ProCite
RefWorks
Reference Manager
BibTeX
Zotero
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1.
Picot S, Olliaro P, De Monbrison F, Bienvenu AL, Price RN, Ringwald P, 2009. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malar J 8: 89.
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2.
Laufer MK, Djimde AA, Plowe CV, 2007. Monitoring and deterring drug-resistant malaria in the era of combination therapy. Am J Trop Med Hyg 77: 160–169.
-
3.
Plowe CV, Roper C, Barnwell JW, Happi CT, Joshi HH, Mbacham W, Meshnick SR, Mugittu K, Naidoo I, Price RN, Shafer RW, Sibley CH, Sutherland CJ, Zimmerman PA, Rosenthal PJ, 2007. World Antimalarial Resistance Network (WARN) III: molecular markers for drug resistant malaria. Malar J 6: 121.
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4.
Liu SF, Mu JB, Jiang HY, Su XZ, 2008. Effects of Plasmodium falciparum mixed infections on in vitro antimalarial drug tests and genotyping. Am J Trop Med Hyg 79: 178–184.
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5.
Juliano JJ, Trottman P, Mwapasa V, Meshnick SR, 2008. Short report: detection of the dihydrofolate reductase-164L mutation in Plasmodium falciparum infections from Malawi by heteroduplex tracking assay. Am J Trop Med Hyg 78: 892–894.
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6.
Farnert A, Arez AP, Babiker HA, Beck HP, Benito A, Bjorkman A, Bruce MC, Conway DJ, Day KP, Henning L, Mercereau-Puijalon O, Ranford-Cartwright LC, Rubio JM, Snounou G, Walliker D, Zwetyenga J, do Rosario VE, 2001. Genotyping of Plasmodium falciparum infections by PCR: a comparative multicentre study. Trans R Soc Trop Med Hyg 95: 225–232.
-
7.
Alonso PL, Smith T, Armstrong Schellenberg JRM, Masanja H, Mwankusye S, Urassa H, Bastos de Azevedo I, Chongela J, Kobero S, Menendez C, Hurt N, Thomas MC, Lyimo E, Weiss NA, Hayes R, Kitua AY, Lopez MC, Kilama WL, Teuscher T, Tanner M, 1994. Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania. Lancet 344: 1175–1181.
-
8.
Nsanzabana C, 2008. Dynamics of Malaria Parasite Resistance Markers in Two Areas of Different Transmission Intensity. PhD thesis: University of Neuchatal, Switzerland.
-
9.
Nsanzabana C, Hastings IM, Marfurt J, Muller I, Baea K, Rare L, Schapira A, Felger I, Betschart B, Smith TA, Beck HP, Genton B, 2010. Quantifying the evolution and impact of antimalarial drug resistance: drug use, spread of resistance and drug failure over a 12 year period in Papua New Guinea. J Infect Dis 201: 435–443.
-
10.
Hartl DL, Clark AG, 2007. Principles of Population Genetics. Fourth edition. Sunderland, MA: Sinauer Associates.
-
11.
Newcombe RG, 1998. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 17: 857–872.
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12.
Williams BG, Dye C, 1994. Maximum likelihood for parasitologists. Parasitol Today 10: 489–493.
-
13.
Hastings IM, Smith TA, 2008. MalHaploFreq: a computer programme for estimating malaria haplotype frequencies from blood samples. Malar J 7: 130.
-
14.
Hill WG, Babiker HA, 1995. Estimation of numbers of malaria clones in blood samples. Proc R Soc Lond B Biol Sci 262: 249–257.
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15.
Alifrangis M, Lemnge MM, Ronn AM, Segeja MD, Magesa SM, Khalil IF, Bygbjerg IC, 2003. Increasing prevalence of wildtypes in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulfadoxine/pyrimethamine resistance after introduction of treated bed nets. Am J Trop Med Hyg 69: 238–243.
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16.
Zimmerman PA, 2003. Roll back of Plasmodium falciparum antifolate resistance by insecticide-treated nets. Am J Trop Med Hyg 69: 236–237.
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Mharakurwa S, Mutambu SL, Mudyiradima R, Chimbadzwa T, Chandiwana SK, Day KP, 2004. Association of house spraying with suppressed levels of drug resistance in Zimbabwe. Malar J 3: 35.
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18.
Anderson TJC, Nair S, Sudimack D, Williams JT, Mayxay M, Newton PN, Guthmann JP, Smithuis FM, Hien TT, Van den Broek IVF, White NJ, Nosten F, 2005. Geographical distribution of selected and putatively neutral SNPs in southeast Asian malaria parasites. Mol Biol Evol 22: 2362–2374.
-
19.
