Table 3.
Biomarker Characteristics of the 26 Included Studies
| Study ID | Sampling type | Assay analyzer & manufacturer/is | Timing of sample collectiona | Assay range/ CV | Cutoff | BM levels in TBI patientsc | BM levels in patients with CT positivec | BM levels in patients with CT negativec | BM levels in controlsc |
|---|---|---|---|---|---|---|---|---|---|
|
S-100B | |||||||||
| Asadollahi 201618 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury |
LOD 0.02μgL range 0.02–30 CV <10% |
0.11 μg/L |
NR |
Mean (95% CI) 0.68 μgL (0.58–0.77) |
Mean (95% CI) 0.10 μgL (0.07–0.11) |
NA |
| Bazarian 201319 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 6 h post-injury |
Range 0.005-39 μgL |
0.10 μg/Lb |
0.149 μg L |
0.292 μg/L |
0.144 μg/L |
0.071 μg/L Negative control group |
| Biberthaler 200120 |
Serum (venous) |
ILMA LIA-mat, Sangtec 100 |
On admission 116’ (18.8) |
NR |
0.10 μg/L |
Mean (SD) 0.470 ng/mL (0.099) |
NR |
NR |
0.05 ng/mL (0.01) Negative control group 7.16 ng/mL (3.77) Positive control group |
| Biberthaler 20063 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury Median 60’ (range 40–80') |
LOD 0.005 μgL range 0.005–39 |
0.10 μg/L |
0.17 μg/L (0.10–0.37) |
0.49 μg/L (0.25–1.46) |
0.16 μg/L (0.09–0.33) |
0.05 μg/L (0.03–0.06) Negative control group 0.45 μg/L (0.19–2.63) Positive control group |
| Bouvier 200921 |
Serum (venous) |
ECLIA Elecsys® Roche |
On admission Median 1 h 36’ |
LOD 0.005 μgL range 0.005–39 |
0.10 μg/Lb |
Mean 0.37 μg/L (SD 0.76) |
Mean 0.88 μg/L (SD 1.52) |
Mean 0.28 μg/L (SD 0.49) |
Mean (SD) 0.05 μg/L (0.02) Negative control group |
| Calcagnile 201222 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury |
LOD 0.005 μgL range 0.005–39 Intra-assay CV <2.1% |
0.10 μg/L |
NR |
NR |
NR |
NA |
| Cervellin 201223 |
Serum (venous) |
ILMA Liaison® Diasorin |
Within 3 h post-injury 62’ |
LOD 0.02- μg/L range 0.02–30 CV <10% |
0.38 μg/L |
NR |
Geometric mean 1.35 μg/L (95% CI 0.73–1.97) |
Geometric mean 0.48 μg/L (95% CI 0.33–0.63) |
NA |
| Cervellin 201424 |
Serum (venous) |
ILMA Liaison® Diasorin |
Within 3 h post-injury 62’ |
LOD 0.02- μg/L range 0.02–30 CV <10% |
0.56 μg/L |
NR |
1.5 μg/L (1.19–2.37) |
0.22 μg/L (0.12–0.48) |
NA |
| Egea-Guerrero 201225 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 6 h post-injury |
LOD 0.005μgL range 0.005–39 |
0.105μg/Lb |
Mean (95% CI) 0.392 μg/L (0.327–0.456) |
Mean (95% CI) 0.585 μg/L (0.363–0.806) Median 0.350 |
Mean (95% CI) 0.369 μg/L (0.302–0.436) Median 0.220 |
NA |
| Ingebrigtsen 200026 |
Serum (venous) |
RIA AB Sangtec |
On admission 3 h (range 0.5–12.0) |
LOD 0.2 μg/L |
0.2 μg/L |
Mean 0.5 μg/L (range 0.2–1.9) Detectable in 69 (38%) pts, undetectable in 113 (62%) |
Mean 0.7 μg/L (range 0.2–1.9) 9/10 with detectable level |
NR |
NA |
| Laribi 201427 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury Median (IQR) 115’ (75–150) |
LOD 0.005 μgL range 0.005–39 Intra-assay CV 2.1% Inter-assay CV 2.8% |
0.10 μg/L |
H0 - 0.14 μg/L (0.08–0.25) H+3 - TBI 0.10 μg/L (0.06–0.16) |
H0 - 0.24 μg/L (0.15–0.34) H+3 - 0.13 μg/L (0.10–0.25) |
H0 - 0.13 μg/L (0.08–0.25) H+3 - 0.10 μg/L (0.06–0.15) |
NA |
