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What is ‘Big Data’ and how are we using it?
“Big data” is a global initiative that countries such as the USA and the UK are investing millions of dollars in to enable secure storage, standardisation, analysis and sharing of large clinical, drug discovery, engineering and broader scientific data. A similar approach has been championed by WWARN since 2009 to support the malaria community to share, store, standardise and analyse malaria clinical trial results.
Research groups and pharmaceutical drug developers have contributed to the WWARN Data Centre – a repository that stores over 350 clinical, molecular, in vitro, and pharmacokinetic malaria studies. The repository is comprised of approximately 90,000 patient records, an estimated 70% of all published clinical patients enrolled in ACT studies. It includes data on some of the current and most widely used artemisinin combination therapies (ACTs) such as artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP).
Why is this Data Centre useful?
Over the last three years this secure centre has enabled Study Groups, comprised of 130 or more malaria researchers, to examine clinical trial results for each of the key antimalarial drugs. Working together they have developed key questions around malaria treatment efficacy to assess whether all patient groups were receiving the optimal dose level of particular drugs, and if not whether patients who are under-dosed are at increased risk of treatment failure. To achieve this, thousands of data sets were analysed to identify key trends and anomalies.
The overall analyses confirm the excellent news that the clinical efficacy of all three ACTs is still very high – in fact they are more than 95% effective. Despite this confirmation, it was also possible to examine large numbers of patients who did fail treatment and consider whether patients that fail treatment share certain factors in common that might increase the risk of treatment failures.
What have we found so far?
- DP Dose Impact Study Group - the WWARN DP Dose Impact Study Group published a study suggesting that the dosing regimens for dihydroartemisinin-piperaquine (DP) should be reviewed. Although DP is still overall a highly efficacious drug, the study highlighted that even when the recommended dose was given, children under five years had a higher risk of treatment failure. Based on these findings, and findings from pharmacometric simulations, the WHO has revised the recommended dose of dihydroartemisinin-piperaquine for young children. These revised dose regimens are predicted to provide similar piperaquine concentrations across all age groups. Read the study.
- Lumefantrine PK/PD Study Group - WWARN’s Lumefantrine Pharmacokinetic/Pharmacodynamic Study Group studied the threshold of this day 7 lumefantrine concentration in a large group of patients. The group found that although this drug is still highly effective overall, there were three groups of patients who had lower concentrations of lumefantrine on day 7 and these patients were at higher risk of treatment failure. These subgroups were: very young children, particularly if they are underweight; patients who present with high numbers of malaria parasites in their blood; and patients who live in areas of very low malaria transmission intensity and with emerging antimalarial resistance. Read the study.
- ACT Africa Baseline Study Group – the ACT Africa Baseline Study Group finds that current indicators of the efficacy of ACT based on persistence of parasites in the first 3 days after treatment may need some adjustment for African populations, due the differences in immunity between African and Asian populations. The results of the study suggest that the recommended threshold could be decreased from 10 per cent to 5 per cent for African populations. Lowering the percentage could mean that monitoring mechanisms would be able to identify areas at high risk of resistance earlier on, so that appropriate intervention measures could be taken. Read the study.
- AS-AQ Dose Impact Study Group –The AS-AQ Dose Impact Study Group found evidence that AS-AQ remains a highly effective malaria treatment in many settings, particularly in sub-Saharan Africa. The study showed that the efficacy of the medicine does, however, vary due to changes in the formulation of the two parts of the ACT, artesunate and amodiaquine. Read the study. Read the study.
- AL Dose Impact Study Group - the results from the AL dose Impact Study Group suggest that AL continues to be efficacious with an overall cure rate of 97.6 per cent. However, the latest results published in the Lancet Infectious Diseases (link is external) also show that children in Asia weighing 10–15 kg who receive lower doses of lumefantrine have lower drug performance results, and malnourished children in Africa were at risk of treatment failure. Read the study.
- Parasite Clearance Study Group - the WWARN Parasite Clearance Study Group combined malaria clinical trial data from across the world to assess the geographical, physiological and external factors that can delay the rate at which malaria parasites are eliminated from the patient’s body after treatment, known as parasite clearance. They also explored the relationship between parasite clearance and the risk of recrudescence to providing valuable baseline data on parasite clearance and information on the confounding factors that influence the rate in which malaria is eliminated from a patient’s system. Read the study.
