Use of high-sensitivity digital ELISA improves the diagnostic performance of circulating brain-specific proteins for detection of traumatic brain injury during triage

O’Connell, Grant; Alder, Megan L.; Smothers, Christine G.; Still, Carolyn H; Webel, Allison R.; Moore, Shirley M.

doi:10.1080/01616412.2020.1726588

Cited by 24 publications

(14 citation statements)

References 17 publications

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“…While this did not hinder our ability to detect the presence of intergroup differences, it could have negatively impacted diagnostic performance. Thus, analysis of these markers in future work using more sensitive immunoassay techniques such as digital ELISA may reveal even higher levels of diagnostic performance than those which we have reported here (60,61). Furthermore, because the capacity of digital ELISA to support multiplexing is increasing (62), it possible that the future development of a multiplexed digital ELISA simultaneously targeting some or all of these proteins as a neuro panel could offer both high levels of analytical performance and convenience.…”

mentioning

confidence: 84%

Large-scale informatic analysis to algorithmically identify blood biomarkers of neurological damage

O’Connell

Alder

Smothers

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The identification of precision blood biomarkers which can accurately indicate damage to brain tissue could yield molecular diagnostics with the potential to improve how we detect and treat neurological pathologies. However, a majority of candidate blood biomarkers for neurological damage that are studied today are proteins which were arbitrarily proposed several decades before the advent of high-throughput omic techniques, and it is unclear whether they represent the best possible targets relative to the remainder of the human proteome. Here, we leveraged mRNA expression data generated from nearly 12,000 human specimens to algorithmically evaluate over 17,000 protein-coding genes in terms of their potential to produce blood biomarkers for neurological damage based on their expression profiles both across the body and within the brain. The circulating levels of proteins associated with the top-ranked genes were then measured in blood sampled from a diverse cohort of patients diagnosed with a variety of acute and chronic neurological disorders, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, Alzheimer’s disease, and multiple sclerosis, and evaluated for their diagnostic performance. Our analysis identifies several previously unexplored candidate blood biomarkers of neurological damage with possible clinical utility, many of which whose presence in blood is likely linked to specific cell-level pathologic processes. Furthermore, our findings also suggest that many frequently cited previously proposed blood biomarkers exhibit expression profiles which could limit their diagnostic efficacy.

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mentioning

confidence: 84%

Large-scale informatic analysis to algorithmically identify blood biomarkers of neurological damage

O’Connell

Alder

Smothers

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…These include (i) existence behind the blood-brain barrier, limitations imposed by the molecular size, direction of flow, and concentration gradients, half-lives in various biological fluid compartments; (ii) effect of preanalytical and analytical variables such as time, quality of sample collection, processing, and storage; and (iii) specificity and sensitivity of antibodies and existing analytical platforms [ 61 ]. In the case of proteins biomarker, digital ELISA-based multi-analyte assays could increase the sensitivity sufficient to detect a single molecule of the biomarker [ 42 , 62 - 64 ]. Similarly, nucleic acid biomarkers for TBI [ 65 , 66 ] detection can be improved via the adoption of the nucleic acid detection platform CRISPR-ENHANCE [ 67 ].…”

Section: Reviewmentioning

confidence: 99%

Advances in Traumatic Brain Injury Biomarkers

Nishimura¹,

Cordeiro²,

Ahmed³

et al. 2022

Cureus

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Traumatic brain injury (TBI) is increasingly a major cause of disability across the globe. The current methods of diagnosis are inadequate at classifying patients and prognosis. TBI is a diagnostic and therapeutic challenge. There is no Food and Drug Administration (FDA)-approved treatment for TBI yet. It took about 16 years of preclinical research to develop accurate and objective diagnostic measures for TBI. Two brain-specific protein biomarkers, namely, ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein, have been extensively characterized. Recently, the two biomarkers were approved by the FDA as the first blood-based biomarker, Brain Trauma Indicator™ (BTI™), via the Breakthrough Devices Program. This scoping review presents (i) TBI diagnosis challenges, (ii) the process behind the FDA approval of biomarkers, and (iii) known unknowns in TBI biomarker biology. The current lag in TBI incidence and hospitalization can be reduced if digital biomarkers such as hard fall detection are standardized and used as a mechanism to alert paramedics to an unresponsive trauma patient.

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“…Up to date, this technique has been commercialized for nearly 7 years. Target molecules that can be detected including bacteria ( Song et al, 2013 ), antibodies (Gaylord et al, 2015a) , various biomarkers ( Gaylord et al, 2015b , Janelidze et al, 2016 ; Khalil et al, 2020 ; O'Connell et al, 2020 ; Rivnak et al, 2015 ; Wu et al, 2015 ), and gene expression ( Yan et al, 2016 ). In 2020, this dELISA was applied to perform the COVID-19 antibody test that can detect antibodies at 1000 × lower concentrations.…”

Section: Surrogate Signal Development For “Digital” Detectionmentioning

confidence: 99%

A critical review: Recent advances in “digital” biomolecule detection with single copy sensitivity

Liu

2021

Biosensors and Bioelectronics

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Use of high-sensitivity digital ELISA improves the diagnostic performance of circulating brain-specific proteins for detection of traumatic brain injury during triage

Cited by 24 publications

References 17 publications

Large-scale informatic analysis to algorithmically identify blood biomarkers of neurological damage

Large-scale informatic analysis to algorithmically identify blood biomarkers of neurological damage

Advances in Traumatic Brain Injury Biomarkers

A critical review: Recent advances in “digital” biomolecule detection with single copy sensitivity

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