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Inferring Developmental Stage Composition from Gene Expression in Human Malaria

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Joice, Regina, Narasimhan, Vagheesh, Montgomery, Jacqui, Sidhu, Amar Bir, Oh, Keunyoung, Meyer, Evan, Pierre-Louis, Willythssa, Seydel, Karl, Milner, Danny, Williamson, Kim, Wiegand, Roger, Ndiaye, Daouda, Daily, Johanna, Wirth, Dyann, Taylor, Terrie, Huttenhower, Curtis and Marti, Matthias (2013) 'Inferring Developmental Stage Composition from Gene Expression in Human Malaria'. PLoS Computational Biology, Vol 9, Issue 12, e1003392.

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Abstract

In the current era of malaria eradication, reducing transmission is critical. Assessment of transmissibility requires tools that can accurately identify the various developmental stages of the malaria parasite, particularly those required for transmission (sexual stages). Here, we present a method for estimating relative amounts of Plasmodium falciparum asexual and sexual stages from gene expression measurements. These are modeled using constrained linear regression to characterize stage-specific expression profiles within mixed-stage populations. The resulting profiles were analyzed functionally by gene set enrichment analysis (GSEA), confirming differentially active pathways such as increased mitochondrial activity and lipid metabolism during sexual development. We validated model predictions both from microarrays and from quantitative RT-PCR (qRT-PCR) measurements, based on the expression of a small set of key transcriptional markers. This sufficient marker set was identified by backward selection from the whole genome as available from expression arrays, targeting one sentinel marker per stage. The model as learned can be applied to any new microarray or qRT-PCR transcriptional measurement. We illustrate its use in vitro in inferring changes in stage distribution following stress and drug treatment and in vivo in identifying immature and mature sexual stage carriers within patient cohorts. We believe this approach will be a valuable resource for staging lab and field samples alike and will have wide applicability in epidemiological studies of malaria transmission.

Item Type: Article
Subjects: QU Biochemistry > Cells and Genetics > QU 350 Cellular structures
QU Biochemistry > Genetics > QU 500 Genetic phenomena
QW Microbiology and Immunology > QW 51 Morphology and variability of microorganisms. Microbial genetics.
QX Parasitology > Protozoa > QX 135 Plasmodia
QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.pcbi.1003392
Depositing User: Lynn Roberts-Maloney
Date Deposited: 23 Feb 2015 12:27
Last Modified: 06 Feb 2018 13:09
URI: https://archive.lstmed.ac.uk/id/eprint/4945

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