Identifying existing, FDA-approved drugs with clinically protective effects against coronavirus disease 2019 using a big data approach

项目总结/文摘

Project Summary/Abstract Coronavirus Disease 2019 (COVID-19) is a national and global public health emergency. Because the causative virus is novel, the present options for treatment are extremely limited, and an effective vaccine could be 1-2 years away. Thus, there is an urgent need for efficacious therapeutics against the disease. While development of new drugs is under way, that process is slow and resource-intensive. In the short-to-medium term, a superior strategy is to repurpose already existing drugs to treat the disease. Over 100 drugs already approved by the Food and Drug Administration (FDA) have shown in vitro, in silico, or theoretical effect against SARS-CoV-2, the virus that causes COVID-19, or the hyperinflammatory immune response it provokes. What is unclear is how many of these have a significant, protective effect on actual patients, as only a tiny fraction of these drugs is in clinical trials. Most of these agents are chronic medications, and thus there are millions of Americans who are already using them. The first aim of this study is to assess the degree of protection any of these drugs confers against the serious complications of COVID-19 while adjusting for known risk factors and confounders. The second aim is to search for additional interactions between drugs or combinations of drugs and specific demographic and/or clinical subgroups that could be protective or harmful. The Change Healthcare Database, a part of the COVID-19 Research Database, contains up-to-date health insurance claims data for about one-third of all Americans. Using this database, this study will evaluate the impact of these drugs on the risk of four important outcomes in patients who are COVID-19-positive: need for hospitalization, use of mechanical ventilation, shock, and death. Results will be risk-adjusted for the risk factors already well established to predict poor outcomes in COVID-19. This study will further mine the data for second- and third- order interactions between drugs or combinations of drugs and different subpopulations of patients using a novel machine learning method called the Feasible Solution Algorithm (FSA). The FSA enables the researcher to uncover higher-order statistical interactions in regression models, which leads to the identification of subgroups and complexities that are not always apparent with traditional regression models. If the results show candidate drugs with highly protective effects, these can be prioritized for prospective clinical studies. Drugs that show harmful effects can be considered for discontinuation in infected or high-risk patients.