Schoepflin S, Marfurt J, Goroti M, Baisor M, Mueller I, Felger I, 2008. Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population. Malar J 7: 78.
-
20.
Hastings IM, Watkins WM, 2006. Tolerance is the key to understanding antimalarial drug resistance. Trends Parasitol 22: 71–77.
-
21.
Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Bjorkman A, Gill JP, 2005. In vivo selection of Plasmodium falciparum pfmdr 1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis 191: 1014–1017.
-
22.
Watkins WM, Mosobo M, 1993. Treatment of Plasmodium falciparum malaria with pyrimethamine-sulphadoxine: selective pressure for resistance is a function of long half-life. Trans R Soc Trop Med Hyg 87: 75–78.
-
23.
Juliano J, Randrianarivelojosia M, Ramarosandratana B, Ariey F, Mwapasa V, Meshnick S, 2009. Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar. Malar J 8: 47.
-
24.
Sibley CH, Hyde JE, Sims PFG, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM, 2001. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol 17: 582–588.
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| Abstract Views | 346 | 247 | 14 |
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A Comparison of Methods to Detect and Quantify the Markers of Antimalarial Drug Resistance
Ian M. Hastings
Ian M. Hastings
Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom; Biostatistics and Computational Sciences, Swiss Tropical and Public Health Institute, Basel, Switzerland
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Christian Nsanzabana
Christian Nsanzabana
Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom; Biostatistics and Computational Sciences, Swiss Tropical and Public Health Institute, Basel, Switzerland
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Tom A. Smith
Tom A. Smith
Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom; Biostatistics and Computational Sciences, Swiss Tropical and Public Health Institute, Basel, Switzerland
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We compare, contrast, and evaluate methods to quantify genetic markers of antimalarial drug resistance. Frequency estimates should be reported along with crude prevalence. There are four main potential methods to estimate frequencies in blood samples: simple counting of single nucleotide polymorphisms (SNPs) and haplotypes in samples with multiplicity of infection (MOI) = 1; SNP counting in samples with MOI ≤ 2; SNP and haplotypes counting in samples with unambiguous genotypes; statistical inference using SNP and MOI data from all samples. Large differences between the methods became apparent when analyzing field data with high MOI. Simple counting dramatically reduced sample size and estimate precision, and we show that analysis of unambiguous samples is biased, leaving maximum likelihood or similar statistical inference as the only practical option. It is essential to account for genotyping missing minor clones; ignoring this phenomenon resulted in a 2-fold underestimation of SNPs and haplotypes present at low frequencies.
Author Notes
Financial support: This work was supported by the Bill and Melinda Gates Foundation Grant 37999.01, the Liverpool School of Tropical Medicine, and the Université de Neuchâtel. The molecular analysis was financed by the Schweizerische Nationalfonds (SNF; Grant 3100-AO-103968) for the Papua New Guinea samples and the Geigy foundation for Tanzanian samples. The morbidity surveillance in PNG was first supported by United States Agency for International Development (USAID) and then by Australian Agency for International Development (AusAID) within the Malaria Vaccine Epidemiology and Evaluation Project.
Authors' addresses: Ian M. Hastings, Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK, E-mail: hastings@liverpool.ac.uk. Christian Nsanzabana, Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, CA, E-mail: nsanzabanac@medsfgh.ucsf.edu. Tom A. Smith, Biostatistics and Computational Sciences, Swiss Tropical and Public Health Institute, Basel, Switzerland, E-mail: Thomas-A.Smith@unibas.ch.
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Picot S, Olliaro P, De Monbrison F, Bienvenu AL, Price RN, Ringwald P, 2009. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malar J 8: 89.
-
2.
Laufer MK, Djimde AA, Plowe CV, 2007. Monitoring and deterring drug-resistant malaria in the era of combination therapy. Am J Trop Med Hyg 77: 160–169.
-
3.
Plowe CV, Roper C, Barnwell JW, Happi CT, Joshi HH, Mbacham W, Meshnick SR, Mugittu K, Naidoo I, Price RN, Shafer RW, Sibley CH, Sutherland CJ, Zimmerman PA, Rosenthal PJ, 2007. World Antimalarial Resistance Network (WARN) III: molecular markers for drug resistant malaria. Malar J 6: 121.
-
4.
Liu SF, Mu JB, Jiang HY, Su XZ, 2008. Effects of Plasmodium falciparum mixed infections on in vitro antimalarial drug tests and genotyping. Am J Trop Med Hyg 79: 178–184.
-
5.
Juliano JJ, Trottman P, Mwapasa V, Meshnick SR, 2008. Short report: detection of the dihydrofolate reductase-164L mutation in Plasmodium falciparum infections from Malawi by heteroduplex tracking assay. Am J Trop Med Hyg 78: 892–894.
