Biomarkers for Traumatic Brain Injury

By Alan H.B. Wu and W. Frank Peacock

Biomarkers for Traumatic Brain Injury provides a comprehensive overview on the selection and implementation of serum-based and saliva-based biomarkers for traumatic brain injury. The book presents an economic analysis for implementing TBI biomarkers into clinical practice. In addition, it discusses the analytical tools needed to implement TBI biomarkers, including specifications for testing instruments and interpretative software. Neurologists, emergency department physicians, intensivists, and clinical laboratorians will find this book a great resource from which to familiarize themselves with the issues and processes regarding TBI biomarkers.

Approximately 2 million people in the U.S. sustain a traumatic brain injury (TBI) each year with over 250,000 hospitalizations and 50,000 deaths. There has been a significant rise in interest in diagnosing mild concussions, particularly in the sports world. While imaging has been the gold standard, these procedures are costly and not always available. There is great potential in using serum-based biomarkers, hence the book seeks to enlighten readers on new possibilities.

• Offers strategies for the selection and implementation of traumatic brain injury biomarkers
• Discusses the importance of autoantibodies and post translational modifications for TBI
• Covers the analytical tools needed to implement TBI biomarkers, including the specifications for testing instruments and interpretative software

• Language: English
• Publisher: Academic Press
• Release date: Jul 10, 2020
• ISBN: 9780128167304

Book preview

2019

Section I

Introduction

Outline

Chapter 1 Introduction—scope of the problem

Chapter 2 The need for traumatic brain injury markers

Chapter 3 Regulatory considerations for diagnostics and biomarkers of traumatic brain injury

Chapter 1

Introduction—scope of the problem

David O. Okonkwo¹ and John K. Yue²,    ¹1Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States,    ²2Department of Neurosurgery, University of California San Francisco, San Francisco, CA, United States

Abstract

Traumatic brain injury (TBI) is a leading source of death and disability worldwide. There is a critical need for TBI biomarkers to guide diagnosis, treatment, and triage to follow-up. Biomarkers for TBI are being developed in blood and biofluids, as well as by neuroimaging and neuroelectric measurement. This textbook highlights the promise of biomarkers in TBI clinical care and research, across the spectrum of injury and continuum of care.

Keywords

Care paradigm; cellular injury; diagnosis; FDA qualification; prognosis; TBI practice

1.1 Scope of the problem

Traumatic brain injury (TBI), caused by external force to the head, remains a leading source of morbidity and mortality worldwide. In the United States, 4.8 million persons seek medical care for TBI annually, with 2.8 million emergency department (ED) visits, 280,000 hospitalizations, and 56,000 deaths [1]—this translates to 6 deaths, 31 hospitalizations, 194 ED visits, and 457 concussions per hour. TBI is the leading cause of death in persons under age 45, and recent evidence shows that the incidence in the elderly is approaching epidemic proportions [2].

TBI clinical care, as well as TBI clinical trials, has been hampered by lack of objective measures of TBI pathophysiology. To date, more than 30 Phase III therapy trials have failed in translating to an FDA-approved treatment for TBI [3]. These failures have largely been driven by the fool’s chase of one drug treating all TBIs. In fact, investigators have likely failed the drugs more than the drugs have failed the patients.

A fundamental reason for the lack of targeted treatment lies in the heterogeneity of TBI. While injuries may present similarly when assessed by the Glasgow Coma Scale (GCS) as mild (GCS 13–15), moderate (GCS 9–12), and severe TBI (GCS 3–8), neuroimaging features including lesion type, location, and volume are equally necessary in defining clinical severity and guiding management considerations. Severe TBI in a comatose patient may be due to extraaxial hemorrhage, intraparenchymal mass lesion, or diffuse brain swelling—different pathophysiologies requiring different forms of treatment. Similarly, on the mild end of the spectrum, the GCS shows ceiling effects, and subclassification of precise mild TBI clinical phenotypes (vestibular, cognitive, migraine, etc. disorders) for targeted treatment has been elusive.

The field of TBI has benefited immensely from the most widely used, and in many respects the only, biomarker available today: the CT scan. The head CT has saved countless lives across the world following trauma, and steered countless more toward effective medical management. Now, the field of TBI needs additional biomarkers in order to advance clinical practice. This next generation of biomarkers must reflect the complex pathophysiology of TBI, including excitotoxic damage, oxidative stress, and neuroinflammation, among others [4]. New biomarkers will derive from neuroimaging, biofluids, and electrophysiology. This textbook will discuss these and other developments as the field of biomarkers for TBI enters a golden era.

