What is a case-control study?

T Marshall

Department of Public Health and Epidemiology, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: t.marshall{at}bham.ac.uk

‘What's in a name? That which we call a rose

By any other name would smell as sweet’1

Sirs—Case-control studies are used in epidemiology to identify factors that differ in their frequency between case and control subjects, and which may therefore be interpreted as possible risk factors for the disease. The essence of the study design is that they look backwards, from disease to putative exposure.

The design has a long history, recently reviewed in two papers by Paneth, Susser and Susser.2,3 Probably the best-known study of this type is that of Doll and Hill,4 conducted in the late 1940s, which was one of the first rigorously designed studies to report on the lung cancer–smoking association.

Recently, a number of studies have been published using the term ‘case-control study’ in the title to describe the study design. On closer examination these studies turn out to be nothing of the kind—at least, not in the sense in which the term is understood by epidemiologists. Four examples will be used to illustrate the issue.

Firstly, babies conceived by intra-cytoplasmic sperm injection (ICSI, ‘cases’) were compared with ‘a control group of normally conceived children.’5 The comparison was made with respect to neurodevelopmental status at 2 years of age, and was thus the consequence of a follow-up over time. The report was accompanied by a commentary extolling the study as a fine example of case-control methodology.6

Another study, of physicians in Switzerland, compared gastroenterologists recruited from the Swiss Society of Gastroenterology and Hepatology with control subjects ‘selected from participants in a large study of Helicobacter pylori prevalence’.7 All subjects had a 13C urea breath test to diagnose the presence of H. pylori, and those who were negative were then followed up for between 5 and 8 years. There was a repeat breath test conducted at the end on these subjects. The inappropriate description of this study was remarked on by Bland,8 and the authors themselves in the text described their study as a ‘prospective, long-term follow-up study’.

In a study of school absences following minor injury, ‘cases’ were defined as ‘a child who attended the local emergency department on a Sunday preceding a school week with an injury that should not prevent school attendance’, whilst ‘control’ subjects were the next child of the same sex on the class register.9 Attendance at school during the week following the injury was the measurement of comparison.

Finally, children between the ages of 2 and 16, one of whose parents had died, were followed up to assess subsequent psychological disturbance.10 Though described as a ‘prospective case-control study’, there does not appear to have been a comparison (control) group of any kind.

There are many other examples from the recent literature, both specialist and general, which could be cited. And in the last 24 hours (at the time of writing), the author has received two grant proposals to review, both of which used the term ‘case-control study’ to describe what are essentially prospective, follow-up studies, which would conventionally be described by an epidemiologist as cohort studies. For obvious reasons, no references can be given.

It may be instructive to consider in parallel how the use of the word ‘cohort’ has evolved. Grimes and Schulz have provided a useful synthesis of this type of study design.11 Originally used to describe a section of a Roman legion, ‘cohort studies’ came to be understood in the 20th century as studies of the disease experience of groups of subjects born around the same period of time. Subsequently, the term was interpreted (by epidemiologists) to mean either, follow-up studies on groups of people identified by exposure (or not) to a possible risk factor; or, studies of groups of people with a common characteristic used to define admission to the study, where the subjects are then evaluated with respect to their level of exposure, and followed forwards to see what happens to them. These are often studies of occupational groups; the best-known such study is probably that by Doll and Hill, the ‘British Doctors’ study.12 Retrospective, or historical, cohort studies are another variation on the design, but one in which the direction of observation within the study is still forwards, from exposure to outcome, even if all the events have taken place in the past. A more recent development, involving a reversion to the earlier meaning of the term, is seen in the development of ‘age-period-cohort’ analyses. The word ‘cohort’ thus has two broad meanings in epidemiology, one implicitly referring to birth cohort, and the other referring to a study in which exposed and not-exposed groups are compared. Both study designs, however, incorporate the concept of follow-up, i.e. forwards-looking, over a period of time.

What, therefore, should we make of the (mis-)use of the term ‘case-control study’ to describe what are essentially prospective, follow-up studies? There have been several e-letters in response to the studies cited above, and others, and a pungent commentary in the same format from Tobin, Kurinczuk and Clarke.13 Does it matter?