| Morochovic 200930 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury 1.8 h |
LLOD 0.005 μg/L Inter-assay CV 4.9% |
0.10 μg/L |
Mean (SD) GCS 13 0.26 μg/L (0.34) GCS 14 0.43 μg/L (0.56) GCS 15 0.85 μg/L (3.11) |
NR |
NR |
NA |
| Muller 200731 |
Serum (venous) |
ILMA Liaison® Diasorin |
Within 12 h post-injury |
LOD 0.013 μg/L Intra-assay CV <5% Inter-assay CV <10% |
0.10 μg/L |
Mean (95% CI) GCS 13 0.32 μg/L (0.16–0.49) GCS 14 0.22 μg/L (0.13–0.30) GCS 15 0.18μg/L (0.16–0.21) |
Mean (95% CI) 0.36 μg/L (0.21–0.50) |
Mean (95% CI) 0.18 μg/L 0.16–0.20 |
NA |
| Muller 201132 |
Serum (venous) |
ECLIA Elecsys® Roche |
NR |
NR |
0.105 μg/Lb |
NR |
NR |
NR |
NA |
| Mussack 200233 |
Serum (venous) |
ILMA Liaison® Diasorin |
On admission Median 24.3’ |
LLOD 0.02 ng/mL |
0.21 ng/mL |
0.24 ng/mL (0.15–0.49) |
0.94 ng/mL (0.39–1.43) |
0.22 ng/mL (0.14–0.39) |
0.06 ng/mL (0.05–0.09) Negative control group |
| Papa 201436 |
Serum (venous) |
ELISA Banyan |
Within 4 h post-injury 3.1 h (95% CI 2.8–3.3) |
LLOQ 0.083 ng/mL LLOD 0.017 ng/mL |
0.020 ng/mL |
NR |
NR |
NR |
NR |
| Poli-de-Figueiredo 200637 |
Serum (venous) |
ECLIA Elecsys® Roche |
On admission Median (IQR) 82’ (60–110) |
NR |
0.10 μg/L |
0.29 μg/L (0.14–0.76) |
0.75 μg/L (0.66–6.5) |
0.26 μg/L (0.12–0.65) |
0.04 μg/L (0.03–0.05) Negative control group |
| Romner 200038 |
Serum (venous) |
RIA Sangtec |
Within 24h post-injury 3.8 h (range 0.5–24.0) |
LOD 0.2 μg/L |
0.2 μg/L (LOD) |
Mean 0.6 m g/L (range 0.2–6.2) Detectable in 35% MHI |
Mean 2.2 μg/L (range 0.2–12.5) Detectable in 23 (92%) mild-severe TBI pts |
NR |
Non detectable levels Negative control group |
| Thaler 201539 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury Median (IQR) 2.05h (1.30–2.30) |
Range 0.005–39 μgL |
0.105 μg/L |
mTBI 0.15μg/L (0.088–0.291) GCS 15 0.139 (0.085–0.267) GCS 14 0.178 (0.102–0.311) GCS 13 0.284 (0.130–0.652) |
0.285 μg/L (0.185–0.532) |
0.143 μg/L (0.085–0.274) |
NA |
| Welch 201640 |
Serum (venous) |
ECLIA Cobas 6000® Roche |
Within 6 h post-injury |
NR |
0.10 μg/Lb |
120 (70–230) All values in detectable range |
NR |
NR |
NA |
| Wolf 201341 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury |
NR |
0.105 μg/Lb |
NR |
Mean (SD) 0.7 μg/L (1.19) |
Mean (SD) 0.21 μg/L (0.26) |
NA |
| Zongo 201242 |
Plasma (venous) |
ECLIA Elecsys® Roche |
Within 6 h post-injury |
NR |
0.10 μg/Lb |
0.23 μg/L (0.14–0.38) |
0.46 μg/L (0.27–0.72) |
0.22 μg/L (0.14–0.36) |
NA |
|
GFAP | |||||||||
| McMahon 201529 |
Plasma (venous) |
ELISA Banyan |
Within 24 h post-injury |
LLOD 0.01 ng/mL Intra-assay CV 4.3–7.8% Inter-assay CV 7.8–14.3% |
0.6 ng/mL |
NR |
Mean (SD) 2.86 ng/mL (3.74) |
Mean (SD) 0.26 ng/mL (0.41) |
NA |
| Papa 201234 |
Serum (venous) |
ELISA Banyan |
Within 4 h post-injury 2.6 h (95% CI 2.4–2.9) |
LLOD 0.020 ng/mL Intra-assay CV 4.3–7.8%, Inter-assay CV 7.8–14.3% |
0.035 ng/mL |
0.316 ng/mL (IQR 0.60) Mean (SD) 0.893 (1.677) (95% CI 0.573 – 1.213) |
NR |
NR |
0.010 ng/mL (0.050) Negative control group 0.216 ng/mL (0.275) Orthopedic control group 0.122 ng/mL (0.373) MVA control group 0.010 ng/mL (0.060) All controls |
| Papa 201436 |
Serum (venous) |
ELISA Banyan |