1.2 Candidate biomarkers

Biomarkers can advance TBI clinical care by improving diagnosis, triage, and treatment. Detecting the pathology of TBI using blood, cerebrospinal fluid (CSF), and other biofluidic biomarkers of sufficient sensitivity constitutes a paradigm shift for the field of neurotrauma. Over the past two decades, a range of candidate biomarkers have been studied extensively. The commercialization efforts to date have focused primarily on biomarkers that predict intracranial injuries visible on CT and prognostication of 3- to 6-month outcome. Biomarkers are also being studied in reference to specific injured cell types. These include markers of glial (GFAP: glial fibrillary acidic protein; S100B: calcium binding protein B; MBP: myelin basic protein), axonal and neuronal (UCH-L1: ubiquitin carboxyl-terminal hydrolase-L1; NSE: neuron-specific enolase; Tau protein and phosphorylated-Tau [p-Tau]; AIIS-BDP: alpha-II-spectrin breakdown products), and immunological (cytokines, autoantibodies) injury [5]. These and other biomarkers will be discussed in depth in the subsequent chapters of this text.

Biomarkers are already in routine clinical use for myocardial ischemia, kidney disease, infection, and cancer and have revolutionized clinical care and research in these diseases. As shown in Table 1.1, biomarkers are applied across several contexts of use, including diagnostic, prognostic, predictive, pharmacodynamic, and efficacy–response biomarkers. Through its qualification process, the FDA provides a pathway for biomarkers to serve as endpoints in clinical trials. Biomarkers specific to their respective context of use can also enable early diagnosis in the field (prior to arrival to a medical facility), serial measurements to detect temporal evolution of injury, as well as prognostic and predictive capabilities to determine risk for disease progression and likelihood of response to treatment, respectively.

Table 1.1

1.3 Blood biomarkers for traumatic brain injury

Since 2015, S100B has been included in an algorithm in the Scandinavian guidelines to triage patients with mTBI to CT after TBI [6]. In a landmark decision on February 14, 2018, the US Food and Drug Administration cleared marketing of the Banyan Brain Trauma Indicator (BTI) as the first diagnostic blood test to evaluate mild TBI (mTBI) in North America (https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN170045.pdf). The FDA decision was based on the 2018 ALERT-TBI pivotal trial, where in 1959 mild-to-moderate TBI patients the combined panel of serum GFAP and UCH-L1 had a negative predictive value (NPV) of 0.996 for detecting intracranial injury on CT [7]. These data are summative of the research to date regarding the discriminability of GFAP and UCH-L1 for CT abnormalities, with areas under the receiver–operating characteristic (ROC) curve (AUCs) of 0.8–0.9 and 0.7–0.9, respectively [8,9]. The Banyan BTI test is a proprietary core lab assay which provides results in 4–6 hours, constituting a barrier for use in acute injury that must be overcome—ideally with point-of-care testing with rapid return of results.

Regarding prognostic biomarkers, Tau is a cytoskeletal protein that contributes to the stabilization of axon microtubules. After TBI, Tau may become hyperphosphorylated by kinases or undergo proteolysis by calpains and caspases to produce p-Tau, which is a precursor to long-term tauopathy. p-Tau has been found to be elevated not only in acute but also chronic TBI, with AUCs of 1.0 in distinguishing mTBI and chronic TBI from healthy controls in a 2017 report from the TRACK-TBI Pilot study [10]. Furthermore, p-Tau was able to weakly distinguish those with good versus less-than-good outcomes (e.g., able to return to work) on the Glasgow Outcome Scale Extended (GOSE) at 6 months (AUC 0.663). Other markers such as BDNF predicted complete versus incomplete recovery in mTBI (AUC 0.65) [11], and MAP-2 and cleaved-Tau in CSF predicted clinical outcome after severe TBI [12]. In severe TBI, monitoring biomarkers include S100B, which is associated with intracranial pressure (ICP) and cerebral perfusion pressure (CPP) [13], as well as GFAP and UCH-L1, which have the ability to distinguish mass lesions from diffuse injuries [14,15]. Several markers have been investigated to assess treatment efficacy, such as NSE and S100B for progesterone [16], and NSE for memantine [17].

