Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision
- Mahidol Oxford Tropical Medicine Research Unit, Thailand
- KEMRI-Wellcome Trust Research Programme, Kenya
- Kenya Medical Research Institute-Wellcome Trust Research Programme, Kenya
- Wellcome Trust Centre for Human Genetics, United Kingdom
- Medical Research Council Clinical Trials Unit, United Kingdom
- Mahidol University, Thailand
- Kilifi KEMRI-Wellcome Trust Collaborative Research Programme, Kenya
- Department of Statistics, University of Oxford, United Kingdom
Abstract
Severe falciparum malaria has substantially affected human evolution. Genetic association studies of patients with clinically defined severe malaria and matched population controls have helped characterise human genetic susceptibility to severe malaria, but phenotypic imprecision compromises discovered associations. In areas of high malaria transmission the diagnosis of severe malaria in young children and, in particular, the distinction from bacterial sepsis, is imprecise. We developed a probabilistic diagnostic model of severe malaria using platelet and white count data. Under this model we re-analysed clinical and genetic data from 2,220 Kenyan children with clinically defined severe malaria and 3,940 population controls, adjusting for phenotype mis-labelling. Our model, validated by the distribution of sickle trait, estimated that approximately one third of cases did not have severe malaria. We propose a data-tilting approach for case-control studies with phenotype mis-labelling and show that this reduces false discovery rates and improves statistical power in genome-wide association studies.
Data availability
A curated minimal clinical dataset is currently available alongisde the code on the github repository. This will also be made available at publication via the KEMRI-Wellcome Harvard Dataverse(https://dataverse.harvard.edu/dataverse/kwtrp).Whole genome data are available from European Genome-Phenome Archive (dataset accession ID: EGAD00010001742).Requests for access to appropriately anonymized clinical data and directly typed genetic variants for the Kenyan severe malaria cohort can be made by application to the data access committee at the KEMRI-Wellcome Trust Research Programme by e-mail to mmunene@kemri-wellcome.org.The FEAST trial datasets are available from the principal investigator on reasonable request (k.maitland@imperial.ac.uk).Requests for access to appropriately anonymized clinical data from the AQ and AAV Vietnam study and the Asian paediatric cohort can be made via the Mahidol Oxford Tropical Medicine Research Unit data access committee by emailing the corresponding author JAW (jwatowatson@gmail.com) or Rita Chanviriyavuth (rita@tropmedres.ac).
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A genome-wide study of resistance to severe malaria in 18,000 samples from eleven worldwide populations, including eight populations sub-Saharan Africa.European Genome-Phenome Archive, EGAD00010001742.
Article and author information
Author details
Funding
Wellcome Trust (209265/Z/17/Z)
- Kathryn Maitland
- Nicholas PJ Day
Wellcome Trust (202800/Z/16/Z)
- Thomas Williams
Wellcome Trust (093956/Z/10/C)
- Nicholas J White
Medical Research Council (MC\UU\12023/26)
- Elizabeth C George
Wellcome Trust (WT077383/Z/05/Z)
- Kirk Rockett
Medical Research Council (G0801439)
- Elizabeth C George
- Kathryn Maitland
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jennifer Flegg, The University of Melbourne, Australia
Ethics
Human subjects: All clinical data are from published studies in which all participants or guardians gave fully informed consent. Access to the human genetic data was approved by the MalariaGen data access committee.
Version history
- Received: April 22, 2021
- Accepted: June 22, 2021
- Accepted Manuscript published: July 6, 2021 (version 1)
- Version of Record published: July 27, 2021 (version 2)
- Version of Record updated: November 22, 2021 (version 3)
Copyright
© 2021, 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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Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision
eLife 10:e69698.
https://doi.org/10.7554/eLife.69698
Further reading
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- Epidemiology and Global Health
Background:
The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission.
Methods:
To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018.
Results:
Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes.
Conclusions:
Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors.
Funding:
This research was funded by the National Institutes of Health, grants R01AI121558, R01AI137395, R01AI155730, F30AI143172, and K24AI134990. Funding was also contributed from the Swedish Research Council, Erling-Persson Family Foundation, and the Yang Fund. RV acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 program supported by the European Union. RV also acknowledges funding by Community Jameel.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background: Few national-level studies have evaluated the impact of 'hybrid' immunity (vaccination coupled with recovery from infection) from the Omicron variants of SARS-CoV-2.
Methods: From May 2020 to December 2022, we conducted serial assessments (each of ~4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels.
Results: Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than six months earlier, spike levels fell notably and continuously for the nine months post-vaccination. By contrast, among adults infected within six months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than six months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% CI 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the COVID-19 weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity.
Conclusions: Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected dried blood spots are a practicable biological surveillance platform.
Funding: Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael's Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.
