Central role of laboratory medicine in public health and patient care

How do we demonstrate value?

To clearly demonstrate the value of laboratory medicine across clinical settings, value measures must be adequately defined and standardized. Studies may focus on the economic value of implementing laboratory-driven patient care protocols to minimize downstream intervention and cost. In contrast, other studies may focus on direct patient impact, including earlier or more accurate diagnosis leading to changes of patient management as well as reduced morbidity and/or mortality. Outcome studies are also complicated by intermediate variables that may indirectly or directly affect measured outcomes. Measured outcomes may also be many steps beyond sample measurement and thus causation can be difficult to establish. The effectiveness of the intervention initiated by a particular test result may also vary across patient populations, requiring several sufficiently powered studies in disease subpopulations. The International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Committee on the Impact of Laboratory Medicine on Clinical Management and Outcomes (TF-ICO) was established in 2012 to “evaluate the available evidence supporting the impact of laboratory medicine in healthcare, and to develop study design for new retrospective and prospective studies capable of generating evidence of the contribution made by laboratory medicine.” In a review by TF-ICO, key examples of evidence supporting the value of laboratory medicine were presented, including screening (e.g., prenatal and cancer), risk stratification (e.g., cardiovascular disease), diagnosis (e.g., kidney disease, infection), and treatment selection (e.g., pharmacogenetics and antibiotics) [2]. However, the authors highlighted the limitations of current evidence, particularly the lack of direct and standardized implementation studies, and suggested potential solutions to address gaps, including developing standardized protocols for prospective patient-centered studies and benchmarking new and existing tests with commonly accepted effectiveness measures [2].

Despite current gaps in standardized evidence, there are key examples of laboratory tests in the past 10 years that have revolutionized patient care and served as major breakthroughs in their respective clinical settings (Figures 1 and 2). These clinical case examples clearly demonstrate the unquestionable impact of laboratory medicine and serve as templates to establish good quality evidence in other instances.

Figure 1:

Overview of the value of laboratory medicine to patient care and public health from research and development to clinical implementation and impact.

Figure 2:

Summary of clinical case examples presented in this review that exemplify the value of laboratory medicine.

Cardiac biomarkers in myocardial infarction (MI) and heart failure (HF)

Cardiovascular disease remains the leading cause of death globally, accounting for approximately 32% of global mortality [6]. The development and clinical implementation of key cardiac biomarkers has led to paradigm shifts in healthcare, enabling more rapid diagnosis and prognostication of common cardiac diseases, including MI and HF, and minimizing downstream resource utilization and strain. In particular, timely diagnosis of acute MI is critical to ensure appropriate initiation of effective evidence-based management and revascularization. Detection of MI was initially limited to symptomatic assessment, echocardiogram, and non-specific biomarkers, including creatinine kinase-MB, myoglobin, and lactate dehydrogenase [7]. Cardiac troponin (cTn) was initially proposed as a potential biomarker of MI in the 1990s due to its fundamental regulatory role in cardiac tissue, myocyte-specific expression, and increased concentration following myocardial injury in circulation [8]. The pathophysiological mechanism behind elevated cTn in MI is unknown but may be related to apoptosis, increased cell wall permeability, and/or myocardiocyte necrosis [8]. The clinical utility of cTn was initially limited due to poor assay performance at low concentrations. IVD development of high-sensitivity cTn (hs-cTn) assays in 2010 has facilitated earlier rule-out of MI, reduced emergency department length of stay, reduced admission rates, and earlier MI treatment [8]. By quantifying cTn at low concentrations with acceptable precision, detecting even small levels of myocardial damage and serial differences in cTn concentrations is now possible. There is overwhelming evidence to support the direct role of hs-cTn measurement in patient outcomes, including reduced length of stay, admissions, and lower rates of adverse events, as reviewed elsewhere [9, 10]. Indeed the Fourth Universal Definition of Myocardial Infarction now defines MI as “the detection of an increase and/or decrease of a cardiac biomarker, preferably high-sensitivity cardiac troponin, with at least one value above the 99th percentile” [8]. Additional guidelines also recommend hs-cTn measurement, including the 2020 European Society of Cardiology guidelines on the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation [11] in addition to the 2021 American Heart Association (AHA) co-sponsored guideline for the evaluation and diagnosis of acute chest pain [12]. This highlights the impact one laboratory test can have on patient care management in hospital and emergent community settings.