Fig. 1.1 shows ranges of time for which biomarkers can become elevated in response to injury. The part of the time continuum that the treatment is affecting will dictate the efficacy–response biomarker to be used. For example, GFAP and UCH-L1 may be appropriate efficacy–response biomarkers on the order of hours, and demyelination markers such as MBP may be more appropriate on the order of weeks.

Figure 1.1 Temporal trends of blood-based biomarkers after TBI.

AD, Alzheimer’s disease; CNPase, 2',3'-cyclic nucleotide 3'-phosphodiesterase; CTE, chronic traumatic encephalopathy; GFAP, glial fibrillary acidic protein; MAP2, microtubule associated protein 2; MBP, myelin basic protein; PD, Parkinson’s disease; SBDP15, spectrin breakdown product 150; SPDP120, spectrin breakdown product 120; UCH-L1, Ubiquitin C-terminal hydrolase L1.

These data and others show the imminent promise of candidate biomarkers undergoing validation in large prospective studies for diagnostic, prognostic, and predictive contexts of use, which will be discussed in detail in the forthcoming chapters. The implications of these biomarkers extend beyond civilian trauma and hospital care. The capability to obtain an objective, diagnostic point-of-care result from a blood-based biomarker on the battlefield, or on the sport sidelines, have high potential to guide resource utilization to remove a soldier from combat and a player from play. Further, the temporal trend of monitoring biomarkers may judiciously triage at-risk patient to follow-up scans, referral to inpatient and outpatient TBI services, and follow-up with primary care.

1.4 Nonblood biomarkers

Other biofluids in addition to blood hold promise and will be explored in this text. For example, several salivary micro-RNAs from the inflammatory cascade are upregulated after concussion and correlate with sideline concussion testing [18]. Neurocognitive and functional testing will be explored in this text in the context of sideline concussion assessment and return-to-play decisions. Objective evaluations of brain function after concussion, such as electroencephalogram (EEG), may be important to compensate for the subjective nature of symptoms’ assessment. The concussed brain produces decreased alpha, beta, gamma, and theta band amplitudes, increased delta band amplitude, and focal network dysfunction that can be evaluated with EEG in both acute and subacute periods after injury [19,20]. Risk stratification and management will be discussed in the context of biomarker qualification, implementation, and discriminability across the course of TBI recovery.

1.5 Conclusions

TBI is a global health epidemic and presents a public health crisis, given the paucity of available diagnostic tests and effective treatments. There is a critical need for TBI biomarkers to guide diagnosis, treatment, and triage to follow-up. The FDA clearance of the first diagnostic biomarkers for TBI (GFAP and UCH-L1) on February 14, 2018, represents a seminal moment in the advancement of TBI practice, which has long relied on the neurologic exam and CT scan. This FDA clearance and subsequent findings from large-scale prospective studies herald the beginning of a Golden Age in TBI research, in which clearing additional candidate biomarkers for clinical use will be a priority. The contents of this book are structured to highlight the promise of multimodal, blood and nonblood biomarkers for integration into TBI clinical care and research, across the spectrum of injury and continuum of care.

Disclaimers and Acknowledgments

None.

References

1. Korley FK, Kelen GD, Jones CM, Diaz-Arrastia R. Emergency department evaluation of traumatic brain injury in the United States, 2009–2010. J Head Trauma Rehabil. 2016;31(6):379–387.

2. Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths—United States, 2007 and 2013. MMWR Surveill Summ. 2017;66(9):1–16.

3. Maas AIR, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics. 2010;7(1):115–126.

4. Galgano M, Toshkezi G, Qiu X, Russell T, Chin L, Zhao L-R. Traumatic brain injury: current treatment strategies and future endeavors. Cell Transpl. 2017;26(7):1118–1130.

5. Wang KK, Yang Z, Zhu T, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn. 2018;18(2):165–180.

6. Undén L, Calcagnile O, Undén J, Reinstrup P, Bazarian J. Validation of the Scandinavian guidelines for initial management of minimal, mild and moderate traumatic brain injury in adults. BMC Med. 2015;13:292.

7. Bazarian JJ, Biberthaler P, Welch RD, et al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol. 2018;17(9):782–789.

