Conceptual causal framework to assess the effect of SARS-CoV-2 variants on COVID-19 disease severity among hospitalized patients

Nina Van Goethem,Herman Van Oyen,Marjan Meurisse,Mathil Vandromme,Lize Cuypers,Ben Serrien,Sofieke Klamer,Koen Blot,Ruben Brondeel,Chloé Wyndham-Thomas,Emmanuel André,Lucy Catteau

doi:10.1186/s13690-021-00709-x

Abstract

BackgroundSARS-CoV-2 strains evolve continuously and accumulate mutations in their genomes over the course of the pandemic. The severity of a SARS-CoV-2 infection could partly depend on these viral genetic characteristics. Here, we present a general conceptual framework that allows to study the effect of SARS-CoV-2 variants on COVID-19 disease severity among hospitalized patients.MethodsA causal model is defined and visualized using a Directed Acyclic Graph (DAG), in which assumptions on the relationship between (confounding) variables are made explicit. Various DAGs are presented to explore specific study design options and the risk for selection bias. Next, the data infrastructure specific to the COVID-19 surveillance in Belgium is described, along with its strengths and weaknesses for the study of clinical impact of variants.DiscussionA well-established framework that provides a complete view on COVID-19 disease severity among hospitalized patients by combining information from different sources on host factors, viral factors, and healthcare-related factors, will enable to assess the clinical impact of emerging SARS-CoV-2 variants and answer questions that will be raised in the future. The framework shows the complexity related to causal research, the corresponding data requirements, and it underlines important limitations, such as unmeasured confounders or selection bias, inherent to repurposing existing routine COVID-19 data registries.Trial registrationEach individual research project within the current conceptual framework will be prospectively registered in Open Science Framework (OSF identifier: https://doi.org/10.17605/OSF.IO/UEF29). OSF project created on 18 May 2021.

Highlights

SARS-CoV-2 strains evolve continuously and accumulate mutations in their genomes over the course of the pandemic
Genetic association studies have identified several host genetic risk factors to become severely ill when infected by SARS-CoV-2 [6], including genetic variants in genes related to the immune system, such as the Human Leukocyte Antigens (HLA) gene complex [7] and cytokine genes, or in genes encoding human receptors of SARS-CoV-2 [8], such as Angiotensin converting enzyme 2 (ACE2) [9] and Transmembrane Serine Protease 2 (TMPRSS2) [10,11,12]
We present a conceptual framework that allows to study the effect of SARS-CoV-2 variants on COVID-19 disease severity among hospitalized patients

Summary

Introduction

SARS-CoV-2 strains evolve continuously and accumulate mutations in their genomes over the course of the pandemic. We present a general conceptual framework that allows to study the effect of SARS-CoV-2 variants on COVID19 disease severity among hospitalized patients. Genetic association studies have identified several host genetic risk factors to become severely ill when infected by SARS-CoV-2 [6], including genetic variants in genes related to the immune system, such as the Human Leukocyte Antigens (HLA) gene complex [7] and cytokine genes, or in genes encoding human receptors of SARS-CoV-2 [8], such as ACE2 [9] and TMPRSS2 [10,11,12]. COVID-19 vaccines have proven to be highly effective against laboratory-confirmed SARS-CoV-2 infections and COVID-19 hospitalizations, severe disease, and deaths [13,14,15,16,17,18,19]. To vaccination and other factors related to the host, severity of outcome can be influenced by aspects related to the healthcare organization and patient management [5, 22, 23]

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