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.
Highlights
Severe falciparum malaria is defined by one or more criteria indicating vital organ dysfunction in the presence of microscopy confirmed asexual blood stages of Plasmodium falciparum in the peripheral blood film (WHO, 2015)
Anaemia in individuals at risk of Plasmodium falciparum infection can be the consequence of red cell genetic polymorphisms frequent in the populations at risk, such as glucose-6-phosphate dehydrogenase deficiency (G6PDd) or haemoglobinopathies
It is to be expected that severe malarial anaemia (SMA) is positively correlated with G6PDd, creating a negative correlation between cerebral malaria (CM) and G6PDd
Summary
Severe falciparum malaria is defined by one or more criteria indicating vital organ dysfunction in the presence of microscopy confirmed asexual blood stages of Plasmodium falciparum in the peripheral blood film (WHO, 2015). Common major clinical manifestations of severe malaria include coma, acidosis, renal failure and anaemia Of these manifestations, anaemia is an inevitable consequence of symptomatic malaria (White et al, 2014). Anaemia in individuals at risk of Plasmodium falciparum infection can be the consequence of red cell genetic polymorphisms frequent in the populations at risk, such as glucose-6-phosphate dehydrogenase deficiency (G6PDd) or haemoglobinopathies. There is considerable interest in understanding the mechanisms conferring protective effects against severe falciparum malaria of the genetic polymorphisms which are common in malaria endemic areas (Weatherall, 2008). Such as the sickle cell trait, several different mechanisms have been proposed.
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