Methodologic considerations in the design and analysis of nested case-control studies: association between cytokines and postoperative delirium

Long H. Ngo, Sharon K. Inouye, Richard N. Jones, Thomas G. Travison, Towia A. Libermann, Simon T. Dillon, George A. Kuchel, Sarinnapha M. Vasunilashorn, David C. Alsop, Edward R. Marcantonio

The nested case-control study (NCC) design within a prospective cohort study is used when outcome data are available for all subjects, but the exposure of interest has not been collected, and is difficult or prohibitively expensive to obtain for all subjects. A NCC analysis with good matching procedures yields estimates that are as efficient and unbiased as estimates from the full cohort study. We present methodological considerations in a matched NCC design and analysis, which include the choice of match algorithms, analysis methods to evaluate the association of exposures of interest with outcomes, and consideration of overmatching. Matched, NCC design within a longitudinal observational prospective cohort study in the setting of two academic hospitals. Study participants are patients aged over 70 years who underwent scheduled major non-cardiac surgery. The primary outcome was postoperative delirium from in-hospital interviews and medical record review. The main exposure was IL-6 concentration (pg/ml) from blood sampled at three time points before delirium occurred. We used nonparametric signed ranked test to test for the median of the paired differences. We used conditional logistic regression to model the risk of IL-6 on delirium incidence. Simulation was used to generate a sample of cohort data on which unconditional multivariable logistic regression was used, and the results were compared to those of the conditional logistic regression. Partial R-square was used to assess the level of overmatching. We found that the optimal match algorithm yielded more matched pairs than the greedy algorithm. The choice of analytic strategy-whether to consider measured cytokine levels as the predictor or outcome-- yielded inferences that have different clinical interpretations but similar levels of statistical significance. Estimation results from NCC design using conditional logistic regression, and from simulated cohort design using unconditional logistic regression, were similar. We found minimal evidence for overmatching. Using a matched NCC approach introduces methodological challenges into the study design and data analysis. Nonetheless, with careful selection of the match algorithm, match factors, and analysis methods, this design is cost effective and, for our study, yields estimates that are similar to those from a prospective cohort study design.