This project is a significant extension of previous research undertaken by this group as part of a Medicines and Healthcare products Regulatory Agency (MHRA) grant (SDS 33437) on "Medicines that may promote suicide: pharmacoepidemiological analysis of risk and risk assessment". The focus of this earlier grant was to investigate whether varenicline caused suicide and self-harm. The investigators produced a written report of the findings for the MHRA and presented these findings orally to the Pharmacovigilance Expert Advisory Group (PEAG) of the Commission on Human Medicines. This committee deliberates on potential new signals of risks associated with pharmacotherapies. Two major questions were identified as future research priorities by the PEAG: how should regulators interpret the results of instrumental variable studies when they conflict with conventional multivariable-adjusted observational analysis? Is it possible to give definitive guidance about when instrumental variable analysis is likely to have lower bias? Currently, the epidemiological literature is not sufficiently developed to conclusively do this. The investigators will address this gap in the literature in the methodological components of this proposal. This will significantly further understanding of when instrumental variable analysis should be used to address problems of confounding by indication. Additionally, this proposal will provide evidence regarding the effectiveness of varenicline with respect to long term smoking cessation and clinically relevant outcomes. This will aid regulators determine whether the benefits of varenicline treatment outweigh possible risks. The investigators will report the results of this research to regulators.