In addition to hs-cTn measurement in the detection of acute MI, natriuretic peptides have revolutionized the identification of HF in acute and ambulatory settings. HF is estimated to affect at least 26 million individuals globally and is increasing alarmingly in prevalence [13]. It is currently one of the costliest medical diagnoses to manage given long hospitalizations and frequent readmissions. Health expenditures related to HF are estimated to increase dramatically with the aging population, placing a heavy burden on patients, families, and healthcare resources. Thus, strategies to prevent delayed diagnosis and resultant higher mortality are essential. B-type natriuretic peptide (BNP) was first discovered in 1988 [13]. Since its discovery, significant resources have been dedicated to immunoassay development for the precise measurement of BNP and its precursor, N-terminal pro-B-type natriuretic peptide (NT-proBNP), for reliable HF diagnosis and prognosis. The pathophysiological mechanisms behind elevated NT-proBNP and BNP in HF settings are not fully elucidated. In theory, upon myocardial wall stress, pre-proBNP is released mainly from the cardiac ventricles and processed into the prohormone, proBNP [14]. ProBNP is further processed into two forms: biologically active BNP and biologically inactive NT-proBNP which are increased with HF-induced wall stress [14]. Findings from large clinical studies support the value of implementing BNP or NT-proBNP into clinical care management of HF [14], [15], [16], [17], [18]. For example, the Canadian Prospective Randomized Multicenter study, IMPROVE-CHF, found that assessing NT-proBNP in patients with dyspnea resulted in decreased duration of the initial ED visit, improved diagnosis, and provided health cost savings [15]. Incorporating NT-proBNP into the diagnostic workup of HF has also been shown to be a cost-effective method to improve patient care [16]. BNP measurement has also demonstrated similar value. For example, one study analyzed the efficacy of a BNP based screening program in patients with patients at-risk for heart failure. It was found that implementing BNP-based screening along with collaborative care reduced the rates of diagnosed HF, emergency cardiovascular hospitalizations, and symptomatic left ventricular dysfunction [17]. Further, NT-proBNP and BNP are both included as key features in clinical practice guidelines on HF diagnosis and management, including those from the ESC, cementing their key role in HF management [18].

Emerging biomarkers of traumatic brain injury (TBI)

TBI is a major source of disability worldwide with an estimated global annual incidence of 27–69 million [26]. Structural brain injury visualized by CT (e.g., contusions, subdural or subarachnoid haemorrhages) and/or MRI (e.g., diffuse axonal or vascular injury) are well established as predictors of TBI outcome [27]. However, clinicians often rely on self-reported symptoms to diagnose concussion or mild TBI (mTBI). In order to longitudinally manage acute and chronic effects of mTBI, more convenient and economic diagnostic measures are needed to diagnose mTBI, distinguish between mild and moderate head injuries, and gauge recovery post-injury. Blood biomarkers for mTBI present unique advantages as they would be minimally invasive and cost-effective with the potential to accurately identify patients who require referrals for neuroradiological assessment or follow-up examination. Until recently, no reliable circulating markers for mTBI existed.

