THE REAL McCOIL: A method for the concurrent estimation of the complexity of infection and SNP allele frequency for malaria parasites

Hsiao-Han Chang, Colin J Worby, Adoke Yeka, Joaniter Nankabirwa, Moses R Kamya, Sarah G Staedke, Grant Dorsey, Maxwell Murphy, Daniel E Neafsey, Anna E Jeffreys, Christina Hubbart, Kirk A Rockett, Roberto Amato, Dominic P Kwiatkowski, Caroline O Buckee and Bryan Greenhouse

PLOS Computational Biology, 2017, vol. 13, issue 1, 1-18

Abstract: As many malaria-endemic countries move towards elimination of Plasmodium falciparum, the most virulent human malaria parasite, effective tools for monitoring malaria epidemiology are urgent priorities. P. falciparum population genetic approaches offer promising tools for understanding transmission and spread of the disease, but a high prevalence of multi-clone or polygenomic infections can render estimation of even the most basic parameters, such as allele frequencies, challenging. A previous method, COIL, was developed to estimate complexity of infection (COI) from single nucleotide polymorphism (SNP) data, but relies on monogenomic infections to estimate allele frequencies or requires external allele frequency data which may not available. Estimates limited to monogenomic infections may not be representative, however, and when the average COI is high, they can be difficult or impossible to obtain. Therefore, we developed THE REAL McCOIL, Turning HEterozygous SNP data into Robust Estimates of ALelle frequency, via Markov chain Monte Carlo, and Complexity Of Infection using Likelihood, to incorporate polygenomic samples and simultaneously estimate allele frequency and COI. This approach was tested via simulations then applied to SNP data from cross-sectional surveys performed in three Ugandan sites with varying malaria transmission. We show that THE REAL McCOIL consistently outperforms COIL on simulated data, particularly when most infections are polygenomic. Using field data we show that, unlike with COIL, we can distinguish epidemiologically relevant differences in COI between and within these sites. Surprisingly, for example, we estimated high average COI in a peri-urban subregion with lower transmission intensity, suggesting that many of these cases were imported from surrounding regions with higher transmission intensity. THE REAL McCOIL therefore provides a robust tool for understanding the molecular epidemiology of malaria across transmission settings.Author Summary: Monitoring malaria epidemiology is critical for evaluating the impact of interventions and designing strategies for control and elimination. Population genetics has been used to inform malaria epidemiology, but it is limited by the fact that a fundamental metric needed for most analyses—the frequency of alleles in a population—is difficult to estimate from blood samples containing more than one genetically distinct parasite (polygenomic infections). A widely used approach has been to restrict analysis to monogenomic infections, which may represent a biased subset and potentially ignores a large amount of data. Therefore, we developed a new analytical approach that uses data from all infections to simultaneously estimate allele frequency and the number of distinct parasites within each infection. The method, called THE REAL McCOIL, was evaluated using simulations and was then applied to data from cross-sectional surveys performed in three regions of Uganda. Simulations demonstrated accurate performance, and analyses of samples from Uganda using THE REAL McCOIL revealed epidemiologically relevant differences within and between the three regions that previous methods could not. THE REAL McCOIL thus facilitates population genetic analysis when there are polygenomic infections, which are common in many malaria endemic areas.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1005348

DOI: 10.1371/journal.pcbi.1005348

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