Table 2.

The summary data

- Reference - Published Year - CountryStudy design- Study setup - Setting- Sample size (total) (IS/C)) (n)a - Target IS population - Comorbidities - Age (median or mean) (range) (in a year) - Male/female (n/n)Prevalence
of IS (%)		All included blood biomarkersBlood biomarker with
optimal performance		Blood biomarker with optimal performance
TPFPTNFNSen (95% CI)Spe (95% CI)AUC (95% CI)

  • - (Fan et al., 2018)

  • - 2018

  • - China

Prospective study

  • - Single-center

  • - Inpatient

  • - 389 (133/144)

  • - Acute lacunar infarction

  • - Comorbidities: Hypertension, diabetes mellitus, hyperlipidemia, CAD, and atrial fibrillation

  • - Acute lacunar infarction 69 (59.5–75.5), control 66.5 (59.25–71)

  • - 227/112

34.19%

  • - Homocysteine (Hcy)

  • - Fibrinogen

Hcy1280192690.65 (0.58–0.72)1.00 (0.98–1.00)0.88 (0.84–0.92)

  • - (Q. X. Qin et al., 2018)

  • - 2018

  • - China

Retrospective study

  • - Multicenter

  • - Inpatient

  • - 228 (114/114)

  • - AIS with active colorectal cancer (CRCIS)

  • - Comorbidities: Colorectal cancer

  • - CRCIS 65.33 ± 12.45, healthy control (HC) 63.67 ± 9.18

  • - 156/72

50.00%

  • - D-dimer

  • - Neutrophil count (NC)

  • - Carcinoembryonic antigen (CEA)

  • - Cancer antigen 125 (CA125)

D-dimer + CEA + NC982391160.86 (0.78–0.92)0.80 (0.71–0.87)0.89 (0.85–0.93)

  • - (Fang et al., 2018)

  • - 2018

  • - China

Retrospective, case-control study

  • - Single-center

  • - Inpatient

  • - 462 (262/200)

  • - AIS

  • - Comorbidities: Hypertension, diabetes, hyperlipidemia

  • - AIS 62.5 ± 11.5, HC 61.8 ± 10.8

  • - 261/201

56.71%

  • - S100 calcium-binding protein B (S100B)

  • - C-reactive protein (CRP)

  • - IL-6

  • - Plasminogen activator inhibitor-1 (PAI-1)

  • - Matrix metallopeptidase 9 (MMP-9)

  • - P-selectin

  • - Intercellular adhesion molecule 1 (ICAM-1)

  • - Tumor necrosis factor α (TNF-α)

  • - Low-density lipoprotein cholesterol

  • - IL-10

  • - Nitric oxide (NO)

  • - Glial fibrillary acidic protein

CRPNANANANANANA0.99 (0.98–1.00)
IL-6NANANANANANA0.96 (0.94–0.98)
PAI-1NANANANANANA0.99 (0.98–1.00)
P-selectinNANANANANANA0.91 (0.88–0.94)
TNF-αNANANANANANA0.99 (0.98–1.00)

  • - (Mohamed et al., 2019)

  • - 2019

  • - Egypt

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 96 (48/48)

  • - CES

  • - Comorbidities: N/A

  • - NA

  • - NA

50.00%

  • - Brain natriuretic peptide (BNP)

  • - D-dimer

  • - Creatine–kinase-MB (CK-MB)

  • - CRP

  • - Globulin/albumin ratio

BNP361830120.75 (0.60–0.86)0.63 (0.47–0.76)0.80 (0.71–0.89)
D-dimer44163240.91 (0.79–0.97)0.66 (0.51–0.79)0.79 (0.70–0.88)
CK-MB41123670.85 (0.71–0.93)0.75 (0.60–0.86)0.91 (0.85–0.97)

  • - (Zuo et al., 2020)

  • - 2020

  • - China

A prospective, cohort study

  • - Dual-center

  • - Inpatient

  • - 300 (200/100)

  • - AIS

  • - Comorbidities: N/A

  • - AIS 72 (61–82), HC 64 (59–71)

  • - 188/112

66.67%

  • - circFUNDC1

  • - circPDS5B

  • - circCDC14A

  • - Combination of the above three circRNAs

Combination of three circRNAs (circFUNDC1, circPDS5B, circCDC14A)144991560.72 (0.65–0.78)0.91 (0.83–0.96)0.88 (0.84–0.91)

