Collider bias and the apparent protective effect of glucose-6-phosphate dehydrogenase deficiency on cerebral malaria
- Mahidol University, Thailand
- The University of Melbourne, Australia
Abstract
Case fatality rates in severe falciparum malaria depend on the pattern and degree of vital organ dysfunction. Recent large-scale case-control analyses of pooled severe malaria data reported that glucose-6-phosphate dehydrogenase deficiency (G6PDd) was protective against cerebral malaria but increased the risk of severe malarial anaemia. A novel formulation of the balancing selection hypothesis was proposed as an explanation for these findings, whereby the selective advantage is driven by the competing risks of death from cerebral malaria and death from severe malarial anaemia. We re-analysed these claims using causal diagrams and showed that they are subject to collider bias. A simulation based sensitivity analysis, varying the strength of the known effect of G6PDd on anaemia, showed that this bias is sufficient to explain all of the observed association. Future genetic epidemiology studies in severe malaria would benefit from the use of causal reasoning.
Data availability
This manuscript is a methodology paper; no new data were generated. The code for the simulation study can be found on the github repository at https://github.com/Stije/SevereMalariaAnalysis.
Article and author information
Author details
Funding
Wellcome Trust
- James A Watson
- Nicholas PJ Day
- Arjen M Dondorp
- Nicholas J White
Australian NHMRC Senior Research Fellowship (1104975)
- Julie A Simpson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Marc Lipsitch, Harvard TH Chan School of Public Health, United States
Publication history
- Received: October 26, 2018
- Accepted: January 22, 2019
- Accepted Manuscript published: January 28, 2019 (version 1)
- Version of Record published: February 4, 2019 (version 2)
Copyright
© 2019, Watson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Collider bias and the apparent protective effect of glucose-6-phosphate dehydrogenase deficiency on cerebral malaria
eLife 8:e43154.
https://doi.org/10.7554/eLife.43154
Further reading
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- Epidemiology and Global Health
- Immunology and Inflammation
COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein–Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.
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- Epidemiology and Global Health
Background:
Denmark was one of the few countries where it was politically decided to continue cancer screening during the COVID-19 pandemic. We assessed the actual population uptake of mammography and cervical screening during this period.
Methods:
The first COVID-19 lockdown in Denmark was announced on 11 March 2020. To investigate possible changes in cancer screening activity due to the COVID-19 pandemic, we analysed data from the beginning of 2017 until the end of 2021. A time series analysis was carried out to discover possible trends and outliers in the screening activities in the period 2017–2021. Data on mammography screening and cervical screening were retrieved from governmental pandemic-specific monitoring of health care activities.
Results:
A brief drop was seen in screening activity right after the first COVID-19 lockdown, but the activity quickly returned to its previous level. A short-term deficit of 43% [CI –49 to –37] was found for mammography screening. A short-term deficit of 62% [CI –65 to –58] was found for cervical screening. Furthermore, a slight, statistically significant downward trend in cervical screening from 2018 to 2021 was probably unrelated to the pandemic. Other changes, for example, a marked drop in mammography screening towards the end of 2021, also seem unrelated to the pandemic.
Conclusions:
Denmark continued cancer screening during the pandemic, but following the first lockdown a temporary drop was seen in breast and cervical screening activity.
Funding:
Region Zealand (R22-A597).
