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Daniels, Rachel

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Daniels

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Rachel

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Daniels, Rachel
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    Development of a Single Nucleotide Polymorphism Barcode to Genotype Plasmodium vivax Infections
    (Public Library of Science, 2015) Baniecki, Mary Lynn; Faust, Aubrey; Schaffner, Stephen F.; Park, Daniel J.; Galinsky, Kevin; Daniels, Rachel; Hamilton, Elizabeth; Ferreira, Marcelo U.; Karunaweera, Nadira D.; Serre, David; Zimmerman, Peter A.; Sá, Juliana M.; Wellems, Thomas E.; Musset, Lise; Legrand, Eric; Melnikov, Alexandre; Neafsey, Daniel E.; Volkman, Sarah K.; Wirth, Dyann; Sabeti, Pardis
    Plasmodium vivax, one of the five species of Plasmodium parasites that cause human malaria, is responsible for 25–40% of malaria cases worldwide. Malaria global elimination efforts will benefit from accurate and effective genotyping tools that will provide insight into the population genetics and diversity of this parasite. The recent sequencing of P. vivax isolates from South America, Africa, and Asia presents a new opportunity by uncovering thousands of novel single nucleotide polymorphisms (SNPs). Genotyping a selection of these SNPs provides a robust, low-cost method of identifying parasite infections through their unique genetic signature or barcode. Based on our experience in generating a SNP barcode for P. falciparum using High Resolution Melting (HRM), we have developed a similar tool for P. vivax. We selected globally polymorphic SNPs from available P. vivax genome sequence data that were located in putatively selectively neutral sites (i.e., intergenic, intronic, or 4-fold degenerate coding). From these candidate SNPs we defined a barcode consisting of 42 SNPs. We analyzed the performance of the 42-SNP barcode on 87 P. vivax clinical samples from parasite populations in South America (Brazil, French Guiana), Africa (Ethiopia) and Asia (Sri Lanka). We found that the P. vivax barcode is robust, as it requires only a small quantity of DNA (limit of detection 0.3 ng/μl) to yield reproducible genotype calls, and detects polymorphic genotypes with high sensitivity. The markers are informative across all clinical samples evaluated (average minor allele frequency > 0.1). Population genetic and statistical analyses show the barcode captures high degrees of population diversity and differentiates geographically distinct populations. Our 42-SNP barcode provides a robust, informative, and standardized genetic marker set that accurately identifies a genomic signature for P. vivax infections.
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    High Plasmodium falciparum longitudinal prevalence is associated with high multiclonality and reduced clinical malaria risk in a seasonal transmission area of Mali
    (Public Library of Science, 2017) Adomako-Ankomah, Yaw; Chenoweth, Matthew S.; Durfee, Katelyn; Doumbia, Saibou; Konate, Drissa; Doumbouya, Mory; Keita, Abdoul S.; Nikolaeva, Daria; Tullo, Gregory S.; Anderson, Jennifer M.; Fairhurst, Rick M.; Daniels, Rachel; Volkman, Sarah K.; Diakite, Mahamadou; Miura, Kazutoyo; Long, Carole A.
