1. Epidemiology and Global Health
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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
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Cite this article as: eLife 2019;8:e43154 doi: 10.7554/eLife.43154

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.

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

Publication 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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Further reading

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    Background:

    Since 2015, the World Health Organisation (WHO) recommends immediate initiation of antiretroviral therapy (ART) for all HIV-positive patients. Epidemiological evidence points to important health benefits of immediate ART initiation; however, the policy’s impact on the economic aspects of patients' lives remains unknown.

    Methods:

    We conducted a stepped-wedge cluster-randomised controlled trial in Eswatini to determine the causal impact of immediate ART initiation on patients’ individual- and household-level economic outcomes. Fourteen healthcare facilities were non-randomly matched into pairs and then randomly allocated to transition from the standard of care (ART eligibility at CD4 counts of <350 cells/mm3 until September 2016 and <500 cells/mm3 thereafter) to the ‘Early Initiation of ART for All’ (EAAA) intervention at one of seven timepoints. Patients, healthcare personnel, and outcome assessors remained unblinded. Data were collected via standardised paper-based surveys with HIV-positive adults who were neither pregnant nor breastfeeding. Outcomes were patients’ time use, employment status, household expenditures, and household living standards.

    Results:

    A total sample of 3019 participants were interviewed over the duration of the study. The mean number of participants approached at each facility per time step varied from 4 to 112 participants. Using mixed-effects negative binomial regressions accounting for time trends and clustering at the level of the healthcare facility, we found no significant difference between study arms for any economic outcome. Specifically, the EAAA intervention had no significant effect on non-resting time use (RR = 1.00 [CI: 0.96, 1.05, p=0.93]) or income-generating time use (RR = 0.94, [CI: 0.73,1.20, p=0.61]). Employment and household expenditures decreased slightly but not significantly in the EAAA group, with risk ratios of 0.93 [CI: 0.82, 1.04, p=0.21] and 0.92 [CI: 0.79, 1.06, p=0.26], respectively. We also found no significant treatment effect on households’ asset ownership and living standards (RR = 0.96, [CI 0.92, 1.00, p=0.253]). Lastly, there was no evidence of heterogeneity in effect estimates by patients’ sex, age, education, timing of HIV diagnosis and ART initiation.

    Conclusions:

    Our findings do not provide evidence that should discourage further investments into scaling up immediate ART for all HIV patients.

    Funding:

    Funded by the Dutch Postcode Lottery in the Netherlands, Alexander von Humboldt-Stiftung (Humboldt-Stiftung), the Embassy of the Kingdom of the Netherlands in South Africa/Mozambique, British Columbia Centre of Excellence in Canada, Doctors Without Borders (MSF USA), National Center for Advancing Translational Sciences of the National Institutes of Health and Joachim Herz Foundation.

    Clinical trial number:

    NCT02909218 and NCT03789448.

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