Abstract
BackgroundPrior to this project, only a handful of online visualizations existed for exploring the published literature on molecular markers of antimalarial drug resistance, and none specifically for the markers associated with Plasmodium falciparum resistance to the partner drugs in artemisinin-based combination therapy (ACT). Molecular information is collected in studies with different designs, using a variety of molecular methodologies and data analysis strategies, making it difficult to compare across studies. The purpose of this project was to develop a free online tool, which visualizes the widely published data on molecular markers of antimalarial drug resistance, starting with the two genes pfcrt and pfmdr-1, associated with resistance to the three most common partner drugs; amodiaquine, lumefantrine and mefloquine.MethodsA literature review was conducted, and a standardized method was used to extract data from publications, and critical decisions on visualization were made. A global geospatial database was developed of specific pfmdr1 and pfcrt single nucleotide polymorphisms and pfmdr1 copy number variation. An informatics framework was developed that allowed flexibility in development of the tool over time and efficient adaptation to different source data.ResultsThe database discussed in this paper has pfmdr1 and pfcrt marker prevalence information, from 579 geographic sites in 76 different countries, including results from over 86,000 samples from 456 articles published January 2001–May 2017. The ACT Partner Drugs Molecular Surveyor was launched by the WorldWide Antimalarial Resistance Network (WWARN) in March 2015 and it has attracted over 3000 unique visitors since then. Presented here is a demonstration of how the Surveyor database can be explored to monitor local, temporal changes in the prevalence of molecular markers. Here publications up to May 2017 were included, however the online ACT partner drug Molecular Surveyor is continuously updated with new data and relevant markers.ConclusionsThe WWARN ACT Partner Drugs Molecular Surveyor summarizes data on resistance markers in the pfmdr1 and pfcrt genes. The database is fully accessible, providing users with a rich resource to explore and analyze, and thus utilize a centralized, standardized database for different purposes. This open-source software framework can be adapted to other data, as demonstrated by the subsequent launch of the Artemisinin Molecular Surveyor and the Vivax Surveyor.
Highlights
Prior to this project, only a handful of online visualizations existed for exploring the published literature on molecular markers of antimalarial drug resistance, and none for the markers associated with Plasmodium falciparum resistance to the partner drugs in artemisinin-based combination therapy (ACT)
Mutations in Plasmodium falciparum genes have long been established as markers of antimalarial resistance [2,3,4,5], and the level of clinical treatment failure has been associated with the presence of these resistance mutations [6, 7]
With respect to the partner drugs used in currently recommended artemisinin-based combination therapy (ACT), resistance to amodiaquine has been associated with single nucleotide polymorphisms (SNPs) in both the P. falciparum chloroquine-resistance transporter MAL7P1.27 and P. falciparum multidrug resistance gene 1 MAL5P1.230 [6, 7, 9] (Table 1)
Summary
Only a handful of online visualizations existed for exploring the published literature on molecular markers of antimalarial drug resistance, and none for the markers associated with Plasmodium falciparum resistance to the partner drugs in artemisinin-based combination therapy (ACT). Molecular information is collected in studies with different designs, using a variety of molecular methodologies and data analysis strategies, making it difficult to compare across studies The purpose of this project was to develop a free online tool, which visualizes the widely published data on molecular markers of antimalarial drug resistance, starting with the two genes pfcrt and pfmdr-1, associated with resistance to the three most common partner drugs; amodiaquine, lumefantrine and mefloquine. Mutations in Plasmodium falciparum genes have long been established as markers of antimalarial resistance [2,3,4,5], and the level of clinical treatment failure has been associated with the presence of these resistance mutations [6, 7] Identification of both copy number variation (CNV) and single nucleotide polymorphisms (SNPs) in the P. falciparum genes allows monitoring of the emergence and spread of declining drug susceptibility in parasite populations [8]. Resistance to mefloquine has been associated with amplification of the pfmdr gene [13]
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