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A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension

A. Josien Smits, Liza Botros, Marijke A.E. Mol, Kirsten A. Ziesemer, Martin R. Wilkins, Anton Vonk Noordegraaf, Harm Jan Bogaard, Jurjan Aman
ERJ Open Research 2022 8: 00009-2022; DOI: 10.1183/23120541.00009-2022
A. Josien Smits
1Dept of Pulmonology, Amsterdam University Medical Center, Amsterdam, Amsterdam, The Netherlands
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Liza Botros
1Dept of Pulmonology, Amsterdam University Medical Center, Amsterdam, Amsterdam, The Netherlands
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Marijke A.E. Mol
2University Library UBVU, Amsterdam University Medical Center, Amsterdam, Amsterdam, The Netherlands
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Kirsten A. Ziesemer
2University Library UBVU, Amsterdam University Medical Center, Amsterdam, Amsterdam, The Netherlands
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Martin R. Wilkins
3National Heart and Lung Institute, Imperial College London, London, UK
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Anton Vonk Noordegraaf
1Dept of Pulmonology, Amsterdam University Medical Center, Amsterdam, Amsterdam, The Netherlands
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Harm Jan Bogaard
1Dept of Pulmonology, Amsterdam University Medical Center, Amsterdam, Amsterdam, The Netherlands
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  • For correspondence: hj.bogaard@amsterdamumc.nl
Jurjan Aman
1Dept of Pulmonology, Amsterdam University Medical Center, Amsterdam, Amsterdam, The Netherlands
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  • FIGURE 1
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    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.

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    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

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  • TABLE 1

    Summary of 26 meta-analyses

    MarkerStudies nParticipants nMean differenceSt. mean differenceOverall effect (p-value)Tau2I2 (%)Heterogeneity (p-value)Forest plot
    Haematological markers
     RDW %44271.83 (1.39–2.26)0.98 (0.61–2.17)<0.000010.07510.11Figure 2a
     PDW %32451.42 (0.16–2.67)0.81 (0.50–1.12)<0.000010.02190.29Figure S2a
     MPV fL53610.95 (0.76–1.13)1.0 (0.81–1.25)<0.000010.0000.68Figure S2b
    6#3950.66 (0.24–1.09)0.72 (0.24–1.19)0.0030.27780.0003
     Thrombocytes (×109 L−1)7334−23.9 (−38.6– −9.2)−0.38 (−0.62– −0.15)0.0010.0150.39Figure S2c
     Hb g dL−19400−0.59 (−1.23–0.06)−0.18 (−0.43–0.07)0.150.04290.19Figure S2d
     Hct %5229−1.07 (−3.91–1.76)−0.21 (−0.76–0.34)0.460.29740.004Figure S2e
     Leukocytes (×109 L−1)7294−0.23 (−0.70,0.24)−0.10 (−0.41–0.21)0.520.07390.13Figure S2f
    Metabolic markers
     LDL-c mg dL−163035−15.82 (−26.18– −5.46)−0.44 (−0.65– −0.22)<0.000010.03460.10Figure 2b
     Total cholesterol mg dL−14408−17.70 (−24.15– −11.26)−0.52 (−0.73– −0.32)<0.000010.00670.67Figure S3a
     TG mg dL−14198−32.56 (−54.17– −10.94)−0.52 (−0.87– −0.17)0.0040.04340.21Figure S3b
     Glucose (fasted) mg dL−1310324.06 (0.54–7.58)0.48 (0.08–0.87)0.020.0000.85Figure S3c
     HDL-c mg dL−16577−6.15 (−2.11–14.40)−0.53 (−1.20–0.15)0.130.6391<0.00001Figure S3d
    Coagulation markers
     D-dimer ng mL−13142245.99 (148.55–343.43)0.69 (0.27–1.11)0.0010.04270.26Figure 2c
     Fibrinogen mg dL−1422773.75 (−2.58–150.08)0.84 (−0.14–1.81)0.090.8890<0.00001Figure S4
    Inflammatory markers
     IL-6 pg mL−153895.01 (2.06–7.96)0.64 (0.28–0.99)0.00050.08470.11Figure 2d
     CRP mg L−183870.74 (0.13–1,6)0.25 (0.04–0.47)0.020.0200.98Figure S5a
    9#4930.13 (0.10–0.17)0.77 (−0.08–1.61)0.081.5794<0.00001
     sVCAM-1 ng mL−13150626.72 (29.38–1224.07)1.03 (0.53–1.52)<0.000010.08400.19Figure S5b
     CXCL-10 pg mL−1317199.77 (54.53–145.01)0.82 (0.49–1.16)<0.000010.0000.46Figure S5c
     TIMP-1 ng mL−1322415.58 (−2.56–33.72)0.40 (0.13–0.67)0.0030.0000.54Figure S5d
    4#32940.15 (1.02–79.29)0.67 (0.14–1.21)0.010.24820.0009
     sP-selectin ng mL−141800.52 (−11.10–12.14)−0.04 (0.35–0.28)0.820.0000.72Figure S5e
    Cardiac markers
     NT-proBNP pg mL−11011521684 (1035–2330)1.13 (0.93–1.33)<0.000010.03300.17Figure 2e
    11#12581004 (787–1221)1.37 (0.96–1.79)<0.000010.3985<0.00001
    Renal markers
     UA mg dL−154411.77 (1.06–2.48)0.89 (0.58–1.12)<0.000010.06510.09Figure 2f
    6#5311.52 (0.77–2.27)0.81 (0.53–1.09)<0.000010.09590.03
     BUN mg dL−158911.76 (0.51–3.01)0.43 (0.29–0.56)<0.000010.0000.48Figure S6a
     Creatinine mg dL−1104750.03 (−0.04–0.10)0.13 (−0.08–0.34)0.230.02200.26Figure S6b
     eGFR mL min−1/1.73 m241801.70 (5.98–9.37)0.09 (−0.32–0.49)0.670.08470.13Figure S6c
    Hepatic markers
     ALT U L−131153.57 (−4.18–11.31)0.18 (−0.56–0.92)0.370.30710.03Figure 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 Materials

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      Supplementary material 00009-2022.SUPPLEMENT

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    A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension
    A. Josien Smits, Liza Botros, Marijke A.E. Mol, Kirsten A. Ziesemer, Martin R. Wilkins, Anton Vonk Noordegraaf, Harm Jan Bogaard, Jurjan Aman
    ERJ Open Research Apr 2022, 8 (2) 00009-2022; DOI: 10.1183/23120541.00009-2022

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    A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension
    A. Josien Smits, Liza Botros, Marijke A.E. Mol, Kirsten A. Ziesemer, Martin R. Wilkins, Anton Vonk Noordegraaf, Harm Jan Bogaard, Jurjan Aman
    ERJ Open Research Apr 2022, 8 (2) 00009-2022; DOI: 10.1183/23120541.00009-2022
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