Real-world and genetic evidence for the management of opioid epidemic and COVID-19 pandemic: population-based studies

Background: The widespread use of opioids and the emergence of SARS-CoV-2 represent two pressing public health crises that require evidence-based decision-making. This thesis comprises six interconnected studies aimed at translating large, routinely-collected and Biobank data into reliable evidence to inform the management of the ongoing opioid epidemic and COVID-19 pandemic. Methods: Four data sources were studied: primary care records from SIDIAP (Spain), US claims, and the UK Biobank. Exposures included opioids, ibuprofen, COVID-19 vaccines, human leucocyte antigen (HLA) genes, and SARS-CoV-2 infections. Cohort studies were used as the primary design, complemented by statistical techniques including regression, propensity scores, survival analyses, and negative and positive control outcomes, as well as Mendelian randomization. Study outcomes were adverse drug events, COVID-19 susceptibility and severity, and related complications. Results: Incident opioid use increased in Catalonia from 2007 to 2019, with Tramadol being the most frequently used opioid in 2019. Compared to codeine, tramadol was associated with a higher risk of all-cause mortality, cardiovascular events, and fractures. No differential risk of COVID-19 was observed among users of ibuprofen versus other analgesics. When compared to two doses of ChAdOx1, vaccination with BNT162b2 was associated with lower risks of COVID-19 infection and hospitalization, respectively, during the study period when the Delta variant was dominant. Six independent HLA alleles significantly affected antibody response to COVID-19 vaccines, and the aggregated genetic score had a strong, collective, and causal influence on breakthrough COVID-19. COVID-19 infection was associated with an increased risk of venous thromboembolism (VTE) within 30 days, with highest risk in unvaccinated individuals. People with older age, male sex, obesity, and inherited thrombophilia were also at a higher VTE risk post-COVID-19. Conclusion: The integration of real-world and linked biobank data can be effectively leveraged using advanced analytical tools to generate timely and actionable evidence to tackle global health crises like the ongoing opioids epidemic and COVID-19 pandemic.