Use of high-sensitivity digital ELISA improves the diagnostic performance of circulating brain-specific proteins for detection of traumatic brain injury during triage.
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ABSTRACT:
SUBMITTER: O'Connell GC
PROVIDER: S-EPMC7192520 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Limited lower detection ranges associated with traditional immunoassay techniques have prevented the use of brain-specific proteins as blood biomarkers of stroke in the acute phase of care, as these proteins are often only present in circulation at low concentrations. Digital ELISA is a newly developed technique with allows for quantification of proteins in biofluids with up to 1000 times greater sensitivity than conventional ELISA techniques. The purpose of this study was to determine whether the extended lower limits of detection associated with digital ELISA could enable the use of brain-specific proteins as blood biomarkers of ischemic stroke during triage. Blood was sampled from ischemic stroke patients (n = 14) at emergency department admission, as well as from neurologically normal controls matched in terms of risk factors for cardiovascular disease (n = 33). Plasma levels of two brain-specific axonal proteins, neurofilament light chain (NfL) and tau, were measured via digital ELISA, and receiver-operating characteristic analysis was used to determine their ability to discriminate between groups. Plasma levels of NfL and tau were both significantly elevated in stroke patients versus controls, and could respectively discriminate between groups with 92.9% sensitivity / 84.9% specificity, and 85.7% sensitivity / 54.6% specificity. Furthermore, adjustment of measured NfL and Tau levels according to the lower-limits of detection associated with commercially-available conventional ELISA assays resulted in a dramatic and statistically significant decrease in diagnostic performance. Collectively, our results suggest that the increased analytical sensitivity of digital ELISA could enable the use of brain-specific proteins as blood biomarkers of ischemic stroke during triage.
| S-EPMC7409378 | biostudies-literature
Project description:Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and regeneration. We investigated the diagnostic and prognostic values of serum BDNF in traumatic brain injury (TBI). We examined serum BDNF in two independent cohorts of TBI cases presenting to the emergency departments (EDs) of the Johns Hopkins Hospital (JHH; n?=?76) and San Francisco General Hospital (SFGH, n?=?80), and a control group of JHH ED patients without TBI (n?=?150). Findings were subsequently validated in the prospective, multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study (n?=?159). We investigated the association between BDNF, glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) and recovery from TBI at 6 months in the TRACK-TBI Pilot cohort. Incomplete recovery was defined as having either post-concussive syndrome or a Glasgow Outcome Scale Extended score <8 at 6 months. Median day-of-injury BDNF concentrations (ng/mL) were lower among TBI cases (JHH TBI, 17.5 and SFGH TBI, 13.8) than in JHH controls (60.3; p?=?0.0001). Among TRACK-TBI Pilot subjects, median BDNF concentrations (ng/mL) were higher in mild (8.3) than in moderate (4.3) or severe TBI (4.0; p?=?0.004. In the TRACK-TBI cohort, the 75 (71.4%) subjects with very low BDNF values (i.e., <the 1st percentile for non-TBI controls, <14.2?ng/mL) had higher odds of incomplete recovery than those who did not have very low values (odds ratio, 4.0; 95% confidence interval [CI]: 1.5-11.0). The area under the receiver operator curve for discriminating complete and incomplete recovery was 0.65 (95% CI: 0.52-0.78) for BDNF, 0.61 (95% CI: 0.49-0.73) for GFAP, and 0.55 (95% CI: 0.43-0.66) for UCH-L1. The addition of GFAP/UCH-L1 to BDNF did not improve outcome prediction significantly. Day-of-injury serum BDNF is associated with TBI diagnosis and also provides 6-month prognostic information regarding recovery from TBI. Thus, day-of-injury BDNF values may aid in TBI risk stratification.
