Listen on the go: Audio Summary of the original articles from the October 2020 issue. 

Chinese Translation of "Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia" interview with Dr. Leo Poon.

In December 2019, a cluster of atypical pneumonia patients epidemiologically linked to a wholesale market in Wuhan, China was detected. A novel betacoronavirus named as 2019-novel coronavirus (2019-nCoV) has been identified in some of these patients. Considerable attention has been given to this virus, that according to the World Health Organization as of this recording at the end of January 2020, has so far thought to have sickened over 6,000 people and is responsible for at least 132 deaths. Because of the potential for pandemic spread, there is a great need for a rapid and accurate test for the detection of the virus. We are fortunate to have with us today Dr. Leo Poon from the School of Public Health, Li Ka Shing Faculty of Medicine at the University of Hong Kong. He and his colleagues described a new molecular diagnostic assay that allows the detection and quantification of this new coronavirus.

Molecular diagnostics is the topic of the January 2020 special issue of Clinical Chemistry.  In that issue, there is a counter point report on the use of circulating tumor cells in the management of cancer patients.  To provide further insight on this topic, we’re joined in this podcast by one of the editors of this special issue, Professor Klaus Pantel, Chairman of the Institute of Tumor Biology at the University Medical Center in Hamburg-Eppendorf in Germany. 

Breakthroughs in sequencing technology and computational biology have provided the basis for studies of the myriad ways in which microbial communities in and on the human body influence human health and disease. In almost every medical specialty, there is now growing interest in accurate and replicable profiling of the microbiome for use in diagnostic and therapeutic application.           In the January 2020 issue of Clinical Chemistry, which is devoted to topics in molecular diagnostics, Dr. Robert Schlaberg reviews microbiome diagnostics.

Molecular diagnostics is now firmly entrenched in laboratory medicine and the January 2020 issue of Clinical Chemistry is devoted to this topic.  In that issue is a case report that presents an unconventional diagnosis based somatic findings through germline whole-exome sequencing.  Joining us in this podcast is the lead author of that case report, Dr. Jaime Lopes, who is currently a fellow at the Genomics Laboratory in the Department of Laboratory Medicine and Pathology at the Mayo Clinic in Rochester, Minnesota. 

Molecular diagnostics is now firmly rooted in laboratory medicine and the January 2020 issue of Clinical Chemistry is devoted to this topic.  In that issue, Dr. Linnea Baudhuin reviews genome and exome sequencing as they’re used in clinical practice.

Molecular Diagnostics is clearly going from strength to strength.  That’s the title of the lead article by the guest editors in the January 2020 issue of Clinical Chemistry that is devoted to this topic.  It has been five years since the last molecular diagnostics theme issue was published in Clinical Chemistry.  In this new edition of the theme issue, the editors have highlighted some of the most exciting developments in the field including the maturation of massively parallel DNA sequencing technology allowing production of genomic data at the hospital or even population level. Joining us in this podcast is one of the guest editors for this special issue, Dr. Carl Wittwer. 

Maintaining high ethical standards is a characteristic we expect in many professionals, but perhaps most in the field of medicine.  Although biomedical ethics is a relatively new field, there have been discussions of moral issues in medicine since ancient times.  The Hippocratic Oath, for instance, was written by Hippocrates at approximately 400 B.C.  It requires that a new physician swear to uphold specific ethical standards.  Over 2000 years later new physicians still swear by the Hippocratic or a similar oath. The December 2019 issue of Clinical Chemistry published a Review paper that provides a broad overview of ethics as it pertains to laboratory medicine.

Science is not just based on interesting findings.  One of the key elements in research reports is an informative description of the methods that were used to develop the experiment, to collect the data, and to analyze them.  Since this process rests on replication, reporting of methods is essential as it allows others to stage a similar experiment, to design an identical study, and to evaluate whether the findings can be replicated.  If they cannot be reproduced, the outcomes from the previous experiment or trial will gradually or immediately lose credibility.   A recent editorial on this topic appeared in the December 2019 issue of Clinical Chemistry. 

Circular RNAs have the unique topological feature of circularity among the RNAs species.  They are single-stranded, covalently closed, circular RNA molecules and are hypothesized to be generated largely through back-splicing of exons from precursor messenger RNAs.  Circular RNAs were once considered as aberrant splicing by-products, which were only present in minute amounts in cells.  The potential of this RNAs species as a disease biomarker is to be explored, but there are biological properties of circular RNAs which make them suitable for biomarker development. An Editorial appearing in the October 2019 issue of Clinical Chemistry by Drs. Jacky Lam and Dennis Lo discussed circular RNAs as potential urinary biomarkers. 

