title: Spatiotemporal mathematical modelling of mutations of the dhps gene in African Plasmodium falciparum.
abstract: BACKGROUND
  Plasmodium falciparum has repeatedly evolved resistance to first-line anti-malarial drugs, thwarting efforts to control and eliminate the disease and in some period of time this contributed largely to an increase in mortality. Here a mathematical model was developed to map the spatiotemporal trends in the distribution of mutations in the P. falciparum dihydropteroate synthetase (dhps) gene that confer resistance to the anti-malarial sulphadoxine, and are a useful marker for the combination of alleles in dhfr and dhps that is highly correlated with resistance to sulphadoxine-pyrimethamine (SP). The aim of this study was to present a proof of concept for spatiotemporal modelling of trends in anti-malarial drug resistance that can be applied to monitor trends in resistance to components of artemisinin combination therapy (ACT) or other anti-malarials, as they emerge or spread.
  
  
  METHODS
  Prevalence measurements of single nucleotide polymorphisms in three codon positions of the dihydropteroate synthetase (dhps) gene from published studies of dhps mutations across Africa were used. A model-based geostatistics approach was adopted to create predictive surfaces of the dhps540E mutation over the spatial domain of sub-Saharan Africa from 1990-2010. The statistical model was implemented within a Bayesian framework and hence quantified the associated uncertainty of the prediction of the prevalence of the dhps540E mutation in sub-Saharan Africa.
  
  
  CONCLUSIONS
  The maps presented visualize the changing prevalence of the dhps540E mutation in sub-Saharan Africa. These allow prediction of space-time trends in the parasite resistance to SP, and provide probability distributions of resistance prevalence in places where no data are available as well as insight on the spread of resistance in a way that the data alone do not allow. The results of this work will be extended to design optimal sampling strategies for the future molecular surveillance of resistance, providing a proof of concept for similar techniques to design optimal strategies to monitor resistance to ACT.
authors.affiliation: WorldWide Antimalarial Resistance Network-WWARN, University of Oxford, Oxford, UK. jennifer.flegg@wwarn.org
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Flegg
authors.forename: Anand P
authors.initials: AP
authors.lastname: Patil
authors.forename: Meera
authors.initials: M
authors.lastname: Venkatesan
authors.forename: Cally
authors.initials: C
authors.lastname: Roper
authors.forename: Inbarani
authors.initials: I
authors.lastname: Naidoo
authors.forename: Simon I
authors.initials: SI
authors.lastname: Hay
authors.forename: Carol Hopkins
authors.initials: CH
authors.lastname: Sibley
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Guerin
mesh_terms: D017954:Africa South of the Sahara; D000962:Antimalarials / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004351:Drug Resistance; D005843:Geography; D006801:Humans; D008962:Models, Theoretical; D059645:Mutation Rate; D020125:Mutation, Missense; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D013413:Sulfadoxine / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D013413:Sulfadoxine; D004094:Dihydropteroate Synthase