Biomarkers in Nutritional Epidemiology: Applications, Needs and New Horizons
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Hum Genet (2009) 125:507–525 DOI 10.1007/s00439-009-0662-5 REVIEW ARTICLE Biomarkers in nutritional epidemiology: applications, needs and new horizons Mazda Jenab · Nadia Slimani · Magda Bictash · Pietro Ferrari · Sheila A. Bingham Received: 16 January 2009 / Accepted: 27 March 2009 / Published online: 9 April 2009 © Springer-Verlag 2009 Abstract Modern epidemiology suggests a potential many functional dietary biomarkers that, if utilized appro- interactive association between diet, lifestyle, genetics and priately, can be very informative, a better understanding of the risk of many chronic diseases. As such, many epidemio- the interactions between diet and genes as potentially deter- logic studies attempt to consider assessment of dietary mining factors in the validity, application and interpretation intake alongside genetic measures and other variables of of dietary biomarkers is necessary. It is the aim of this interest. However, given the multi-factorial complexities of review to highlight how some important biomarkers are dietary exposures, all dietary intake assessment methods being applied in nutrition epidemiology and to address are associated with measurement errors which aVect dietary some associated questions and limitations. This review also estimates and may obscure disease risk associations. For emphasizes the need to identify new dietary biomarkers and this reason, dietary biomarkers measured in biological highlights the emerging Weld of nutritional metabonomics specimens are being increasingly used as additional or sub- as an analytical method to assess metabolic proWles as mea- stitute estimates of dietary intake and nutrient status. sures of dietary exposures and indicators of dietary pat- Genetic variation may inXuence dietary intake and nutrient terns, dietary changes or eVectiveness of dietary metabolism and may aVect the utility of a dietary biomarker interventions. The review will also touch upon new statisti- to properly reXect dietary exposures. Although there are cal methodologies for the combination of dietary question- naire and biomarker data for disease risk assessment. It is clear that dietary biomarkers require much further research M. Jenab (&) Lifestyle, Environment and Cancer Group, in order to be better applied and interpreted. Future priori- International Agency for Research on Cancer (IARC-WHO), ties should be to integrate high quality dietary intake infor- Lyon, France mation, measurements of dietary biomarkers, metabolic e-mail: [email protected] proWles of speciWc dietary patterns, genetics and novel sta- N. Slimani tistical methodology in order to provide important new Nutritional and Database Resource Team, insights into gene-diet-lifestyle-disease risk associations. International Agency for Research on Cancer (IARC-WHO), Lyon, France M. Bictash Introduction Division of Epidemiology, Public Health and Primary Care, Imperial College London, London, UK Over the past decades, the Weld of nutritional epidemiology has generated a large body of evidence for a potential inter- P. Ferrari Data Collection and Exposure Unit, active association between diet, lifestyle and genetics and European Food Safety Authority (EFSA), Parma, Italy the risk of many chronic diseases. Much of the evidence relating food groups, speciWc S. A. Bingham foods and nutrients to chronic disease risk relies on infor- MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, mation gathered using various dietary assessment instru- University of Cambridge, Cambridge, UK ments, such as dietary/food frequency questionnaires, food 123 508 Hum Genet (2009) 125:507–525 diaries, food records or 24-h recalls. In most cases, these Applications of dietary biomarkers methodologies require a systematic estimation of the fre- quency of consumption and the portion size of the foods A dietary biomarker can be loosely deWned as a biochemi- consumed as well as more or less detailed information on cal indicator of dietary intake/nutritional status (recent or the recipe ingredients, combinations of foods consumed long term), or it may be an index of nutrient metabolism, or together, and cooking methods, which may aVect the esti- a marker of the biological consequences of dietary intake mation of exposure to a particular dietary component. In (Potischman and Freudenheim 2003). The main advantage addition, the estimation of nutrient intakes relies almost of—or the main assumption behind—dietary biomarkers is entirely on the existence of appropriate and reliable food that they are objective measures and are independent of all composition tables for the target population. When these the biases and errors associated with study subjects and