    The effects of persistent Plasmodium falciparum (Pf) infection and multiclonality on subsequent risk of clinical malaria have been reported, but the relationship between these 2 parameters and their relative impacts on the clinical outcome of infection are not understood. A longitudinal cohort study was conducted in a seasonal and high-transmission area of Mali, in which 500 subjects aged 1–65 years were followed for 1 year. Blood samples were collected every 2 weeks, and incident malaria cases were diagnosed and treated. Pf infection in each individual at each time point was assessed by species-specific nested-PCR, and Pf longitudinal prevalence per person (PfLP, proportion of Pf-positive samples over 1 year) was calculated. Multiclonality of Pf infection was measured using a 24-SNP DNA barcoding assay at 4 time-points (two in wet season, and two in dry season) over one year. PfLP was positively correlated with multiclonality at each time point (all r≥0.36; all P≤0.011). When host factors (e.g., age, gender), PfLP, and multiclonality (at the beginning of the transmission season) were analyzed together, only increasing age and high PfLP were associated with reduced clinical malaria occurrence or reduced number of malaria episodes (for both outcomes, P<0.001 for age, and P = 0.005 for PfLP). When age, PfLP and baseline Pf positivity were analyzed together, the effect of high PfLP remained significant even after adjusting for the other two factors (P = 0.001 for malaria occurrence and P<0.001 for number of episodes). In addition to host age and baseline Pf positivity, both of which have been reported as important modifiers of clinical malaria risk, our results demonstrate that persistent parasite carriage, but not baseline multiclonality, is associated with reduced risk of clinical disease in this population. Our study emphasizes the importance of considering repeated parasite exposure in future studies that evaluate clinical malaria risk.
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    Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal
    (BioMed Central, 2013) Van tyne, Daria; Dieye, Baba; Valim, Clarissa; Daniels, Rachel; Sène, Papa Diogoye; Lukens, Amanda; Ndiaye, Mouhamadou; Bei, Amy; Ndiaye, Yaye Die; Hamilton, Elizabeth; Ndir, Omar; Mboup, Souleymane; Volkman, Sarah K; Wirth, Dyann; Ndiaye, Daouda
    Background: Malaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites. Simple assays to monitor parasite drug response in direct patient samples (ex vivo) can detect drug resistance before it becomes clinically apparent, and can inform changes in treatment policy to prevent the spread of resistance. Methods: Parasite drug responses to amodiaquine, artemisinin, chloroquine and mefloquine were tested in approximately 400 Plasmodium falciparum malaria infections in Thiès, Senegal between 2008 and 2011 using a DAPI-based ex vivo drug resistance assay. Drug resistance-associated mutations were also genotyped in pfcrt and pfmdr1. Results: Parasite drug responses changed between 2008 and 2011, as parasites became less sensitive to amodiaquine, artemisinin and chloroquine over time. The prevalence of known resistance-associated mutations also changed over time. Decreased amodiaquine sensitivity was associated with sustained, highly prevalent mutations in pfcrt, and one mutation in pfmdr1 – Y184F – was associated with decreased parasite sensitivity to artemisinin. Conclusions: Directly measuring ex vivo parasite drug response and resistance mutation genotyping over time are useful tools for monitoring parasite drug responses in field samples. Furthermore, these data suggest that the use of amodiaquine and artemisinin derivatives in combination therapies is selecting for increased drug tolerance within this population.
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    Polymorphism in dhfr/dhps genes, parasite density and ex vivo response to pyrimethamine in Plasmodium falciparum malaria parasites in Thies, Senegal☆
    (Elsevier, 2013) Ndiaye, Daouda; Dieye, Baba; Ndiaye, Yaye D.; Tyne, Daria Van; Daniels, Rachel; Bei, Amy; Mbaye, Aminata; Valim, Clarissa; Lukens, Amanda; Mboup, Souleymane; Ndir, Omar; Wirth, Dyann; Volkman, Sarah
    Resistance to sulfadoxine–pyrimethamine (SP) in Plasmodium falciparum malaria parasites is associated with mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes, and these mutations have spread resistance worldwide. SP, used for several years in Senegal, has been recommended for intermittent preventive treatment for malaria in pregnancy (IPTp) and has been widely implemented since 2003 in this country. There is currently limited data on SP resistance from molecular marker genotyping, and no data on pyrimethamine ex vivo sensitivity in Senegal. Molecular markers of SP resistance and pyrimethamine ex vivo sensitivity were investigated in 416 parasite samples collected from the general population, from the Thies region between 2003 and 2011. The prevalence of the N51I/C59R/S108N triple mutation in dhfr increased from 40% in 2003 to 93% in 2011. Furthermore, the prevalence of the dhfr N51I/C59R/S108N and dhps A437G quadruple mutation increased, from 20% to 66% over the same time frame, then down to 44% by 2011. There was a significant increase in the prevalence of the dhfr triple mutation, as well as an association between dhfr genotypes and pyrimethamine response. Conversely, dhps mutations in codons 436 and 437 did not show consistent variation between 2003 and 2011. These findings suggest that regular screening for molecular markers of antifolate resistance and ex vivo drug response monitoring should be incorporated with ongoing in vivo efficacy monitoring in areas where IPTp-SP is implemented and where pyrimethamine and sulfa drugs are still widely administered in the general population.
