Commentary

What can variations in cJiseaseoutcome teii us about risk?

Firoze MarijT and Nico Nagelkerke^'International Development Research Center,Healtb Sciences Division, Regional Office forEastern and Souttiern Africa, PO Box 62084,^Kenya Medical Researcti Institute, MedicalResearch Centre, PO Box 20752, Nairobi,Kenya

In recent years there has been a growinginterest in risk assessment in dental dis-eases, with several major internationalconferences held to address the issue. Theidentification of risk factors and/or riskgroups is of interest for two principalreasons: first, knowledge of risk factorscan shed light on the etiology of the dis-ease; secondly, knowledge of risk factorsmay provide guidance as to priorities inthe allocation of resources. In the searchfor predictors of disease, it has often beenassumed that considerable informationabout potential risk factors may begained by examining the distribution ofthe outcome variable (disease) in a pop-ulation. In this paper we consider someof the problems of doing so.

It may be useful to begin by sayingthat risk should be distinguished fromouteome. Risk is the probability of anoutcome rather than the outcome itselfWhen tossing a coin, the probability ofheads or tails is fixed (e.g. 0.5), but theoutcome varies. The reason for this isthat we cannot make any better predic-tion of the outcotne of the toss than the"mean". It is important to note here thatit is of no concern whether the outcome isthe result of intrinsically random events(e.g. as is, according to quantum theory,the outcome of atomic events), or wheth-er the influences on the outcome aremany and unknown, turning a theoreti-cally deterministic event into an effectiye-ly random one.

Risk is not something that exists inde-pendent of the knowledge of the personwho assesses it. For exatnple, considertwo tumors, one benign and the othermalignant, occurring, say, with the samefrequency. If we were ignorant as to thedistinction between them, we would con-sider both as one clinical entity, and wewould therefore "know" that individualswith such tutnors have a 50% probabilityof survival. Once, however, we know howto distinguish between the lesions (say,as a consequence of the development of

a new technique) then we could state thatindividuals with the malignant type have,if untreated, a near zero chance of survi-val, whereas those with the benign typehave a near 100% chance (i.e. the risk isnow qualitatively different merely as aresult of a change in our knowledge).Insurance companies are constantly try-ing to improve their capability of makingaccurate predictions (i.e. their knowledgeof outcome); the irony is that were theyto be completely successful they wouldsoon be out of business!

For many diseases, including bothdental caries and periodontal disease, itis possible to identify two "sources" ofignorance which may lead to random (orunpredictable) outcome: first, ignoranceof the exact etiological mechanisms in-volved in the disease (e.g. genetic, immu-nological, microbial, etc.), i.e. the less weknow about the exact mechanisms, theless accurately we can predict the out-come; secondly, ignorance about exposi-tion to etiological factors between timeof risk assessment and time of outcome,which may also lead to unpredictableoutcomes: for example, supposing weknew everything about etiological mech-anisms involved in dental caries, wewould still have no idea how each of thefactors involved (e.g. sugar consumptionhabits, salivary flow rates, salivary buffercapacity of an individual) will vary overthe period between risk assessment andoutcome. The combined effect of thesetwo sources of ignorance can, perhaps,best be illustrated by the example of thedecline in caries prevalence in industrial-ized countries over the last two decades.Had we endeavored to predict in the1960s the likely trends in dental cariesprevalence in the 1980s, we would havepredicted considerably higher levels thanin fact occurred. Part of the change inthe prevalence of dental caries over thisperiod has occurred as a result of unpre-dictable changes in known risk factors(e.g. use of topical fluorides), and part

due to changes in parameters that arehitherto poorly understood (i.e. aboutwhich we are ignorant).

From the above it should be apparentthat variations in outcome (levels, distri-butions, etc.) will say little about varia-tions in risk.

Recently, there has been sotne interestin trying to estimate the potential forassessing risk from the shape of the distri-bution of the outcome variable (e.g. lossof attachment, DMF scores, etc.), theargument being that if the distribution ofthe outcome variable is not nortnal (i.e.it has a long "tail", or is skewed), then itcannot merely be the outcome of a tnyri-ad of stnall unidentifiable effects but, in-stead, must be evidence for the existenceof at least one major etiological factorwhich merely needs to be identified. Theunderlying statistical idea behind this is,perhaps, the central limit theorem whichstates that the sum of the effects of manysmall random variables will be approxi-mately normally distributed. However, ifeffects work multiplicatiyely, then the re-sult of many small effects will certaitilynot be normal. Conversely, an outcomevariable which is linearly related to an(itnportant) risk factor will neverthelessbe normally distributed if the risk factoris itself normally distributed. In short,the shape of the distribution of the out-come variable is completely uninforma-tive (unless, of course everyone has exact-ly the same outcome!) - and the existenceof long "tails" or skewness is thus not apriori evidence for the existence of riskgroups.

The only evidence for the existence ofrisk factors or groups is by actually iden-tifying them lotigitudinally. If we find anassociation between a variable x and theoutcome variably y, t years later, then wecan try to predict the state of y, t yearslater, from x. If this is successful, we haveidentified a risk factor - and those inwhom we find a high value for this factorare the "risk group". In many instances, x

Commentary 107

is identical to y, t years earlier, e.g. caries The search for risk factors in dental to the intrinsic randomness or unpredict-at age 6 yr predicting (being a risk factor) diseases is clearly itnportant. Many have ability of the inputs. There is, however,for caries at age 15 yr (i.e. previous disease been found, and no doubt many others no way to tell a priori where the searchexperience being a good predictor of sub- will be found. However, there is clearly for risk factors will be successful andsequent disease development). a limit to what can be predicted owing where it won't.