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Project description:Smooth pursuit eye movements have been investigated as a diagnostic tool for mild traumatic brain injury (mTBI). However, the degree to which smooth pursuit differentiates mTBI patients from healthy controls (i.e. its diagnostic performance) is only moderate. Our goal was to establish if simultaneous performance of smooth pursuit and a working memory task increased the diagnostic performance of pursuit metrics following mTBI. We integrated an n-back task with two levels of working memory load into a pursuit target, and tested single- and dual-task pursuit in mTBI patients and healthy controls. We assessed pursuit using measures of velocity accuracy, positional accuracy and positional variability. The mTBI group had higher pursuit variability than the control group in all conditions. Performing a concurrent 1-back task decreased pursuit variability for both the mTBI and control groups. Performing a concurrent 2-back task produced differential effects between the groups: Pursuit variability was significantly decreased in the control group, but not in the mTBI group. Diagnostic indices were improved when pursuit was combined with the 2-back task, and increased by 20% for the most sensitive variable. Smooth pursuit with simultaneous working memory load may be a superior diagnostic tool for mTBI than measuring smooth pursuit alone.
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Project description:Online symptom checkers are increasingly popular health technologies that enable patients to input their symptoms to produce diagnoses and triage advice. However, there is concern regarding the performance and safety of symptom checkers in diagnosing and triaging patients with life-threatening conditions. This retrospective cross-sectional study aimed to evaluate and compare commercially available symptom checkers for performance in diagnosing and triaging myocardial infarctions (MI). Symptoms and biodata of MI patients were inputted into 8 symptom checkers identified through a systematic search. Anonymised clinical data of 100 consecutive MI patients were collected from a tertiary coronary intervention centre between 1st January 2020 to 31st December 2020. Outcomes included (1) diagnostic sensitivity as defined by symptom checkers outputting MI as the primary diagnosis (D1), or one of the top three (D3), or top five diagnoses (D5); and (2) triage sensitivity as defined by symptom checkers outputting urgent treatment recommendations. Overall D1 sensitivity was 48±31% and varied between symptom checkers (range: 6-85%). Overall D3 and D5 sensitivity were 73±20% (34-92%) and 79±14% (63-94%), respectively. Overall triage sensitivity was 83±13% (55-91%). 24±16% of atypical cases had a correct D1 though for female atypical cases D1 sensitivity was only 10%. Atypical MI D3 and D5 sensitivity were 44±21% and 48±24% respectively and were significantly lower than typical MI cases (p<0.01). Atypical MI triage sensitivity was significantly lower than typical cases (53±20% versus 84±15%, p<0.01). Female atypical cases had significantly lower diagnostic and triage sensitivity than typical female MI cases (p<0.01).Given the severity of the pathology, the diagnostic performance of symptom checkers for correctly diagnosing an MI is concerningly low. Moreover, there is considerable inter-symptom checker performance variation. Patients presenting with atypical symptoms were under-diagnosed and under-triaged, especially if female. This study highlights the need for improved clinical performance, equity and transparency associated with these technologies.
| S-EPMC11299816 | biostudies-literature
Project description:Although traumatic brain injury (TBI) is recognized as one of the leading causes of death from trauma to the central nervous system (CNS), no known treatment effectively mitigates its effects. Lithium, a primary drug for the treatment of bipolar disorder, has been known to have neuroprotective effects in various neurodegenerative conditions such as stroke. Until this study, however, it has not been investigated as a post-insult treatment for TBI. To evaluate whether lithium could have beneficial effects following TBI, lithium at a dose of 1.5 mEq/kg was administered after injury. Assessed at 3 days and 3 weeks post-injury using hematoxylin and eosin staining, lithium treatment was found to reduce lesion volume. Lithium at doses of 2.0 and 3.0?mEq/kg also significantly reduced lesion volume at 3 days after injury, and the therapeutic window was at least 3?h post-injury. TBI-induced neuronal death, microglial activation, and cyclooxygenase-2 induction were all attenuated by lithium at 3 days after injury. In addition, lithium treatment reduced TBI-induced matrix metalloproteinase-9 expression and preserved the integrity of the blood-brain barrier. As for behavioral outcomes, lithium treatment reduced anxiety-like behavior in an open-field test, and improved short- and long-term motor coordination in rotarod and beam-walk tests. Lithium robustly increased serine phosphorylation of glycogen synthase kinase-3? (GSK-3?), suggesting that the underlying mechanisms responsible for lithium's protective effects are triggered by increasing phosphorylation of this kinase and thereby inhibiting its activity. Our results support the notion that lithium has heretofore unrecognized capacity to mitigate the neurodegenerative effects and improve functional outcomes in TBI.
