Visualizing and diagnosing spillover within randomized concurrent controlled trials through the application of diagnostic test assessment methods.

ABSTRACT

BACKGROUND: Spillover of effect, whether positive or negative, from intervention to control group patients invalidates the Stable Unit Treatment Variable Assumption (SUTVA). SUTVA is critical to valid causal inference from randomized concurrent controlled trials (RCCT). Spillover of infection prevention is an important population level effect mediating herd immunity. This herd effect, being additional to any individual level effect, is subsumed within the overall effect size (ES) estimate derived by contrast-based techniques from RCCT's. This herd effect would manifest only as increased dispersion among the control group infection incidence rates above background. METHODS AND RESULTS: The objective here is to explore aspects of spillover and how this might be visualized and diagnosed. I use, for illustration, data from 190 RCCT's abstracted in 13 Cochrane reviews of various antimicrobial versus non-antimicrobial based interventions to prevent pneumonia in ICU patients. Spillover has long been postulated in this context. Arm-based techniques enable three approaches to identify increased dispersion, not available from contrast-based techniques, which enable the diagnosis of spillover within antimicrobial versus non-antimicrobial based infection prevention RCCT's. These three approaches are benchmarking the pneumonia incidence rates versus a clinically relevant range, comparing the dispersion in pneumonia incidence among the control versus the intervention groups and thirdly, visualizing the incidence dispersion within summary receiver operator characteristic (SROC) plots. By these criteria there is harmful spillover effects to concurrent control group patients. CONCLUSIONS: Arm-based versus contrast-based techniques lead to contrary inferences from the aggregated RCCT's of antimicrobial based interventions despite similar summary ES estimates. Moreover, the inferred relationship between underlying control group risk and ES is 'flipped'.