  • - (O'Connell et al., 2017)

  • - 2017

  • - USA

Prospective study

  • - Single-center

  • - Inpatient

  • - 63 (43/20)

  • - AIS

  • - Comorbidities: Hypertension, dyslipidemia, diabetes, atrial fibrillation

  • - AIS 72.5 ± 15.5, mimic stroke 58.0 ± 17.0

  • - 29/31

68.25%Peripheral blood cell-free DNA (cfDNA)cfDNA3751560.86 (0.72–0.95)0.75 (0.51–0.91)0.90 (0.72–0.95)

  • - (Nezu et al., 2022)

  • - 2022

  • - Japan

Prospective study

  • - Multicenter

  • - Inpatient

  • - 120 (47/73)

  • - CAS

  • - Comorbidities: Hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, atrial fibrillation, cancer

  • - AIS patients with active cancer and CAS 72.4 ± 11.5, AIS patients with active cancer 76.3 ± 10.2

  • - 74/46

39.17%

  • - Carbohydrate antigen (CA) 125

  • - CEA

  • - CA 19–9

CA 125351657120.75 (0.59–0.86)0.78 (0.67–0.87)0.81 (0.72–0.88)

  • - (Comertpay et al., 2020)

  • - 2020

  • - Turkey

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 72 (36/36)

  • - AIS

  • - Comorbidities: N/A

  • - AIS 66.06 ± 14.59 (23–94), HC 66.1 ± 14.4 (25–94)

  • - 46/26

50.00%Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK)sTWEAK2833380.78 (0.60–0.89)0.92 (0.76–0.98)0.84 (0.74–0.94)

  • - (C. Tian et al., 2022)

  • - 2022

  • - China

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 78 (39/39)

  • - AIS

  • - Comorbidities: Diabetes mellitus, hypertension, hyperlipidemia, coronary heart disease

  • - AIS 74, control 76.62 ± 10.34

  • - 36/42

50.00%

  • - nc-KRTCAP3-2:1

  • - Inc-OSBPL10

  • - nc-OSBPL10-2:1

  • - NR_120420

  • - Inc-AP002414.1.1

  • - nc-AP002414.1.1-5:8

  • - nc-GCH1-2:3

  • - NR_003529.

  • - Inc-DENR

  • - nc-DENR-2:3

  • - nc-CMPK2-5:39

NR_120420 (total anterior circulation infarction subgroup)3463350.86 (0.69–0.94)0.85 (0.69–0.94)0.86 (0.73–0.99)

  • - (P. F. Liu et al., 2017)

  • - 2017

  • - China

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 49 (26/23)

  • - AIS

  • - Comorbidities: hypertension, hyperlipidemia

  • - AIS 59.08 ± 8.51, control 56.96 ± 2.70

  • - 33/16

53.06%

  • - Ornithine

  • - Proline

  • - Acetylcarnitine

  • - Threonine

  • - PC (1:0/16:0)

  • - LysoPC (16:0)

  • - LysoPE (20:4)

  • - Carnitine

  • - Lysine

  • - Aspartic acid

  • - LysoPE (18:2)

  • - Betaine

  • - Isoleucine

  • - Serine

  • PC (5:0/5:0)

Combination of five biomarkers (serine, isoleucine, betaine, PC (5:0/5:0), LysoPE (18:2))NANANANANANA0.97 (0.92–1.02)

  • - (Cheng et al., 2018)

  • - 2018

  • - China

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 119 (77/42)

  • - AIS

  • - Comorbidities: Hypertension, diabetes mellitus

  • - AIS 61 ± 10.4, control 59 ± 4.7

  • - 35–79 (61)

  • - 83/36

64.71%

  • - miR-148b-3p

  • - miR-151b

  • - miR-27b-3p

Combination of miR-148b-3p and miR-27b-3p52339250.67 (0.46–0.67)0.93 (0.70–0.97)0.81 (0.70–0.92)

  • - (H. Tian et al., 2021)

  • - 2021

  • - China

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 140 (76/64)

  • - AIS

  • - Comorbidities: Hypertension, diabetes, hyperlipidemia

  • - AIS 57.0 ± 6.4, control 56.4 ± 6.2

  • - 87/53

54.29%

  • - miR-210

  • - miR-137

  • - miR-153

miR-210461462180.72 (0.59–0.82)0.82 (0.71–0.89)0.82 (0.76–0.91)
miR-137451165190.70 (0.57–0.81)0.86 (0.75–0.92)0.84 (0.78–0.91)
miR-153522056120.81 (0.69–0.90)0.74 (0.62–0.83)0.84 (0.78–0.91)

