Lectura No.2 Causas

8/13/2019 Lectura No.2 Causas

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40 Evilutumol Epidzmufurycdcas

IIIi

Artrucrn Jounnrr,or Eportrctocvcopyright@ 9?6bv Thc JohnrHoplinr univcnity school f Hygiena nd public Hcalth

CAUSESKENNETH J. ROTHMAN

The conceptual framework for causespresented here is intended neither as a. review nor an ex;iansion ofknowledge, butrather as a viewpoint which bridges he gapbetween metaphysical notions of causeandbasicepidemiologic parameters.The focus,then, is neither metaphysics nor epidemiol-ogy, but the gulf between them. In thesame spirit as recent discussionon thesepages about definitions of basic epidemi-ologic lerms such as rate (l), commonagreementon the conceptual nterrelation-ihip of causesmay facilitate communica-tion about causesof illness.A strong motivation for presenting thisscheme is the often-heard confusion of twoimportant l. . t distinct epidemiologicissues: confounding and effect modifica-tion. These two properties of variablehave different areas of relevance (2). Theconfounding property is not an intrinsiccharacteristicof any variable. Confounding.defined as distortion in an efl'ect measureintroduced by an extraneous variate, oc-curs only in the contert of a particularstudy, and the same variable which con-founds in one study may not confound thesame association in another study,setting.

V o l . 0 { . N q . 6It inted n IJ.S.A.

In fact, the principles f good tudydesignmay call for.preventing potentiallycon-founding variable from beingconfounding-for erample,by matching n the selectionof subjects.On the otherhand,reffectmodi-ficatlC& defined as differing valuesof th-eeffect measureat different evelsof anothervariate, s an inherent haracteristicf therelationship between wo causesof anillness (effect). This relationship s notgoverned y the particulars fany study; tis an unalterableactofnature.To be sure,the magnitudeof effect modificationde-pends on the scaleof measurementf theeffect-for example,a risk ratio which isconstantover agegenerallympliesa riskdiffc:o-ncewhich changeswith age.But ithas beenproposed hat the risk differencescale s the appropriate cale or assessingeffectmodification,otherscales epresent-ing metameters f the risk difference hichdistort to varyingdegreesheassessmentfeffect modification (3). Effect modifiersmay o; may not beconfoundersn a given

study, or they may confound in somestudiesbut not in others.Conversely,on-foundersmay or may not be effectmodifi-ers. The following discussion resentsascheme or the interrelationship f causeswhich may providea usefulway or think-ing about effectmodification s a descrip-tion of nature.Depanment of Epidemiology, Harvard School ofPublicHealth 67? Huntin4on Avenue,Boston,MA02r 5.

87


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Is.rurs n C,ausal nferent:e 4I588

Typss oF cAUsEsA cause is an act or event or a stdte ofnature which init iates or permits, alone orin conjunction with other causes, asequenceof events resulting in an effect. Acause which inevitably produces he effecris sufficient The inevitability of diseaseafter a sufficient cause calls for qualifi-cation: disease usually requires time tobecome manifest, and during this gesta-tion, while diseasemay no longer be pre-ventable, it might be fortuitously cured, ordeath might intervene.Common usagemakes no distinction be-tween that constellation of phertomenawhich constitutesa sufficient causeand thecomponents of thefOnstellqtion which arelikewise referred to as "causes". Anotherqualification for sufficient causes s restric-tion to the minimum number of requiredcomponent causes; this implies that thelack of any component cause renders theremaining component catises nsufficient.Thus, measles virus is referred to as thecause of measles, whereas a sufficientcause for contracting measles involveslack of immunity to measles virus and

possibly other factors in addition to ex-posure to measles virus. The term ccuse,then, does not specify whither the refer-ence is to q-sufficient causeor to a compe-_n lr-t_f_e,stltfiqlgn{ cause-.Mosr causes that are of interest in thehealth field are components of sufficient'causes, but are not sufficient in them-selves.Drinking contaminatedwater is no tsufficient to producecholera,and smokingis not sufficient o produce ung cancer,bu tboth of theseare componentsof sufficientcauses. Identification of all the compo-nents ofa given sufficientcause s unneces_sary for prevention, in that blocking thecausal role of but one component of asufficient cause enders he joint action ofthe other cornponentsnsufficient,and pre-vents the effect.Even without beingable toidentif l ' the other components f the suffi-cient cause or lung cancer,of which smok-ing is one component. it is possible to

