in Cancer Epidemiology. 1.42.Lyon: IARC, 1997, i, Mocarelli P, Gerthoux eedham L, et al. Serum ns and breast cancer risk nen's Health Study. En- Conceptsin Cancer Epidemiologyand Etiology :ct 2002;1.10:625-28. rs CI, \Wang LE, Guo Z, :pair of tobacco carcino- PAGONA LAGIOU, DIMITRIOS TRICHOPOULOS, adducts and lung cancer idemiologic study. J Natl AND HANS-OLOV ADAMI Zzl764-72. Toniolo P, Boffetta P, man N, Hulka B, Pearce ,n of Biomarkers in Can- IARC Sci Publ No. 142. pp 1-18. Epiderniology has been a powerful tool in understanding the logic underlying cancer 'the identification of causes of infectious epidemiology, however, central concepts diseasesand the elucidation of the condi- in epidemiology-the study of disease 'We tions underlying epidemic outbreaks that etiology-will be reviewed. examine :..trefrequently, but not always, of infectious cohort and case-control studies (with spe- edology. Around the middle of the twenti- cial reference to studies of genetic epide- eth century, first in the United Kingdom miology), we considerthe impact of chance {Doll and Hill, 1950) and later in the United and systematic errors (confounding and Statesand the rest of the world (Wynder bias), and we trace the process of causal and Graham, 1950; Clemmesen and Niel- reasoning. Familiarity with these concepts *en, 1.957; MacMah on,'1.957 ), epidemi ol ogy is essentialfor critical reading and under- expanded in scope by focusing also on the standing of the chapterson specificcancers. etiology of chronic diseases,irrespective of A glossary found at the end of the chapter the nature of the causal agents. Sincethen, provides a summary of definitions for epidemiology has developed and matured words in italics. to become a rich and powerful toolbox for the study of biologic phenomenain humans. !(lith a number of fine textbooks nowa- ETIOLOGY days available to students of epidemiology instance Miettinen, 1985; Hennekens Causality {for 'S7alker, snd Buring, 1,987; 1,991,;MacMa- The definition of a causeshould apply to all hon and Trichopoulos, L996; Rothman and diseases,whether defined on the basis of a Greenland,1,998; Rothman, 2002; and sev- pafticular exposure, such as many infectious eral others), this chapter is not intended and occupational diseases,or documented to expand on methods or quantitative by ^ constellation of clinical andf or lab- considerations. For the purpose of better oratory findings-for example, malignant 1,27 t28 BACKGROUND tumors, connectivetissue disorders, or psy- the pie is complete, diseaseis, in a deter*r fFl. choses.In terms of a particular individual, ministic context, inevitable. Table 6-t prw BLNI exposure to a causeof a diseaseimplies that vides a summary of the attributes of th*'i the individual is now more likely to develop causal pie model. the diseasg-although there is no certainry Causalityis rarely,if ever,characterizedt that this will happen. The complexiry of by a simple one-to-one correspondence lx'., biological phenomena and our ignorance fween a particular exposure and a specifie or limited understanding of many of the disease.If so, the presenceof the exposure underlying processeshinder a deterministic, would be both necessaryand sufficientfsr:;, logically unassailable,explanation of dis- the occurrence of the disease.By necessary easecausation. Hence, causation of disease we mean that the disease cannot occur ion can only be conceptualizedin a probabilis- without the presenceof that exposure (al. r ;able (stochastic) tic sensethat involves srarisrical though otherexposures may be requiredfor Pre' terms and procedures. For instance, while the occurrenceof the disease).By sufficient heavy smokers are much more likely to de- we meana setof exposuresthat inevitably * Rothr velop lung cancer than nonsmokers, most producedisease. There may of coursebc smokers never develop lung cancer and some different ways by which one could get dis': nonsmokersdo. ease,and thus sufficient causesmay not k,l ing, In epidemiology, there are severalmodels necessary. con of causality that have been applied to help In cancerepidemiology, the only known, ,d. clarify the role of various exposures in the examples of exposures that are sufficient to etiology of disease.The causal pies pre- cause diseaserefer to the genetic origin of ftrtair sentedby Rothman (1976) provide perhaps some rare cancers due to dominant genei ry (al the most coherent approach to conceptual- with complete penetrance.In this instance, izing causality in a variety of epidemio- the causal pie would require only one factot , chror logic settings (Rothman, 1,986ir.Each of for the pie to be complete and this would h these pies describesa set of exposuresthat the way that carriers would get the specific, le inju work together on the same pathway to cancer. Also rare is the existenceof single:. r vel cause disease (Fig. 5-1). Different expo- factors that are in and by themselvessuffi.., 5; Ro suresmay occur within a short time span, or cient (although not necessary)for the cau-,, hon r may happen decadesapaft. Once every ex- sation of a certain disease. Even powerful ilethe, posure in a causal