Table 1 Summary of included studies in the scoping review of proteomics in setting of prematurity
From: The use of proteomics for blood biomarker research in premature infants: a scoping review
Author Year Country | Outcome | Aim | Population | Comparative groups (n =) | Proteomic methods | Pathway analysis | Key findings | Limitations |
|---|---|---|---|---|---|---|---|---|
Byung et al. [23] 2004 Korea | PDA | To investigate the usefulness of rapid BNP assay as a diagnostic marker of symptomatic PDA in preterm infants | Preterm infants aged 25–34 weeks’ gestation | Symptomatic PDA (n = 23) Control (n = 43) | Immunoassay kits | None | Circulating BNP measurements correlated with clinical and echocardiographic assessments of PDA BNP concentration was significantly higher in the infants with symptomatic PDA 3 days after birth BMP concentration measurements were correlated with ductal shunts | Not listed |
Ng et al. [16] 2010 Hong Kong | LOS NEC | To identify novel biomarkers for early and accurate diagnosis of NEC and/or septicaemia in premature infants Develop a novel clinical strategy of antibiotic treatment in different risk categories of infants | Infants born < 31 weeks’ gestation and with a birth weight of < 1500 g | Sepsis/NEC (n = 77) No sepsis infants (n = 77) | MALDI-TOF MS Immunoassay kits Protein microarray 2D-Gel Electrophoresis | None | The ApoSAA score can potentially formulate antibiotic treatment strategies for suspected LOS and NEC patients The ApoSAA Score equation is practical and clinically useful for accurate identification of NEC and LOS in preterm infants Proteins that are useful biomarkers of NEC and LOS: Pro-apoC2 and a des-arginine variant of SAA | Proteomic protocol may not differentially detect low-plasma concentration proteins |
Stewart et al. [12] 2015 UK | LOS NEC | To investigate serum and metabolome longitudinally in preterm infants with NEC and LOS | Infants born 23–30 weeks’ gestation | NEC (n = 6) LOS (n = 4) Control (n = 9) | LC–MS/MS | None | All proteins and metabolites were comparable among all patient groups C-reactive protein increased in all NEC patients Upregulated proteins associated with NEC diagnosis: C-reactive protein (1–205), MIF and SAA-2 Proteins associated with LOS diagnosis: Haptoglobin, transthyretin and U5 small nuclear ribonucleoprotein | Study was not sufficiently powered to determine biomarkers for clinical diagnosis Serum samples were salvaged post routine clinical tests |
Ruiz-Gonzalez et al. [17] 2015 Spain | IUGR | To analyse and identify serum proteome changes in IUGR and AGA infants | Infants born 29- ≥ 37 weeks’ gestation | Very preterm (29–32 weeks’ gestation) (n = 28) Moderate preterm (33–36 weeks’ gestation) (n = 30) Term (≥ 37 weeks’ gestation) (n = 30) | MALDI-TOF MS 2D-Gel Electrophoresis Western blot | None | MBOAT7 was only detected in IUGR across all GA groups Lower levels of APOL1 and SUMO3 were detected in UGR compared to AGA FCN2 was downregulated in IUGR after one week in the very preterm group, whereas TF was upregulated in the very preterm and term groups | Extremely preterm infants (< 29 weeks) were not included in the study |
Lynch et al. [18] 2016 USA | ROP | Identify plasma proteins associated with ROP | Infants born < 31 weeks’ gestation or birth weight < 1500 g | No ROP (n = 23) Clinically significant ROP (n = 12) Low-grade ROP (n = 27) | SOMAscan proteomic assay | None | Proteins associated with clinically significant ROP: MnSOD, CRDL1 and PCSK9 MnSOD could be used as a therapeutic intervention target Proteins associated with a high risk of ROP included: FGF-19, MST1R, LH, cystatin M and Plasminogen IGFBP-7 was linked to the signalling pathway for ROP | Small sample size Proteomic analysis was conducted on one sample from neonatal period |
Suski et al. [13] 2018 Poland | GA | To compare plasma proteome compositions in preterm infants from varying gestational ages To identify signalling pathways that could be differentially regulated due to the duration of a pregnancy | Infants born < 30 weeks’ gestation | Preterm Group 1 (< 26 weeks’ gestation) (n = 19) Preterm Group 2 (27–28 weeks’ gestation) (n = 19) Preterm Group 3 (29–30 weeks’ gestation) (n = 19) | iTRAQ LC–MS/MS | None | Protein changes between gestation ages across several pathways for inflammation, immunomodulation, complement activation and coagulation As gestational age increased there was an increase in plasma protease inhibitor (C1Inh) and fibrinogen isoforms As gestational age increased there was a decrease in Complement C3, Factor V and C4-A Concentration of LRG1 increased over time SAP correlated with gestation age Significant changes in plasma concentrations of Apolipoprotein compositions, specifically Apo-D | Not listed |