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Ertolocrc FRAcrto\-Causal research f diseaseocuses ncomponents f sufficientcauses. hethernecessaryr not.The publichealth mpor-tanceof a component ause f diseasen aparticularpopulations determined v thefraction of the diseasethe effect)whichresults from the sufficientcauses(sl owhich the component ausebelongs. heepidemiologicarameterg;[jologict'racton

prevent those casesof lung cancer whichwould result from that sull jcient causebyremovingsmoking rom the constellationoIcomponents.A specific effect may result from a vari-ety of different sufficient causes.The dif-ferent constellationsof component causeswhich produce the effect may or may nothave common elements. If there e*irt, "component cause which is a member ofevery sufficient cause,such a component istermed I p;ece5t1ry .^&'rsc Necessarvcausesare often identifiable as part of th;definition of effect. For example, the pos-sessionof a vermiform appendix is neces_sary for appendicitis, and infection withthe tubercle bacil lus is a necessary ausefor'tuberculosis.Though sometimes devoidof useful significance, a necessary causecan be a uspful component cause to iden-tify. Whereas many different componentcauses have been identified for severaltypes of cancer, the hope exists for identi-fication of a final common pathway repre-senting a necessarycause or cancer of al ltypes.Figure I is a schematic llustration of the

causal componentsof a disease.The dis-ease (effect) has three sufficient causalcomplexes, each having f ive componentcausqs. n this scheme "A" is a necessarycause,since t appears s a memberof eachsufficient cause. On the other hand, th ecomponent causes "B", ..C" and .,F'.,which eachappear n more than one suffi-cient cause, are not necessarv causes.because they fail to appear in all fhreesufficient causes.


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47 Eu,llni,n t,f Epidtmi,,hrytc dc:as

SUFFICIENTCAUSEI

llxpqprdal$na$dbllleuErhj ) meas resthis dimension of a cause-effectrelation-ship. Each component of a sufficientcausehas,as its etiologic fraction, the fraction ofdiseaseattributable to that sufficient cause(plus the fraction attributable to any othersufficient causes which contain the samecomponent). Consider, for example, thecausesschematically represented n figure1. If Sufficient Cause I accountsfor 50 percent of a disease,Sufficient Cause I 30 percent, and Sufficient Cause III 20 per cent,the etiologic fractions for each of the com-ponent causesare: A, 100 per cent; B, 80per cent; C, ?0 per cent; D, 50 per cent; E,50 per cent; F, 50 per cent; G, 30 per cent;H, 30 per cent; I, 20 per cent; and J, 20 percent. (The example would have to bemodified slightly if there were individualswith more than one sufficient causebecause or these peop.le locking one suffi-cient cause would not prevent disease.)This example illustrates that the sum ofetiologic fractions of a set of factorsis notlimited above by unity, as is obsewedwithalcohol and tobacco as etiologic agents formouth cancer, each having an etiologicfraction greater than 50 per cent.

RIsxThe notion of a risk_a_q_ cont_inugusm-easureobscures the concipt of risk- as

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Ftcuna 1. Conceptual scheme for the causcs ofa hypothetical disease.