die- issues are coupled to the overwhelming complexities of tary assessment methods (Day et al. 2001; Kaaks et al. diVerent dietary patterns, varying dietary habits, multitudes 2002; Sugar et al. 2007). An ‘ideal’ dietary biomarker of lifestyle confounders, numerous reporting biases, daily would accurately reXect its dietary intake level and it would variations in food intake, combinations of foods, timing of be speciWc, sensitive and applicable to many populations. meals, etc., it is of no surprise that all dietary assessment Existing dietary biomarkers are not ‘ideal’, but they are instruments are associated, to one extent or another, with functional and have found wide spread applicability in diVerent, and sometimes considerable, random and systematic modern nutritional epidemiology. In general, dietary bio- measurement errors. markers can be divided into several classes (recovery, pre- In fact, both nutritional epidemiologists and their many dictive, concentration, replacement) which are described in critics are acutely aware of the complexities and limitations more detail below and in Fig. 1. of various dietary assessment methods (Kaaks and Riboli One of the main applications of dietary biomarkers is to 2005; Michels 2005a, b). This reality of nutritional epidemio- use them as reference measurements to assess the validity logy is being met with intense methodological research and and accuracy of dietary assessment methods (Bingham not only are innovative methods (e.g. internet based assess- 2002; Potischman and Freudenheim 2003; Tasevska et al. ment, use of digital cameras, cellular telephones and personal 2005). The most important dietary biomarkers for this digital assistants) being developed and validated (Dowell and application are the ‘recovery’ biomarkers (i.e. doubly Welch 2006; Kikunaga et al. 2007; Subar et al. 2007; Wang labeled water which is utilized to measure the metabolic et al. 2006), but traditional ones are also constantly being rate and total energy expenditure; urinary total nitrogen/ reWned and improved (e.g. computerized 24-h recall: EPIC potassium which are utilized to estimate total daily protein Soft) (Slimani et al. 1999, 2002; Slimani and Valsta 2002). consumption and potassium intake, respectively) (Bingham More recently, various statistical techniques have also 2003; Day et al. 2001; Livingstone and Black 2003). been developed to account for some of the apparent mea- Recovery biomarkers are based on the concept of the meta- surement errors (Fraser and Yan 2007; GorWne et al. 2007; bolic balance between intake and excretion over a Wxed Rosner et al. 2008) and to better estimate usual food intakes period of time and so provide an estimate of absolute intake (Dodd et al. 2006; Tooze et al. 2006). Nevertheless, in the levels (Kaaks et al. 1997). In other words, excretion levels absence of any ‘independent’ observation of food con- are highly correlated with intake (Bingham 2002). How- sumption, true intake cannot really be assessed. In order to ever, before being applied to the task of questionnaire vali- obtain such ‘independent’ observations (i.e. uncorrelated dation, such biomarkers need to be tested in calibration measurement errors), nutrition epidemiologists have uti- studies under controlled conditions (e.g. in a metabolic lized diVerent biomarkers assessed in biological samples suite) in order to establish that their predictability in not only as measures of dietary intake and nutrient status, humans consuming varying diets is comparable to the die- but also as predictors of disease risk. tary intake method under consideration. Unfortunately, the It is the aim of this review to highlight how some impor- cost and complexity of these techniques makes them tant biomarkers are being applied in the Weld of nutrition largely inapplicable for widespread epidemiologic use and epidemiology and also to address some of the questions and they are best applied either in post hoc analyses of on- shortfalls associated with their use. There is a need to going investigations, or built-in to the design of new develop new dietary biomarkers, and in this respect, the studies, for example the use of doubly labeled water in the review will also highlight metabonomics as an analytical OPEN study (Schatzkin et al. 2003) and markers of method that can be utilized to assess metabolic proWles as potassium and nitrogen in 24 h urine collections (Bingham measures of dietary exposures and indicators of dietary pat- 2002). The recently deWned class of ‘predictive’ biomark- terns or dietary changes. Also, new statistical methodolo- ers can also be utilized to assess the degree of measurement gies for the combination of dietary questionnaire and errors in dietary assessment methods. Like recovery biomarker data will be touched upon. biomarkers,