Abstract
The classical role of the clinical laboratory, seen as the central place where the samples converge and from where the results are distributed, will be challenged by the development of digital health, the application of information technology (big data) and genomics to health care. When the development of disruptive new technologies will allow the production of accurate results outside the laboratory, its role will dramatically change. However, several factors are slowing down these evolutions. The quality of the existing data is relatively poor: lack of standardization of results, different units, different reference intervals, etc. The lab-on-a-chip technology is still relatively far from broad range application and the costs are higher than the traditional methods. There is the need for regulations of direct to consumer approaches that are posing big ethical problems. In the future, the clinical laboratory will maintain part of the “classical” role in the areas of research education and services. The large production will continue, favored by consolidation and reduction of the number of laboratories. The specialists of laboratory medicine have the task of collaborating with the national scientific societies and with the industry for improving harmonization of all the production phases, thus allowing the production of meaningful big data. Clinical laboratories have the role of implementing translational medicine. The new point-of-care (POC) technologies still need validation, the clinical laboratory is the place to do it. The advisory role toward clinicians and patients has to be improved, and a role in validating laboratory data interpretation apps and in controlling and supervising the functionality and the quality of the POC devices has to be developed.
Introduction
The question of the classical role of the clinical laboratory is challenging. The classical role is to provide information to the clinicians to help in diagnosing, treating and monitoring diseases. This typical “hospital setting” view of the clinical laboratory’s role expanded in the last 30 years to include well-being monitoring, screening and disease susceptibility moving more toward outpatients that nowadays represents more than 50% of the laboratory workload. This shift has also made patients (or better, citizens) contact the laboratory directly, frequently with their physicians only marginally involved.
Nowadays, the clinical laboratory can be defined as ‘the nerve center of diagnostic medicine’ [1]. In 1972, a microchip was chosen as logo of the second congress of the Italian Society of Clinical Biochemistry (Figure 1) because, besides being it an integral part of the automatic instrumentation that was entering at that time into the clinical laboratory, it represented the clinical laboratory itself: a central place where most of the clinical requests converge and from where the answers to them originate. In a higher view, it symbolized a vision of the clinical laboratory as a unit where the progresses of the basic sciences converge and are elaborated and used for the technological and organizational evolution of the diagnostic activity. In the clinical laboratory, basic sciences can merge with biology, physiology and clinical observations to produce better diagnostic tools [2]. This visionary view of Giovanni Ceriotti remains valid after 45 years and still represents an effective picture of what we can consider “a classical role” of the clinical laboratory. A role that is not limited to diagnosis and monitoring but spans to translational research, method validation and consultation for clinicians and patients.
Logo of the second National Congress of SIBioC (Italian Society of Clinical Biochemistry and Clinical Molecular Biology) (1972) with a schematic representation of a microchip to symbolize both the importance of technology and the central role of the clinical laboratory in the health-care system.
The laboratory testing started as an extension of the five senses of the physician at the bedside (urine observation) or in the wards, with simple tests performed directly by the physician itself. When the needs and the technical possibilities increased, it was natural to have dedicated spaces and personnel and the central laboratories were created. With the development of digital health, there is the opportunity to decentralize again. Paraphrasing Mario Plebani and his view of the application of the Giambattista Vico’s theory of recurring cycles to the clinical laboratory [3], there are periods of centralization and periods of decentralization of the clinical tests.
Digital health scenario
Digital health derives from the convergent application of digital and genomic technologies to health care, to enhance the efficiency of health-care delivery and make medicine more “precise” and personalized [4]. The discipline involves the use of information and communication technologies to help address the health problems.
With the development of digital health, the final question could be: “If I have automated analyses in a near-to or in-patient setting and the data are going to smartphones and information portals with deep learning algorithms, then why would the clinician/patient need laboratory expertise”?
In such a futuristic scenario, the clinical laboratory will probably not exist anymore. My personal feeling is that this scenario is far away from realization, if it will ever happen, unless the development of some disruptive analytical technology. However some scientists, like Eric Topol, have different views: “Laboratory medicine will undergo the biggest shakeup in its history over the next decade – from “central” laboratories to “mobile” laboratories owned and operated by consumers” [5].
