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PLoS Comput Biol DOI:10.1371/journal.pcbi.1003392

Inferring developmental stage composition from gene expression in human malaria.

Publication TypeJournal Article
Year of Publication2013
AuthorsJoice, R, Narasimhan, V, Montgomery, J, Sidhu, ABir, Oh, K, Meyer, E, Pierre-Louis, W, Seydel, K, Milner, D, Williamson, K, Wiegand, R, Ndiaye, D, Daily, J, Wirth, D, Taylor, T, Huttenhower, C, Marti, M
JournalPLoS Comput Biol
Date Published2013
KeywordsAnimals, Biomarkers, Gene Expression, Humans, Malaria, Falciparum, Models, Biological, Oligonucleotide Array Sequence Analysis, Plasmodium falciparum, Polymerase Chain Reaction, Real-Time Polymerase Chain Reaction, Selection, Genetic

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.


Alternate JournalPLoS Comput. Biol.
PubMed ID24348235
PubMed Central IDPMC3861035
Grant ListR01A107755801 / / PHS HHS / United States
100890 / / Wellcome Trust / United Kingdom
5R01AI034969-14 / AI / NIAID NIH HHS / United States
T32 AI007638 / AI / NIAID NIH HHS / United States
1R01HG005969 / HG / NHGRI NIH HHS / United States