Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

A preliminary study on the reference intervals of serum tumor marker in apparently healthy elderly population in southwestern China using real-world data.

BACKGROUND: The aim is to establish and verify reference intervals (RIs) for serum tumor markers for an apparently healthy elderly population in Southwestern China using an indirect method. METHODS: Data from 35,635 apparently healthy elderly individuals aged 60 years and above were obtained in West China Hospital from April 2020 to December 2021. We utilized the Box-Cox conversion combined with the Tukey method to normalize the data and eliminate outliers. Subgroups are divided according to gender and age to examine the division of RIs. The Z-test was used to compare differences between groups, and 95% distribution RIs were calculated using a nonparametric method. RESULTS: In the study, we observed that the RIs for serum ferritin and Des-γ-carboxy prothrombin (DCP) were wider for men, ranging from 64.18 to 865.80 ng/ml and 14.00 to 33.00 mAU/ml, respectively, compared to women, whose ranges were 52.58 to 585.88 ng/ml and 13.00 to 29.00 mAU/ml. For other biomarkers, the overall RIs were established as follows: alpha-fetoprotein (AFP) 0-6.75 ng/ml, carcinoembryonic antigen (CEA) 0-4.85 ng/ml, carbohydrate antigen15-3 (CA15-3) for females 0-22.00 U/ml, carbohydrate antigen19-9 (CA19-9) 0-28.10 U/ml, carbohydrate antigen125 (CA125) 0-20.96 U/ml, cytokeratin 19 fragment (CYFRA21-1) 0-4.66 U/ml, neuron-specific enolase (NSE) 0-19.41 ng/ml, total and free prostate-specific antigens (tPSA and fPSA) for males 0-5.26 ng/ml and 0-1.09 ng/ml. The RIs for all these biomarkers have been validated through our rigorous processes. CONCLUSION: This study preliminarily established 95% RIs for an apparently healthy elderly population in Southwestern China. Using real-world data and an indirect method, simple and reliable RIs for an elderly population can be both established and verified, which are suitable for application in various clinical laboratories.

A guide to conducting systematic reviews of clinical laboratory tests.

Clinical laboratory professionals have an instrumental role in supporting clinical decision making with the optimal use of laboratory testing for screening, risk stratification, diagnostic, prognostic, treatment selection and monitoring of different states of health and disease. Delivering evidence-based laboratory medicine relies on review of available data and literature. The information derived, supports many national policies to improve patient care through clinical practice guidelines or best practice recommendations. The quality, validity and bias of this literature is variable. Hence, there is a need to collate similar studies and data and analyse them critically. Systematic review, thus, becomes the most important source of evidence. A systematic review, unlike a scoping or narrative review, involves a thorough understanding of the procedure involved and a stepwise methodology. There are nuances that need some consideration for laboratory medicine systematic reviews. The purpose of this article is to describe the process of performing a systematic review in the field of laboratory medicine, describing the available methodologies, tools and software packages that can be used to facilitate this process.

Personalized laboratory medicine in the digital health era: recent developments and future challenges.

Interpretation of laboratory data is a comparative procedure and requires reliable reference data, which are mostly derived from population data but used for individuals in conventional laboratory medicine. Using population data as a "reference" for individuals has generated several problems related to diagnosing, monitoring, and treating single individuals. This issue can be resolved by using data from individuals' repeated samples, as their personal reference, thus needing that laboratory data be personalized. The modern laboratory information system (LIS) can store the results of repeated measurements from millions of individuals. These data can then be analyzed to generate a variety of personalized reference data sets for numerous comparisons. In this manuscript, we redefine the term "personalized laboratory medicine" as the practices based on individual-specific samples and data. These reflect their unique biological characteristics, encompassing omics data, clinical chemistry, endocrinology, hematology, coagulation, and within-person biological variation of all laboratory data. It also includes information about individuals' health behavior, chronotypes, and all statistical algorithms used to make precise decisions. This approach facilitates more accurate diagnosis, monitoring, and treatment of diseases for each individual. Furthermore, we explore recent advancements and future challenges of personalized laboratory medicine in the context of the digital health era.

EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) recommendations for reinforcing cyber-security and managing cyber-attacks in medical laboratories.

The healthcare systems are a prime target for cyber-attacks due to the sensitive nature of the information combined with the essential need for continuity of care. Medical laboratories are particularly vulnerable to cyber-attacks for a number of reasons, including the high level of information technology (IT), computerization and digitization. Based on reliable and widespread evidence that medical laboratories may be inadequately prepared for cyber-terrorism, a panel of experts of the Task Force Preparation of Labs for Emergencies (TF-PLE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has recognized the need to provide some general guidance that could help medical laboratories to be less vulnerable and better prepared for the dramatic circumstance of a disruptive cyber-attack, issuing a number of consensus recommendations, which are summarized and described in this opinion paper.