Suski et al. [14] 2018 Poland | Signalling Pathways | To analyse plasma proteome changes in preterm infants that are stratified by their gestational age in order to identify proteins of malfunctioning signalling pathways | Infants born < 30 weeks’ gestation | Preterm Group 1 (< 26 weeks’ gestation) (n = 19) Preterm Group 2 (27–28 weeks’ gestation) (n = 19) Preterm Group 3 (29–30 weeks’ gestation) (n = 19) | iTRAQ LC–MS/MS | None | Changes in plasma protein concentrations were associated with preterm delivery LRG1 was negatively correlated with gestation age Downregulation of ORM 1 and 2 isoforms ZAG and afamin downregulated in all groups Changes in the inflammatory, coagulation and complement pathways identified among infants born preterm | Not listed |
Wagner et al.[21] 2018 USA | PVD | Identify proteins associated with pathogenesis of PVD | Preterm infants aged 23–29 weeks’ gestation | PVD (n = 44) Non-PVD group (n = 56) | SOMAscan proteomic assay | None | 18 proteins associated with PVD at day 7 (PF-4, MST1R, APP and STK16) Proteins associated with novel pathways: Platelet degranulation, signalling by MST1 | Single centre study Circulating proteins may not correctly represent target organ |
Zasada et al. [10] 2018 Poland | ROP | To identify biomarkers of ROP To validate the findings with a gene expression study | Infants born < 30 weeks’ gestation | Preterm infants with ROP (n = 28) Preterm infants without ROP (n = 29) | iTRAQ Protein Microarray MS/MS | None | Significant difference in 33 proteins among those who developed ROP compared with infants who did not Concentrations of complement C3 and fibrinogen increased in infants who developed ROP Microarray results for fibrinogen did not validate the findings from the proteomic analysis | Results may not be generalised due to differences across varying NICUs An additional validation method could have been used to strengthen the reported findings |
Zasada et al. [15] 2019 Poland | BPD | To identify plasma biomarkers of BPD and provide a further molecular understanding of BPD | Infants born < 30 weeks’ gestation | Preterm infants with BPD (n = 36) Preterm infants without BPD (n = 21) | iTRAQ MS/MS | None | Infants with BPD had a decrease in the following protein concentrations: afamin, gelsolin, apolipoprotein A-1 and galectin-3 binding protein t 36 weeks’ postmenstrual (PMA) infants with BPD had increasing plasma concentrations of TF | Sample size of infants with severe BPD is small An additional validation method could have been used to strengthen the reported findings |
Arjaans et al. [19] 2020 USA | BPD PH | Determine changes in circulating angiogenic peptides during the first week of life and their association with developing BPD and PH later in life Determine peptides and relevant signalling pathways associated with risk of BPD and PH | Infants born < 34 weeks’ gestation and a birthweight between 500 and 1250 g | No BPD (n = 20) Mild BPD (n = 34) Moderate BPD (n = 26) Severe BPD (n = 22) | SOMAscan proteomic assay | Reactome | Proteins associated with BPD severity include: FGF-19, PF-4, CTAP-III and PDGF-AA Proteins associated with BPD diagnosis: PF-4, VEGF121, ANG-1, ANG-2, BMP10 AND HGF Increasing BMP10 levels were associated with Preterm infants developing BPD and PH later in life | Relatively small sample size Circulating proteins may not represent expression in lung tissue |
Tosson et al. [24] 2020 Egypt | Sepsis | To investigate S100A12 and additional cytokines as biomarkers for neonatal sepsis | Infants born 24–36 weeks’ gestation | Controls (n = 22) Not infected (n = 22) Infection probable (n = 37) Infected (n = 37) | ELLSA Magnetic bead array assay | None | S100A12 demonstrated high specificity and sensitivity between infected and control groups IL-6 and IL-10 were significantly different between infected and control group S100A12 was also significantly different among control and infected groups | Not listed |
Zhong et al. [25] 2020 Sweden | Blood protein profiles | To investigate protein profiles in extremely preterm infants | Infants born < 28 weeks’ gestation | Extremely preterm infants (n = 14) | Multiplex PEA technology | None | Proteins that increased after birth: C3dCR2, Factor VII, Factor XI, INHBC, SELL, IL2-RA and GP6 Proteins that decreased after birth: COLEC12, IGFBP-1, FSTL3, GDF15 and CGA Infants born extremely preterm have similar serum profiles directly at birth which changes dramatically during the first week of life | Small sample size Some infants received blood products during the study period, which could have impacted the results |