| S-EPMC3261788 | biostudies-literature
Project description:Digital and online symptom checkers are an increasingly adopted class of health technologies that enable patients to input their symptoms and biodata to produce a set of likely diagnoses and associated triage advice. However, concerns regarding the accuracy and safety of these symptom checkers have been raised. This systematic review evaluates the accuracy of symptom checkers in providing diagnoses and appropriate triage advice. MEDLINE and Web of Science were searched for studies that used either real or simulated patients to evaluate online or digital symptom checkers. The primary outcomes were the diagnostic and triage accuracy of the symptom checkers. The QUADAS-2 tool was used to assess study quality. Of the 177 studies retrieved, 10 studies met the inclusion criteria. Researchers evaluated the accuracy of symptom checkers using a variety of medical conditions, including ophthalmological conditions, inflammatory arthritides and HIV. A total of 50% of the studies recruited real patients, while the remainder used simulated cases. The diagnostic accuracy of the primary diagnosis was low across included studies (range: 19-37.9%) and varied between individual symptom checkers, despite consistent symptom data input. Triage accuracy (range: 48.8-90.1%) was typically higher than diagnostic accuracy. Overall, the diagnostic and triage accuracy of symptom checkers are variable and of low accuracy. Given the increasing push towards adopting this class of technologies across numerous health systems, this study demonstrates that reliance upon symptom checkers could pose significant patient safety hazards. Large-scale primary studies, based upon real-world data, are warranted to demonstrate the adequate performance of these technologies in a manner that is non-inferior to current best practices. Moreover, an urgent assessment of how these systems are regulated and implemented is required.
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Project description:ImportanceData on the performance of traumatic brain injury (TBI) biomarkers within minutes of injury are lacking.ObjectivesTo examine the performance of glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein 2 (MAP-2) within 30 and 60 minutes of TBI in identifying intracranial lesions on computed tomography (CT) scan, need for neurosurgical intervention (NSI), and clinically important early outcomes (CIEO).Design, setting, and participantsThis cohort study is a biomarker analysis of a multicenter prehospital TBI cohort from the Prehospital Tranexamic Acid Use for TBI clinical trial conducted across 20 centers and 39 emergency medical systems in North America from May 2015 to March 2017. Prehospital hemodynamically stable adult patients with traumatic injury and suspected moderate to severe TBI were included. Blood samples were measured for GFAP, UCH-L1, and MAP-2. Data were analyzed from December 1, 2023, to March 15, 2024.Main outcomes and measuresThe presence of CT lesions, diffuse injury severity on CT, NSI within 24 hours of injury, and CIEO (composite outcome including early death, neurosurgery, or prolonged mechanical ventilation ≥7 days) within 7 days of injury.ResultsOf 966 patients enrolled, 804 patients (mean [SD] age, 41 [19] years; 418 [74.2%] male) had blood samples, including 563 within 60 minutes and 375 within 30 minutes of injury. Among patients with blood drawn within 30 minutes of injury, 212 patients (56.5%) had CT lesions, 61 patients (16.3%) had NSI, and 112 patients (30.0%) had CIEO. Among those with blood drawn within 60 minutes, 316 patients (56.1%) had CT lesions, 95 patients (16.9%) had NSI, and 172 patients (30.6%) had CIEO. All biomarkers showed significant elevations with worsening diffuse injury on CT within 30 and 60 minutes of injury. Among blood samples taken within 30 minutes, GFAP had the highest area under the receiver operating characteristic curve (AUC) to detect CT lesions, at 0.88 (95% CI, 0.85-0.92), followed by MAP-2 (AUC, 0.78; 95% CI, 0.73-0.83) and UCH-L1 (AUC, 0.75; 95% CI, 0.70-0.80). Among blood samples taken within 60 minutes, AUCs for CT lesions were 0.89 (95% CI, 0.86-0.92) for GFAP, 0.76 (95% CI, 0.72-0.80) for MAP-2, and 0.73 (95% CI, 0.69-0.77) for UCH-L1. Among blood samples taken within 30 minutes, AUCs for NSI were 0.78 (95% CI, 0.72-0.84) for GFAP, 0.75 (95% CI, 0.68-0.81) for MAP-2, and 0.69 (95% CI, 0.63-0.75) for UCH-L1; and for CIEO, AUCs were 0.89 (95% CI, 0.85-0.93) for GFAP, 0.83 (95% CI, 0.78-0.87) for MAP-2, and 0.77 (95% CI, 0.72-0.82) for UCH-L1. Combining the biomarkers was no better than GFAP alone for all outcomes. At GFAP of 30 pg/mL within 30 minutes, sensitivity for CT lesions was 98.1% (95% CI, 94.9%-99.4%) and specificity was 34.4% (95% CI, 27.2%-42.2%). GFAP levels greater than 6200 pg/mL were associated with high risk of NSI and CIEO.Conclusions and relevanceIn this cohort study of prehospital patients with TBI, GFAP, UCH-L1, and MAP-2 measured within 30 and 60 minutes of injury were significantly associated with traumatic intracranial lesions and diffuse injury severity on CT scan, 24-hour NSI, and 7-day CIEO. GFAP was the strongest independent marker associated with all outcomes. This study sets a precedent for the early utility of GFAP in the first 30 minutes from injury in future clinical and research endeavors.
