title: Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis.
abstract: Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)). Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of "sleeping sickness". Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity). A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control.
authors.affiliation: Wellcome Trust Centre of Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Vincent
authors.affiliation: Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Rónán
authors.initials: R
authors.lastname: Daly
authors.affiliation: INSERM U1094, Tropical Neuroepidemiology, Limoges, France; Université de Limoges, Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Courtioux
authors.affiliation: Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Cattanach
authors.affiliation: Foundation for Innovative New Diagnostics, Geneva, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Biéler
authors.affiliation: Foundation for Innovative New Diagnostics, Geneva, Switzerland.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ndung'u
authors.affiliation: INSERM U1094, Tropical Neuroepidemiology, Limoges, France; Université de Limoges, Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bisser
authors.affiliation: Wellcome Trust Centre of Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
mesh_terms: D006916:5-Hydroxytryptophan / Q000097:blood / Q000134:cerebrospinal fluid / Q000302:isolation & purification / Q000652:urine; D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D001812:Blood-Brain Barrier; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods; D019798:Neopterin / Q000097:blood / Q000134:cerebrospinal fluid / Q000302:isolation & purification / Q000652:urine; D012044:Regression Analysis; D012680:Sensitivity and Specificity; D014347:Trypanosoma brucei gambiense / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000175:diagnosis* / Q000469:parasitology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D019798:Neopterin; D006916:5-Hydroxytryptophan