I think it does. The standard index of risk calculated from case-control studies is the odds ratio (OR), whilst that from a cohort study is the relative risk (RR). Using incidence-density sampling in a case-control study is becoming more common, and makes it possible to use RR as the index of association. However, many examples from the past have used prevalent rather than incident cases, where the OR is required. Though in certain circumstances OR is an approximation to RR, they are not the same index. More importantly, the two types of study involve different considerations in their design, and they are subject to different types of biases which need to be taken into account in both design and analysis. Use of the term ‘case-control study’ implies a backwards-looking study, which is not how any of the studies cited were carried out. They are forwards-looking, with ‘exposure’ being defined as ‘ICSI fertilisation’,5 being a gastroenterologist,7 a child having had a minor injury,9 and parental bereavement in childhood.10

It is easy to see how, for some of the examples quoted, the term ‘case-control study’ has been thought appropriate. How better to describe children sustaining minor injuries, or children conceived via ICSI, than as cases? And from that, how natural to describe the comparison group as controls. The danger is that the term ‘case-control study’ will come to mean any epidemiological study where there is a comparison between two groups of people, irrespective of whether they are defined by disease status or exposure status, and irrespective of whether, having defined the two groups, the subsequent direction of the study is forwards or backwards.

Using the same words to describe studies with diametrically opposite study designs is a recipe for confusion at best. Since it seems unlikely that (mis-)use of the term will go away, some clarity would be introduced (however much it might grate with ‘classical’ epidemiologists) if we used the terms ‘retrospective’ and ‘prospective’ in future to qualify our case-control studies. At least we would then know in which direction we were looking.

‘When I use a word,’ Humpty Dumpty said in a rather scornful tone, ‘it means just what I choose it to mean—neither more nor less.’14

Acknowledgments

I thank Professor KK Cheng for useful discussions about the paper. He is not responsible for the views expressed.

References

1 Shakespeare W. Romeo and Juliet. Act 2 Scene 2.

2 Paneth N, Susser E, Susser M. Origins and early development of the case-control study: Part 1. Early evolution. Soz Praventivmed 2002;47:282–88.[ISI][Medline]

3 Paneth N, Susser E, Susser M. Origins and early development of the case-control study: Part 2. The case-control study from Lane-Claypon to 1950. Soz Praventimed 2002;47:359–65.

4 Doll R, Hill AB. Smoking and carcinoma of the lung. Preliminary report. BMJ 1950;221:739–48.

5 Sutcliffe AG, Taylor B, Saunders K et al. Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: a UK case-control study. Lancet 2001;357:2080–84.[CrossRef][ISI][Medline]

6 Oehninger S. Place of intracytoplasmic sperm injection in management of male infertility. Lancet 2001;357:2068–69.[CrossRef][ISI][Medline]

7 Hildebrand P, Meyer-Wyss B M, Mossi S, Beglinger C. Risk among gastroenterologists of acquiring Helicobacter pylori infection: case-control study. BMJ 2000;321:149.

8 Bland JM. Study was not a case-control study. e-letter, BMJ 14 July 2000.

9 Barnes PM, Price L, Maddocks A, Lyons RA, Nash P, McCabe M. Unnecessary school absence after minor injury: case-control study. BMJ 2001;323:1034–35.[Free Full Text]

10 Dowdney L, Wilson R, Maughan B et al. Psychological disturbance and service provision in parentally bereaved children: prospective case-control study. BMJ 1999;319:354–57.[Abstract/Free Full Text]

11 Grimes DA, Schulz KF. Cohort studies: marching towards outcomes. Lancet 2002;359:341–45.[CrossRef][ISI][Medline]

12 Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking. BMJ 1956;233:1071–81.

13 Tobin M, Kurinczuk JJ, Clarke M. Study design: who gives a damn? e-letter, BMJ 28 September 1999.

14 Carroll L. Through the Looking Glass. London: Macmillan, 1872.





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