Within 4 h post-injury 3.1 h (95% CI 2.8–3.3) |
LLOQ 0.030 ng/mL ULOQ 50.000 ng/mL LLOD 0.008 ng/mL |
0.067 ng/mL |
NR |
NR |
NR |
NR |
| Welch 201640 |
Serum (venous) |
ELISA Banyan |
Within 6 h post-injury |
NR |
0 pg/mL |
10.3 pg/mL (3.5, 37.4) 45 pts below LOD (4 with CT+) |
NR |
NR |
NA |
|
NSE | |||||||||
| Cervellin 201424 |
Serum (venous) |
IFMA Kryptor (BRAHMS AG) |
Within 3 h post-injury 62’ |
LOD 0.08 μgL CV <6% |
9.0 μg/L |
NR |
13.3 μg/L (12.1–20.3) |
9.6 μg/L (8.2–12.3) |
NA |
| Mussack 200233 |
Serum (venous) |
ECLIA Elecsys® Roche |
On admission Median 24.3’ |
LLOD 0.01 ng/mL |
12.28 ng/mL |
17.50 ng/mL (14.40–21.34) |
18.43 ng/mL (15.31–26.03) |
17.46 ng/mL (14.31–20.77) |
15.55 ng/mL (14.90–17.00) Negative control group |
| Wolf 201341 |
Serum (venous) |
ECLIA Elecsys® Roche |
Within 3 h post-injury |
NR |
14.7 μg/Lb |
Missing values in 47 pts (44%) |
Mean (SD) 18.1 μg/L (10.84) |
Mean (SD) 12.4 μg/L (4.82) |
NA |
|
UCH-L1 | |||||||||
| Papa 201235 |
Serum (venous) |
ELISA Banyan |
Within 4 h post-injury 2.7 h (95% CI 2.4–2.9) |
LLOD 0.030 ng/mL |
0.029 ng/mL |
Mean (SEM) 0.955ng/mL (0.248) (range 0.015–19.25) |
Mean (SEM) 1.618 ng/mL (0.474) |
Mean (SEM) 0.620 ng/mL (0.254) |
Mean (SEM) 0.083 ng/mL (0.005) (range 0.015–0.490) All controls (Negative, orthopedic, MVA controls) |
| Welch 201640 |
Serum (venous) |
ELISA Banyan |
Within 6 h post-injury |
NR |
40 pg/mL |
65.8 (39.6, 125.2) 2 pts below LOD (none with CT+) |
NR |
NR |
NA |
|
Tau | |||||||||
| Ma 200828 | Serum (venous) | ELISA | On admission 5.0 h (2.8) |
LOD 1.5 ng/mL | NR | Mean (SD) 5.0 ng/mL (2.98) 15 pts with detectable levels |
NR | NR | NA |
a
Mean (SD) unless stated otherwise.
b
Additional thresholds have been evaluated.
c
Median (IQR) unless stated otherwise.
Control group definition:
• Negative Control Group: healthy individuals (e.g., healthy volunteers, voluntary blood donors, outpatients for routine blood work) who were checked on their health and potential head trauma status.
• Positive Control Group: patients with moderate to severe brain injury.
• Orthopedic Control Group: non–brain-injured patients presenting to the ED with a single-limb orthopedic injury without blunt head trauma.
• MVA Control Group: patients presenting to the ED after a motor vehicle crash without blunt head trauma
BM, biomarker; CV, coefficient of variation; ECLIA, electrochemiluminescence immunoassay; ED, emergency department; ELISA, enzyme-linked immunosorbent assay; GCS, Glasgow Coma Score; GFAP, glial fibrillary acidic protein; H0, within 3 h after the clinical event; H+3, 3 h after the first sampling; IFMA, immunofluorometric assay; ILMA, immunoluminometric assay; IQR, interquartile range; LIA, luminescence immunoassay; LLOD, lower limit of detection; LLOQ, lower limit of quantification; LOD, limit of detection; mTBI, mild traumatic brain injury; MVA, motor vehicle accident; NA, not applicable; NR, not reported; NSE, neuron specific enolase; pts, patients; RIA, radioimmunoassay; S100B, S100 calcium binding protein B; SEM, standard error of the mean; TBI, traumatic brain injury; UCH-L1, ubiquitin C-terminal hydrolase-L1; ULOQ, upper limit of quantification.