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1.
Am J Epidemiol ; 190(11): 2280-2283, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1722199

ABSTRACT

Dimitris and Platt (Am J Epidemiol. 2021;190(11):2275-2279) take on the challenging topic of using "shocks" such as the severe acute respiratory system coronavirus 2 (SARS-CoV-2) pandemic as instrumental variables to study the effect of some exposure on some outcome. Evoking our recent lived experiences, they conclude that the assumptions necessary for an instrumental variable analysis will often be violated and therefore strongly caution against such analyses. Here, we build upon this warranted caution while acknowledging that such analyses will still be pursued and conducted. We discuss strategies for evaluating or reasoning about when such an analysis is clearly inappropriate for a given research question, as well as strategies for interpreting study findings with special attention to incorporating plausible sources of bias in any conclusions drawn from a given finding.


Subject(s)
COVID-19 , Pandemics , Bias , Humans , Pandemics/prevention & control , SARS-CoV-2
2.
Am J Epidemiol ; 190(11): 2280-2283, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1270731

ABSTRACT

Dimitris and Platt (Am J Epidemiol. 2021;190(11):2275-2279) take on the challenging topic of using "shocks" such as the severe acute respiratory system coronavirus 2 (SARS-CoV-2) pandemic as instrumental variables to study the effect of some exposure on some outcome. Evoking our recent lived experiences, they conclude that the assumptions necessary for an instrumental variable analysis will often be violated and therefore strongly caution against such analyses. Here, we build upon this warranted caution while acknowledging that such analyses will still be pursued and conducted. We discuss strategies for evaluating or reasoning about when such an analysis is clearly inappropriate for a given research question, as well as strategies for interpreting study findings with special attention to incorporating plausible sources of bias in any conclusions drawn from a given finding.


Subject(s)
COVID-19 , Pandemics , Bias , Humans , Pandemics/prevention & control , SARS-CoV-2
3.
Nat Med ; 27(4): 668-676, 2021 04.
Article in English | MEDLINE | ID: covidwho-1174686

ABSTRACT

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.


Subject(s)
COVID-19/genetics , Drug Repositioning , Mendelian Randomization Analysis/methods , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , COVID-19/drug therapy , Genome-Wide Association Study , Humans , Interleukin-10 Receptor beta Subunit/genetics , Interleukin-10 Receptor beta Subunit/physiology , Quantitative Trait Loci , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/physiology
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