Classification and Regression Tree (CRT) models classify children with clinical pneumonia based on radiological findings.

<p>Abbreviations: CHI3L1, Chitinase 3-like-1; CRP, C-reactive protein; CRT, Classification and Regression Tree; CXR, chest x-ray; MC, misclassification cost; NLR, negative likelihood ratio; NPV, negative predictive value; PCT, procalcitonin; PLR, positive likelihood ratio; PPV, positive predictive value; sTie-2, soluble Tie-2; vWF, von Willebrand Factor.</p><p>^a Minimum number of cases was 10 per parent node (prior to split) and 5 per child node (following split). Misclassification cost is how many fold worse it is to misclassify the group of interest versus the other group. Pruning reduces overfitting by trimming trees down to simpler structures.</p><p>^b Generated using cross-validation with 10 sample folds.</p><p>^c x2 = model contains 2 different cut-points for a single biomarker.</p><p>^d Other infiltrates and normal CXR groups were combined into “non-end-point pneumonia.”</p><p>^e CRP and PCT were entered as categorical variables based on cut-points used in available point-of-care tests: CRP 40 μg/mL and PCT 0.5 ng/mL.</p><p>Classification and Regression Tree (CRT) models classify children with clinical pneumonia based on radiological findings.</p

Receiver operating characteristic (ROC) curves and cut-points of biomarkers that significantly discriminate between radiological findings.^a

<p>Abbreviations: AUROCC, area under receiver operating characteristic curve; CHI3L1, Chitinase 3-like-1; CRP, C-reactive protein; CXR, chest x-ray; NLR, negative likelihood ratio; NPV, negative predictive value; PCT, procalcitonin; PLR, positive likelihood ratio; PPV, positive predictive value; ROC, receiver operating characteristic curve; sTie-2, soluble Tie-2; vWF, von Willebrand Factor.</p><p>^a Children with WHO-defined clinical pneumonia were categorized based on CXR findings: end-point pneumonia, other infiltrates, or normal CXR.</p><p>^b Cut-points based on Youden index: J = max(sensitivity + specificity – 1).</p><p>Receiver operating characteristic (ROC) curves and cut-points of biomarkers that significantly discriminate between radiological findings.<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137592#t002fn002" target="_blank">^a</a></p

Biomarkers of host response in febrile children with WHO-defined clinical pneumonia, categorized by radiological findings.

<p>Plasma collected at presentation was assayed for biomarkers, and biomarker levels were compared between children with end-point pneumonia (End-point PNA; n = 30), other infiltrates (n = 31), and no abnormalities on chest x-ray (Normal CXR; n = 94). * p<0.05, ** p<0.01, and *** p<0.001 by Kruskal-Wallis test with Dunn’s post-tests. All other comparisons were not statistically significant. CHI3L1, Chitinase 3-like-1; CRP, C-reactive protein; CXR, chest x-ray; PCT, procalcitonin; PNA, pneumonia; sTie-2, soluble Tie-2; vWF, von Willebrand Factor; WBC, white blood cell.</p

Classification and Regression Tree model uses biomarkers to discriminate between end-point pneumonia and non-end-point pneumonia.

<p>Classification and Regression Tree (CRT) modelling was used to improve upon performance of single biomarkers for distinguishing between end-point pneumonia and non-end-point pneumonia (comprising “other infiltrates” and “normal chest x-ray (CXR)” groups combined). All 7 biomarkers were entered into the CRT analysis as independent variables. Minimum number of cases was designated as 10 for parent nodes (prior to split) and 5 for child nodes (following split). Children in terminal nodes of the tree were classified into the category indicated (i.e., “Predicted:…”). Shown here is a representation of Model 9 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137592#pone.0137592.t003" target="_blank">Table 3</a>. For this model, cut-points were pre-specified for CRP (40 μg/mL) and PCT (0.5 ng/mL) based on commercially available tests. Performance characteristics were as follows: sensitivity 93.3% (76.5–98.8), specificity 80.8% (72.6–87.1), positive likelihood ratio 4.9 (3.4–7.1), negative likelihood ratio 0.083 (0.022–0.32), positive predictive value 53.8% (39.6–67.5), negative predictive value 98.1% (92.5–99.7), misclassification risk 0.20 (standard error 0.038). CHI3L1, Chitinase 3-like-1; CRP, C-reactive protein; CRT, Classification and Regression Tree; CXR, chest x-ray; PCT, procalcitonin; PNA, pneumonia.</p

Adjusted associations for biomarkers of host response in children with abnormal versus normal chest x-ray (CXR).

<p>Odds ratios were calculated comparing groups using multivariate logistic regression, adjusting for statistically significant demographic and clinical differences between groups. All markers except endoglin and WBC were log transformed since distributions were non-normal. Forest plots show odds ratio point estimates (black squares) and 95% confidence intervals (lines). (A) Odds ratios for end-point pneumonia versus normal CXR, adjusted for age and sex. (B) Odds ratios for other infiltrates versus normal CXR, adjusted for temperature. CHI3L1, Chitinase 3-like-1; CRP, C-reactive protein; CXR, chest x-ray; PCT, procalcitonin; sTie-2, soluble Tie-2; vWF, von Willebrand Factor; WBC, white blood cell.</p

Demographic and clinical characteristics of study participants with WHO-defined clinical pneumonia, categorized by radiological findings.^a

<p>Abbreviations: CXR, chest x-ray.</p><p>^a Kruskal-Wallis test with Dunn’s post-tests used to compare continuous variables; Chi-square test with Bonferroni correction used to compare categorical variables.</p><p>*, p<0.05 for other infiltrates versus end-point pneumonia.</p><p>^#, p<0.05 for normal CXR versus end-point pneumonia. Other comparisons were not significantly different.</p><p>^b All continuous variables had non-normal distributions and are represented as: Median [Interquartile range].</p><p>^c Study sites were located in Dar es Salaam and Ifakara.</p><p>^d Severe disease defined according to WHO criteria for the district hospital level.</p><p>^e Participants were subdivided according to age, as normal values for respiratory rate are age-dependent [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137592#pone.0137592.ref007" target="_blank">7</a>].</p><p>^f One child in the normal CXR group did not have a <i>S</i>. <i>pneumoniae</i> swab performed.</p><p>Demographic and clinical characteristics of study participants with WHO-defined clinical pneumonia, categorized by radiological findings.<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137592#t001fn002" target="_blank">^a</a></p