Systematic review of Plasmodium falciparum and Plasmodium vivax polyclonal infections: Impact of prevalence, study population characteristics, and laboratory procedures

López, Luis Fernández; Koepfli, Cristian

doi:10.1371/journal.pone.0249382

Cited by 20 publications

(25 citation statements)

References 37 publications

(51 reference statements)

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“…Unfortunately, the relationship between the COI and malaria prevalence remains an area of much debate, with many individual studies finding different relationships between the COI and malaria prevalence [65,66]. Lopez and Koepfli report in their review article that across the 153 studies examined there was a weak correlation between mean COI and prevalence, an observation that agrees with our findings [55]. As previously noted, there are multiple patient-level factors (e.g., age and clinical status) which may affect the relationship between malaria prevalence and the COI.…”

Section: Discussionsupporting

confidence: 89%

“…An application of coiaf on several thousand P. falciparum samples from malaria-endemic countries in four continents from 2002-2015 [43] resulted in a comprehensive map of the complexity of infection worldwide. This study builds on previous reviews of the distribution of the COI globally [55], and is the first study to our knowledge to provide a holistic view of the COI based on allelic read depth as opposed to traditional methods leveraging msp1 and msp2 haplotyping.…”

Section: Discussionmentioning

confidence: 96%

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coiaf: directly estimating complexity of infection with allele frequencies

Paschalidis

Watson

Aydemir

et al. 2022

Preprint

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In malaria, individuals are often infected with different parasite strains; the complexity of infection (COI) is defined as the number of genetically distinct parasite strains in an individual. Changes in the mean COI in a population have been shown to be informative of changes in transmission intensity with a number of probabilistic likelihood and Bayesian models now developed to estimate the COI. However, rapid, direct measures based on heterozygosity or FwS do not properly represent the COI. In this work, we present two new methods that use easily calculated measures to directly estimate the COI from allele frequency data. Using a simulation framework, we show that our methods are computationally efficient and comparably accurate to current methods in the literature. Through a sensitivity analysis, we characterize how the bias and accuracy of our two methods are impacted by the distribution of parasite densities and the assumed sequencing depth and number of sampled loci. We further estimate the COI globally from Plasmodium falciparum sequencing data using our developed methods and compare the results against the literature. We show significant differences in estimated COI globally between continents and a weak relationship between malaria prevalence and COI.Author summaryComputational models, used in conjunction with rapidly advancing sequencing technologies, are increasingly being used to help inform surveillance efforts and understand the epidemiological dynamics of malaria. One such important metric, the complexity of infection (COI), indirectly quantifies the level of transmission. Existing “gold-standard” COI measures rely on complex probabilistic likelihood and Bayesian models. As an alternative, we have developed the statistics and software package coiaf, which features two rapid, direct measures to estimate of the number of genetically distinct parasite strains in an individual (the COI). Our methods were evaluated using simulated data and subsequently compared to current “state-of-the-art” methods, yielding comparable results. Lastly, we examined the distribution of the COI in several locations across the world, identifying significant differences in COI between continents. coiaf, therefore, provides a new, promising framework for rapidly characterizing polyclonal infections.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 96%

coiaf: directly estimating complexity of infection with allele frequencies

Paschalidis

Watson

Aydemir

et al. 2022

Preprint

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“…In almost all transmission settings, polyclonal P. falciparum infections are frequent ( Lopez and Koepfli, 2021 ). Using a gel-based assay for deletion typing, in a mixed infection with a wild-type parasite and a parasite carrying a deletion, the wild-type parasite will produce a band and mask the deletion.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion status might remain unresolved if results differ among replicates. As an additional problem, multiple clone P. falciparum infections are common in most endemic settings ( Lopez and Koepfli, 2021 ; Grignard et al, 2020 ). In case of a multiple clone infection with a wild-type parasite and a parasite carrying the deletion, the wild-type parasite will result in a band on the gel when using the nPCR assay.…”

Section: Introductionmentioning

confidence: 99%

High-throughput Plasmodium falciparum hrp2 and hrp3 gene deletion typing by digital PCR to monitor malaria rapid diagnostic test efficacy

Vera-Arias

Holzschuh

Oduma

et al. 2022

eLife

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Most rapid diagnostic tests for Plasmodium falciparum malaria target the Histidine-Rich Proteins 2 and 3 (HRP2 and HRP3). Deletions of the hrp2 and hrp3 genes result in false-negative tests and are a threat for malaria control. A novel assay for molecular surveillance of hrp2/hrp3 deletions was developed based on droplet digital PCR (ddPCR). The assay quantifies hrp2, hrp3, and a control gene with very high accuracy. The theoretical limit of detection was 0.33 parasites/µl. The deletion was reliably detected in mixed infections with wild-type and hrp2-deleted parasites at a density of >100 parasites/reaction. For a side-by-side comparison with the conventional nested PCR (nPCR) assay, 248 samples were screened in triplicate by ddPCR and nPCR. No deletions were observed by ddPCR, while by nPCR hrp2 deletion was observed in 8% of samples. The ddPCR assay was applied to screen 830 samples from Kenya, Zanzibar/Tanzania, Ghana, Ethiopia, Brazil, and Ecuador. Pronounced differences in the prevalence of deletions were observed among sites, with more hrp3 than hrp2 deletions. In conclusion, the novel ddPCR assay minimizes the risk of false-negative results (i.e., hrp2 deletion observed when the sample is wild type), increases sensitivity, and greatly reduces the number of reactions that need to be run.

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“…It is sometimes used to reflect the transmission intensity. However, the relationship between parasite prevalence and COI is often non-linear, likely sensitive to other factors, and in some cases, potentially more spurious in P. vivax than P. falciparum ( Fola et al, 2017 ; Lopez and Koepfli, 2021 ). As genomics techniques have improved the ability to determine how closely related co-infections are, it also allows us to gleam the likelihood of a superinfection (from more than two separate mosquito bites) or co-transmission (more than two parasite clones from one mosquito bite) ( Cowell et al, 2018 ).…”

Section: Understanding Epidemiology From Estimates Of the Complexity ...mentioning

confidence: 99%

Population genomics in neglected malaria parasites

Brashear

2022

Front. Microbiol.

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Malaria elimination includes neglected human malaria parasites Plasmodium vivax, Plasmodium ovale spp., and Plasmodium malariae. Biological features such as association with low-density infection and the formation of hypnozoites responsible for relapse make their elimination challenging. Studies on these parasites rely primarily on clinical samples due to the lack of long-term culture techniques. With improved methods to enrich parasite DNA from clinical samples, whole-genome sequencing of the neglected malaria parasites has gained increasing popularity. Population genomics of more than 2200 P. vivax global isolates has improved our knowledge of parasite biology and host-parasite interactions, identified vaccine targets and potential drug resistance markers, and provided a new way to track parasite migration and introduction and monitor the evolutionary response of local populations to elimination efforts. Here, we review advances in population genomics for neglected malaria parasites, discuss how the rich genomic information is being used to understand parasite biology and epidemiology, and explore opportunities for the applications of malaria genomic data in malaria elimination practice.

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Systematic review of Plasmodium falciparum and Plasmodium vivax polyclonal infections: Impact of prevalence, study population characteristics, and laboratory procedures

Cited by 20 publications

References 37 publications

coiaf: directly estimating complexity of infection with allele frequencies

coiaf: directly estimating complexity of infection with allele frequencies

High-throughput Plasmodium falciparum hrp2 and hrp3 gene deletion typing by digital PCR to monitor malaria rapid diagnostic test efficacy

Population genomics in neglected malaria parasites

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