Ethical Checklists for Clinical Research Projects and laboratory medicine: two tools to evaluate compliance with bioethical principles in different settings.

OBJECTIVES: To develop two ethical checklists to evaluate (i) management of ethical concerns in research projects and (ii) awareness of ethical conduct of healthcare laboratory professionals. METHODS: Comprehensive discussion among the members of IFCC Task Force on Ethics based on pertinent literature. RESULTS: This Checklist for Clinical Research Projects should be useful to evaluate research proposals from an ethical perspective before submitting it to an IRB or its equivalent, thereby diminishing rejection rates and resulting in more time-effective projects. The checklist designed to evaluate the ethical conduct in laboratory medicine could be useful for self evaluation (internal audits) and for certification/accreditation processes performed by third parties. CONCLUSIONS: These checklists are simple but powerful tools useful to guide professionals to adhere to ethical principles in their practice, especially in developing countries where accredited ethics committees may be difficult to find.

Evaluation of five multisteroid LC‒MS/MS methods used for routine clinical analysis: comparable performance was obtained for nine analytes.

OBJECTIVES: A mass spectrometry (LC‒MS/MS)-based interlaboratory comparison study was performed for nine steroid analytes with five participating laboratories. The sample set contained 40 pooled samples of human serum generated from preanalyzed leftovers. To obtain a well-balanced distribution across reference intervals of each steroid, the leftovers first underwent a targeted mixing step. METHODS: All participants measured a sample set once using their own multianalyte protocols and calibrators. Four participants used in-house developed measurement platforms, including IVD-CE certified calibrators, which were used by three participants; the 5th lab used the whole LC‒MS kit from an IVD manufacturer. All labs reported results for 17-hydroxyprogesterone, androstenedione, cortisol, and testosterone, and four labs reported results for 11-deoxycortisol, corticosterone, cortisone, dehydroepiandrosterone sulfate (DHEAS), and progesterone. RESULTS: Good or acceptable overall comparability was found in Bland‒Altman and Passing‒Bablok analyses. Mean bias against the overall mean remained less than ±10 % except for DHEAS, androstenedione, and progesterone at one site and for cortisol and corticosterone at two sites (max. -18.9 % for androstenedione). The main analytical problems unraveled by this study included a bias not previously identified in proficiency testing, operator errors, non-supported matrix types and higher inaccuracy and imprecision at lower ends of measuring intervals. CONCLUSIONS: This study shows that intermethod comparison is essential for monitoring the validity of an assay and should serve as an example of how external quality assessment could work in addition to organized proficiency testing schemes.

A global perspective on the status of clinical metabolomics in laboratory medicine - a survey by the IFCC metabolomics working group.

OBJECTIVES: Metabolomics aims for comprehensive characterization and measurement of small molecule metabolites (<1700 Da) in complex biological matrices. This study sought to assess the current understanding and usage of metabolomics in laboratory medicine globally and evaluate the perception of its promise and future implementation. METHODS: A survey was conducted by the IFCC metabolomics working group that queried 400 professionals from 79 countries. Participants provided insights into their experience levels, knowledge, and usage of metabolomics approaches, along with detailing the applications and methodologies employed. RESULTS: Findings revealed a varying level of experience among respondents, with varying degrees of familiarity and utilization of metabolomics techniques. Targeted approaches dominated the field, particularly liquid chromatography coupled to a triple quadrupole mass spectrometer, with untargeted methods also receiving significant usage. Applications spanned clinical research, epidemiological studies, clinical diagnostics, patient monitoring, and prognostics across various medical domains, including metabolic diseases, endocrinology, oncology, cardiometabolic risk, neurodegeneration and clinical toxicology. CONCLUSIONS: Despite optimism for the future of clinical metabolomics, challenges such as technical complexity, standardization issues, and financial constraints remain significant hurdles. The study underscores the promising yet intricate landscape of metabolomics in clinical practice, emphasizing the need for continued efforts to overcome barriers and realize its full potential in patient care and precision medicine.

Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice.

Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death of the nervous system's cells. The diagnosis is challenging, especially in the early stages, due to no specific clinical signs and symptoms. In this context, laboratory medicine could support clinicians in detecting and differentiating NDs. Indeed, biomarkers could indicate the pathological mechanisms underpinning NDs. The ideal biofluid for detecting the biomarkers of NDs is cerebrospinal fluid (CSF), which has limitations, hampering its widespread use in clinical practice. However, intensive efforts are underway to introduce high-sensitivity analytical methods to detect ND biomarkers in alternative nonivasive biofluid, such as blood or saliva. This study presents an overview of the ND molecular biomarkers currently used in clinical practice. For some diseases, such as Alzheimer's disease or multiple sclerosis, biomarkers are well established and recommended by guidelines. However, for most NDs, intensive research is ongoing to identify reliable and specific biomarkers, and no consensus has yet been achieved.

Reference intervals: past, present, and future.

Clinical laboratory test results alone are of little value in diagnosing, treating, and monitoring health conditions; as such, a clinically actionable cutoff or reference interval is required to provide context for result interpretation. Healthcare practitioners base their diagnoses, follow-up treatments, and subsequent testing on these reference points. However, they may not be aware of inherent limitations related to the definition and derivation of reference intervals. Laboratorians are responsible for providing the reference intervals they report with results. Yet, the establishment and verification of reference intervals using conventional direct methods are complicated by resource constraints or unique patient demographics. To facilitate standardized reference interval best practices, multiple global scientific societies are actively drafting guidelines and seeking funding to promote these initiatives. Numerous national and international multicenter collaborations demonstrate the ability to leverage combined resources to conduct large reference interval studies by direct methods. However, not all demographics are equally accessible. Novel indirect methods are attractive solutions that utilize computational methods to define reference distributions and reference intervals from mixed data sets of pathologic and non-pathologic patient test results. In an effort to make reference intervals more accurate and personalized, individual-based reference intervals are shown to be more useful than population-based reference intervals in detecting clinically significant analyte changes in a patient that might otherwise go unrecognized when using wider, population-based reference intervals. Additionally, continuous reference intervals can provide more accurate ranges as compared to age-based partitions for individuals that are near the ends of the age partition. The advantages and disadvantages of different reference interval approaches as well as the advancement of non-conventional reference interval studies are discussed in this review.

Laboratory biomarkers in the diagnosis and follow-up of treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA), a severe inflammatory respiratory disease, is caused by a hypersensitivity reaction to the colonization of the airways with Aspergillus fumigatus. It is most often described in patients with asthma or cystic fibrosis. The diagnosis of ABPA is based on a combination of clinical, radiological, and immunological findings that have been included in different diagnostic criteria over the years. In this paper, we review the biomarkers included in these diagnostic criteria and novel research biomarkers that may be used in the diagnosis and treatment follow-up of ABPA in cystic fibrosis.

Microfluidic systems in clinical diagnosis.

The use of microfluidic devices is highly attractive in the field of biomedical and clinical assessments, as their portability and fast response time have become crucial in providing opportune therapeutic treatments to patients. The applications of microfluidics in clinical diagnosis and point-of-care devices are continuously growing. The present review article discusses three main fields where miniaturized devices are successfully employed in clinical applications. The quantification of ions, sugars, and small metabolites is examined considering the analysis of bodily fluids samples and the quantification of this type of analytes employing real-time wearable devices. The discussion covers the level of maturity that the devices have reached as well as cost-effectiveness. The analysis of proteins with clinical relevance is presented and organized by the function of the proteins. The last section covers devices that can perform single-cell metabolomic and proteomic assessments. Each section discusses several strategically selected recent reports on microfluidic devices successfully employed for clinical assessments, to provide the reader with a wide overview of the plethora of novel systems and microdevices developed in the last 5 years. In each section, the novel aspects and main contributions of each reviewed report are highlighted. Finally, the conclusions and future outlook section present a summary and speculate on the future direction of the field of miniaturized devices for clinical applications.

Determination of a Serum 25-Hydroxyvitamin D Reference Ranges in Japanese Adults Using Fully Automated Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Despite an increasing interest in vitamin D status, a reference range of the nutrient has not been fully established. This is partly due to a paucity of standardized measuring systems with high throughput. In addition, the range may vary by populations and may change with modernization of lifestyles. OBJECTIVES: This study aims to calculate the current reference concentration of 25-hydroxyvitamin D (25(OH)D) among healthy people living in an urban area in Japan. METHODS: A newly developed fully automated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system was used to measure serum 25(OH)D concentrations. Reproducibility was assessed by measuring standardized samples. Accuracy was validated by comparing with commercially available immunoassays. Then, mass screening was conducted targeting participants who received medical checkups in Tokyo from April 2019 to March 2020, and the reference ranges were calculated. RESULTS: The coefficients of variations of interoperator and interday reproducibility were 4.1%-8.5% and 3.7%-8.0% for 25-hydroxyvitamin D2 (25(OH)D2) and 4.7%-7.0% and 4.0%-6.9% for 25-hydroxyvitamine D3, respectively. The measured total 25(OH)D concentrations correlated well with those measured by immunoassays. In total, 5518 participants were measured for 25(OH)D concentrations, among whom 98% showed inadequate concentrations (<30 ng/mL). The reference ranges of total 25(OH)D for female, male, and total participants were 7-30 ng/mL, 5-27 ng/mL, and 6-29 ng/mL, respectively. After excluding those with abnormal renal and liver function, the range was 6-30 ng/mL. CONCLUSIONS: The high prevalence of vitamin D insufficiency among seemingly healthy population may be attributed to lifestyle characteristics of people living in urban areas of Japan, including spending less time outdoors and lower intake of traditional foods. Longitudinal follow-up and mass screenings targeting different population will help elucidate reasons for discrepancies between official guidelines and the observed concentrations, to which the well-validated measurement system is essential.

