Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision.
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Author(s)
Type
Journal Article
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.
Date Issued
2021-07-06
Date Acceptance
2021-06-22
Citation
eLife, 2021, 10, pp.1-39
ISSN
2050-084X
Publisher
eLife Sciences Publications Ltd
Start Page
1
End Page
39
Journal / Book Title
eLife
Volume
10
Copyright Statement
© 2021 Watson et al. This
article is distributed under the
terms of the Creative Commons
Attribution License, which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.
article is distributed under the
terms of the Creative Commons
Attribution License, which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.
License URL
Sponsor
Wellcome Trust
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34225842
PII: 69698
Grant Number
202800/Z/16/Z
Subjects
epidemiology
genetics
genomics
global health
human
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2021-07-06