Among cohort designs, cross over studies are intervention studies in which the same group of people is exposed to two different interventions in two separate periods of time. This requires that the effect of the intervention is short enough not to impact on the effect of the second intervention and that a time gap between the two interventions is respected. [1]

Case cross over studies are the case control version of crossover studies. This concept was introduced by Maclure et al. [2] [3] In a case cross over design all subjects are cases and exposure is measured in two different periods of time. The general principle is to find an answer to the question: “Was the case-patient doing anything peculiar and unusual just before disease onset?” or “Did the patient do anything unusual compared to his routine?”. The assumption is that if there are triggering events, these events should occur more frequently immediately prior to disease onset than at any similar period distant from disease onset.

 In case cross over studies, instead of obtaining information from two groups (cases and controls), the exposure information is obtained from the same case group but during two different periods of time. In the first period exposure is measured immediately before disease onset. In the second period exposure is measured at an earlier time (supposed to represent background exposure in the same person). Exposure among cases just prior disease onset is then compared to exposure among the same cases at an earlier time. Each case and its matched control (himself) are therefore automatically matched on many characteristics (age, sex, socio economic status, etc.)

To illustrate that point Maclure used the following example. Let suppose we study the role of heavy physical activity in the occurrence of myocardial infraction (MI). Using a case cross over design we could document exposure to heavy physical activity among cases in the hour immediately preceding MI. We would then document exposure to heavy physical activity among those same cases at another earlier time.

The following figure illustrates periods of exposures taken into account in a case cross over study.
Source: Adapted from Jean Claude Desenclos, InVS, France

In the above figure the period immediately before onset is called the « current » period and the other period “the reference period”. The two periods are separated by a “wash out period” in order to avoid that exposure in the reference period is mixed with exposure in the current period. The reference period of exposure is used to reflect average exposure experience among cases. Case 1 was unexposed in current period (just prior to onset) and exposed in the reference period. Case 2 was exposed just prior onset and unexposed in the reference period. Case 3 was exposed in both periods and case 4 in none.
 

From the above we should consider that the same case and its 2 periods of exposure constitute a matched pair. Cases 1 and 2 are discordant pairs and cases 3 and 4 concordant. This is why with a case cross over design a matched pair analysis is required. Only discordant matched pairs will be used in the analysis (see chapter on matching for rational).

In addition some characteristics of exposure and outcome are noteworthy.

Exposure should change over time in the same person and over short period of time.

Exposure should not be changing in a systematic way over time. In the example of physical activity let’ suppose we have documented exposure in the hour immediately before onset and that we have documented reference exposure two days before at the same time. This would not be appropriate if physical activity occurs in a systematic timing (every second day at the same time).


Exposure should have a short term effect. Duration of exposure effect should be shorter than average time between two routine exposures in the same individual. The effect of a first exposure should have stopped before the next exposure.
 
Induction time between exposure and outcome should be short.

Disease must have an abrupt onset. Case cross over are not appropriate if the exact date/time of onset is not available or if abrupt onset does not exist (some chronic disease).

Several reference time periods can be used to document average exposure among cases. In that instance, an average of time being exposed is computed and compared to exposure just prior disease onset. The efficiency of the case cross over method increases with the number of reference periods included.

As in any case control study the capacity to properly document exposure should be identical in the two periods of time. In case cross over designs information biases are a sensitive issue.

Even if confounding is controlled since a case is its own control, within-person confounding can occur. In the example of heavy physical activity and MI, another factor (anger) may be linked both to exposure (heavy physical activity) and outcome (MI).

Case cross over and food borne outbreaks.

Case cross over design was sometime used by epidemiologists to try to identify a food item as the vehicle for a food borne disease outbreak. Several of the above listed points merit to be challenged. A recall (exposure) period of around three days may be too large to use this design. In addition food habits (average exposure) do not happen randomly in an individual. Finally, comparing consumption of a potentially infected food item in the “current” period to average consumption of a similar un-infected food item in the reference period does not relate to the same exposure. Consumption of a food item could be identical in the current and reference time periods and still only the food item in the current period was contaminated.

References

1. Rothman KJ. Epidemiology. An Introduction. New York, Oxford University Press 2002.
2. Maclure MA, Maclure M, Robins MJ. The case-crossover design: a method for studying transient effects on the risk of acute events. American Journal of Epidemiology 1991; 133(2):144-153
3. Maclure, M, Mittleman MA. Should we use a case-crossover design? Annu. Rev. Public Health. 2000; 21:193-221