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    Genomic Tools Reveal Changing Plasmodium falciparum Populations
    (2013-09-25) Daniels, Rachel; Wirth, Dyann Fergus; Marti, Matthias; Berger, Bonnie; Udhayakumar, Venkatachalam; Clardy, Jon
    A new era of malaria eradication programs relies on increased knowledge of the parasite through sequencing of the Plasmodium genome. Programs call for re-orientation at specific epidemiological markers as regions move from control towards pre- and total elimination. However, relatively little is known about the effects of intervention strategies on the parasite population or if the epidemiological cues correspond to effects on the parasite population. We hypothesized that genomic tools could be used to track population changes in Plasmodium falciparum to detect significant shifts as eradication programs apply interventions. Making use of new whole-genome sequencing data as well as GWAS and other studies, we used SNPs as biological markers for regions associated with drug resistance as well as a set of neutral SNPs to identify individual parasites. By utilizing tools developed as proxy for full genomic sequencing of the human pathogen Plasmodium falciparum, we characterized and tracked parasite populations to test for changes over time and between populations. When applied to markers under selection - those associated with reduced antimalarial drug sensitivity - we were able to track migration of resistance-associated mutations in the population and identify new mutations with potential implications for resistance. Using a population genetic analysis toolbox to study changes in neutral allele frequencies in samples from the field, we found significant population changes over time that included restricted effective population size, reduced complexity of infections, and evidence for both clonal and epidemic propagation of parasites.
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    Modeling malaria genomics reveals transmission decline and rebound in Senegal
    (Proceedings of the National Academy of Sciences, 2015) Daniels, Rachel; Schaffner, Stephen; Wenger, Edward A.; Proctor, Joshua L.; Chang, Hsiao-Han; Wong, Wesley; Baro, Nicholas; Ndiaye, Daouda; Fall, Fatou Ba; Ndiop, Medoune; Ba, Mady; Milner, Danny; Taylor, Terrie E.; Neafsey, Daniel; Volkman, Sarah; Eckhoff, Philip A.; Hartl, Daniel; Wirth, Dyann
    To study the effects of malaria-control interventions on parasite population genomics, we examined a set of 1,007 samples of the malaria parasite Plasmodium falciparum collected in Thiès, Senegal between 2006 and 2013. The parasite samples were genotyped using a molecular barcode of 24 SNPs. About 35% of the samples grouped into subsets with identical barcodes, varying in size by year and sometimes persisting across years. The barcodes also formed networks of related groups. Analysis of 164 completely sequenced parasites revealed extensive sharing of genomic regions. In at least two cases we found first-generation recombinant offspring of parents whose genomes are similar or identical to genomes also present in the sample. An epidemiological model that tracks parasite genotypes can reproduce the observed pattern of barcode subsets. Quantification of likelihoods in the model strongly suggests a reduction of transmission from 2006-2010 with a significant rebound in 2012-2013. The reduced transmission and rebound were confirmed directly by incidence data from Thiès. These findings imply that intensive intervention to control malaria results in rapid and dramatic changes in parasite population genomics. The results also suggest that genomics combined with epidemiological modeling may afford prompt, continuous, and cost-effective tracking of progress toward malaria elimination.
