An online mapping database of molecular markers of drug resistance in Plasmodium falciparum: the ACT Partner Drug Molecular Surveyor

Abstract

Background: 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 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.

Methods: A 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.

Results: The 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.

Conclusions: The 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.

Keywords: Drug resistance; Geovisualization; Malaria; Molecular markers; pfcrt; pfmdr1.

Fig. 1

Flow diagram outlining study selection

Fig. 2

Number of studies published each year, coloured by region where samples were collected

Fig. 3

Pie chart displaying where samples were collected, pooling years 1956–2017

Fig. 4

Screen shot of Surveyor, displaying data on the pfmdr1 86Y mutation allele

Fig. 5

Temporal changes in prevalence of pfmdr1 N86 and pfcrt K76 Tororo, Uganda

Fig. 6

Prevalence of pfmdr1 N86 in sub-Saharan countries by study and year. Each point depicts one study, sized according to the number of tested samples. The line represents the annual mean of all studies in a country. Mixed infections 86 N + Y were included together with N86 in the analysis. The countries either have a AL as first-line treatment, b ASAQ as first-line treatment or c multiple first line treatments. This data was extracted from 42 source publications, details of which can be found in Additional file 3