-app -edg an indigidual- For an individual,rrsk lbr disease properly defined takes ononly two values: zero and unity. The appli-cation of some intermediate value for riskto an individual is only a nieansof estimat-ing the individual's risk by the mean risk ofmany other presumably similar individu-als. The actual risk for an individual is amatter of whether or not a sufficient causehas been or will be formed, whereas themean risk for a group indicates the propor-tion of individuals for whom sufficientcausesare formed. An individual's risk canbe viewed as a probability statement aboutthe likelihood of a sufficient cause fordisease existing within the appropriate'----:eframe.SrRpxcrH oF A CAUSAL ISKFAcroR

The model proposedalso illustrates howcharacterization of risk factors as "strong"or "weak" has no universal basis.A compo-nent causewhich requires, to cornplete thesufficienc cause, other components withlow prevalence is thereby a "weak" (com-ponent) cause. The presence of such acomponent cause modifies the probabilityof the outcome only slightly, from zero. oan average value just slightly greater thanzero, reflecting the rarity of the comple-mentary component causes.On the otherhand, a component cause which requires,


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590 KHNNI: 'I 'H.,to complete the sufficient cause, othercomponentswhich are nearly ubiquitous isa "strong" (component)cause. n epidemi-ologic terms, a weak cause confers only asmall increment n disease isk, whereasastrong causewill increasedisease isk sub-stantially.

Thus the strength of a causal risk factordepends on the prevalenceof the comple-mentary component causes in the samesufficient cause. But this prevalence isoften a matter of custom, circumstance orchance, and is not a scientifically general-izable characteristic. Consider the follow-ing simplified example (5): in a societywhere most people eat high phenylalaninediets, inheritance of the (rare) gene forPKU would appear to be a "strong" riskfactor for phenylketonuric mental retarda-tion, and phenylalanine in the diet wouldappear to be a weak risk factor. In anothersociety, however, in which the gene forPKU is very common and few people eathigh phenylalanine iets, nheritanceof thegene would be a weak risk factor and phen-ylalanine in the diet would be a strong riskfactor. Thus, the strength of a causal riskfactor, as it might be measured by the"risk ratio" (relative risk) parameter, isdependent on the distribution in the popu-lation of,the other causal factors in thesame sufficient cause. The term strengthof a causal isk factor retainssome meaninga: a description of the public health im-portance of a factor. However, the commonepidemiologic parlance about strength ofcausal risk factors is devoid of meaning inthe biologic description of diseaseetiology.

. SYNencv-S ne 91,,a so t-qrm-e e l eq -mod fi at g1ror posrtlve nteractlon. may be dettned al ;

the relationshipbetrveen actors rvhich ex -hibit a joint effect hat exceeds he sum oithe separateeffects, vith'the effects mea-sured on an appropriate scale (3,6). S-vn-ergy implies that two component causesare membersof the same sufficient cause.Neither of nvo suchcausalcomponentsof a

, R(}THMA:\sufficient cause can have any effect (asparr,of that sufficient cause)without thepresenceof the other causal comp


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44 Evtiutv,n ,l Epid,emtriogr &as(;ArsEs ltgl

