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Design Considerations in Molecular Epidemiology

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Design Considerations in Molecular Epidemiology ,l DesignConsiderations in Molecular Epidemiology MontserratGarcia-Closas, Qing Lan, and Nathaniel Rothman Divisionof CancerEpidemiology and Cenetics,National Cancer lnsttute, Departmentof Healthand HumanServices, Bethesda, Maryland, U.S.A. INTRODUCTION There is a wide range of biomarkers that can be used in population-based molecular epidemiological studies of cancer. These include biomarkers of exposure, intermediate endpoints (e.g., biomarkers of early biological effect), disease, and susceptibility (1-7) (Fig. l). Hypothesis-driven biomarkefs have been used for many years in molecular epidemiology studies of cancer (e.9., measurement of xenobiotics and endogenous carcinogens, macromolecular adducts, cytogenetic endpoints in cultured lymphocytes, DNA mutations in tumor suppressor genes, and phenotypic and genotypic measures of genetic variation in candidate genes). Perhaps the most revolutionary change that has occurred in molecular epidemiology in the past several years has been the emergence of discovery technologies that can been incorporated into a variety of study designs and include genome-wide scans of common genetic variants, messenger RNA (mRNA) and microRNA expression rurays, proteomics, and metabolomics (also referred to as metabonomics) (8-14). These approachesare allowing investigators to explore biological responsesto exogenous and endogenous exposures,to evaluate potential modification of those responsesby variants in essentially the entire genome, and to define tumors at the chromosomal, DNA, RNA, and protein levels. At the same time, with the incorporation of more powerful technologies into molecular epidemiology studies, there has been greater concern that the rights and confidentiality of study subjects be protected. A discussion of informed consent is outside the scope of this chapter, but we do note the critical need to consider ethical issuesand informed consent proceduresat the outset ofdesigning a study. The focus of this chapter is on design considerations for epidemiological studies of cancer that use biomarkers primarily in the context of etiological research. We first discuss the advantagesand disadvantages of classical epidemiological study designs for the application of biomarkers. We then describe biospecimen collections and sample size requirements for certain types of molecular epidemiology studies. Garcia-Closas et al' SUSCEPTIBILITY Exposure + reflecting the carcinogenicprocess resulting from Figure 1 A continuum of biomarker categories xenobiotic exposures.Source" From Ref' l ' STUDY DESIGNS IN MOLECULAR EPIDEMIOLOGY (fS-tZ) is outsidethe scopeofthis A descriptionofrhe generalprinciples ofstudy design and disadvantages of classical chapter. Instead, we will discuss the advantages epidemiologicalstudydesigns(i.e.,cross-sectional,case-control,andprospectivecohort) use of biological specimens'Potential that are particularly relevait to the collection and arise becauseof advancesin new biomarkers for epidemiologicalresearch continually laboratory techniques'when a the understandingof dir"ur" eti,ologyand in molecular some very basic issues'such as promising new biomarker emergesiio. ttt. laboratory, before considering its application in assayaccuracy and reliability, ieed to be assessed biomarkers for use in stuaies it). iit"t" initial efforts to characterize "pial*iorrgicat studiesby someinvestigators (18',1)' epidemiologicalstudies rtuu" u""n calledtransitional the critical need to characterizethe a term that serves to heighten awarenessabout before they are used in molecular determinants of biomarker levels and assays biological samples' In this epidemiological studies with precious, nonreplenishable for the use of biomarkersthat have section,we will focus on studyiesign considerations alreadYbeen characterized' Cross'sectionalStudies with BiomarkerEndpoints interest in studying the relationship Cross-sectionalstudies are used when there is and a biomarker' which is between particular or demographiccharacteristics "*forur", generally carried out on healthy subjects' treated as the outcome variable, and are can be measuredat one or several Biomarkers of exposureand intermediateendpoints in the exposureand intraindividual points in time, dependingon the temporal variauility variation in the resPonse' Thestandarddesignistohaveonegroupof..exposed''studysubjectsanda drawn from-the same basepopulation comparably ,ir"o groufif "unexposed"subjicts, sex, and tobacco use, to improve and often matched on several factors, such as age, short halflives and a population efficiency. When biomarker endpointshave relatively design can be used' where subjects can be studiedbetore blgins, an alternative "*po.ur. aresampledbefore"*p*o,.beginsandagainafteranappropriatelengthoftime. Cross-sectionalstudiesgenerallyfocusonbiomarkersofexposureandintermediate a study populationhas been exposed endpoints.This design is ofte"nused todetermine if and the determinantsof the exposure to a particulu. the level of exposure, "o*iound, (22,23),andsometimesisusedtovalidatevariousapproachestomeasuringexternal 3 in MolecularEpidemiology a-Closas et al. Design Considerations Biomarkers of exposure, exposure (e.g., questionnaires, environmental monitoring). of exogenous or endogenously discussed in chapter 7, measure internal exposure levels tissues or body fluids. A wide range of exposures can be froduced compounds in either nutrients, infectious agents' and measured biologically, including environmental factors, endogenouscomPounds. endpoints from cross-sectional studies also can be used to evaluate intermediate \ as well as from lifestyle ----+loisease exposures in the diet, general environment, and workplace, design can be used to provide I factors such as obesit/and reproductive status. This relationships and to supple- mechanistic insight inio well-eitablished exposure-disease essresulting from of an exposure (24)' As ment suggestiveLut inconclusive evidence of the carcinogenicity that use cancer endpoints' In such, they complement classic epidemiological studies clues about the carcinogenic addition, intermediate biomarkers can provide initial (1'6'25-27)' potential of new exposuresyears before cancerdevelops biological effect (l'28) One group of interr"iiut" biomarkers, biomarkers of early (Fig.1),generallymeasuresearlybiologicalchangesthatreflectearly,nonclonal,and effect biomarkers include the scope of this generally nonpersistent effects. d^umpt"i of early biological alterations, DNA, RNA, and protein ;es of classical measures of cellular toxicity, chromosomal (e.g., altered DNA repair' lspective cohort) expression and early nonneopLstic alterations in cell function effect markers are measured in :imens. Potential altered immune function). denerally, early biological (e.g', blood cells, white blood cells' : of advancesin substancessuch as blood and blood components red rniques. When a DNA,RNA,plasma,sera)becausetheyareeasilyaccessibleandbecauseinsome as surrogates for other organs' c issues,such as instances it is reasonable to assume that they can serve in other accessible tissues such as its application in Early biological effect markers also can be measured surface tissue scrapings or sPutum arkers for use in skin, ceruical and colon biopsies, epithelial cells from cells in feces, and epithelial cells in stigators(18-21), samples, exfoliated urothefi;l cells in urine, colonic include measures of circulating characterize the breast nipple aspirates. other early effect markers have epigenetic effects on cancer ld in molecular biologicaily active compounds in plasma that may samples. In this devel-opment(e. g., hormones, growth factors, cytokines)' narkers that have Cross-sectionalstudiescanalsobeusedtoextensivelyevaluatethegenetic the candidate gene approach has determinants of a biomarker endpoint. Traditionally, beenemployed,wherefunctionalorputativelyfunctionalvariantsinbiologicallyrelevant levels (22,23,29)' with genes are analyzed to determine how they influence biomarker generation of studies is being the advent of genome-wide scanning technology, a new of genetic variants for their launched that will agnostically-on evaluate a large number 1 the relationshiP include classic genotoxicity' potential influence biomarker endpoints. These )marker, which is a new generation of assays cytogenetic, hematological, and immunological biomarkers; healthy subjects. alterations such as telomere that include measures-of genomic stability and epigenetic at one or several identified by discovery and global methylition status (30-32); and biomarkers urd intraindividual length technologies described earlier' a Adistinctadvantageofthecross-sectionalstudyisthatverydetailedandaccurate ly subjects and past exposure patterns (23,33) and information can be collected on current as well as re base poPulation sample size in these studies potential confounders and effect modifiers. Further, as o use, to imProve prospective cohort studies, it is typically can be much smaller than in case-control or ; and a poPulation processing of biological to invest substantial resources into very extensive ed, where subjects feasible samples,oftenbeyondwhatresourcesallowinalargerstudy.Thisalsoenablesan ngth of time. to be collected and of new technologies that require biological samples e and intermediate evaluation processedin very precise and intensive ways (23'33)' r has been exPosed is that it is often unknown if At the sametime, an important caveat in thesesstudies Its of the exPosure (25)' As such' biomark", und", study is predictive of developing
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