- AS-AQ/AL Molecular Marker Study Group - have confirmed that patients infected with parasites that carry particular mutations in pfcrt and pfmdr1 are at higher risk of treatment failure after artemether-lumefantrine. This direct connection between the molecular markers and clinical treatment outcome provides solid evidence that the molecular markers can be used to identify sites with early risk of declining efficacy of the ACT. Read the study.
Optimal sampling designs for estimation of Plasmodium falciparum clearance rates in patients treated with artemisinin derivativesMalaria Journal, 2013; 12: 411. Flegg JA, Guerin PJ, Nosten F, Ashley EA, Phyo AP, Dondorp AM, Fairhurst RM, Socheat D, Borrmann S, Björkman A, Mårtensson A, Mayxay M, Newton PN, Bethell D, Se Y, Noedl H, Diakite M, Djimde AA, Hien TT, White NJ, Stepniewska K Doi: 10.1186/1475-2875-12-411. PMID: 24225303
The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data. PLoS Medicine, 2013; 10(12): e1001564 WorldWide Antimalarial Resistance Network (WWARN) DP Study Group, Achan J, Adam I, Arinaitwe E, Ashley EA, Awab GR, Ba MS, Barnes KI, Bassat Q, Borrmann S, Bousema T, Dahal P, D' Alessandro U, Davis TM, Dondorp AM, Dorsey G, Drakeley CJ, Fanello CI, Faye B, Flegg JA, Gaye O, Gething PW, González R, Guerin PJ, Hay SI, Hien TT, Janssens B, Kamya MR, Karema C, Karunajeewa HA, Kone M, Lell B, Marsh K, Mayxay M, Menéndez C, Mens PF, Meremikwu M, Moreira C, Mueller I, Nabasumba C, Nambozi M, Ndiaye JL, Newton PN, Nguyen TN, Nosten F, Nsanzabana C, Omar SA, Ouédraogo JB, Penali LK, Pene M, Phyo AP, Piola P, Price RN, Rosenthal PJ, Same-Ekobo A, Sawa P, Schallig HD, Shekalaghe SA, Hopkins Sibley C, Smith J, Smithuis F, Fabrice Somé A, Stepniewska K, Talisuna AO, Tarning J, Tjitra E, Tine RC, Tinto H, Valecha N, Van Herp M, Van Vugt M, White NJ, Woodrow CJ, Yavo W, Yeka A, Zongo I. Doi: 10.1371/annotation/3db421e4-3e27-4442-8092-2ad1b778f371 PMID: 24311989
Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors that Affect Treatment Outcomes for P. falciparum Malaria after ArtemetherLumefantrine and Artesunate-Amodiaquine. American Journal of Tropical Medicine, 2014; 91(4): 833-43 Venkatesan M, Gadalla N.B, Stepniewska K, Dahal P, Nsanzabana C, Moriera C, Price R.N, Mårtensson A, Rosenthal P.J, Dorsey G, Sutherland C.J, Guérin P, Davis T.M, Ménard D, Adam I, Ademowo G, Arze C, Baliraine F.N, Berens-Riha N, Björkman A, Borrmann S, Checchi F, Desai M, Dhorda M, Djimdé A.A, El-Sayed B.B, Eshetu T, Eyase F, Falade C, Faucher J.F, Fröberg G, Grivoyannis A, Hamour S, Houzé S, Johnson J, Kamugisha E, Kariuki S, Kiechel J.R, Kironde F, Kofoed PE, LeBras J, Malmberg M, Mwai L, Ngasala B, Nosten F, Nsobya SL, Nzila A, Oguike M, Otienoburu S.D, Ogutu B, Ouédraogo J.B, Piola P, Rombo L, Schramm B, Somé A.F, Thwing J, Ursing J, Wong RP, Zeynudin A, Zongo I, Plowe CV, Sibley CH, WWARN AL ASAQ Molecular Marker Study Group Doi: 10.4269/ajtmh.14-0031 PMID: 25048375
The effect of dose on the antimalarial efficacy of artemether–lumefantrine: a systematic review and pooled analysis of individual patient data Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group Doi: 10.1016/S1473-3099(15)70024-1 PMID: 25788162
The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data BMC Medicine, 2015; 13: 6 Worldwide Antimalarial Resistance Network (WWARN) AS-AQ Study Group. Doi: 10.1186/s12916-015-0301-z PMID: 25888957
Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data. BMC Medicine, 2015; 13: 227 WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group Doi: 10.1186/s12916-015-0456-7 PMID: 26381375
Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data BMC Medicine, 2015; 13(1): 212 WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group. Doi: 10.1186/s12916-015-0445-x PMID: 26343145