8. Papa L, Brophy GM, Welch RD, et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol. 2016;73(5):551–560.

9. Diaz-Arrastia R, Wang KKW, Papa L, et al. Acute biomarkers of traumatic brain injury: relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. J Neurotrauma. 2014;31(1):19–25.

10. Rubenstein R, Chang B, Yue JK, et al. Comparing plasma phospho tau, total tau, and phospho tau-total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol. 2017;74(9):1063–1072.

11. Korley FK, Diaz-Arrastia R, Wu AHB, et al. Circulating brain-derived neurotrophic factor has diagnostic and prognostic value in traumatic brain injury. J Neurotrauma. 2016;33(2):215–225.

12. Welch RD, Ayaz SI, Lewis LM, et al. Ability of serum glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, and S100B to differentiate normal and abnormal head computed tomography findings in patients with suspected mild or moderate traumatic brain injury. J Neurotrauma. 2016;33(2):203–214.

13. Olivecrona Z, Bobinski L, Koskinen L-OD. Association of ICP, CPP, CT findings and S-100B and NSE in severe traumatic head injury Prognostic value of the biomarkers. Brain Inj. 2015;29(4):446–454.

14. Posti JP, Takala RSK, Runtti H, et al. The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 during the first week after a traumatic brain injury: correlations with clinical and imaging findings. Neurosurgery. 2016;79(3):456–464.

15. Okonkwo DO, Yue JK, Puccio AM, et al. GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective transforming research and clinical knowledge in traumatic brain injury study. J Neurotrauma. 2013;30(17):1490–1497.

16. Shahrokhi N, Soltani Z, Khaksari M, Karamouzian S, Mofid B, Asadikaram G. The serum changes of neuron-specific enolase and intercellular adhesion molecule-1 in patients with diffuse axonal injury following progesterone administration: a randomized clinical trial. Arch Trauma Res. 2016;5(3):e37005.

17. Mokhtari M, Nayeb-Aghaei H, Kouchek M, et al. Effect of memantine on serum levels of neuron-specific enolase and on the Glasgow Coma Scale in patients with moderate traumatic brain injury. J Clin Pharmacol. 2018;58(1):42–47.

18. Di Pietro V, Porto E, Ragusa M, et al. Salivary microRNAs: diagnostic markers of mild traumatic brain injury in contact-sport. Front Mol Neurosci. 2018;11:290.

19. Jacquin A, Kanakia S, Oberly D, Prichep LS. A multimodal biomarker for concussion identification, prognosis and management. Comput Biol Med. 2018;102:95–103.

20. Munia TTK, Haider A, Schneider C, Romanick M, Fazel-Rezai R. A novel EEG based spectral analysis of persistent brain function alteration in athletes with concussion history. Sci Rep. 2017;7(1):17221.

Chapter 2

The need for traumatic brain injury markers

Martin Paul Than¹, Daniel Fatovich², Melinda Fitzgerald³, Aleksandra Gozt³, Audrey McKinlay⁴ and Deborah Snell⁵,    ¹1Emergency Department, Christchurch Hospital, Christchurch, New Zealand,    ²2Royal Perth Hospital, Perth, WA, Australia,    ³3Curtin University, Bentley, WA, Australia,    ⁴4University of Canterbury, Christchurch, New Zealand,    ⁵5University of Otago, Christchurch, New Zealand

Abstract

This chapter will discuss the context within which traumatic brain injury (TBI) and in particular mild TBI is investigated principally in an emergency setting. It provides background in relation to health system burden and discusses the cognitive processes involved in the assessment and follow-up of patients with TBI. This then leads to a discussion of the information gaps in such assessment pathways and how biomarkers are needed to fill these crucial information gaps in order to provide optimized acute and follow-up patient care.

Keywords

Traumatic brain injury; decision-making; diagnostics; biomarkers

2.1 Introduction

Traumatic brain injury (TBI), and the subgroup of patients with mild traumatic brain injury (mTBI) represent an important public health system and societal burden. It is estimated that 42 million people worldwide experience an mTBI annually [1]. Males are 1.6 times more likely than females to present to the emergency department (ED) with a TBI [2].