In 2018, the US Food and Drug Administration (FDA) approved the use of two blood biomarkers, specifically glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) to assist clinicians in deciding whether to order a head CT following suspicion of mTBI [28]. GFAP is a structural protein found in astrocytes, while UCH-L1 is an enzyme found in high abundance in neurons. Both have been shown to correlate with structural brain injury and TBI clinical severity [28]. Recent studies have reported day-of-injury GFAP and UCH-L1 plasma concentrations have good to excellent prognostic value for predicting death and unfavourable outcome when using point-of-care assays [28]. In addition to GFAP and UCH-L1, there is increasing interest in the measurement of circulating tau for mTBI prognostication. Tau is a microtubule-associated binding protein that helps stabilize microtubules within the axon under normal physiological conditions [27]. Post-translational modifications, including phosphorylation, are necessary for the biological functioning of tau. However, abnormal phosphorylation following TBI contributes to cleavage from the microtubules and subsequent aggregation [28]. Furthermore, following TBI, tau undergoes proteolytic cleavage and leaks into the circulation and cerebrospinal fluid (CSF). Recent evidence in small patient studies has supported the clinical utility of tau in the diagnosis and prognosis of patients with TBI [29], [30], [31]. Specifically, tau measurement demonstrated value as a prognostic biomarker for informing safe return to play decisions for athletes who experienced sport-related concussions [29, 30]. One study noted that tau concentrations 1 h after concussion incidence was predictive of the number of days it took for concussion symptoms to resolve and have the athlete safely return to play [30]. Other non-sports-related evidence also supports the use of tau as a biomarker for TBI [31]. Aside from adult settings, preliminary evidence suggests that serum tau concentrations may assist in the differentiation of child and adolescent patients with degrees of mTBI [32].

While the field of TBI blood biomarkers is in its infancy, emerging evidence supports value in a setting where laboratory medicine was thought to have limited impact. With that, studies analyzing the clinical outcomes are urgently needed to support patient and healthcare value. Indeed, TBI blood biomarkers are already being incorporated into clinical use for adults with TBI, including S100B to the Scandinavian Guidelines and the US FDA’s approval of GFAP and UCH-L1 for reducing unnecessary and expensive CT head scans [33, 34].

Molecular and serological tests in COVID-19

The central role of laboratory medicine in public health and patient care is perhaps best illustrated by coronavirus disease 2019 (COVID-19). Following the first global wave of the SARS-CoV-2 pandemic in early 2020, laboratory professionals mobilized quickly to isolate the genetic information of SARS-CoV-2 and develop molecular tests to diagnose current infection and support public health protocols. Initially, nucleic acid amplification tests (NAATs), including RT-PCR, were developed and approved by regulatory bodies to detect SARS-CoV-2 infection, even at low viral loads. Additional efforts were dedicated to developing rapid tests, including antigen tests (e.g., lateral flow assays) and point-of-care loop-mediated isothermal amplification (LAMP) assays to support community testing as well as rapid isolation and return to work strategies. As of September 2022, it is estimated that 682 RNA-based assays and 985 antigen-based assays have been developed globally to detect SARS-CoV-2 [35]. Laboratory medicine continues to contribute vitally as we transition into an ‘endemic’ by developing bivalent assays for the detection of multiple flu/coronaviruses as well as ensuring assays remain accurate as new variants emerge. In addition to molecular and antigen test development, laboratory professionals have been instrumental in guiding appropriate test implementation, utilization, and quality standards. The IFCC Task Force on COVID-19 developed and published guidelines on molecular and rapid antigen SARS-CoV-2 testing, providing recommendations on clinical indications and target population, assay selection, verification of assay performance, as well as test interpretation and limitations [36, 37]. These resources have been invaluable to laboratories and public health programs around the world.

In addition to the detection of SARS-CoV-2 infection through molecular and antigen assays, laboratory medicine has supported the pandemic by developing serological assays for the detection of antibodies against SARS-CoV-2. These assays have been key to evaluating vaccine efficacy and the use of monoclonal antibody therapies in immuno compromised patients. The IFCC Task Force on COVID-19 also published guidelines on the utility of serological antibody assays against SARS-CoV-2 in addition to the use of routine biochemical and hematological testing for patient monitoring and management in community and critical care settings [38, 39]. Taken together, laboratory medicine has played a leading role in managing patients with SARS-CoV-2 from initial identification to management of severe cases. Without the objective patient-level data supplied by laboratories throughout the pandemic, this global public health crisis would have been unmanageable and likely resulted in considerably higher morbidity and mortality.