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    Methods to Increase the Sensitivity of High Resolution Melting Single Nucleotide Polymorphism Genotyping in Malaria
    (MyJove Corporation, 2015) Daniels, Rachel; Hamilton, Elizabeth J.; Durfee, Katelyn; Ndiaye, Daouda; Wirth, Dyann; Hartl, Daniel; Volkman, Sarah K.
    Despite decades of eradication efforts, malaria remains a global burden. Recent renewed interest in regional elimination and global eradication has been accompanied by increased genomic information about Plasmodium parasite species responsible for malaria, including characteristics of geographical populations as well as variations associated with reduced susceptibility to anti-malarial drugs. One common genetic variation, single-nucleotide polymorphisms (SNPs), offers attractive targets for parasite genotyping. These markers are useful not only for tracking drug resistance markers but also for tracking parasite populations using markers not under drug or other selective pressures. SNP genotyping methods offer the ability to track drug resistance as well as to fingerprint individual parasites for population surveillance, particularly in response to malaria control efforts in regions nearing elimination status. While informative SNPs have been identified that are agnostic to specific genotyping technologies, high-resolution melting (HRM) analysis is particularly suited to field-based studies. Compared to standard fluorescent-probe based methods that require individual SNPs in a single labeled probe and offer at best 10% sensitivity to detect SNPs in samples that contain multiple genomes (polygenomic), HRM offers 2-5% sensitivity. Modifications to HRM, such as blocked probes and asymmetric primer concentrations as well as optimization of amplification annealing temperatures to bias PCR towards amplification of the minor allele, further increase the sensitivity of HRM. While the sensitivity improvement depends on the specific assay, we have increased detection sensitivities to less than 1% of the minor allele. In regions approaching malaria eradication, early detection of emerging or imported drug resistance is essential for prompt response. Similarly, the ability to detect polygenomic infections and differentiate imported parasite types from cryptic local reservoirs can inform control programs. This manuscript describes modifications to high resolution melting technology that further increase its sensitivity to identify polygenomic infections in patient samples.
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    COIL: a methodology for evaluating malarial complexity of infection using likelihood from single nucleotide polymorphism data
    (BioMed Central, 2015) Galinsky, Kevin; Valim, Clarissa; Salmier, Arielle; de Thoisy, Benoit; Musset, Lise; Legrand, Eric; Faust, Aubrey; Baniecki, Mary Lynn; Ndiaye, Daouda; Daniels, Rachel; Hartl, Daniel; Sabeti, Pardis; Wirth, Dyann; Volkman, Sarah K; Neafsey, Daniel
    Background: Complex malaria infections are defined as those containing more than one genetically distinct lineage of Plasmodium parasite. Complexity of infection (COI) is a useful parameter to estimate from patient blood samples because it is associated with clinical outcome, epidemiology and disease transmission rate. This manuscript describes a method for estimating COI using likelihood, called COIL, from a panel of bi-allelic genotyping assays. Methods: COIL assumes that distinct parasite lineages in complex infections are unrelated and that genotyped loci do not exhibit significant linkage disequilibrium. Using the population minor allele frequency (MAF) of the genotyped loci, COIL uses the binomial distribution to estimate the likelihood of a COI level given the prevalence of observed monomorphic or polymorphic genotypes within each sample. Results: COIL reliably estimates COI up to a level of three or five with at least 24 or 96 unlinked genotyped loci, respectively, as determined by in silico simulation and empirical validation. Evaluation of COI levels greater than five in patient samples may require a very large collection of genotype data, making sequencing a more cost-effective approach for evaluating COI under conditions when disease transmission is extremely high. Performance of the method is positively correlated with the MAF of the genotyped loci. COI estimates from existing SNP genotype datasets create a more detailed portrait of disease than analyses based simply on the number of polymorphic genotypes observed within samples. Conclusions: The capacity to reliably estimate COI from a genome-wide panel of SNP genotypes provides a potentially more accurate alternative to methods relying on PCR amplification of a small number of loci for estimating COI. This approach will also increase the number of applications of SNP genotype data, providing additional motivation to employ SNP barcodes for studies of disease epidemiology or control measure efficacy. The COIL program is available for download from GitHub, and users may also upload their SNP genotype data to a web interface for simple and efficient determination of sample COI. Electronic supplementary material The online version of this article (doi:10.1186/1475-2875-14-4) contains supplementary material, which is available to authorized users.