pie has occurred, that is exogenous factors, such as life-long heavy addit nP, cervlc; being: ncersd Figure 6.1. The causal pie modef describesa set of exposures that work together in the same the pathway to cause disease.These are hypothesized ways in which a series of exposures could ill cases. interact biologically over time to cause disease.This figure provides an example of suffi- ' m, cient causesfrom cancer epidemiology. Tobacco is an established component cause in many Ilor casesof oral cancer. However, tobacco use by itself is not enough for the diseaseto occur; in lnry cau{ addition, oral cancer can occur among people who have never used tobacco. In a given .SousalPi, causal pie, the complementary exposures can occur simultaneously, or many years apart. If In examl even one of the component causesdid not occur, diseasewould be prevented by this pathway, Iuggeste( although a person could develop the diseaseby another mechanism (a different causal pie). the first ' CONCEPTS IN CANCER EPIDEMIOLOGY AND ETIOLOGY 129 diseaseis, in a deter- Table 6-1. Aaributes of the causal pie itable. Table 5-1 pro- ATTRIBUTE DESCRIPTION the attributes of the Inevitability Completion of a sufficient cause (causal pie) is synonymous with eventual occurrence if ever, characterized (though not necessarily diagnosis) of the disease. le correspondencebe- Causality A component cause (piece of a causal pie) can involve presence of a detrimental :posure and a specific exposure or absence of a preventive exposure. senceof the exposure llurden of disease The amount of diseasecaused by a sufficient cause depends on the prevalence of all ;ary and sufficient for complementary component caus€s. 'femporaliry disease.By necessary ., Component caus€scan act far apart in time lisease cannot occur lnteraction Component causesin the same pie interact biologically to cause disease of that exposure (al- Attributable fraction Different component causesare responsible for more than 100 percent of diseasecases. esmay be required for Diseaseprevenrion Blocking the action of any component cause prevents completion of the respective disease).By sufficient sufficient cause and therefore prevents disease by that pathway. osuresthat inevitably Source: Rothman. 1976. :re may of course be ich one could get dis- :nt causesmay not be smoking, and strong geneticinfluences, like alcohol over time are contributing factors those conveyed by dominant breast cancer (component cnuses)in the etiology of oral logy, the only known genes,do not always cause diseasein an cancer.However, the oral cancerwould not s that are sufficienr to individual. have occurred in the presence of a dental the genetic origin of Certain exposuresare by definition nec- visit that could have treated precancerous re to dominant genes essary (although not sufficient) for the oc- lesionsand might haveprevented the disease. rnce. In this instance, currenceof a particular disease.For exam- \7hile smoking is a component cause in equire only one factor ple, chronic lead diseasecannot occur in the many causalpies for oral cancer,people can lete and this would be absenceof lead exposure, and a motor ve- get oral cancer without smoking, as shown would get the specific hicle injury requires the involvement of a by the second causal pie in this figure. he existence of single motor vehicle (MacMahon et aL,1,950;Hill, C by themselvessuffi- 1965;Rothman, 1.975;Susser, 1991,; Mac- Interventional Epidemiology ecessary)for the cau- Mahon and Trichopoulos, t996). Again, How do we design a scientific study to eval- sease.Even powerful while theserepresent necessory causes, there uate whether a particular exposure (for ich as life-long heavy are additional cofactors that must work in example, asbestos)is a cause of a specific concert before diseaseis inevitable. Most disease(for example, lung cancer)?To un- human cancerscan occur via severalpath- derstand the most appropriate design in ways, so it is hard to define any single practice, it is useful to begin by describing necessarycause. Asbestos, in relation to the ideal scientificstudy. Imagine for a mo- mesothelioma (cancer of the pleura), and ment that we have accessto a time machine. human papillomavirus infection, in relation In an imaginary study, we follow a group to cervical squamous cell cancer, are close of individuals from birth to death, where to being necessary.However, casesof these everyone is exposed to asbestos,and we cancersdo arisewithout the exposurebeing observe whether they develop lung cancer. documentable,either becausethe exposure We then send everyone back in a time ma- occurred but could not be identified, or be- chine, to live the exact samelives they lived, ther in the same causethese exposures are not necessaryfor except that we completely remove asbestos :xposurescould all cases. from the environment so that no one is ex- .ple of suffi- For most diseases,there is no neces- posed. r causein many one I7e then compare whether there are :aseto occur; in sary cause.Indeed there may be numerous changes in the frequency of occurrence of In a given causalpies by which diseasecan occur.