There are several reasons for which I believe that clinical laboratory will keep its role also in the digital health era, and maybe enhancing it with intelligent developments.
poor quality of the existing big data (difference in technology, standardization, units, reference intervals),
technical problems in developing high quality POCT systems for a large number of tests,
costs of POCT,
ethical problems in direct to consumers (DTC) practice and need to validate “App” and diagnostics algorithms.
Big data
Information technology is performing incredible and unpredictable progresses, so it is reasonable to imagine that it will be possible to merge and treat enormous amount of data and information. Even if it is difficult to believe that a slow, bureaucratic and underfunded area like the public health system will rapidly adopt new information technology tools, the efforts of giants of information technology like Google, Apple, Facebook or Microsoft will probably drive the changing of this sector. Privacy regulations and the ethical implications connected with the treatment of sensible health related data will create difficulties, but I am sure that they will be overcome. It is also realistic to predict that artificial intelligence could be applied to extract from the data useful medical conclusions. The real problem is not the collection or the treatment of the data, but the poor quality of the input data, the principle of “garbage in, garbage out” remains valid and to be able to derive useful information from big data we should improve the quality and comparability of the laboratory output. The aspects to be solved before the quality of the starting data could be considered sufficient for effective elaboration are the following:
nomenclature
units of measurement
analytical quality (method dependent results, lack of traceability, large uncertainty)
reference intervals
If the first two points can be solved in a relatively easy way by data elaboration software, but do not forget the crash on Mars of NASA’s spacecraft due to the different units used by two teams [6], the third still requires big efforts and quite long time, the fourth depends, or should depend, upon the third. There are at least 400 types of tests that are commonly performed by the majority of the laboratories, the menu of the bigger laboratories reaches 1000 tests, but adding rare measurands, the list grows up to more than 2500 entries, and the list is always increasing. Even if we limit our interest to the most commonly performed tests, the way to effective standardization (or just harmonization) is quite long. The Joint Committee for Traceability in Laboratory Medicine (JCTLM) maintains a database listing the reference measurement procedures, the reference materials and the reference laboratories [7]. In this database, reference materials for 295 measurands and reference measurement procedures for 82 measurands are reported. Thus, a complete reference measurement system, including method, material and reference laboratory, is available only for a minority of measurands. Moreover, traceability to a JCTLM-listed method or material is not mandatory by law and this leaves room to manufactures for selecting different references. As an example, in Italy, about 20% of clinical laboratories still use an ALP method with diethanolamine buffer that produces values almost double than those obtained with the IFCC reference method based on amino-propanol buffer [8]. It may be noted that the methods that claim traceability to the IFCC method frequently produce results outside the acceptability limits for bias [9]. Activities are in place to improve the situation, an example is represented by thyroid hormones [10], [11]. Such a situation will improve slowly, not only for the technical difficulties and the costs related to the modifications of the methods, but also for the limitations of the control system, represented by the External Quality Assessment Schemes (EQAS). In fact, the large majority of EQAS uses non-commutable materials. It is impossible to obtain absolute information on accuracy of laboratories and analytical methods, only information relative to the concordance of laboratories that are using the same analytical systems, with limited utility for general improvement [12].
Having methods that produce different results implies the necessity of different reference intervals. Unfortunately, the reference intervals in use, instead of correcting for the differences produced by the different analytical methods, introduce a further level of confusion because they are often not related with the method in use or do not take into account age- or gender-related differences. A solution could be the application of common reference intervals, implying an homogeneity of the population that is not demonstrated and a nice level of standardization [13].
Point-of-care testing
POCT encompasses a wide variety of procedures and technologies. POCT devices are used in a wide variety of health-care settings. Nevertheless, to perform all the tests, an array of different instruments is needed. With a single blood draw of several tubes you can perform today hundreds of tests, it is difficult to imagine something similar on few drops of blood or directly in vivo, not with the current technologies. Even if miniaturization and microfluidics are promising tools, the first publications on “lab-on-a-chip” are almost 20 years old [14], [15], but systems based of these technologies are still not widespread. Currently, several companies are working in this field and are entering into the market; a comprehensive review on these newly developing technologies is presented by Waltz [16].
