Improving The Efficiency of The Case-Crossover Design

The case-crossover design has been used by many researchers to study the transient effect of an exposure on the risk of a rare outcome. In a case-crossover design, only cases are sampled and each case will act as his/her own control. The time of failure acts as the case and non failure times act as the controls. Case-crossover designs have frequently been used to study the effect of environmental exposures on rare diseases or mortality. Time trends and seasonal confounding may be present in environmental studies and thus need to be controlled for by the sampling design. Several sampling methods are available for this purpose. In time-stratified sampling, disjoint strata of equal size are formed and the control times within the case stratum are used for comparison. The random semi-symmetric sampling design randomly selects a control time for comparison from two possible control times. The fixed semi-symmetric sampling design is a modified version of the random semi-symmetric sampling design that removes the random selection. Simulations show that the fixed semi-symmetric sampling design improves the variance of the random semi-symmetric sampling estimator by at least 35% for the exposures we studied. We derive expressions for the asymptotic variance of risk estimators for these designs, and show, that while the designs are not theoretically equivalent, in many realistic situations, the random semi-symmetric sampling design has similar efficiency to a time-stratified sampling design of size two and the fixed semi-symmetric sampling design has similar efficiency to a time-stratified sampling design of size three.