Population-Based Study Designs in Molecular Epidemiology Montserrat García-Closas, Roel Vermeulen, David Cox, Qing Lan, Neil E
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UNIT 4. INTEGRATION OF BIOMARKERS INTO EPIDEMIOLOGY STUDY DESIGNS CHAPTER 14. Population-based study designs in molecular epidemiology Montserrat García-Closas, Roel Vermeulen, David Cox, Qing Lan, Neil E. Caporaso, and Nathaniel Rothman Summary Introduction This chapter will discuss design There is a wealth of existing and by these technologies can still be considerations for epidemiological emerging opportunities to apply a classified into the classic biomarker studies that use biomarkers in the vast array of new biomarker discovery categories defined more than 20 framework of etiologic investigations. technologies, such as genome- years ago (Figure 14.1), which The main focus will be on describing wide scans of common genetic include biomarkers of exposure, the incorporation of biomarkers variants, mRNA and microRNA intermediate endpoints (e.g. into the main epidemiologic study expression arrays, proteomics, biomarkers of early biologic effect), designs, including cross-sectional metabolomics and adductomics, disease and susceptibility (10–17). UNIT 4 or short-term longitudinal designs to further our understanding of Biomarkers in epidemiological to characterize biomarkers, and the etiology of a broad range of studies can also be used to evaluate prospective cohort and case– diseases (1–9). These approaches behavioural characteristics that 14 CHAPTER control studies to evaluate are allowing investigators to explore affect the likelihood of exposure, biomarker-disease associations. biologic responses to exogenous such as tobacco smoking, as well as The advantages and limitations of and endogenous exposures, clinical behaviour and progression each design will be presented, and evaluate potential modification of disease. The use of biomarkers the impact of study design on the of those responses by variants associated with exposure, feasibility of different approaches in essentially the entire genome, disease development, and clinical to exposure assessment and and define disease processes progression within the same overall biospecimen collection and at the chromosomal, DNA, RNA design is of increasing interest and processing will be discussed. and protein levels. At the same has recently been termed ‘integrative time, most biomarkers analysed epidemiology’ (18,19). Unit 4 • Chapter 14. Population-based study designs in molecular epidemiology 241 Figure 14.1. A continuum of biomarker categories reflecting the carcinogenic process resulting from xenobiotic exposures Figure compiled from (10) and (21, copyright © 2008, Informa Healthcare. Reproduced with permission of Informa Healthcare). Regardless of the appellation The focus of this chapter is with respect to exposure variables used to describe the use of on design considerations for and intermediate endpoints, and, biomarkers in epidemiologic epidemiological studies that use in some instances, disease at a research, be it “molecular biomarkers, primarily in the context specific point in time. Short-term epidemiology,” “integrative of etiologic research, including longitudinal biomarker studies epidemiology,” or the more limited cross-sectional or short-term are studies in which subjects are “genetic epidemiology,” the longitudinal designs to characterize prospectively followed for a short successful application of new and biomarkers, and prospective cohort period of time (usually a few weeks established biomarker technologies and case–control studies to evaluate to up to a year). Investigations still depends on integrating them into biomarker–disease associations. A are usually performed on healthy the appropriate study design with description of the general principles subjects exposed to particular careful attention to the time-tested of study design (29–31) is outside exogenous or endogenous agents principles of the epidemiologic the scope of this chapter. Instead, where the biomarker is treated as method (16,20–24). Basic principles the focus is on describing the the outcome variable. These studies in vetting new biomarkers and incorporation of biomarkers into the generally focus on exposure and technologies in pilot or transitional main epidemiologic study designs, intermediate endpoint biomarkers, studies apply now more than ever pointing out the advantages and and sometimes evaluate genetic and (25–28). Understanding how to limitations of each, and showing other modifiers of the exposure– collect, process and store biologic how study design affects the endpoint relationship. samples (see Chapter 3), and the feasibility of different approaches factors that influence biomarker to both exposure assessment Questions addressed by levels, with particular attention and