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    Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia
    (BioMed Central, 2017) Mukherjee, Angana; Bopp, Selina; Magistrado, Pamela; Wong, Wesley; Daniels, Rachel; Demas, Allison; Schaffner, Stephen; Amaratunga, Chanaki; Lim, Pharath; Dhorda, Mehul; Miotto, Olivo; Woodrow, Charles; Ashley, Elizabeth A.; Dondorp, Arjen M.; White, Nicholas J.; Wirth, Dyann; Fairhurst, Rick; Volkman, Sarah K.
    Background: Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin–piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. Methods: Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA0–3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. Results: Among these 36 parasites one isolate demonstrated increased ring-stage survival for a PfKelch13 mutation (D584V, RSA0–3h = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. Conclusions: This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V PfKelch13 mutation with increased ring-stage survival and identified parasites that lack pfkelch13 mutations yet exhibit increased ring-stage survival. These data suggest mutations other than those found in pfkelch13 may be involved in conferring artemisinin resistance in P. falciparum. Piperaquine resistance was also detected among the same Cambodian samples, consistent with reports of emerging piperaquine resistance in the field. These culture-adapted parasites permit further investigation of mechanisms of both artemisinin and piperaquine resistance and development of strategies to prevent or overcome anti-malarial resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-1845-5) contains supplementary material, which is available to authorized users.
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    Case report of Plasmodium ovale curtisi malaria in Sri Lanka: relevance for the maintenance of elimination status
    (BioMed Central, 2017) Gunawardena, Sharmini; Daniels, Rachel; Yahathugoda, Thishan C.; Weerasooriya, Mirani V.; Durfee, Katelyn; Volkman, Sarah K.; Wirth, Dyann; Karunaweera, Nadira D.
    Background: Following its recent certification as malaria-free, imported infections now pose the greatest threat for maintaining this status in Sri Lanka. Imported infections may also introduce species that are uncommon or not previously endemic to these areas. We highlight in this case report the increasing importance of less common malaria species such as Plasmodium ovale in elimination settings and discuss its relevance for the risk of malaria resurgence in the country. Case presentation: A 41-year-old patient from southern Sri Lanka was diagnosed with malaria after 8 days of fever. Microscopy of blood smears revealed parasites morphologically similar to P. vivax and the rapid diagnostic test was indicative of non-P. falciparum malaria. He was treated with chloroquine over 3 days and primaquine for 14 days. He was negative for malaria at a one-year follow-up. Molecular testing performed subsequently confirmed that infection was caused by P. ovale curtisi. The patient gave a history of P. vivax malaria treated with chloroquine and primaquine. He also provided a history of travel to malaria endemic regions, including residing in Liberia from May 2012 to November 2013, throughout which he was on weekly malaria prophylaxis with mefloquine. He had also visited India on an eight-day Buddhist pilgrimage tour in September 2014 without malaria prophylaxis. Conclusions: It is crucial that every case of malaria is investigated thoroughly and necessary measures taken to prevent re-introduction of malaria. Accurate molecular diagnostic techniques need to be established in Sri Lanka for the screening and diagnosis of all species of human malaria infections, especially those that may occur with low parasitemia and are likely to be undetected using the standard techniques currently in use. In addition, ascertaining whether an infection occurred through local transmission or by importation is critical in the implementation of an effective plan of action in the country. This new era emphasizes the global nature of regional malaria elimination. Increasing global surveillance and tool development are necessary in order to “fingerprint” parasites and identify their origin.