  • - (Wang et al., 2017)

  • - 2017

  • - China

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 69 (40/29)

  • - AIS

  • - Comorbidities: Hypertension, diabetes mellitus, atrial fibrillation

  • - AIS 65.7, control 61.0

  • - 38/31

57.97%

  • - Alanine

  • - Citrate

  • - Glycine

  • - Leucine

  • - Isoleucine

  • - Serine

  • - Tyrosine

  • - Methionine

  • - Tryptophan

  • - Erythronic acid

  • - Urea

  • - Purine

  • - Proline

  • - Hypoxanthine

Tyrosine, lactate, and tryptophan panelNANANANANANANA

  • - (D. Lu et al., 2020)

  • - 2020

  • - China

Phase 1: Experimental design

Phase 2: Bioinformatics analysis, case-control study

  • - Multicenter

  • - Inpatient

  • - 16 (8/8)

  • - AIS

  • - Comorbidities: N/A

  • - AIS 55.4 ± 12.3, control 54.11 ± 10.1

  • - 14/2

50.00%140,732 out of 140,790 human circRNAs

  • - circPHKA2

  • - circBBS2

NANANANANANANA

  • - (Augello et al., 2018)

  • - 2018

  • - USA

A prospective, case-control study

  • - Single-center

  • - Inpatient and outpatient

  • - 50 (24/26)

  • - AIS

  • - Comorbidities: Hypertension, CAD, CAD, diabetes mellitus, atrial fibrillation

  • - AIS 58 (51–74), control 61 (51–76)

  • - 31/19

48.00%

  • - Gp130/sIL-6Rb

  • - IFN-β

  • - IL-28A/IFN-λ2

  • - MMP-2

  • - Osteopontin (OPN)

  • - sTNF-R1

  • - sTNF-R2

  • - TSL

IL-28A/IFN-λ2, MMP-2, sTNF-R2, and TSLP panel2112530.88 (0.67–0.97)0.96 (0.78–1.00)0.96 (0.89–1.02)

  • - (Guo et al., 2018)

  • - 2018

  • - China

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 20 (10/10)

  • - AIS

  • - Comorbidities: N/A

  • - AIS 63.2 ± 10.7, control 69.3 ± 5.9

  • - 14/6

50.00%560 upregulated and 690 downregulated differentially expressed lncRNAsCombination of lncRNAs (lncRNA-ENST00000568297, lncRNA-ENST00000568243, and lncRNA-NR_046084)82820.83 (0.44–0.96)0.80 (0.44–0.96)0.84 (0.66–1.02)

  • - (Huang et al., 2021)

  • - 2021

  • - China

A prospective, cohort study

  • - Single-center

  • - Inpatient

  • - 305 (155/150)

  • - AIS

  • - Comorbidities: Hypertension

  • - AIS 56.0 (median), control 55.0 (median)

  • - AIS 84/71, control 76/74

50.82%

  • - Serum Interleukin-34 (IL-34)

  • - Glycosylated hemoglobin (HbA1c)

IL-341065145490.68 (0.60–0.75)0.97 (0.92–0.98)0.87 (0.83–0.91)

  • - (L. J. Zhang et al., 2020)

  • - 2020

  • - China

Prospective study

  • - NA

  • - NA

  • - 78 (48/30)

  • - Fist-ever IS (FS) and recurrent IS (RS)

  • - Comorbidities: High blood pressure, coronary heart disease, valvular disease of the heart, heart failure, atrial fibrillation

  • - FS 64.2 ± 8.9, RS 75.8 ± 9.4, HC 65.5 ± 8.2

  • - FS 21/17, RS 7/3, HC 17/13

61.54%

  • - Model 1: fatty acid metabolite levels including DHA, 8-iso-PGF3α, arachidonic acid, 8-iso-15-keto-PGF2a, 13-HODE, and 14,15-DHET

  • - Model 2: clinical biochemical parameter levels, including HDL, blood glucose, and TG

  • - Model 3: both fatty acid metabolites and clinical biochemical parameters: arachidonic acid, DHA, 13-HODE, 8-iso-15-keto-PGF2a, and HDL

