Biomarkers: A Useful Asset in Predicting, Diagnosing & Treating Disease

Have you ever thought about why different individuals can each respond differently after being administered an approved drug?  Or whether we could improve people’s health through earlier diagnosis and personalised treatments?  Biomarker research has entered a new phase, and could hold part of the solution, offering the potential for early detection, preventing disease development, and guiding clinical decisions towards more effective, and individualised, treatment for a wide range of diseases.

What are Biomarkers?

In medicine, the term biomarker refers to a broad group of medical signs which can be measured accurately and reproducibly to give indications on a patient’s medical state. They may be used individually or in conjunction with other methods to measure an individual’s health or disease status at a given time, as well as being used to predict the likelihood of disease or the effects of treatment [1].  Biomarkers can be molecular, cellular, chemical or physiological and range from the presence of a particular antibody or gene, to brain imaging, to routine indicators of health such as heart rate.  

Biomarkers are quantifiable medical indicators, as opposed to patient-reported symptoms.  Some biomarkers are used to identify preclinical symptoms (i.e. where clinical symptoms have not yet developed, but there is a biomarker change present) of disease, enabling earlier diagnosis and treatment. These surrogate signs of illness represented by biomarkers can be used effectively for screening or diagnosis [2].

Biomarkers are also becoming more widely used to aid the prediction of prognosis and, in some situations, help to determine doses of medications in treatment; this enables them to be applied in selecting the most appropriate patients for certain treatment options, and they play a key role in personalised medicine [3].

While biomarkers have been shown to be an effective tool for diagnosis and predicting various clinical outcomes in clinical trials, they are a relatively new tool in medical diagnosis and treatment, so they need to continue to be thoroughly tested to ensure validity, reliability, and sensitivity [1].

Applications of Biomarkers

There are many different types of biomarkers: biochemical, histologic, radiographic, or physiological [4]. One particular category is chronotherapeutics - a treatment approach in which in vivo drug availability is timed to match illness rhythms in order to improve therapeutic success and reduce side effects [5]. Chronotherapeutics aim to cure diseases based on endogenous biological cycles (cycles that happen automatically in biological systems) that regulate xenobiotic metabolism (the way in which the molecules that enter the body are converted from hydrophobic to hydrophilic, so they can be more readily removed) and cellular drug response [5]. 

Molecular biomarkers have biophysical properties that allow them to be measured in biological samples such as cerebrospinal fluid or biopsy [6]. Such biomarkers are utilised in processes like grading tumors, where cancer cells are graded in accordance to abnormality in order to assist doctors in finding a suitable treatment.

Biomarkers depicting prodromal signs (early indications of an illness) enable earlier identification or allow for the outcome of interest to be determined at a more primitive stage of disease [2]. Blood, urine, and cerebrospinal fluid are examples of samples containing biomarkers which can provide the necessary biological information for certain diagnoses [2].

Some biomarkers, such as liquid biopsies to monitor hepatocellular carcinoma, can offer a less invasive diagnostic tool compared to current widely-used procedures and in these applications can result in less tissue damage, less hospital time and reduced use of narcotics [7, 8]. While our understanding of biomarkers is continuing to expand, these examples demonstrate the potential impact of biomarkers in modern medicine.

A Current Limitation of Biomarkers

One potential limit to the current use of biomarkers is the difference in biomarker reference ranges between different groups of the population.  One example of this is a case in the USA where Dr. Laura Boucai noticed an unusually high proportion of elderly white female patients were being diagnosed with high thyroid-stimulating hormone levels, and consequently were being treated with thyroid hormone replacement therapy [9]. Boucai et al. therefore conducted a study, which concluded that typical thyroid-stimulating hormone levels varied with age, sex and race [9]. In this case, patients were being overtreated with thyroid hormone replacement therapy, which can cause palpitations and osteoporosis. This example demonstrates that it is vital for medical professionals to avoid applying laboratory reference ranges to everyone in the population, and the importance of medical advancement that accounts for the diversity of our population.

Understanding Our Health With Biomarkers in Clinical Trials

Some biomarkers can be used in clinical trials, and while they don’t replace clinical endpoints (objective measurements on whether the intervention has been beneficial), they can serve as a surrogate endpoint - “a feature or variable that indicates how a patient feels, functions, or survives” - for the effect of a treatment on a patient [2].  According to the ClinicalTrials.gov database, more than 33,000 clinical studies utilising biomarkers had been filed as of April 2020 [10].  This includes over 4000 Phase 3 and Phase 4 investigations, which compare the new medication's effectiveness to that of other medicines for the same disease, and involve clinical trials to learn more about the medication's long-term safety, efficacy, and any additional advantages, respectively [10].

One example of the use of biomarkers as a surrogate endpoint in clinical trials is the development of antiretroviral medicines (drugs which prevent the virus from replicating in the body) for HIV and AIDS. Historically, studies were based upon challenging clinical endpoints. However, cell changes such as the level of CD4 lymphocytes, commonly known as T cells (white blood cells that help your immune system combat disease), can now be utilised as surrogate endpoints [11, 12]. CD4 levels have long been used to monitor disease progression and guide therapy in HIV-positive people. However, due to the cost of CD4 testing, a biomarker - the total leukocyte (white blood cell) count - is being used as a less expensive alternative [12].