biospecimen collection and cross-sectional and short-term to within- and between-person processing. longitudinal studies variation for non-fixed biomarkers (see Chapter 9), are key concerns. Study designs in molecular Cross-sectional and/or short-term Testing for and optimizing laboratory epidemiology longitudinal studies are often used accuracy and precision are also as follows: critical to the successful use of Cross-sectional and short- 1) To answer questions about biomarkers in epidemiology studies term longitudinal studies with whether or not a given population (see Chapter 8). Finally, selecting biomarker endpoints has been exposed to a particular the most appropriate, effective, and compound, the level of exposure, logistically feasible study design to In epidemiological terms, a cross- the range of the exposure, and the use a given biomarker technology sectional study refers to a study external and internal determinants that answers a particular research design in which all of the information of the exposure. For instance, question remains of paramount refers to the same point in time. recent studies on haemoglobin importance. As such, these studies provide a adducts of acrylamide have shown ‘snapshot’ of the population status that exposure to this toxic chemical 242 is widespread in the general recent introduction into commerce, patterns. Sometimes a biomarker of population, due to dietary and the time between first exposure and exposure can be used only in cross- lifestyle habits (32,33). the occurrence of any chronic health sectional studies to determine if a 2) To evaluate intermediate effect is most likely too short. In this population is exposed to an agent of biologic effects from a wide range particular example, the assessment concern, or used as an independent of exposures in the diet and of preclinical indicators of disease marker of exposure in studies environment, as well as from lifestyle (e.g. markers of pulmonary evaluating intermediate biomarker factors (e.g. obesity and reproductive inflammation) in asymptomatic endpoints. status). This design can be used individuals would be of importance The applicability of exposure to provide mechanistic insight into to identify potential adverse health biomarkers in cross-sectional well established exposure–disease effects at an early stage. studies depends on certain intrinsic relationships, and to supplement 4) To study changes in exposure features related to the marker suggestive but inconclusive evidence and/or intermediate endpoints to itself (e.g. half-life, variability, and on the possible adverse health determine the effectiveness of specificity of the marker) and the effects of an exposure. For instance, intervention studies. For instance, exposure pattern (see Chapter 9). studies have used haematological the effect of exercise and weight The first requirements for successful endpoints to investigate the effects loss interventions on serum application of an exposure marker of benzene on the blood forming levels of four biomarkers related are that the assay is reliable and system at low levels of exposure to knee osteoarthritis (cartilage accurate (see Chapter 8), the marker (34,35). These studies have found oligometric matrix protein (COMP), is detectable in human populations, decreased levels in peripheral blood hyaluronan, antigenic keratin and important effect modifiers (e.g. cell counts at exposures below 1 sulfate, and transforming growth nutrition and demographic variables) ppm, indicating that at low levels of factor-β-1 (TGF-β1)), and clinical and kinetics are known (20). Second, exposure, perturbations in the blood outcome measures (e.g. medial joint the timing of sample collection in forming system can be detected. space, pain) were examined (37). combination with the biological half- These results hinted at the possibility Intervention programmes indeed life of a biomarker of exposure is key, of increased risk of leukaemia at resulted in changes in COMP (which as this determines the exposure time low levels of benzene exposure, was associated with decreased knee window that a marker of exposure given the putative link between pain) and TGF-β1. reflects. The time of collection may benzene poisoning (a severe form of be critical if, as is often the case in haematotoxicity) and increased risk Cross-sectional and short- cross-sectional studies, only one for leukaemia. term longitudinal studies using sample per subject can be obtained 3) To evaluate whether or not exposure markers on a given occasion, and if the there are early biologic perturbations exposure is of brief duration, highly caused by new exposures, or recent Biomarkers of exposure measure variable in time, or has a distinct changes in lifestyle factors that have the level of an external agent, exposure pattern (e.g. diurnal not been present long enough to have