Costs of POCT
According to Carl T. Wittwer: “Highly efficient, centralized laboratories for human diagnostics have a cost/benefit ratio that decentralized efforts (point of care [POC], etc.) will never reach” [5]. Unless the development of some disrupting technologies, in the health-care system where cost containment is a mantra, this problem will certainly limit the diffusion of POCT systems.
Ethical problems
The possibility that patients can order and/or even perform laboratory tests directly, without seeing a physician, especially when genetic testing is involved, could lead to negative consequences for the whole health system opening the way to unnecessary overtesting and creating conditions for possible misinterpretation of the results and consequently unnecessary follow-up diagnostic tests. It is not yet clear if this technology will yield a net benefit to society [17]. Smart technologies may create a double-edged sword for patient safety and effective therapeutic relationships. They may increase self-monitoring and facilitate patient engagement in the care delivery process. The accuracy and reliability of the results in the hands of non-technical people have to be granted. Considerations regarding analytical and biological variability are not known and can generate anxiety and induce requests for further testing and compromise therapeutic relationship with physicians and appropriate allocation of the scarce resources. All this would will need regulations and controls, consumers/patients will need to be educated about the appropriate use and limits of these devices [18].
Having listed the obstacles that will certainly slow down the implementation of digital health in the near future, we must be prepared to embrace some evolutions. The number of laboratories will reduce, driven by outsourcing of laboratory services, competition between laboratories for hospital work and the commoditization of laboratory tests. Greater emphasis will be placed on refocusing laboratory services. The laboratory will be expected to deal with demand management, and will be responsible for providing additional consultative services related to laboratory testing. The future role of laboratories will be more geared toward quality control, reducing laboratory errors, eliminating unnecessary testing and focusing on the challenges of global harmonization. Two simultaneous trends seem to be emerging in this field. One is the consolidation of traditional laboratory testing and second is the expanding new market for near-patient testing.
We do not know exactly in which part of the curve of the development of biomedicine we are. If really we are beyond the inflection point, as indicated by Hawgood et al. [19], we should expect a very rapid evolution.
Classical roles of the clinical laboratory in digital health
In the digital health era, laboratory medicine will evolve and the following is a possible scenario.
Large production. The trend to consolidation in fewer centers will continue up to the development of some disruptive POC technology. Theranos was a fraud [20], [21], [22], but the credit that such an initiative rose, even without any scientific base, indicated the large expectations that such type of technology could suddenly appear. Even if it would really happen shortly, it is not possible to believe that it could rapidly substitute the existing technology and organization, at least for large part of the tests. Moreover new ways of samples transportation like drones, will facilitate the concentration of samples [23]. Automation, robotics and information technology will improve the efficiency and efficacy of the laboratory process. It is believed that the demand for automation and robotics will continue to rise. It is not entirely unreasonable to hope that in the future machines may play an important role in clinical laboratories [24]. A different situation may apply to the detection of infectious diseases where the development of fast and miniaturized molecular biology-based devices might rapidly drive these types of test out of the laboratory to physicians’ studies or to the hospital wards. This opens new role for the clinical laboratory (see the following points).
Improve the quality of the analytical procedures. As underlined before, there is a great need of improving the standardization and harmonization of tests’ results. The clinical laboratory, in collaboration with industry, international organizations, EQAS organizers has a long and great work to do to assure comparability of tests’ results in time and space. This starts from the definition of which is the acceptable quality [25], [26] to end with the application of suitable analytical techniques. Only when an acceptable level of analytical quality could be granted the application of big data algorithms, merging data from different sources and looking at time trends will be really effective. This will allow the development of the so called “precision medicine” that I would rename “accuracy medicine”, that is an essential step toward the “personalized medicine”.
