Is surgery a risk factor for Creutzfeldt-Jakob disease? Outcome variation by control choice and exposure assessments

objective. To determine whether methodological differences explain divergent results in case-control studies examining surgery as a risk factor for Creutzfeldt-Jakob disease (CJD). Methods. After case-control studies were systematically identified using PubMed, we performed a homogeneity analysis and applied models to effect sizes (odds ratio [OR] with 95% confidence interval [CI]) using 2 parameters: type of control subject used and consistency of data ascertainment. The hospitals and communities were located in Europe, Japan, and Australia. Patients were CJD case subjects and age- and sex-matched control subjects in the hospital or community. Because of the natural history of the disease, CJD subjects are not considered reliable sources of information for these studies. Therefore, individuals who are considered close to the subjects and who have knowledge of their medical history, including spouses and relatives, are necessarily identified as proxy informants for the surgical record of the case subjects. Results. Overall, the effect sizes lacked homogeneity (P<.0001). Three studies that used control subjects from the community revealed a significantly elevated risk of CJD for patients who underwent surgery (OR, 1.82; 95% CI, 1.41- 2.35 [p<.0001]), whereas 3 investigations that used control subjects from the hospital revealed a significantly reduced risk (OR, 0.69; 95% CI, 0.52-0.90 [P = .0069]). Two studies that used proxy informants to acquire information about case subjects and control subjects ( consistent ascertainment) found that the risk of CJD was significantly lower in those subjects who underwent surgery (OR, 0.65; 95% CI, 0.48- 0.87 [P =.0043]). Conversely, 4 studies in which proxy informants acted only on behalf of case subjects (inconsistent data ascertainment) found a significant positive association between surgery and CJD (OR, 1.67; 95% CI, 1.32-2.12 [P<.0001]). Both models fit the data very well, leaving no remaining variance in effect sizes to explain. Conclusion. Variation in the type of control subjects used and in exposure assessment in case-control studies may partially explain conflicting data regarding the association between surgery and CJD. However, there was almost complete confounding of these 2 parameters, making interpretation more difficult. Planning of future investigations must carefully consider these design elements.