Collider bias and the apparent protective effect of glucose-6-phosphate dehydrogenase deficiency on cerebral malaria

  1. James A Watson  Is a corresponding author
  2. Stije J Leopold  Is a corresponding author
  3. Julie A Simpson
  4. Nicholas PJ Day
  5. Arjen M Dondorp
  6. Nicholas J White  Is a corresponding author
  1. Mahidol University, Thailand
  2. 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

  1. James A Watson

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    For correspondence
    jwatowatson@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5524-0325
  2. Stije J Leopold

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    For correspondence
    stije@tropmedres.ac
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0482-5689
  3. Julie A Simpson

    Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicholas PJ Day

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  5. Arjen M Dondorp

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicholas J White

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    For correspondence
    nickw@tropmedres.ac
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1897-1978

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

  1. Marc Lipsitch, Harvard TH Chan School of Public Health, United States

Version history

  1. Received: October 26, 2018
  2. Accepted: January 22, 2019
  3. Accepted Manuscript published: January 28, 2019 (version 1)
  4. 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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  1. James A Watson
  2. Stije J Leopold
  3. Julie A Simpson
  4. Nicholas PJ Day
  5. Arjen M Dondorp
  6. Nicholas J White
(2019)
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

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https://doi.org/10.7554/eLife.43154

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