Pragmatic considerations for negative control outcome studies to guide non-randomized comparative analyses: A narrative review

Purpose: This narrative review describes the application of negative control outcome (NCO) methods to assess potential bias due to unmeasured or mismeasured confounders in non-randomized comparisons of drug effectiveness and safety. An NCO is assumed to have no causal relationship with a treatment under study while subject to the same confounding structure as the treatment and outcome of interest; an association between treatment and NCO then reflects the potential for uncontrolled confounding between treatment and outcome. Methods: We focus on two recently completed NCO studies that assessed the comparability of outcome risk for patients initiating different osteoporosis medications and lipid-lowering therapies, illustrating several ways in which confounding may result. In these studies, NCO methods were implemented in claims-based data sources, with the results used to guide the decision to proceed with comparative effectiveness or safety analyses. Results: Based on this research, we provide recommendations for future NCO studies, including considerations for the identification of confounding mechanisms in the target patient population, the selection of NCOs expected to satisfy required assumptions, the interpretation of NCO effect estimates, and the mitigation of uncontrolled confounding detected in NCO analyses. We propose the use of NCO studies prior to initiating comparative effectiveness or safety research, providing information on the potential presence of uncontrolled confounding in those comparative analyses. Conclusions: Given the increasing use of non-randomized designs for regulatory decision-making, the application of NCO methods will strengthen study design, analysis, and interpretation of real-world data and the credibility of the resulting real-world evidence

Laboratory measurements of radon diffusion through multilayered cover systems for uranium tailings

Laboratory measurements of radon fluxes and radon concentration profiles were conducted to characterize the effectiveness of multilayer cover systems for uranium tailings. The cover systems utilized soil and clay materials from proposed disposal sites for the Vitro, Durango, Shiprock, Grand Junction and Riverton tailings piles. Measured radon fluxes were in reasonable agreement with values predicted by multilayer diffusion theory. Results obtained by using air-filled porosities in the diffusion calculations were similar to those obtained by using total porosities. Measured diffusion coefficients were a better basis for predicting radon fluxes than were correlations of diffusion coefficient with moisture or with air porosity. Radon concentration profiles were also fitted by equations for multilayer diffusion in the air-filled space. Layer-order effects in the multilayer cover systems were examined and estimated to amount to 10 to 20 percent for the systems tested. Quality control measurements in support of the multilayer diffusion tests indicated that moisture absorption was not a significant problem in radon flux sampling with charcoal canisters, but that the geometry of the sampler was critical. The geometric design of flux-can samplers was also shown to be important. Enhanced radon diffusion along the walls of the test columns was examined and was found to be insignificant except when the columns had been physically disturbed. Additional moisture injected into two test columns decreased the radon flux, as expected, but appeared to migrate into surrounding materials or to be lost by evaporation. Control of moisture content and compaction in the test columns appeared to be the critical item affecting the accuracies of the experiments