In the United States, which has a population of ~327 million people, approximately 2.8 million people per year are affected by TBI, with 2.5 million of these injuries related to ED visits [3]. Similar burden is experienced in other developed countries; for example, in New Zealand (population ~5 million), a recent population-based incidence study reported a total incidence of TBI of 790 cases per 100,000 person-years [4]. A New Zealand government report states that there are approximately 14,000 people who are treated for TBI each year [5]. In Australia, which has a population of ~25 million, there were over 14,000 hospitalizations for TBI in 2004/2005 [6]. However, mTBI (or concussion) accounts for 70%–85% of TBI [7] and most of these patients do not attend hospital. Indeed, only 10%–25% of people seek medical attention for TBI, so these injuries are substantially underreported. The incidence rates in New Zealand of 790 cases per 100,000 person-years (which is greater than the incidence of cancer) [8] equates to 190,000 to 200,000 cases per year in Australia.

As TBI disproportionally affects young people, chronic disability following TBI is particularly costly both in terms of productive years lost and burden on the healthcare system. A recent Centers for Disease Control and Prevention (CDC) report estimated the economic cost of TBI in the United States (including direct and indirect medical costs) to be approximately US$76.5 billion. Severe TBI accounted for approximately 90% of the total TBI medical costs. New Zealand government statistics estimate the annual cost of mTBI to be NZ$83.5 million. The lifetime cost of each TBI in Australia is estimated at AU$2.5 million for moderate and AU$4.8 million for severe injuries. New cases of moderate and severe TBI add more than AU$2 billion in lifetime costs to the Australian healthcare system annually, and the total annual cost of TBI in Australia is AU$8.6 billion [9]. The costs from mTBI are minimally documented and not included in these estimates.

2.2 Context

This chapter will focus upon the need for better tests in the assessment of TBI in three areas:

• The acute assessment of patients in the ED.

• The identification of who will have ongoing morbidity following their TBI.

• The prediction of the extent of such morbidity.

2.3 Probabilities, decision-making, and test thresholds

It is now almost 40 years since Stephen Pauker and Jerome Kassirer (a future editor-in-chief of the New England Journal of Medicine) wrote their article entitled the threshold approach to clinical decision-making [10]. The logic explained then remains relevant today. For a specific diagnosis of interest, clinicians are constantly determining and reevaluating the likely probability of that diagnosis. This process starts with the first information the clinician has available from the history (and also even from precontact information such as primary care, ambulance, or nursing records), and is then refined as new information, such as examination findings, laboratory results, and imaging, becomes available. Pauker and Kassirer described that at some point during medical assessment, the disease probability will either (1) pass a lower threshold at which more testing does more harm than good because the disease is very unlikely, or (2) pass above the threshold at which the probability of the disease is already high enough to begin treatment with confidence (Fig. 2.1). These thresholds will vary according to the clinical scenario. The test/treatment threshold concept is applicable to the assessment of patients with TBI.

Figure 2.1 Test/treat thresholds.

Medical assessment determines the probability of the disease of interest with each new piece of information making small or large adjustments to this probability. Below the test/no treatment threshold the optimal strategy is for no further testing because the harms outweigh the benefits. Above the test/treatment threshold the probability that the disease is present is enough to begin evidence-based treatment for that disease despite any potential side effects that might occur.

2.4 Acute assessment of patients with traumatic brain injury in the emergency department

Patients presenting to the ED with TBI can do so via ambulance, primary care physician, or through self-presentation. Ambulance presentations are usually more serious. There is therefore a range of severity from very minor injury through to the comatose patient. In an isolated TBI, the primary ED decision-making focuses upon the identification of those patients with significant intracranial injury, for example, epidural or subdural hematoma. The focus is identifying those patients who require neurosurgical intervention.

In the context of decision thresholds, a very high (near certain) degree of probability of major intracranial injury is required before the patient has neurosurgery. Fortunately, CT scanning is very specific for injury identification (very accurate for rule-in).

The decision of when to request CT scanning is heavily influenced by the fact that missed intracranial injury can be catastrophic. As a result, clinicians are motivated to request a CT scan in order to avoid the risk of missing intracranial injury. This has led to a progressive increase in usage of CT scanning in this context. The use of CT in the ED increased sixfold from 1995 to 2007 and the use of CT has increased at a higher rate in the ED than in other settings [11]. As many as 63% of patients with mTBI in the ED undergo CT scanning [12]. While up to 15% of ED patients with mTBI have an acute finding on CT, <1% require neurosurgical intervention [13,14]. This has also led to the development of clinical decision aids to identify which patients require imaging with the aim of rationalizing usage.