Biomarkers can be used to help determine the benefit-risk profile - a method of weighing the advantages of a therapy against the hazards of that treatment - for a medicine being created. Benefit-risk analysis should be examined on a regular basis during a drug's therapeutic use [13].

Further, the use of biomarkers in clinical trials can help to reduce the number of patients needed to demonstrate clinical benefit, or provide early indications of likely (positive or negative) effects of trial drugs [1]. Biomedical scientists can therefore more efficiently test potential treatments, and can increase efficacy of treatments for particular individuals.  In this way, a moral benefit is offered.  The usefulness of biomarkers allows health professionals to better understand the progression of disease and ensure every individual receives the best possible care, supporting Sustainable Development Goal 3: Good Health and Wellbeing.                                     

Digital Biomarkers

Digital biomarkers are data about individuals’ health or disease management that can be gathered using digital health technology. Many digital health technologies make it easier for physicians to gather discrete health indicators, such as blood pressure and glucose, for use in decision-making.  There are also increasingly many ways of self-monitoring and forecasting health-related outcomes, such as smartwatches, heart monitors and pulse oximeters. Kardia, for example, is a mobile app developed by AliveCor, Inc. that allows users to take an electrocardiogram (ECG) at home or on the road and can detect common arrhythmias [14]. Abnormalities can then be forwarded to a doctor who can investigate further the symptoms, to make an earlier diagnosis if necessary. 

Such tools generate vast amounts of data, which when combined with analytical tools, can be used to identify trends for both individuals and groups. Individuals can be alerted to take preventive measures or present themselves to a clinical care environment for high acuity situations based on known connections between data (e.g. physical activity and heart rate) and clinical outcomes (e.g. hospitalisation for cardiovascular disease) [15].

Digital biomarkers are facilitated by new technologies that enable the generation and storage of complex data, so criteria for evaluating these biomarkers are only now being established [16].  But, we can recognise the significance of this technology by noticing how doctors are in a better place to gather more data on health-related issues [17].  Advances in scientific research and innovation will continue to enable individuals to monitor indicators of their health through a variety of biomarkers.

Conclusion

Overall, biomarkers are vital in providing insight to underlying illnesses and enhancing precision in decisions regarding disease detection and progression. They enable doctors to better control the outcome of a disease by indicating symptoms of disease at an earlier stage, and helping identify the most suitable treatment options for an individual patient. While there is work to be done on establishing different biomarker reference ranges for different groups of the population, there are many advantages of using biomarkers and, with the support of technology, we can further expand our knowledge on the causes of, and treatment for, disease. With their potential for improving health outcomes and usefulness in clinical trials, further investment in biomarker research to identify new biomarkers could result in real progress towards SDG 3.

How do you think that biomarkers will continue to enhance our understanding of disease-related issues?

References

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[2] R. Mayeux, “Biomarkers: Potential Uses and Limitations,” NeuroRx, vol. 1, no. 2, pp. 182-188, 2004. Available: https://doi.org/10.1602/neurorx.1.2.182. 

[3] L. Landeck, C. Kneip, J. Reischl and K. Asadullah, ‘‘Biomarkers and personalized medicine: current status and further perspectives with special focus on dermatology,’’ Experimental Dermatology, vol. 25, no. 5, pp. 333-339, 2016. Available: https://doi.org/10.1111/exd.12948.

[4] Robin Haskell, MSN, RN and CRNP,  ‘‘What is a Biomarker?,’’ NursingCenter, November 13, 2019. [Online]. Available: https://www.nursingcenter.com/ncblog/november-2019/biomarker. [Accessed 18 April 2020].

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[6] L. Eldridge, ‘‘What Does In Vivo and In Vitro Mean? Definitions, similarities and differences,’’ Verywell Health, September 30, 2021. [Online]. Available: https://www.verywellhealth.com/what-does-in-vivo-and-in-vitro-mean-2249118. [Accessed 18 October 2021].

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[8] França de Lima et al., “The use of minimally invasive biomarkers for the diagnosis and prognosis of hepatocellular carcinoma,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, vol. 1874, no. 2, 2020.  Available: https://doi.org/10.1016/j.bbcan.2020.188451.

[9] Albert Einstein College of Medicine, ‘‘How "Set" Should Biomarker Reference Ranges Be?,’’ Albert Einstein College of Medicine, July 25, 2011. [Online]. Available: https://einsteinmed.org/features/stories/671/how-set-should-biomarker-reference-ranges-be/. [Accessed 4 March 2021].

[10] M. Gromova, A. Vaggelas, G. Dallmann and D. Seimetz, ‘‘Biomarkers: Opportunities and Challenges for Drug Development in the Current Regulatory Landscape,” Biomarker Insights, vol. 15, 2020. Available: https://doi.org/10.1177%2F1177271920974652.

[11] M. Koester, ‘‘Biomarkers: What are they? Why they matter? And how to use them to improve our health?,” Mark Koester, February 22, 2018. [Online]. Available: http://www.markwk.com/what-are-biomarkers.html. [Accessed 18 July 2020].

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