completelysynergisticwith each other and part of causal chains which lead t, aneach s-part ia l ly ynergist ic i th "A" , "B" element being included jn a suf l ic ientand "C" ' Part ia l synergyexists between cause; hejo intact ionof thecomponentsof8" and "C"-their ef fect s dependenton a sufficient cause could be consideredantheir joint presence n one sufficient cause, effect with its own constellationsof suffi-but each also has independent effects in cient causes. Alternatively, the differentanother sufficient cause. The extent to "pies" in figure I might beconstructed sawhich two factors are synergisticdepends, sequenceof causal events, with branchinglike the strength of a causal risk factor, on p"ih*"y, representing those segments ofthe distribution of other factors n a partic- pies which diff"r, ,ru."rsary causes beingular population. Considersynergybetween common to all pathways,eti. fne por.iUit-factors "8" and "F" in figure 1. This ities for adapting this framework to vigu-synergy results from both factors'presence ally any complicated causal relationshipin Sufficient Cause I, atthough "8" exerts reinforcl its uiility as an intuitive base fora separateeffect in Sufficient CauseI, and causal thinking.F" in Sufficient Cause II. In a population The model ilso provides a conceptualwhere factor "H" were absent, ';B" and framework for the understanding of latentF" would exert their "{ft_._t-rnly through neriod, the time interval between thesufficient causes I and III, because tf,e acdion "r " r.".ponentr cause and theabsenceof "H" would eliminate any dis- manifestation of disease.When a compo-ease from Sufficient Cause II. Thus, "8" nent cause ,,actsl, or occurs, the otherand "F" would be completely independent. components needed to complete a suffi-In another population in which factor "c" "i"ni ""u."1 -", ,* be on hand. u the*'ere absent' all diseasewouid result from component cause of interest has a long-Sufficient Cause I, and ..8" and ,.F" would f"rtiifll.ife;; , ;. rime passes he otherbe fully synergistic. complementar_v omponentsmay add theirAn example of incompletesynergywould ..effects,,and jradually complete the suffi-be the mixture of independent and interac- cient cause.ni tne point in time at whichtive effects that alcohol consumption and the sufficient cause is completed. the dis-smoking have on risk of mouth and phar- ease process s set in motion, though usu-ynx cancer (7)- Evidence suggests that ally not yet manifest. The latent plriod iseither of these factors will increasecancer the interval ariits *hi"tt a sufficient causerisk in the absenceof the other, but the accumulates plus the time it takes for thecombined effect of both exceeds he sum of disease o becomemanife-;. Early recogni-the individual effecrs.This would suggest tion could theoretically reduce the latentat least three different causal compleies, period to coincide with the interval duringone involving alcohol but not smoking, one which the sufficient causeaccumulates.involving smoking but not alcohol, and one For some diseases, uch as rabies.virtu-involving both. (some scientists have allythe "rtir; ;;;; from internatiring rhearguedthat alcohol n the absenceof smok- viral agent to ihe occurrenceof s-vmptomsing has no effect, which leads to a model represents time during rvhich the diseasewith two sufficientcauses' ne with smok- becomes "nii.ri f .cause ..internalizing..ing but not alcohol,and another with both the viral "s;ni is effectivel,va sufficientcause (a qualif ication rvouldbe that inter-smokingand alcohol . )

DrscussroN entive treatment during the ..incubation... rhe oncepruarchemen igurecourdfiil:"T',t#"ffiil:j]'n ii#.1;l1Tl;be modified o permitgreatercomplexity. the 10-20-yearatent period or the de'el-Antagonisticauses ightbe ncluded sa opment of vaginal cancer after n utero


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exposure to diethylstilbesterol probablyrepresents accumulation of a sufficientcause (which might ordinarily be com-pleted at menarche or during adolescence)with only a few years for the disease o be-come manifest after the sufficient causeis complete. The term incubation geLio(thas often been applied'to the period be-tween the accumulation of a sufficientcause and the time at which diseasebe-comes manifest. Because reversal of dis-ease may be possible during the preclin_ical development, as in the example ofrabies treatment, or catalysts may act toshorten the incubation period of diseaseswhich might otherwise fester in a preclini-cal state interminably (growth enhancersfor neoplasmsare an example), it might bebetter to view the latent period as olelythe accumulation of a sufficient ""ur",components of which might include devel-opmental catalysts and/or the lack of inter_ventive treatment.Chronic exposuresmake it more difficultto quantify, and, indeed, to conceptualizelatent period; different dosesof an expo-sure accumulated over time may give riseto different risks. Such situations may beviewed as reflecting a set of different suffi-cient causes,each with a different dose ofthe exposureas a component cause.Srnaltdoses would presumably require a morecomplex set of complementary componentcauses to complete the suffic.,-r.t causethan large doses. This extension of thecausal model accommodates the descrip-tion of dose-response elationships, andprovides a basis for the common findingthat for many carcinogens the dose is rellated directly to risk and inversell,to Iatentperiod.

