Summary metabolite features characteristic for patients with non-malaria, BSI, non-survival and severe anemia.

<p>Summary metabolite features characteristic for patients with non-malaria, BSI, non-survival and severe anemia.</p

Plot showing correlation between clinical patient data and the metabolite features characterizing BSI.

<p>The plot consists of 2 panels: (i) in the lower panel, the color and size of the circles correspond to the strength of the correlation, with increasing circle size and color intensity indicating increasing correlation; shades of blue are used for negative correlations and shades of red for positive correlations, crosses indicate correlations that were statistically insignificant (p-value < 0.05), and (ii) the upper panel shows the corresponding Pearson’s correlation coefficient r. The left labels for metabolites include the feature ID of the metabolite as listed in S1 data and one putative identification. The following eight patient variables were included: confirmed BSI = confirmed or no confirmed BSI diagnosis; malaria = positive or negative malaria blood smear; parasite density = number of asexual <i>Plasmodium</i> parasites in the bloodstream (x10³/mL); disease duration = duration illness prior to hospital admission expressed in days; non-survival = clinical outcome survival or no survival; age = age expressed in months; Hb = blood hemoglobin level (g/dL); % neutrophils = neutrophils as % of total WBC. Lipids are abbreviated with PC, PE, SL, DG or TG for phosphatidylcholines, phosphatidylethanolamines, sphingolipids, diacylglycerides and triacylglycerides respectively, and the total number of acyl side-chain carbons and the double bonds in the side-chains.</p

Plot showing correlation between clinical patient data and the metabolite features characterizing non-malaria illness.

<p>The plot consists of 2 panels: (i) in the lower panel, the color and size of the circles correspond to the strength of the correlation, with increasing circle size and color intensity indicating increasing correlation; shades of blue are used for negative correlations and shades of red for positive correlations, crosses indicate correlations that were statistically insignificant (p-value < 0.05), and (ii) the upper panel shows the corresponding Pearson’s correlation coefficient r. The left labels for metabolites include the feature ID of the metabolite as listed in S1 data and one putative identification. The following eight patient variables were included: confirmed BSI = confirmed or no confirmed BSI diagnosis; malaria = positive or negative malaria blood smear; parasite density = number of asexual <i>Plasmodium</i> parasites in the bloodstream (x10³/mL); disease duration = duration illness prior to hospital admission expressed in days; non-survival = clinical outcome survival or no survival; age = age expressed in months; Hb = blood hemoglobin level (g/dL); % neutrophils = neutrophils as % of total WBC. Lipids are abbreviated with PC, PE, SL, DG or TG for phosphatidylcholines, phosphatidylethanolamines, sphingolipids, diacylglycerides and triacylglycerides respectively, and the total number of acyl side-chain carbons and the double bonds in the side-chains.</p

Non-malarial clinically significant organisms identified in the study participants.

<p>Non-malarial clinically significant organisms identified in the study participants.</p

Diagnostic performance of bile metabolite signature for BSI.

<p>The metabolite signature consists of 2 bile metabolites detected by C₁₈-UHPLC-MS: a C26 bile alcohol (ID_4741_ON, m/z M+FA-H = 483.331, putative ID: C26H46O5 27-Nor-5b-cholestane-3a,7a,12a,24,25-pentol bile alcohol) and a C27 bile acid (ID_6663_ON, m/z M+FA-H = 493.316, putative ID: C27H44O5 C27 bile acid). The figure includes: (i) a ROC curve along with the optimal cut-off value (excluding patients with BSI/malaria co-infection, incomplete or possible BSI diagnosis), (ii) check for over-fitting by Monte-Carlo cross-validation based on 200 rounds of balanced subsampling in all cases and controls and the significance permutation test, and (iii) a boxplot with the test result for all 61 patients (x-axis categories indicate the patient groups based on the study case definitions, y-axis shows the test-value of the diagnostic test which is based on the sum of the signal intensity of the two metabolites, here called composite signal intensity, included in each model, the orange dashed line indicates the cut-off value determined in the ROC analysis).</p

Estimation of diagnostic performance of BSI tests by Bayesian latent class models.

<p>Estimation of diagnostic performance of BSI tests by Bayesian latent class models.</p

Spiderplot showing the results of the 27 regression analyses modeling the co-variance between metabolome measurements and the listed patient characteristics.

<p>The plotted validation metric Q2 allows assessing the relative impact of the patient characteristics on the metabolome. The following 27 patient variables were included in the analysis from center top in clockwise direction: BSI = confirmed or no confirmed BSI diagnosis; malaria RDT = positive or negative malaria rapid diagnostic test; parasite density = number of asexual <i>Plasmodium</i> parasites in the bloodstream (x10³/mL); prior AB Rx = reported or no reported antibiotic treatment in the past 48 hrs; prior AM Rx = reported or no reported antimalarial treatment in the past 48 hrs; temp. = axillary temperature at time of hospital admission (°C); duration illness = duration illness prior to hospital admission (days); survival = clinical outcome survival or no survival; sex = male or female; age = age expressed in months; weight = weight expressed in kg; height = height expressed in cm; malnutrition = presence or absence of severe malnutrition defined as weight for height score < 70% according to national guidelines or report of kwashiorkor; blood glucose = blood glucose level (mg/dL); WBC = white blood cell count in blood (x10³/μl); RBC = red blood cell count in blood (x10⁶/μl); hemoglobin = blood hemoglobin level (g/dL); hematocrit = blood hematocrit (%); MCV = mean corpuscular volume (fL); MCH = mean corpuscular hemoglobin (pg); MCHC = mean corpuscular hemoglobin concentration (g/dl); platelet count = platelet blood count (x10³/μL); % neutr. = neutrophils as % of total WBC; % lymph. = lymphocytes as % of total WBC; % monoc. = monocytes as % of total WBC; % eosin. = eosinophils as % of total WBC; % basoph. = basophils as % of total WBC.</p

Overview characteristics study participants.

<p>Overview characteristics study participants.</p

Overview plasma metabolome coverage.

<p>Overview plasma metabolome coverage.</p

Diagnostic performance of corticosteroid signature for non-malaria febrile illness (panel A) and non-survival (panel B).

<p>The metabolite signature consists of 2 corticosteroid compounds detected by C₁₈-UHPLC-MS: a C21-corticosteroid (ID_2094_ON, m/z M-H = 377.196, putative ID: C₂₁H₃₀O₆ 18-hydroxycortisol) and a C19-steroid-glucuronide (ID_3388_ON, m/z M-H = 481.243, putative ID: C₂₅H₃₈O₉ 11-beta-hydroxyandrosterone-3-glucuronide). Each panel shows: (i) a ROC curve along with the optimal cut-off value (the non-malaria analysis excluded BSI/malaria co-infection patients; the non-survival analysis excluded patients that left hospital against medical advice), (ii) check for over-fitting by Monte-Carlo cross-validation based on 200 rounds of balanced subsampling in all cases and controls and the significance permutation test, and (iii) a boxplot with the test result for all 61 patients (x-axis categories indicate the patient groups based on the study case definitions, y-axis shows the test-value of the diagnostic test which is based on the sum of the signal intensity of the two metabolites, here called composite signal intensity, included in each model, the orange dashed line indicates the cut-off value determined in the ROC analysis). (Abbreviations: LAMA = left against medical advice)</p