of biomarker scores) than for other outcomes (range ~0.90-0.95). Chapter 7: I conducted an outcome-wide analysis of 27 incident noncommunicable diseases in the EPIC-Norfolk study using as exposures the biomarker scores derived throughout the thesis (n range ~7,000-11,000) and dietary self-report of the Mediterranean diet (n ~22,000). Controlling for multiple testing, inverse associations were robustly detected across ≥2 of 4 methods of exposure assessment for type 2 diabetes, chronic obstructive pulmonary disease, and heart failure. At the nominal α = 0.05, corresponding relationships were identified for ischaemic heart disease, renal disease, oesophageal and stomach cancers, and cataracts. This PhD identified combinations of nutritional biomarkers as plausible biomarkers of the Mediterranean diet for application in epidemiological investigations. These findings contribute towards development of methods of objective assessment of diet and strengthen the evidence on the inverse relationship between the Mediterranean diet and cardiometabolic disease.
Epidemiology, Mediterranean diet, Nutrition, Nutritional Epidemiology, Type 2 diabetes
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