Model 3: both fatty acid metabolites and clinical biochemical parameters: arachidonic acid, DHA, 13-HODE, 8-iso-15-keto-PGF2a, and HDL4822801.00 (0.91–1.00)0.93 (0.77–0.99)0.99 (0.98–1.00)

  • - (Rahmati et al., 2021)

  • - No. 22

  • - 2021

  • - Iran

Prospective study

  • - Single-center

  • - Inpatient

  • - 104 (52/52)

  • - IS

  • - Comorbidities: N/A

  • - NA

  • - NA

50.00%

  • - micronRNA-210 (miR-210)

  • - Hypoxia inducible factor-1α (HF-1α)

HF-1α342032180.65 (0.50–0.78)0.62 (0.47–0.75)0.73 (0.64–0.82)

  • - (Zhao et al., 2021)

  • - 2021

  • - China

Prospective study

  • - Single-center

  • - Inpatient

  • - 100 (50/50)

  • - IS

  • - Comorbidities: Hypertension, diabetes mellitus

  • - IS 66.76 (median), control 66.74 (median)

  • - IS 31/19, control 30/20

50.00%

  • - microRNA-148a (has-miR-148a)

  • - microRNA-342-3p (has-miR-342-3p)

  • - microRNA-19a (has-miR-19a)

  • - microRNA-320d (has-miR320d)

  • - has-miR-148a + has-miR-342-3p

  • - has-miR148a + has-miR-342-3p + has-miR-19a

  • - has-miR148a + has-miR-342-3p + has-miR-19a + has-miR-320d

has-miR148a + has-miR-342-3p + has-miR-19a + has-miR-320d4794130.94 (0.83–0.98)0.82 (0.68–0.91)0.89 (0.77–1.00)

  • - (Park et al., 2018)

  • - 2017

  • - USA

A prospective, case-control study

  • - Multicenter

  • - Inpatient and outpatient

  • - 305 (172/133)

  • - AIS

  • - Comorbidities: Hypertension, diabetes mellitus, hyperlipidaemia, CAD, atrial fibrillation

  • - AIS 68.8 ± 14.7, control 71.0 ± 10.5

  • - 147/158

56.39%

  • - Glycogen phosphorylase isoenzyme BB (GPBB)

Glycogen phosphorylase isoenzyme BB (GPBB)1609124120.93 (0.88–0.96)0.93 (0.87–0.97)0.96 (0.94–0.98)

  • - (H. T. Zhang et al., 2020)

  • - 2020

  • - China

Case-control study

  • - Single-center

  • - Inpatient

  • - 163 (93/70)

  • - IS

  • - Comorbidities: Hypertension, diabetes mellitus

  • - IS 67.5 ± 11.2, control 66.2 ± 10.8

  • - 96/67

57.06%

  • - Endothelial microvesicles (EMVs)

  • - EMVs carrying miRNA-155

EMVs + EMVs-miR-15570885230.75 (0.65–0.83)0.91 (0.83–0.96)0.89 (0.84–0.94)

  • - (Sun et al., 2017)

  • - 2017

  • - China

Case-control study

  • - Single-center

  • - Inpatient and outpatient

  • - 60 (30/30)

  • - IS

  • - Comorbidities: N/A

  • - IS 59.77 ± 12.41, control 57.83 ± 11.08

  • - 34/26

50.00%12 Metabolites

  • - Uric acid

  • - LysoPE (0:0/18:3)

  • - LysoPC (18:2)

  • - Bilirubin

  • - Sphinganine

  • - Linoelaidyl carnitine

  • - LysoPC (16:0)

  • - Adrenoyl ethanolamide

  • - PE (15:0/22:1)

  • - PS (14:1/22:6)

  • - PC (14:0/20:4)

  • - PC (16:0/22:6)

Uric acid2272380.73 (0.54–0.87)0.77 (0.57–0.89)0.78 (0.66–0.90)
Sphinganine2152590.70 (0.50–0.85)0.83 (0.65–0.94)0.75 (0.63–0.88)
Adrenoyl ethanolamide2372370.77 (0.57–0.89)0.77 (0.57–0.89)0.81 (0.70–0.92)

  • - (C. Qin et al., 2019)

  • - 2019

  • - China

  • - A retrospective, case-control study

  • - Single-center

  • - Inpatient

  • - 66 (33/33)

  • - AIS due to large-vessel occlusion (LVO)

  • - Comorbidities: Hypertension, diabetes mellitus, coronary heart disease, hypercholesterolemia

