Collider bias and the apparent protective effect of glucose-6-phosphate dehydrogenase deficiency on cerebral malaria
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.
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
- 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.
- Marc Lipsitch, Harvard TH Chan School of Public Health, United States
- 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)
© 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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