Method evaluation in the clinical laboratory.

Method evaluation is one of the critical components of the quality system that ensures the ongoing quality of a clinical laboratory. As part of implementing new methods or reviewing best practices, the peer-reviewed published literature is often searched for guidance. From the outset, Clinical Chemistry and Laboratory Medicine (CCLM) has a rich history of publishing methods relevant to clinical laboratory medicine. An insight into submissions, from editors' and reviewers' experiences, shows that authors still struggle with method evaluation, particularly the appropriate requirements for validation in clinical laboratory medicine. Here, we consider through a series of discussion points an overview of the status, challenges, and needs of method evaluation from the perspective of clinical laboratory medicine. We identify six key high-level aspects of clinical laboratory method evaluation that potentially lead to inconsistency. 1. Standardisation of terminology, 2. Selection of analytical performance specifications, 3. Experimental design of method evaluation, 4. Sample requirements of method evaluation, 5. Statistical assessment and interpretation of method evaluation data, and 6. Reporting of method evaluation data. Each of these areas requires considerable work to harmonise the practice of method evaluation in laboratory medicine, including more empirical studies to be incorporated into guidance documents that are relevant to clinical laboratories and are freely and widely available. To further close the loop, educational activities and fostering professional collaborations are essential to promote and improve the practice of method evaluation procedures.

Emerging technology: a definition for laboratory medicine.

The term "emerging technology" (ET) is used extensively, and there are numerous definitions offered, but to our knowledge, none specifically encompass the field of laboratory medicine. An ET definition that incorporates the overarching IFCC aim of "Advancing excellence in laboratory medicine to support healthcare worldwide" would clarify discussions. We discuss key aspects of the term "emerging technology(ies)" as it applies to laboratory medicine with a view to laying the foundations for a practical definition for the profession and propose the definition of an ET as "An analytical method or device that by virtue of its stage of development, translation into broad routine clinical practice, or geographical adoption and implementation has the potential to add value to clinical diagnostics".

Central role of laboratory medicine in public health and patient care.

Clinical laboratories play a vital role in the healthcare system. Objective medical data provided by clinical laboratories supports approximately 60-70% of clinical decisions, however, evidence supporting this claim is poorly documented and laboratories still lack visibility, despite their indisputable impact on patient care and public health. The International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Outcome Studies in Laboratory Medicine (TF-OSLM) was recently developed to support directed research evaluating the role of laboratory medicine on clinical outcomes. Establishing and documenting this evidence is key to enhance visibility of the field in the eye of the public and other healthcare professionals together with optimizing patient outcomes and health care system operations. In this review, we discuss four areas that exemplify the contribution of laboratory medicine directly to patient care. This includes high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptides (NT-proBNP/BNP) for the diagnosis and prognosis of myocardial infarction and heart failure, respectively, and procalcitonin for the management of sepsis and antibiotic stewardship. Emerging markers of traumatic brain injury and the role of laboratory medicine in the fight against the COVID-19 pandemic are discussed along with an introduction to plans of IFCC TF-OSLM.

Direct-to-consumer laboratory testing (DTCT): challenges and implications for specialists in laboratory medicine.

In vitro diagnostics (IVD) testing is a powerful tool for medical diagnosis, and patients' safety is guaranteed by a complex system of personnel qualification of the specialist in laboratory medicine, of process control, and legal restrictions in healthcare, most of them under national regulation. Direct-to-consumer laboratory testing (DTCT) is testing ordered by the consumer and performed either by the consumer at home or analysis of self-collected samples in a laboratory. However, since DTCT are not always subject to effective competent authority oversight, DTCT may pose risks to lay persons using and relying on it for healthcare decision-making. Laboratory medicine specialists should be very cautious when new DTCTs are introduced. As qualified professionals, they should feel obliged to warn and educate patients and the public about the risks of inappropriate and harmful DTCT.

