title: THE REAL McCOIL: A method for the concurrent estimation of the complexity of infection and SNP allele frequency for malaria parasites.
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.
authors.affiliation: Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States.
authors.forename: Hsiao-Han
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Worby
authors.affiliation: Makerere University School of Public Health, College of Health Sciences, Kampala, Uganda.|Infectious Disease Research Collaboration, Kampala, Uganda.
authors.forename: Adoke
authors.initials: A
authors.lastname: Yeka
authors.affiliation: Infectious Disease Research Collaboration, Kampala, Uganda.|Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Joaniter
authors.initials: J
authors.lastname: Nankabirwa
authors.affiliation: Infectious Disease Research Collaboration, Kampala, Uganda.|Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Staedke
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States.
authors.forename: Grant
authors.identifier: 0000-0003-0740-0317
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States.
authors.forename: Maxwell
authors.identifier: 0000-0003-0332-4388
authors.initials: M
authors.lastname: Murphy
authors.affiliation: Genome Sequencing and Analysis Program, Broad Institute, Cambridge, Massachusetts, United States.
authors.forename: Daniel E
authors.identifier: 0000-0002-1665-9323
authors.initials: DE
authors.lastname: Neafsey
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna E
authors.identifier: 0000-0002-6454-3093
authors.initials: AE
authors.lastname: Jeffreys
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Hubbart
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Kirk A
authors.identifier: 0000-0002-6369-9299
authors.initials: KA
authors.lastname: Rockett
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Roberto
authors.initials: R
authors.lastname: Amato
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States.
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Buckee
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States.
authors.forename: Bryan
authors.identifier: 0000-0003-0287-9111
authors.initials: B
authors.lastname: Greenhouse
mesh_terms: D005787:Gene Frequency / Q000235:genetics*; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000145:classification / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011159:Population Surveillance / Q000379:methods*; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D014454:Uganda / Q000453:epidemiology