Proposal, development, validation of new assays. Clinical laboratory should maintain the role designed by Prf. Giovanni Ceriotti in 1972: merge basic sciences with biology, physiology and clinical observations to produce better diagnostic tools, in other, more trendy words, be the place where translational medicine develops [2]. This is probably the most important role for the clinical laboratory and it will be sustained through the introduction of emerging new technologies:
molecular biology applied to genomics to identify new disease-related genes and DNA abnormalities helping to develop new drugs, applied to pharmacogenomics and targeted treatment, applied to the detection of circulating cell free DNA for prenatal diagnosis or for cancer detection and cancer therapy monitoring, to identify and quantify microRNA, to study the microbiome, etc.
mass spectrometry for accurate clinical chemistry and toxicology measurements but also for proteomics and metabolomics
biochemical NMR for metabolomics
Validation of new POC technology. Citing Kricka et al. [24] “Many views of the future of laboratory medicine include a trend toward more testing at the POC (or near to the patient), greater integration of POC testing into patient management strategies and pathways of care, and more testing in the home. The recent growth in POC testing has been facilitated by low-cost, portable, simple and flexible hand-held devices with built-in quality control systems and very broad menus. Specific predictions point to handheld devices for monitoring the top eight infectious pathogens”. Thus, the validation of these devices will become more and more important. Eugene Chan says: “the standards by which technologies are accepted are the same. They need to meet performance, sensitivity, and specificity requirements for providing values that can be trusted by physicians and individuals. Disruption in laboratory medicine needs to pass this critical step” [5]. As well as Lackner and Plebani, “For all innovative IVD methods and systems, accurate validation is needed to ensure the essential role of laboratory information and its increasing importance for patient safety” [20], and Bhavnani, “To reach the transformative potential of mHealth, a great deal of validation of the technical capabilities and accuracy, as well as the clinical impact of these technologies, is needed before we know they are effective” [5]. The lessons learned from Theranos include the transparency and peer reviewed data [22]. This role can be accomplished only by the clinical laboratory in this moment.
Advice to patients and to clinicians. The idea of recentering diagnostics on people, rather than using the centralized diagnostic laboratory model, launched by Theranos, despite Theranos debacle, continues to gain traction. As Lackner and Plebani say very well only “Laboratory services may provide the foundation for a safe, effective and equitable health care delivery not only assuring accurate analytical quality but covering the entire steps of the process starting from appropriate request and ending with accurate interpretation/utilization of laboratory information” [20]. Nonetheless, POC inevitably will expand and the empowerment of patients will increase the DTC testing. As told before, if carefully controlled, it could be a positive scenario, facilitating the follow-up and the control of chronic diseases and the participation of the patient to the cure and possibly also the disease prevention. In this context, the clinical laboratory should develop a role of advisor, offering on-line consultation for the interpretation of the POC results and tutorials for the use of the devices.
Validation of test interpretation algorithms. A lot of “health-related apps” are already developing. A PubMed search for “health-related apps” produced 42 titles, the older of them dated 2011. Presently, not one of them is related to the interpretation of laboratory tests. The majority are related to diet, fitness or medications [27], [28]. This does not mean that these kinds of apps does not exist and for sure they will appear and develop, to support the DTC approach. The role of the clinical laboratory will be the help in development of scientifically sound algorithms and in validating the related apps.
Control and supervise the functionality of the devices and the quality of the results produced in near patient settings. This is a more technical role that will gain importance with the increase of diffusion of POC analyses, especially in hospital settings. The activity that is performed today to supervise blood gas analyzers will be extended to the numerous other tests that will be developed.
Conclusions
With the premise that nothing is so difficult as predicting the future, predictions about the future of laboratory medicine continue to be a source of interest for health-care professionals [24]. We can imagine that clinical laboratory will maintain large part of its classical role even in the era of Digital Health to be more effective and more precise for the eradication of the diseases. Major genome projects are anticipated to provide greater insight into the link between DNA sequence and disease. The clinical laboratory will move toward a more specialized role of translational medicine, high level technology, clinical information management and control of the quality of the results produced also outside the laboratory. Two simultaneous trends seem to be emerging. One is the consolidation of traditional laboratory testing and second is the expanding new market for near-patient testing. The development of informatics will favor the remote control of POC analyzers and the direct contact with the patients, increasing the advisory role of the clinical laboratory.
Author contributions: The author has accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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Article note
Lecture given by Prof. Feruccio Ceriotti at the 2nd EFLM Strategic Conference, 18–19 June 2018 in Mannheim (Germany) (https://elearning.eflm.eu/course/view.php?id=38).
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