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Project description:The current four-symptom screen recommended by the World Health Organization (WHO) is widely used as screen to initiate diagnostic testing for active pulmonary tuberculosis (TB), yet the performance is poor especially when TB prevalence is low. In contrast, more sensitive molecular tests are less suitable for placement at primary care level in low-resource settings. In order to meet the WHO End TB targets, new diagnostic approaches are urgently needed to find the missing undiagnosed cases. Proteomics-derived blood host biomarkers have been explored because protein detection technologies are suitable for the point-of-care setting and could meet cost targets. This study aimed to find a biomarker signature that fulfills WHO's target product profile (TPP) for a TB screening. Twelve blood-based protein biomarkers from three sample populations (Vietnam, Peru, and South Africa) were analyzed individually and in combinations via advanced statistical methods and machine learning algorithms. The combination of I-309, SYWC and kallistatin showed the most promising results to discern active TB throughout the data sets meeting the TPP for a triage test in adults from two countries (Peru and South Africa). The top-performing individual markers identified at the global level (I-309 and SYWC) were also among the best-performing markers at country level in South Africa and Vietnam. This analysis clearly shows that a host protein biomarker assay is feasible in adults for certain geographical regions based on one or two biomarkers with a performance that meets minimal WHO TPP criteria.
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Project description:The diagnosis of mild traumatic brain injury (TBI) is challenging in the acute setting because the symptoms are nonspecific and often transient, or they develop with a delay. In these cases, the criteria for acute head imaging are frequently not fulfilled. This may lead to missed diagnoses in emergency care. There is a need for developing a rapid diagnostic test to verify the presence of TBI using body fluids. Blood, urine, and saliva samples from 11 adult patients (mean age 64 years, SD 24 years) with acute and clinically diagnosed TBI, and 12 healthy volunteers were collected at Turku University Hospital during a period of 5 months. The injuries necessitated hospitalization for at least one day. The TBIs were classified mild in nine cases and severe in two cases. The mean period between the trauma and the time for obtaining the samples was 27 h, SD 11 h. The samples were analyzed in an ISO-certified laboratory for the number of lectin-bound glycan molecules indicating destruction of nerve tissue. The screening was performed on several possible glycans for binding, and the measurement by degree of fluorescence. In the analysis, the group of patients with TBI was compared with healthy volunteers. The results showed a significant decrease (p < 0.05, Wilcoxon rank-sum two-sided test) in the level of two glycans in plasma, but no significant increase for any glycan; in saliva, one glycan showed a significant increase in the TBI group; in urine, three glycans were significantly different between the groups (one showed an increase, whereas two showed a decrease). The results support the idea of conducting more research on how diagnostic glycans could be detected in body fluids after TBI. As a proof-of-concept, significant changes in the concentration of five glycans were found in plasma, saliva, and urine between TBI patients and healthy controls. This may enable the development of a rapid body fluid-based point-of-care test to identify patients with TBI after a head injury.
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