-
6.
Farnert A, Arez AP, Babiker HA, Beck HP, Benito A, Bjorkman A, Bruce MC, Conway DJ, Day KP, Henning L, Mercereau-Puijalon O, Ranford-Cartwright LC, Rubio JM, Snounou G, Walliker D, Zwetyenga J, do Rosario VE, 2001. Genotyping of Plasmodium falciparum infections by PCR: a comparative multicentre study. Trans R Soc Trop Med Hyg 95: 225–232.
-
7.
Alonso PL, Smith T, Armstrong Schellenberg JRM, Masanja H, Mwankusye S, Urassa H, Bastos de Azevedo I, Chongela J, Kobero S, Menendez C, Hurt N, Thomas MC, Lyimo E, Weiss NA, Hayes R, Kitua AY, Lopez MC, Kilama WL, Teuscher T, Tanner M, 1994. Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania. Lancet 344: 1175–1181.
-
8.
Nsanzabana C, 2008. Dynamics of Malaria Parasite Resistance Markers in Two Areas of Different Transmission Intensity. PhD thesis: University of Neuchatal, Switzerland.
-
9.
Nsanzabana C, Hastings IM, Marfurt J, Muller I, Baea K, Rare L, Schapira A, Felger I, Betschart B, Smith TA, Beck HP, Genton B, 2010. Quantifying the evolution and impact of antimalarial drug resistance: drug use, spread of resistance and drug failure over a 12 year period in Papua New Guinea. J Infect Dis 201: 435–443.
-
10.
Hartl DL, Clark AG, 2007. Principles of Population Genetics. Fourth edition. Sunderland, MA: Sinauer Associates.
-
11.
Newcombe RG, 1998. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 17: 857–872.
-
12.
Williams BG, Dye C, 1994. Maximum likelihood for parasitologists. Parasitol Today 10: 489–493.
-
13.
Hastings IM, Smith TA, 2008. MalHaploFreq: a computer programme for estimating malaria haplotype frequencies from blood samples. Malar J 7: 130.
-
14.
Hill WG, Babiker HA, 1995. Estimation of numbers of malaria clones in blood samples. Proc R Soc Lond B Biol Sci 262: 249–257.
-
15.
Alifrangis M, Lemnge MM, Ronn AM, Segeja MD, Magesa SM, Khalil IF, Bygbjerg IC, 2003. Increasing prevalence of wildtypes in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulfadoxine/pyrimethamine resistance after introduction of treated bed nets. Am J Trop Med Hyg 69: 238–243.
-
16.
Zimmerman PA, 2003. Roll back of Plasmodium falciparum antifolate resistance by insecticide-treated nets. Am J Trop Med Hyg 69: 236–237.
-
17.
Mharakurwa S, Mutambu SL, Mudyiradima R, Chimbadzwa T, Chandiwana SK, Day KP, 2004. Association of house spraying with suppressed levels of drug resistance in Zimbabwe. Malar J 3: 35.
-
18.
Anderson TJC, Nair S, Sudimack D, Williams JT, Mayxay M, Newton PN, Guthmann JP, Smithuis FM, Hien TT, Van den Broek IVF, White NJ, Nosten F, 2005. Geographical distribution of selected and putatively neutral SNPs in southeast Asian malaria parasites. Mol Biol Evol 22: 2362–2374.
-
19.
Schoepflin S, Marfurt J, Goroti M, Baisor M, Mueller I, Felger I, 2008. Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population. Malar J 7: 78.
-
20.
Hastings IM, Watkins WM, 2006. Tolerance is the key to understanding antimalarial drug resistance. Trends Parasitol 22: 71–77.
-
21.
Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Bjorkman A, Gill JP, 2005. In vivo selection of Plasmodium falciparum pfmdr 1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis 191: 1014–1017.
-
22.
Watkins WM, Mosobo M, 1993. Treatment of Plasmodium falciparum malaria with pyrimethamine-sulphadoxine: selective pressure for resistance is a function of long half-life. Trans R Soc Trop Med Hyg 87: 75–78.
-
23.
Juliano J, Randrianarivelojosia M, Ramarosandratana B, Ariey F, Mwapasa V, Meshnick S, 2009. Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar. Malar J 8: 47.
-
24.
Sibley CH, Hyde JE, Sims PFG, Plowe CV, Kublin JG, Mberu EK, Cowman AF, Winstanley PA, Watkins WM, Nzila AM, 2001. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? Trends Parasitol 17: 582–588.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 346 | 247 | 14 |
| Full Text Views | 393 | 5 | 0 |
| PDF Downloads | 90 | 9 | 0 |