Normal or Optimal: How to Read Biomarkers Correctly
A biomarker is a characteristic that is used to determine the condition of a human body. Any lab report consists of a set of biomarkers. For example, a general blood test includes more than 10 indicators, including hemoglobin, white blood cells, red blood cells, and platelets. A reference value is a range of conventionally normal values determined for each biomarker in a presumably healthy population.
Your result for each biomarker is expressed as one number, while the reference is in the form of a range. The rules of the game are simple — you want your results to fit within the reference values. If something is out of bounds, whether above or below the laboratory norm, you should consult a specialist.
What is the optimal reference value?
Overly broad reference values are a common problem. Here’s one example: in one of the largest laboratories in Russia, a range of 3.78–6.99 mmol/l has been declared the norm for total blood cholesterol level. However, they have also specified that only levels below 5.0 mmol/l guarantee a low risk of coronary heart disease. At levels up to 6.3, the risk is considered moderate. Levels above that are considered high risk. Using this information, a cholesterol level of 6.5 mmol/L would be considered normal in the laboratory reference system, but dangerous in the long run.
Discrepancies like this called for another idea — the optimal biomarker reference value. This serves as the range that values can fall in and be completely normal. If test results fall within the standard reference range but are outside the optimal range, it is a call for further monitoring. Moving forward, the biomarker should be observed dynamically, and the results from all recent tests analyzed.
Four reasons for doubts
In theory, the test result analysis process is simple. Look at the results, check with the reference range, and prescribe the appropriate treatment. In reality, things are more complicated. Different specialists may have an infinite number of opinions from reading one report. It is also possible that some deviation from the standard laboratory range is normal. There are at least four reasons this could happen:
1. The instruments.
The result of a single biomarker in a single sample can vary depending on the test method, sample preparation, reagents, controls, and equipment. For example, if a lab measures a biomarker on a chromato-mass spectrometer and a spectrophotometric analyzer, the results will be different. Each instrument has its own level of accuracy, sensitivity, and measurement range.
Even two identical instruments may show a small error on the same sample. This depends on the settings and calibration. This is not really an issue when the biomarker is within a normal reference range. However, when results are close to the border, this should not be overlooked.
2. There are no universal reference values.
Consider, for example, Russia and the United States. The two countries have different customs, dietary habits, population statistics, and more. The Russian population consists of 81% Russians and 4% Tatars, while the remaining 15% come from 39 other nations. The United States is about 65% European, 15% Hispanic (mostly Latin American), and 13% African American. Genotype varies dramatically, and the normal range for many biomarkers depends on characteristic parts of the DNA.
The World Health Organization (WHO) only complicates things. According to its representatives, reference values need to be standardized across the board. This aspiration arouses skepticism among professionals.
Doctors who disagree with the WHO’s position recommend first referring to regional norms established by local ministries of health. After these have been exhausted, then the WHO reference values should be used.
3. Everybody is different
Even for one person, there are no absolute norms. The medical reference system is an attempt to create some kind of consistency for the general population. In most cases, only sex and age are considered when setting normal ranges. However, for some biomarkers, other personal characteristics also play a role. What’s bad for one person may be normal for another.
Biomarkers can go outside the reference values for short periods of time, even in the same person. There are endless reasons for these spikes, but they happen most often due to eating unfamiliar foods, changes in waking and sleeping patterns, and changes in physical activity.
4. Dynamics are important.
Specialists pay great attention to biomarkers with results at the boundaries of reference values. These can indicate the start of a pathological process in the body before the biomarker has left the normal range.
A value on the borderline can also be that person’s normal level. Doctors will often check this by retesting about a week after the first exam, or by looking at the patient’s medical history. You can help save money, time, and nerves by providing your own history of your lab results.
So how do we get treated if it’s so complicated?
Everything is individual. Experienced specialists will account for more than just the patient’s sex and age, such as their full medical history. There’s only one thing wrong with this approach — it only works as long as the doctor isn’t confronted with an unfamiliar biomarker. Specialists are human too, and nobody can memorize thousands of biomarkers and reference values.
To account for this, doctors get used to working with specific interpretations. They will often have one laboratory they use for most testing and grow accustomed to their instruments and conditions. Numbers from unfamiliar places can be confusing, and medical schools don’t teach lab diagnostics to doctors. Labs do not make this easy either, as they forgo additional information like what equipment and conditions were used.