Heart failure is a leading cause of morbidity and mortality worldwide with prevalence expected to increase over the next 20 years.  Early diagnosis and optimal management of heart failure are key to reducing its impact. Because B-type natriuretic peptide, or BNP, and amino terminal proBNP, or NT-proBNP, as well as their precursor proBNP, are secreted by the heart in direct proportion to the degree of cardiac dysfunction and clinical severity, measurement of these peptides is now mandated by authoritative international guidelines for the diagnosis and risk stratification of the disease.  However, circulating concentrations of both BNP and NT-proBNP are reduced by obesity, and this phenomenon is one of the key weaknesses of the diagnostic performance of the natriuretic peptides in heart failure. A paper appearing in the September 2019 issue of Clinical Chemistry shows that obesity is associated with decreased concentrations of proBNP that is not glycosylated at threonine at position 71 of the peptide.  Decreased proBNP substrate amenable to processing could partially explain the lower NT-proBNP and BNP concentrations measured in obese individuals, including those presenting with heart failure.  

Measurement of plasma adrenocorticotropic hormone, or ACTH, is key in the differential diagnosis of hypothalamic pituitary adrenal disorders. Two-site sandwich immunoassay dominate clinical testing of ACTH in North America.  However, discordant results among different assays have been repeatedly reported.  To help resolve this discrepancy, a multicenter effort developed a liquid chromatography tandem mass spectrometry assay for the intended measurand, that is the biologically active intact ACTH.  A report on that initiative appears in the November 2019 issue of Clinical Chemistry.  We are pleased to have the senior author of that paper , Dr. Mari DeMarcoas our guest in this podcast. 

Obesity is on the rise worldwide and it’s a risk factor for systemic hypertension, hyperlipidemia, diabetes mellitus, and left ventricular hypertrophy, all of which are conditions associated with an increased prevalence of heart failure.  However, the applications of BNP and NT-proBNP as biomarkers in obese patients are limited, as the relationship between their levels and myocardial stiffness is complex.  An Editorial appearing in the September 2019 issue of Clinical Chemistry examines the interrelationship between obesity and BNP and NT-proBNP measurements.  

A paper appearing in the October 2019 issue of Clinical Chemistry found that fragments of proCNP could be measured in urine from subjects with diabetes mellitus.  The urinary NT-proCNP to creatinine ratio was also more reproduceable than the now commonly used albumin to creatinine ratio and strongly associated with the presence of chronic kidney disease. 

Sacubitril/Valsartan, known as Entresto, is a new dual drug therapy that includes an angiotensin receptor inhibitor and is indicated to reduce the risk of cardiovascular death and hospitalization in patients with chronic heart failure.  Since its approval for the treatment of chronic heart failure with reduced injection fraction, a commonly raised question is whether treatment with this drug challenges the use of B-type natriuretic peptide, or BNP, testing compared to the N terminal proBNP assay because Sacubitril may interfere with BNP clearance. The clinical and analytical studies addressing this issue are limited, along with the fact the diversity of both BNP and NT-proBNP assays used in clinical laboratory practice have not been adequately evaluated in clinical trials or studies to provide an evidenced-based on final decision as to what assay or assays should be used or eliminated from use when a patient is on Entresto. In the September 2019 issue of Clinical Chemistry, a Q&A feature titled, “Role of BNP vs NT-proBNP Testing in the Age of New Drug Therapies” asked five experts with different roles in this field to discuss this issue. 

Overutilization of laboratory services is an important unresolved issue in health care.  A recent study that appears in the September 2019 issue of Clinical Chemistry attempts to address this issue.  That paper titled ” Once-Per-Visit Alerts: A Means to Study Alert Compliance and Reduce Repeat Laboratory Testing,” examined reorders of a laboratory test within the same admission. 

B-type natriuretic peptides, or BNP, and N-terminal proBNP, or NT-proBNP, are peptides produced in the heart in response to increased wall stretch and volume overload.  Their production and secretion increases in the heart with the progression of heart failure and they have emerged as useful heart failure biomarkers.  Since the discovery of BNPs in the 1980s, much effort has been made to precisely determine the BNP and NT-proBNP levels via immunoassays for reliable heart failure diagnostics. Entresto™ is a new heart failure therapy that includes sacubitril as one of its components.  Sacubitril is a specific inhibitor of neprilysin. This is a zinc-dependent metalloproteinase that cleaves various peptides including BNP.  In fact, augmentation of circulating BNP due to neprilysin inhibition is considered as a possible mechanism of Entresto’s positive effects.  A paper appearing in the October 2019 issue of Clinical Chemistry examines the circulating products of BNP proteolysis by neprilysin and how they might reflect impact on the metabolism of active BNP. 