  • - AIS due to LVO 54 (46–59), HC 55 (45–62)

  • - 41/25

50.00%

  • - IGF2

  • - LYVE1

  • - PPBP, THBS1

The 4-protein panel (IGF2, LYVE1, PPBP, THBS1)NANANANANANA0.95 (0.90–1.01)

  • - (Lee et al., 2020)

  • - 2020

  • - South Korea

A prospective, case-control study

  • - Single-center

  • - Inpatient

  • - 61 (30/31)

  • - AIS

  • - Comorbidities: Cardiovascular disease, hypertension, diabetes, atrial fibrillation

  • - AIS 59.9 ± 10.9, HC 56.12 ± 5.6

  • - 30/31

49.18%

  • - Prothrombin (F2)

  • - Plasminogen (PLG)

  • - Fibrinogen alpha chain (FGA)

  • - Histidine-rich glycoprotein (HRG)

F22642740.87 (0.68–0.96)0.87 (0.69–0.96)0.92 (0.84–0.99)
PLG2913010.97 (0.81–1.00)0.97 (0.82–1.00)0.98 (0.94–1.02)
FGA2722930.90 (0.72–0.97)0.93 (0.77–0.99)0.92 (0.85–0.99)
HRG2913010.97 (0.81–1.00)0.97 (0.815–1.00)0.98 (0.944–1.02)

  • - (Tiedt et al., 2017)

  • - 2017

  • - Germany

Case-control study

  • - Single-center

  • - Inpatient

  • - 300 (200/100)

  • - IS

  • - Comorbidities: Hypertension, hypercholesterolemia, diabetes mellitus

  • - IS 74.1 ± 13.4, HC 65.6 ± 13.4

  • - 148/152

66.67%

  • - 33 microRNAs (miRNAs)

A set of miR-125a-5p, miR-125b-5p and miR-143-3p1712476290.86 (0.80–0.90)0.76 (0.66–0.84)0.90 (0.87–0.93)

  • - (L. S. Dolmans et al., 2019)

  • - 2019

  • - the Netherlands

Cross-sectional study

  • - NA

  • - Outpatient and home

  • - 206 (126/80)

  • - TIA

  • - Comorbidities: Hypertension, diabetes mellitus, hyperlipidemia, cerebrovascular disease, renal insufficiency, migraine, epilepsy

  • - TIA 71.4 ± 12.0, control 62.0 ± 14.2

  • - 122/84

61.17%

  • - NR2

  • - NR2Ab

  • - B-FABP

  • - H-FABP

  • - NDKA

  • - UFD1

  • - PARK7

H-FABP442852820.35 (0.27–0.44)0.65 (0.53–0.75)NA

  • - (J. Liu et al., 2020)

  • - 2020

  • - China

Prospective study

  • - Single-center

  • - Inpatient

  • - 137 (72/65)

  • - AIS

  • - Comorbidities: Hypertension, diabetes mellitus, dyslipidemia, cervical artery plaques

  • - AIS 58.7 ± 9.7, control 56.6 ± 8.5

  • - 81/56

52.55%

  • - Sphingosine 1-phosphate (S1P)

  • - High-density lipoprotein cholesterol (HDL-C)

S1P442540280.61 (0.49–0.72)0.62 (0.49–0.73)0.62 (0.53–0.72)
S1P within 24 h of symptom onset49857230.68 (0.56–0.78)0.87 (0.77–0.94)0.83 (0.74–0.92)

  • - (Z. Z. Chen et al., 2018)

  • - 2018

  • - China

Prospective study

  • - NA

  • - Inpatient

  • - 230 (128/102)

  • - AIS

  • - Comorbidities: Hypertension, diabetes, coronary disease, dyslipidemia

  • - AIS 68.42 ± 17.26, control 65.36 ± 16.32

  • - 109/19

55.65%

  • - Plasma hs-CRP

  • - Serum miR-146b, miR-21, miR-145, miR-29b, miR-221

  • - Interleukin (IL-6)

Combination of hs-CRP, IL-6 and miR-146bNANANANANANA0.87 (0.80–0.93)

  • IS, ischemic stroke group; C, control group; TP, true positive; FP, false positive; TN, true negative; FN, false negative; Sen, sensitivity; Spe, specificity; AUC, area under the curve; N/A, not applicable.

  • ↵a The one generated the final diagnostic value.