Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision

Author:

Watson James AORCID,Ndila Carolyne MORCID,Uyoga SophieORCID,Macharia Alexander WORCID,Nyutu GideonORCID,Shebe MohammedORCID,Ngetsa CarolineORCID,Mturi NeemaORCID,Peshu NorbertORCID,Tsofa BenjaminORCID,Rockett KirkORCID,Leopold StijeORCID,Kingston HughORCID,George Elizabeth C,Maitland KathrynORCID,Day Nicholas PJORCID,Dondorp ArjenORCID,Bejon PhilipORCID,Williams Thomas N,Holmes Chris C,White Nicholas JORCID

Abstract

AbstractSevere 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.

Publisher

Cold Spring Harbor Laboratory

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