Diagnostic medicine is moving toward the prognosis and early detection of issues. The formal approach to prevention and treatment, based on the deviation of biomarkers from strict reference values, is outdated. Many diseases are more expensive and much more difficult to treat when test results finally indicate their presence. The value of personalization is growing. Doctors are increasingly accounting for additional information for each patient, such as physiology, genetic predisposition, and even psychosocial context.
What is Ornament?
This personalized approach is fully realized in Ornament. By aggregating clinical studies and data from the world’s leading medical universities, we have derived optimal values for biomarkers to indicate high safety levels for the body.
In the future, we plan to add databases of reference values from different sources and allow users to select intervals in whole sets rather than editing individually. This will save people a lot of time.
We are also already collecting a database of optimal ranges that describe the real condition of the body much more accurately. They will help identify problems early on and, as a consequence, our users will be able to cope more effectively and successfully with ailments.
As a result, the concept of optimal ranges has been created by healthcare professionals. The optimal range is where results are not associated with any danger now or in the future. Values within the optimal range prove that the patient is in good shape and has a higher chance of living a long and happy life.
What does this mean for the future?
It’s evident that a formal approach to disease prevention and management based on biomarker value deviations from strictly set reference values is obsolete. Effective reference ranges make disease prevention easier, reducing the cost of medicine. Prevention of diseases is much cheaper than official diagnosis and treatment by doctors.
Diagnostic medicine has now trended toward disease prognosis and early detection. Personalization is becoming increasingly more valuable as doctors more often try to take parameters other than just sex and age into consideration. Aspects such as the patient’s physiology, genetic predisposition, and even psychosocial context are all being more widely considered.
References and Notes
- An example of measuring the levels of lactate by various methods: the kinetic colorimetric assay (https://helix.ru/kb/item/06-024/) has the reference range of 0.5–2.2 mmol/L; while the range for gas chromatography-mass spectrometry (GC-MS), https://helix.ru/kb/item/06-192/) is 9.0‑13.0 µmol/L. The difference in precision is 1000-fold.
- Sources of instrument errors may also include inaccurate calibration of a device and zero offset or variations in device readings during its operation (L.N. Tretyak, 2004, Processing Results of Observations: Training Book, Orenburg: State Educational Institution Orenburg State University, 2004, p. 171)
- Unification of laboratory test value ranges was discussed at the Russian Congress of Laboratory Medicine in 2018. The speakers were: A.V. Moshkin, L.I. Savelyev, N.B. Teryaeva, S.A. Evgina http://www.congress.fedlab.ru/announcements-sections/28909/
- Analytical variations are associated with variations in measurement results for the content of the analytes in biological material samples, caused by factors of random and systematic errors of analytical procedures (GOST R 53022.3–2008). With that, systemic errors are associated with the principle of the method, properties of the calibrator, foreign substances in reagents or the sample, and malfunctioning of the device itself. This causes measurement inaccuracies. Random errors are associated with the impact of transitional factors — the operator’s inaccuracy, line voltage fluctuations, etc. They cause defects of the method reproducibility. Read more about variations in laboratory tests in O.V. Lyang, A.G. Kochetov. Informative Value of Laboratory Tests https://dpo-ilm.ru/media/uploads/Материалы/2 Информативность лаб исследований.pdf
- Biological inter-individual (intragroup) variation is formed within a certain group of people and caused by race, sex, age, and environmental parameters. As a result, these factors form margins of value variations for healthy people, taking into consideration environmental and genetic factors. Also read: I.A. Volkova, Peculiar Characteristics of Interpretation of Laboratory Tests Results, 2016, http://mma-expo.ru/lab/2016/visitors/presentations/2-1-06.pdf
- A biological intragroup (individual) variation that reflects differences in a value in one person depending on their biological rhythms and lifestyle — diet, pregnancy, physical activity, and the smoking status — (GOST R 53022.3–2008). For more information: M.A. Paltsev, Personified Medicine, 2011, Science in Russia, №1, ISSN 0869–7078, pp. 12–17.
- The WHO Europe NCDs Office held a meeting on personalized medicine at the Almazov National Medical Research Center in St. Petersburg, Russia [http://www.almazovcentre.ru/?p=48216]
