Figures
- FIGURE 1
Flow chart visualising identification of publications, inclusion and exclusion criteria, and selection of publications eligible for meta-analysis. a) Biomarker search; b) omics search. #: excluding conference abstracts; ¶: transcriptomics, proteomics, metabolomics, glycomics and lipidomics. iPAH: idiopathic pulmonary arterial hypertension; hPAH: hereditary pulmonary arterial hypertension.
- FIGURE 2
Forest plots of selected biomarkers. a) The haemtological biomarker RDW: red cell distribution width; b) the metabolic biomarker LDL-c: low density lipid-cholesterol; c) the coagulation biomarker d-dimer; d) the inflammatory biomarker IL-6: interleukin-6; e) the cardiac biomarker NT-proBNP: N-terminal prohormone of brain natriuretic peptide; f) the renal biomarker UA: uric acid; CVD: cardiovascular disease. Risk of bias (QUADAS-2) – P: patient inclusion; I: index test (biomarker); R: reference standard (diagnosis); T: flow and timing. Publications in bold type represent biomarker levels of idiopathic pulmonary arterial hypertension (iPAH) and/or hereditary pulmonary arterial hypertension (hPAH) uniquely.
Tables
- TABLE 1
Summary of 26 meta-analyses
Marker Studies n Participants n Mean difference St. mean difference Overall effect (p-value) Tau2 I2 (%) Heterogeneity (p-value) Forest plot Haematological markers RDW % 4 427 1.83 (1.39–2.26) 0.98 (0.61–2.17) <0.00001 0.07 51 0.11 Figure 2a PDW % 3 245 1.42 (0.16–2.67) 0.81 (0.50–1.12) <0.00001 0.02 19 0.29 Figure S2a MPV fL 5 361 0.95 (0.76–1.13) 1.0 (0.81–1.25) <0.00001 0.00 0 0.68 Figure S2b 6# 395 0.66 (0.24–1.09) 0.72 (0.24–1.19) 0.003 0.27 78 0.0003 Thrombocytes (×109 L−1) 7 334 −23.9 (−38.6– −9.2) −0.38 (−0.62– −0.15) 0.001 0.01 5 0.39 Figure S2c Hb g dL−1 9 400 −0.59 (−1.23–0.06) −0.18 (−0.43–0.07) 0.15 0.04 29 0.19 Figure S2d Hct % 5 229 −1.07 (−3.91–1.76) −0.21 (−0.76–0.34) 0.46 0.29 74 0.004 Figure S2e Leukocytes (×109 L−1) 7 294 −0.23 (−0.70,0.24) −0.10 (−0.41–0.21) 0.52 0.07 39 0.13 Figure S2f Metabolic markers LDL-c mg dL−1 6 3035 −15.82 (−26.18– −5.46) −0.44 (−0.65– −0.22) <0.00001 0.03 46 0.10 Figure 2b Total cholesterol mg dL−1 4 408 −17.70 (−24.15– −11.26) −0.52 (−0.73– −0.32) <0.00001 0.00 67 0.67 Figure S3a TG mg dL−1 4 198 −32.56 (−54.17– −10.94) −0.52 (−0.87– −0.17) 0.004 0.04 34 0.21 Figure S3b Glucose (fasted) mg dL−1 3 103 24.06 (0.54–7.58) 0.48 (0.08–0.87) 0.02 0.00 0 0.85 Figure S3c HDL-c mg dL−1 6 577 −6.15 (−2.11–14.40) −0.53 (−1.20–0.15) 0.13 0.63 91 <0.00001 Figure S3d Coagulation markers D-dimer ng mL−1 3 142 245.99 (148.55–343.43) 0.69 (0.27–1.11) 0.001 0.04 27 0.26 Figure 2c Fibrinogen mg dL−1 4 227 73.75 (−2.58–150.08) 0.84 (−0.14–1.81) 0.09 0.88 90 <0.00001 Figure S4 Inflammatory markers IL-6 pg mL−1 5 389 5.01 (2.06–7.96) 0.64 (0.28–0.99) 0.0005 0.08 47 0.11 Figure 2d CRP mg L−1 8 387 0.74 (0.13–1,6) 0.25 (0.04–0.47) 0.02 0.02 0 0.98 Figure S5a 9# 493 0.13 (0.10–0.17) 0.77 (−0.08–1.61) 0.08 1.57 94 <0.00001 sVCAM-1 ng mL−1 3 150 626.72 (29.38–1224.07) 1.03 (0.53–1.52) <0.00001 0.08 40 0.19 Figure S5b CXCL-10 pg mL−1 3 171 99.77 (54.53–145.01) 0.82 (0.49–1.16) <0.00001 0.00 0 0.46 Figure S5c TIMP-1 ng mL−1 3 224 15.58 (−2.56–33.72) 0.40 (0.13–0.67) 0.003 0.00 0 0.54 Figure S5d 4# 329 40.15 (1.02–79.29) 0.67 (0.14–1.21) 0.01 0.24 82 0.0009 sP-selectin ng mL−1 4 180 0.52 (−11.10–12.14) −0.04 (0.35–0.28) 0.82 0.00 0 0.72 Figure S5e Cardiac markers NT-proBNP pg mL−1 10 1152 1684 (1035–2330) 1.13 (0.93–1.33) <0.00001 0.03 30 0.17 Figure 2e 11# 1258 1004 (787–1221) 1.37 (0.96–1.79) <0.00001 0.39 85 <0.00001 Renal markers UA mg dL−1 5 441 1.77 (1.06–2.48) 0.89 (0.58–1.12) <0.00001 0.06 51 0.09 Figure 2f 6# 531 1.52 (0.77–2.27) 0.81 (0.53–1.09) <0.00001 0.09 59 0.03 BUN mg dL−1 5 891 1.76 (0.51–3.01) 0.43 (0.29–0.56) <0.00001 0.00 0 0.48 Figure S6a Creatinine mg dL−1 10 475 0.03 (−0.04–0.10) 0.13 (−0.08–0.34) 0.23 0.02 20 0.26 Figure S6b eGFR mL min−1/1.73 m2 4 180 1.70 (5.98–9.37) 0.09 (−0.32–0.49) 0.67 0.08 47 0.13 Figure S6c Hepatic markers ALT U L−1 3 115 3.57 (−4.18–11.31) 0.18 (−0.56–0.92) 0.37 0.30 71 0.03 Figure S7 Per biomarker the number of studies included, total sample size, mean difference, and the standardised difference between iPAH and non-PH control with 95% confidence interval, p-value of the difference, and heterogeneity of the result (I2, Tau2 and p-heterogeneity) are shown. St. mean difference; standardised mean difference; RDW: red cell distribution width; PDW: platelet distribution width; MPV: mean platelet volume; Hb: haemoglobin; Hct: haematocrit; TG: triglycerides; LDL-c: low density lipoprotein; HDL-c: high density lipoprotein; IL-6: interleukin-6; CRP: c-reactive protein; sVCAM-1: circulating vascular cell adhesion molecule-1; CXCL-10: C-X-C motif chemokine ligand-10; TIMP-1: tissue inhibitors of metalloproteinases-1; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; UA: uric acid; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate: ALT: alanine transaminase. #: publication excluded due to heterogeneity.
Supplementary Material
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Supplementary material 00009-2022.SUPPLEMENT