CT scan usage in the ED for TBI varies according to nation, health system, age, and setting [15–17]. Where CT scans are easily available with no resource or funding impediment then there is little downside (other than radiation dosage in children) to scanning large numbers of patients. In systems or settings where access to CT is problematic, then the decision to test must be weighed against other priorities.

In taxation-based health systems (such as New Zealand’s National Healthcare System), requests for CT scans for TBI need to be balanced against CT scanning resource availability (particularly out of hours) and large numbers of requests for other clinical problems both from the ED and other hospital areas. The rational use of CT scanning for TBI in the ED has been strongly advocated by the Choosing Wisely movement. Choosing Wisely is a multinational initiative of the American Board of Internal Medicine (ABIM) Foundation which is strongly supported at a government level. It seeks to advance dialogue on avoiding unnecessary duplication of tests and procedures, and to empower patients to choose care that is supported by evidence, in the context of shared decision-making.

Since the use of CT scanning is still rising despite low numbers of a CT-identified intracranial injury in mTBI, it would be very useful if there was an inexpensive and accurate biomarker that could rule out significant intracranial injury (and therefore the need for CT scanning) with high accuracy. This need is already driving research, and this is described in other chapters.

2.5 Identification of those patients who will have ongoing problems following traumatic brain injury and the prediction of the extent of such problems

The assessment of patients with TBI in the ED has historically focused on the identification (and then onward treatment, especially neurosurgery) of serious intracranial injuries such as cerebral hemorrhage. Once such serious injury is ruled out, then if the patient is reasonably well, ambulant, coherent, and able to look after themselves, they are suitable for discharge with variable degrees of patient information guidance regarding possible ongoing injury symptoms [13].

It is now clear that mTBI is common and has significant impact on patients and society. As a result, research interest has reached fever pitch as more and more implications are discovered in multiple contexts such as the armed forces, contact sport, and workforce employment. The understanding of the pathology and science relating to ongoing symptoms from mTBI is now improving but remains substantially incomplete. This is compounded by the fact that management solutions for ongoing symptoms are poorly developed.

Most people recover fully after a mTBI, but 20% or more can have a delayed recovery due to persisting symptoms, more recently referred to as persisting post-concussion symptoms (PCS). Persisting PCS are known to occur following even the mildest forms of TBI, and there is currently no way of knowing which individuals will go on to develop persistent difficulties.

A range of physiological, structural, and neuropsychological outcomes have been assessed for their capacity to predict outcome following mTBI, most being limited to investigating a single type of measure. The results reported have been mixed [18–21]. Given that PCS is complex and multifactorial, affecting several important aspects of functioning, it is unlikely that any single measure will be able to predict the likelihood of an individual experiencing ongoing symptoms. Current predictors of outcomes following mTBI use algorithms that may be useful for groups of patients but are not helpful at the level of the individual [22–24]. It is thus becoming apparent that a suite of markers is likely to be required to effectively predict poor recovery at the level of the individual. Against this background there is a need for additional tests that can provide guidance in relation to the specific issues below.

1. Prediction of the severity of injury and the likelihood of ongoing symptoms and disability

Some may argue that such a test is of little value if there is not a clear intervention that can then be applied to improve outcomes, but this is not completely true. Clarification of a diagnosis conveys information about injury severity and expected symptoms and can be beneficial for treatment providers, funders, and the patient. From a patient’s perspective, this can be reassuring. Early troubling and unexpected symptoms after mTBI have been associated with increased anxiety and risk for slow recovery [25–27]. Earlier prediction of injury severity and likely associated symptoms can guide return to work planning and expectations. If it were possible to give patients this information, it might be reasonable to provide it. In fact, accurate forewarning of specific problems might prompt an individual to change their career or life path or simply just rearrange their life (if possible), for example, from working full time to part time.

Such information could be valuable to the patient’s employer and insurer, although the access to and use of this information would have to be handled with great care given the complexity of clinical issues especially over time, and with stringent safeguards. However, negative consequences of atypical outcomes, especially after mTBI, include unfair labels such as feigned symptoms or malingering; tests capable of determining ongoing injury-related impairment would be useful in this context. Further to this, it is important to recognize that most people recover in a timely fashion following mTBI and undue anxiety about continuing symptoms can contribute to poor outcomes. If a sufficiently accurate and specific predictive test could be developed it may allow unnecessary fears to be