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

Watson, James A; Ndila, Carolyne; Uyoga, Sophie; Macharia, Alexander; Nyutu, Gideon; Mohammed, Shebe; Ngetsa, Caroline; Mturi, Neema; Peshu, Norbert; Tsofa, Benjamin; Rockett, Kirk A.; Leopold, Stije J.; Kingston, Hugh; George, Elizabeth C.; Maitland, Kathryn; Day, Nicholas P. J.; Dondorp, Arjen M.; Bejon, Philip; Williams, Thomas N.; Holmes, Chris; White, Nicholas J.

doi:10.7554/elife.69698

Cited by 26 publications

(40 citation statements)

References 53 publications

(123 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We re-estimated case-control odds-ratios under a data-tilting framework for the five major red blood cell genetic polymorphisms evaluated using previously published probability weights based on the plasma Pf HRP2 and the platelet count to downweigh probabilistically data from patients who were unlikely to have true severe malaria (Fig. 4 ) 13 , 15 . This increased the strength of the evidence that HBB , ABO , HBA1-2 , and FREM3/GYP are associated with protection against severe malaria compared with the non-weighted case–controls odds-ratios (for HBA1-2 : p = 10 −5 versus p = 10 −4 ; ABO : p = 10 −13 versus p = 10 −8 ; FREM3 : p = 10 −12 versus p = 10 −11 ).…”

Section: Resultsmentioning

confidence: 99%

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

et al. 2022

View full text Add to dashboard Cite

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.

show abstract

Section: Resultsmentioning

confidence: 99%

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

et al. 2022

View full text Add to dashboard Cite

show abstract

“…We re-estimated case-control odds-ratios under a data-tilting framework for our five major red blood cell genetic polymorphisms using previously published probability weights based on the plasma Pf HRP2 and the platelet count to probabilistically downweigh patients who were unlikely to have true severe malaria 13,24 . This increased the evidence that HBB, ABO, HBA1-2 and FREM3/GYP are associated with protection against severe malaria when comparing against the non-weighted case-controls odds-ratios (for HBA1-2 : p=10 −5 versus p=10 −4 ; ABO : p=10 −13 versus p=10 −8 ; FREM3 : p=10 −12 versus p=10 −11 ).…”

Section: Resultsmentioning

confidence: 99%

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

Uyoga

Watson

Wanjiku

et al. 2022

Preprint

View full text Add to dashboard Cite

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. The sequestration of parasitized erythrocytes in the microvasculature of vital organs is a central pathophysiological feature. The plasma concentration of the parasite protein P. falciparum Histidine-Rich Protein 2 (PfHRP2) has diagnostic and prognostic value in severe malaria. In the current study we investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of plasma PfHRP2 to circulating parasites) as quantitative traits in the conduct of case-only genetic association studies of severe malaria. We demonstrate the utility of this approach using data from over 2,000 Kenyan children with severe malaria, genotyped for 14 major candidate genes that were found to be associated with protection against severe malaria in previous studies. We show that PfHRP2 is a more informative quantitative trait than peripheral parasite density, and that polymorphisms in four major red cell genes (the βS sickle mutation in HBB, the blood group mutation O in ABO, the α-thalassaemia mutation in HBA, and the Dantu blood group mutation in GYP) are associated with substantially lower concentrations of plasma PfHRP2 at admission. Further, the effect sizes we observed were considerably larger than those relating to peripheral parasite density. An unexpected outlier was the rs1541255 A>G polymorphism in ATP2B4 for which we saw higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for how this might be explained in the context of this specific protective allele.

show abstract

“…Conversely, incorporating platelet counts into case definitions of severe falciparum malaria using >200,000 per μL to rule out severe malaria has been proposed as a means to improve the specificity of clinical and parasitological diagnosis in a mathematical modeling study. Results suggested that one-third of 2,220 Kenyan children included in studies had been misdiagnosed as having severe malaria [ 99 ]. Very few articles reported platelet counts associated with severe syndromes in our review so we were unable to explore this.…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of vivax malaria: A collection review

et al. 2022

View full text Add to dashboard Cite

Background Plasmodium vivax infects an estimated 7 million people every year. Previously, vivax malaria was perceived as a benign condition, particularly when compared to falciparum malaria. Reports of the severe clinical impacts of vivax malaria have been increasing over the last decade. Methods and findings We describe the main clinical impacts of vivax malaria, incorporating a rapid systematic review of severe disease with meta-analysis of data from studies with clearly defined denominators, stratified by hospitalization status. Severe anemia is a serious consequence of relapsing infections in children in endemic areas, in whom vivax malaria causes increased morbidity and mortality and impaired school performance. P. vivax infection in pregnancy is associated with maternal anemia, prematurity, fetal loss, and low birth weight. More than 11,658 patients with severe vivax malaria have been reported since 1929, with 15,954 manifestations of severe malaria, of which only 7,157 (45%) conformed to the World Health Organization (WHO) diagnostic criteria. Out of 423 articles, 311 (74%) were published since 2010. In a random-effects meta-analysis of 85 studies, 68 of which were in hospitalized patients with vivax malaria, we estimated the proportion of patients with WHO-defined severe disease as 0.7% [95% confidence interval (CI) 0.19% to 2.57%] in all patients with vivax malaria and 7.11% [95% CI 4.30% to 11.55%] in hospitalized patients. We estimated the mortality from vivax malaria as 0.01% [95% CI 0.00% to 0.07%] in all patients and 0.56% [95% CI 0.35% to 0.92%] in hospital settings. WHO-defined cerebral, respiratory, and renal severe complications were generally estimated to occur in fewer than 0.5% patients in all included studies. Limitations of this review include the observational nature and small size of most of the studies of severe vivax malaria, high heterogeneity of included studies which were predominantly in hospitalized patients (who were therefore more likely to be severely unwell), and high risk of bias including small study effects. Conclusions Young children and pregnant women are particularly vulnerable to adverse clinical impacts of vivax malaria, and preventing infections and relapse in this groups is a priority. Substantial evidence of severe presentations of vivax malaria has accrued over the last 10 years, but reporting is inconsistent. There are major knowledge gaps, for example, limited understanding of the underlying pathophysiology and the reason for the heterogenous geographical distribution of reported complications. An adapted case definition of severe vivax malaria would facilitate surveillance and future research to better understand this condition.

show abstract

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

Cited by 26 publications

References 53 publications

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

Clinical impact of vivax malaria: A collection review

Contact Info

Product

Resources

About