KI:NNT:TH. ' .ROTHMANThis presentation dtrs not treat the

subtle issueswhich arise in arriving at aworkabledefinit ion of disease. uch issuesobviously pertain to a full considerationofcauses, nasmuch as disease efinition maybe based on experiential criteria (S), buttheseconsiderationsgo beyondthe scopeofthis paper.It might be argued that the schemepresented here is superficial beceuse iheoccurrence of disease in any individualinvolves a collection of component causeswhich constitute a sufficient cause that isunique, by its complexity. Individuallyunique sufficient causes,however, woulddetract equally from all generalizedcausalmodels. Furthermore, despite individualdistihctions it seems likely that therewould be broad similarities in the compo_nents of sufficient causesor different indi-viduals.

RersRrNcesl. Elandt-Johnson RC: Definition of rates: Someremarks on their use and misuse.Am J Epidemiol102:267-271, 19752. Miettinen OS: Confounding and effect modifica.tion. Am J Epidemiol 100:3iG-3b3, 9? 43. Rothman KJ: Synergy and antagonism in cause.effect relationships. Am J Epidemiol 99:3g5_3gg.t9744. Miettinen OS: Proportion of diseage caused orprevented by a given erposure, trait, or interven-tion. Am J Epidemiol 99:325-332, 9? 4

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5. MacMahon B: Gene-environmentnteraction nhumandisease. PsychiatRes6 (supp ):l9S-402.19686. RothmanKJ: Estimationof synergy nd antago_nism.Am J Epidemiol103:506-5il,19267. RothmanKJ, KellerAZ: The effectof oinr expo-sure o alcohol nd obacco n riskof cancer f ihemouth and pharynx.J. Chronic Dis 25:7il-716.t9728. MaclUahonB, PughTF. Epidemiologl.. rincrolesand Methods.. oston, it t le. Brownand CLm.pany. 9?0


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t-7.Kenneth . Rothman:Causes.American ournalof Epidemiology 976; 04:58?-592.

Rothman's Causes" is an exceptionally ucid outline of a point of view regardingcausarionthat has come to be known as rhe "sufficient/compon.nt ."ur. theory." r07hii-ethe iheory is aclear descendantof ideas n earlier works (suchas MacMahon and Pugh's),t wasRoth*"n *hofirst presenteda generalschematic orm for deducing the relationshifsbetween h. occurr.rrceof component causes nd epidemiologicmeasuresof effect.This schematic orm, illusrrated nFig_ure of the paper,allowsone to visualize and thus makeprecise)he meaning'of t..rns ,rchas "synergy" (which, under the theory, becomesco-participation n a sufhcient ause).I do haveone semanticcriticism of the paper:Af the start of the usynergy"section,Rorhmanequated synergy'with "effectmodi6cation." It is clear o me, howev.r, i'r"r i'Mietrinen's originaluseof the term, and much of the usagesince,"Cfrect6odi6cation" meansonlv "differins valuesof the e6-qcL.m""sure t differg-gq.-levrl"f-another.yariare,' to quote from th. introJulrf;;iKothman's paper.As Rothman noted, this implies that the effectmodifcation dependson thescaleof measurement. t follows then that "effict modification" cannor in general or..spond ro"sJnerqy]or co'partjcipation n a sufficientcause,, lthough, asRothman wasaware, ertain rype,.of modification of the risk differencewould imply the pr.t.n.. of synergisricnteracrions.Moreimport antl y, ffeg m od i cation' as dqfinedis [email protected]*"is.q-prooertvgk*ntsln uwvfrit4LsJMiettinen, 19821.Perhapsatl thii only poinrs;G;i; ,fi,"eftect modihcation' was a poor term to choose for the phenomenon of effict-measureiariarionacrosspopulations,since it evokes he concept of synergy.Reference:MiettinenOS.Causal ndpreventiventerdependence:lemenraryrinciples.cand WorkEnyHlth lggZ;8:159-168. I

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Lectura No.2 Causas