Blood-based biomarkers for traumatic brain injury: Evaluation of research approaches, available methods and potential utility from the clinician and clinical laboratory perspectives

Highlights

• Biomarkers for TBI are reviewed with emphasis on validation and quality control.

• Analytical techniques for blood-based biomarker measurements are highlighted.

• Sex and gender issues in TBI blood-based biomarker research are discussed.

• A review of current clinical guidelines for traumatic brain injury is provided.

Abstract

Blood-based biomarkers for traumatic brain injury (TBI) have been investigated and proposed for decades, yet the current clinical assessment of TBI is largely based on clinical symptoms that can vary widely amongst patients, and have significant overlap with unrelated disease states. A careful review of current treatment guidelines for TBI further highlights the potential utility of a blood-based TBI biomarker panel in augmenting clinical decision making. Numerous expert reviews on blood-based TBI biomarkers have been published but a close look at the methods used and the astonishing paucity of validation and quality control data has not been undertaken from the vantage point of the clinical laboratory. Further, the field of blood-based TBI biomarker research has failed to adequately examine sex and gender differences between men and women with respect to the clinical care settings, as well as differences in physiological outcomes of TBI biomarker studies. Discussions of tried-and-true laboratory techniques in addition to a few new ones already operating in the clinical laboratory are summarized with a consideration of their utility in TBI biomarker assessment. In the context of TBI biomarkers, the central concerns discussed in this review are the readiness of the clinical laboratory, the willingness of the research environment and the inherent ability of each to radically affect patient outcomes in TBI.

Introduction

Blood-based biomarkers for traumatic brain injury (TBI) have been investigated and proposed for decades. In recent years, there has been increased focus on mild TBI and concussion with substantial media coverage surrounding concussion in sports [1] and the recognition of TBI as the defining injury for veterans of the Iraq and Afghanistan wars [2]. The current clinical assessment of TBI is largely based on clinical symptoms that can vary widely amongst patients and have significant overlap with unrelated disease states [1], [3], [4].

Findings generated in the basic research arena have been rapidly integrated into clinically-based studies very often using methods that would not be allowed to operate in the clinical laboratory. Further, many of the published studies provide limited information on assay validation or the use of fundamental laboratory techniques such as statistical quality control. Instead of adding to the accumulating number of expert reviews on TBI biomarkers, we focused on identifying methods used in the study of five of the most prominent biomarkers in the literature. We report on the limited amount of validation and quality control data provided. In fairness, it is possible that the authors of the reviewed publications completed a full, CLIA-approved validation for a high complexity test with the use of established quality control ranges to validate all published data. More likely, the publications selected for review illustrate a pervasive lack of appreciation for the rigorous quality standards required from clinical testing in an attempt to fulfill the promise of translational research expectations.

The clinical laboratory continues to grow in its ability to transform novel, highly complex research assays into routine clinical tests, while at the same time more advanced technology continues to find its way from research into the clinical laboratory. In addition, if sex and gender influences are not fully understood TBI research may fail to address important issues pertaining to the assessment and treatment of TBI. Due to a general ambiguity towards TBI in terms of definition, assessment, and treatment [3] and the fact that 77% of individuals with TBI are male [5], TBI research appears especially prone to gender bias. The subsequent focus of this review is on the clinical approach to TBI, methods used in TBI research, methods available in the modern clinical laboratory and sex and gender differences in TBI biomarker studies.