Where is laboratory medicine headed in the next decade? Partnership model for efficient integration and adoption of artificial intelligence into medical laboratories.

OBJECTIVES: The field of artificial intelligence (AI) has grown in the past 10 years. Despite the crucial role of laboratory diagnostics in clinical decision-making, we found that the majority of AI studies focus on surgery, radiology, and oncology, and there is little attention given to AI integration into laboratory medicine. METHODS: We dedicated a session at the 3rd annual European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) strategic conference in 2022 to the topic of AI in the laboratory of the future. The speakers collaborated on generating a concise summary of the content that is presented in this paper. RESULTS: The five key messages are (1) Laboratory specialists and technicians will continue to improve the analytical portfolio, diagnostic quality and laboratory turnaround times; (2) The modularized nature of laboratory processes is amenable to AI solutions; (3) Laboratory sub-specialization continues and from test selection to interpretation, tasks increase in complexity; (4) Expertise in AI implementation and partnerships with industry will emerge as a professional competency and require novel educational strategies for broad implementation; and (5) regulatory frameworks and guidances have to be adopted to new computational paradigms. CONCLUSIONS: In summary, the speakers opine that the ability to convert the value-proposition of AI in the laboratory will rely heavily on hands-on expertise and well designed quality improvement initiative from within laboratory for improved patient care.

Positivization time of a COVID-19 rapid antigen self-test predicts SARS-CoV-2 viral load: a proof of concept.

OBJECTIVES: This proof of concept study was aimed to validate the hypothesis that the time of positivization of SARS-CoV-2 self-performed rapid diagnostic tests (RDTs) may reflect the actual viral load in the specimen. METHODS: A SARS-CoV-2 positive sample with high viral load was diluted and concomitantly assayed with molecular assay (Xpert Xpress SARS-CoV-2) and RDT (COVID-VIRO ALL IN RDT). The (mean cycle threshold; Ct) values and RDT positivization times of these dilutions were plotted and interpolated by calculating the best fit. The parameters of this equation were then used for converting the positivization times into RDT-estimated SARS-CoV-2 Ct values in routine patient samples. RESULTS: The best fit between measured and RDT-estimated Ct values could be achieved with a 2-degree polynomial curve. The RDT-estimated Ct values exhibited high correlation (r=0.996) and excellent Deming fit (y=1.01 × x - 0.18) with measured Ct values. In 30 consecutive patients with positive RDT test, the correlation between RDT positivization time and measured Ct value was r=0.522 (p=0.003). The correlation of RDT-estimated and measured Ct values slightly improved to 0.577 (Deming fit: y=0.44 × x + 11.08), displaying a negligible bias (1.0; 95% CI, -0.2 to 2.2; p=0.105). Concordance of RDT-estimated and measured Ct values at the <20 cut-off was 80%, with 0.84 sensitivity and 0.73 specificity. CONCLUSIONS: This proof of concept study demonstrates the potential feasibility of using RDTs for garnering information on viral load in patients with acute SARS-CoV-2 infection.

Implementing metrological traceability of C-reactive protein measurements: consensus summary from the Joint Committee for Traceability in Laboratory Medicine Workshop.

The Joint Committee for Traceability in Laboratory Medicine (JCTLM) currently lists the secondary commutable certified reference material (CRM) ERM DA-474/IFCC (DA-474) "C-Reactive Protein in Human Serum" and two generic immunoassay-based method principles as the basis for implementing the metrological traceability of C-reactive protein (CRP) measurements by end-user measurement procedures used by medical laboratories. The current metrological traceability has produced well harmonized results for clinical samples among different end-user measurement procedures. New higher-order pure substance and secondary commutable CRMs have been nominated for listing by the JCTLM. However, the data supporting performance of these new candidate CRMs, including use of new mass spectrometry based candidate reference measurement procedures (RMPs), was not clear regarding the influence that introducing these new CRMs would have on the current well harmonized results achieved with the existing metrological traceability to DA-474. The clinically relevant CRP measurand in blood serum or plasma is a pentamer of identical subunits, which adds complexity to the application of higher-order CRMs and RMPs. The JCTLM convened a workshop in December 2022 to review the appropriate implementation of metrological traceability of CRP measurements. The workshop consensus was that the extent-of-equivalence data must include considerations about the impact of a new CRM when used for its intended purpose in the calibration hierarchies of existing end-user measuring systems; and that a new RMP must compare results with another existing well validated candidate RMP or with a globally available end-user measurement system.