In the August 2019 issue of Clinical Chemistry, a Q&A feature titled “Optimal Use of Biomarker for Chronic Kidney Disease” asked five experts in laboratory medicine and nephrology to examine laboratory ordering, testing, and reporting practices, and recommend how those practices should be optimized to better serve patients with CKD. In this podcast, Dr. Greg Miller from the Department of Pathology at Virginia Commonwealth University in Richmond who moderated the Q&A will summarize the expert advice from his colleagues. 

Analyzing quality control specimens is a daily component of modern medical laboratories to help assure that correct results are reported for patient samples.  That involves periodic analysis of materials with a known analyte concentration and estimating if measurement error is within acceptable criteria.  The QC samples may be obtained commercially or prepared within the laboratory.  However, how adequately do those samples represent authentic patient samples?  What if we were to use the patient samples themselves as a source of quality control data?  That’s not as radical as one might think as implementation and application of moving averages of patient results was suggested as early as the 1960s, but the practice never really caught on. A Review paper appearing in the August 2019 issue of Clinical Chemistry re-examines this concept and perhaps newer software can provide such data in near real-time, or as the paper calls it, patient-based real-time quality control. 

Measurement of hemoglobin A1c in blood is essential for the management of patients with diabetes mellitus.  Hemoglobin A1c reflects the average blood glucose concentration over the proceeding 8 to 12 weeks.  While the clinical value of hemoglobin A1c was initially limited by large differences in results among various methods, the investment of considerable effort to implement standardization has brought about a marked improvement in analysis. In the July 2019 issue of Clinical Chemistry, a Review article chronicles the substantial progress that has been achieved in enhancing the accuracy of these measurements and the role of the National Glycohemoglobin Standardization Program in those efforts. 

Bladder cancer is the ninth most common cancer worldwide.  The current diagnosis and monitoring of bladder cancer is still heavily reliant on cystoscopy, an invasive procedure where the tumor is directly visualized.  However, a paper appearing in the July 2019 issue of Clinical Chemistry from Dr. Dennis Lo’s laboratory in Hong Kong reports that bladder cancer can be detected noninvasively in urinary cell-free DNA by methylomic and copy number analysis.  Such analyses could be used as a liquid biopsy to aid in the diagnosis and monitoring of bladder cancer.

High-density lipoprotein or HDL is one of the most important of the lipoproteins in most species and there is evidence that points towards a role of HDL in normal immune function.  A paper appearing in the May 2019 issue of Clinical Chemistry tested the hypothesis that concentrations of HLD cholesterol are associated with risk of autoimmune disease. That study from the Copenhagen General Population Study and the Copenhagen City Heart Study included over 100,000 individuals.  We are pleased to have the senior author of that paper with us today, Dr. Borge Nordestgaard. 

In 2014, the U.S. Congress passed the Protecting Access to Medicare Act (PAMA) which required CMS, the Centers for Medicare & Medicaid Services, to revise the clinical laboratory fee schedule to reflect private sector payment rates.  Many in the laboratory community believed that the cuts are too deep and have urged CMS to recalculate fees to more accurately reflect the spectrum of laboratories that provide testing for patients. To gain greater insight on the potential impact of PAMA, a Q&A feature in the June 2019 issue of Clinical Chemistry asked six experts with different roles in this field to give their opinions on several of the key issues pertaining to the new reimbursement rates, particularly its potential impact on the laboratory marketplace and patient care.

The standard course for academic promotion has primarily been based on the number and quality of peer-reviewed papers published and the number of peer-reviewed grants received.  Other academic activities such as teaching, book editing, mentoring, and service to scientific organizations have also been considered.  But this process often falls short for those whose interests are in biomedical education or in translational and clinical applications. In the June 2019 issue of Clinical Chemistry, Nader Rifai, Brian Smith, and Maureen Connelly published an editorial titled, “A Message to Medical School Promotion Committees:  Proper Credit for Peer-Reviewed Online Educational Materials.”

Non-invasive prenatal testing based on cell-free DNA is now a widely used technique. However, quality control materials that have properties identical to clinical samples and that are applicable to a wide range of procedures are not available to support assay development, internal or external quality control, and proficiency testing. The June 2019 issue of Clinical Chemistry includes a study describing the development of such quality control materials that comprise simulated human plasma and mixtures of mother cell line derived cell-free DNA based on DNA fragmentation factor digestion.

Inborn errors of metabolism are rare diseases in which a single gene defect causes a clinically significant block in a metabolic pathway resulting either in an accumulation of substrate behind the block or a lack or deficiency of the product.  Profiling metabolites in the pathway could allow for accurate and timely identification of patients who have these diseases and help physicians to devise effective treatment.   Congenital disorders of glycosylation represent one of the largest groups of such metabolic disorders.  In May 2019, Clinical Chemistry published a study on the development and validation of a plasma protein N-glycan assay using a flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry.

