Is case-chaos methodology an appropriate alternative to conventional case-control studies for investigating outbreaks?

Case-chaos methodology is a proposed alternative to case-control studies that simulates controls by randomly reshuffling the exposures of cases. We evaluated the method using data on outbreaks in Sweden. We identified 5 case-control studies from foodborne illness outbreaks that occurred between 2005 and 2012. Using case-chaos methodology, we calculated odds ratios 1,000 times for each exposure. We used the median as the point estimate and the 2.5th and 97.5th percentiles as the confidence interval. We compared case-chaos matched odds ratios with their respective case-control odds ratios in terms of statistical significance. Using Spearman's correlation, we estimated the correlation between matched odds ratios and the proportion of cases exposed to each exposure and quantified the relationship between the 2 using a normal linear mixed model. Each case-control study identified an outbreak vehicle (odds ratios = 4.9-45). Case-chaos methodology identified the outbreak vehicle 3 out of 5 times. It identified significant associations in 22 of 113 exposures that were not associated with outcome and 5 of 18 exposures that were significantly associated with outcome. Log matched odds ratios correlated with their respective proportion of cases exposed (Spearman ρ = 0.91) and increased significantly with the proportion of cases exposed (b = 0.054). Case-chaos methodology missed the outbreak source 2 of 5 times and identified spurious associations between a number of exposures and outcome. Measures of association correlated with the proportion of cases exposed. We recommended against using case-chaos analysis during outbreak investigations.