Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-039Case-control StudiesScott HendersonNHMRC Psychiatric Epidemiology Research Centre, Australian National University, Canberra, ACT 0200, AustraliaThe case-control study is aimed at aetiology. Schlesselman 1 saysthat it has two distinctive features: it proceeds backwards fromeffect to cause by trying to identify exposures or other factors thatled to a given disorder; and it uses a control or comparison groupwithout the disorder, so that a causal effect for a given exposurecan be supported or refuted. The first of these features is reallywhat a clinician does in daily practice when taking a history, butas a rule, the clinician does not go on to determine how manynormal persons have had the same exposure. The strength of thecase-control method lies in these two features. It is on the basis ofthem that the fundamental comparison in the case-control studylies: the frequency of an exposure in the cases, and the frequencyin the controls. Such a comparison is disarmingly simple, mainlybecause of the biases that can bring about misleading results.Some readable accounts can be found in Cole 2 , Lilienfeld andLilienfeld 3 , Feinstein 4 and Anthony 5 . A non-technical overviewhas been set out by Henderson 6 . An entire issue of EpidemiologicReviews devoted to the case-control method has provided anexcellent conspectus of this powerful tool, including the diverseapplications now being made of case-control designs for problemsolvingin the health field, including evaluation of serviceinterventions 7 .In case-control parlance, ‘‘exposure’’ refers not only toenvironmental exposures, but to other properties of the individual,such as a family history of a particular disease or some otherpersonal attribute. To identify an exposure that may contribute tothe onset of a disorder, the investigator has firstly to choose anumber of candidate exposures. This may be based on theory, onspeculation, or on a mindless search. The first of these isparticularly desirable, because it means that from the start thereis some plausible biological or psychosocial basis for the putativeeffect. Speculation can be the vehicle for a gifted insight. Theatheoretical examination of a large array of factors is undesirableand carries the risk of capitalization on chance.CONDUCTING A CASE-CONTROL STUDYThere are five issues that deserve close attention:1. The cases should be newly diagnosed, not ones which havebeen known for some time; and they should be representativeof all incident cases in the population. If longer-establishedcases were used, the findings might be related more to factorsinfluencing survival or chronicity than to aetiology (seebelow).2. The cases should include no errors in diagnosis, which wouldlead to misclassification and therefore errors in estimating therelative risk for exposures.3. The controls should either be matched demographically or besimilar in overall attributes. Much thought needs to beaccorded to the source of the controls if misleading biasesare to be avoided.4. In obtaining information on exposures from cases andcontrols, as well as from their informants, it is likely thatselection effects will operate, causing information bias. That is,people may selectively recall certain experiences, or selectivelyreport what they do recall. A likely example is a history of pasthead injury in Alzheimer’s disease, or any other situationwhere ‘‘effort after meaning’’ may operate. Ideally, theinterviewers should themselves be blind to the purpose of thestudy, lest they unwittingly influence the information that theyelicit.5. A case-control study that has too few cases to provide asatisfactory estimate of risk is of little value. The sample sizeneeded can be determined beforehand by establishing theminimum size of the effect to be demonstrated, and thefrequency of exposure in the controls. The more the frequencyof the exposure departs from 50% of the subjects, the morecases will be needed for an association to be shown.The assessment of risk for an exposure is obtained by calculatingits odds ratio as an approximation of the relative risk, and the95% confidence intervals for that estimate (Schlesselman 1 ,p.32etseq.) (Henderson 6 ,p.16et seq.). An odds ratio of 1.0 means thatthe exposure occurs as often in cases as in controls. Theconfidence interval should keep the estimate above unity if theexposure is to be accorded attention. It is misleading to reportodds ratios without also giving their confidence intervals. Forexample, an odds ratio of 1.7 with a 95% confidence interval of0.9–2.5 should be seen as a negative finding, because the lowerlimit is below unity.RESULTS OF CASE-CONTROL STUDIES OFDEMENTIANearly all the case-control studies of dementia have been focusedon Alzheimer’s disease (AD). Within this diagnostic group, thestudies have covered several categories, although not alwaysmaking this explicit. The cases have often been heterogeneous inage of onset and, indeed, in age since onset. The latter introducesthe problem of Neyman’s bias 5 and factors related to survivalafter the onset of the dementia. In looking critically at casecontrolstudies of dementia, their strengths and deficiencies can beseen by using the above points as a checklist, to assess the valuethat can be attached to each observation. Most studies have hadonly modest sample sizes. In case-control studies of AD, thePrinciples and Practice of Geriatric Psychiatry, 2nd edn. Edited by J. R. M. Copeland, M. T. Abou-Saleh and D. G. Blazer&2002 John Wiley & Sons, Ltd