For about the past 15 years, the public has become aware that genetic testing can provide medical diagnosis and inform specific medical therapies.  In addition to being used for medical purposes, genetics has also become a popular recreational tool for genealogy and general wellness.  The number of customers for direct-to-consumer genetic testing has now grown to greater than 12 million and continues to rise. In the May 2019 issue of Clinical Chemistry, a Q&A feature titled “Privacy in Direct-to-Consumer Genetic Testing” asked four experts with different roles in this field to discuss the current state of genomics and privacy.

Hospital pneumatic tube systems provide rapid transportation of patient samples to the laboratory.  However, it is known that the physical movement through a pneumatic tube system can agitate blood samples and sometimes cause cells to break open and leak intracellular components.  As a result, multiple laboratory results are susceptible to error. The May 2019 issue of Clinical Chemistry published a paper by Dr. Ann Gronowski and Dr. Christopher Farnsworth and their colleagues at the Washington University School of Medicine in St. Louis that describes parameters for evaluating a hospital pneumatic tube system. 

Mendelian randomization is a genetic epidemiological approach that is made substantial inroads into our understanding of the causes and consequences of disease, but can that same technique be run in reverse? In the March 2019 issue of Clinical Chemistry, a paper investigated potential blood markers of early chronic kidney disease which are caused by loss of kidney function, using an innovative reverse Mendelian randomization approach. That same issue included an editorial that was authored by Dr. Michael Holmes from the University of Oxford and by Dr. George Davey Smith from the University of Bristol, both from the United Kingdom and both are our guests in this podcast.

Polycystic ovary syndrome is a complex endocrine-mediated disorder in women with an estimated prevalence of about 10%. Women with PCOS typically present with heterogeneous clinical signs and symptoms such as excess hair growth, irregular menstrual cycles, infertility and metabolic issues. Currently, there are no universal criteria for diagnosis of this condition and as a result, women with the disorder often reports significant delays in diagnosis and poor follow-up care. A Q&A feature in the March 2019 issue of Clinical Chemistry asked five experts with different roles in this field to discuss recent advances and ongoing challenges surrounding the current diagnostic criteria, available biomarkers, and the timely diagnosis and management of women with polycystic ovary syndrome.

Identifying markers of chronic kidney disease that occur early in the disease process and are specific to loss of kidney function may allow timely more accurate identification of patients who will eventually develop the disease. In the March 2019 issue of Clinical Chemistry, a paper investigated potential blood markers of early chronic kidney disease which are caused by loss of kidney function using an innovative reverse Mendelian randomization approach.

Glomerular filtration rate, or GFR, is generally accepted as the best overall index of kidney function, and a decrease in GFR has important implications for prognosis in patient management.  GFR is most commonly estimated by calculation, using the serum concentration of an endogenous filtration marker such as creatinine and demographic variables such as age, sex, and race.  In the March 2019 issue of Clinical Chemistry, a paper investigated the possibility of developing a more accurate estimate of GFR, using a panel of metabolites measured by quantitative liquid chromatography, tandem mass spectrometry without creatinine, cystatin C, or demographic variables.

In the March 2019 issue of Clinical Chemistry, Professor Andrew Levey and others from a multinational consortium of institutions, published a study titled, “Validation of a Metabolite Panel for a More Accurate Estimation of Glomerular Filtration Rate Using Quantitative LC-MS-MS.”  In fact, we have another podcast from one of the authors of that paper available.  But today, we’re joined by Dr. Anders Berg, the Associate Medical Director of the Core Laboratories at Cedars-Sinai in Los Angeles, who co-authored an editorial that accompanied the paper. Dr. Berg is here to help us deconvolute the significance of this intriguing study and where this research might lead us in the future. 

Acute abdominal pain is one of the most common presenting symptoms in emergency department patients and its differential diagnosis can be extensive and challenging.  Rapid and accurate diagnosis of urgent causes of abdominal pain is essential for the early initiation of effective therapy and efficient patient flow. To see how the clinical laboratory can help in this process, a recent study that appeared in the February 2019 issue of Clinical Chemistry examined inflammatory biomarkers in the emergency diagnosis of urgent abdominal pain.

Cardiovascular risk is so high in type III hyperlipoproteinemia that is typically a “treat immediately on diagnosis” disorder.  In the February 2019 issue of Clinical Chemistry, a paper presented the advantages of a non-high density lipoprotein cholesterol ratio with apolipoprotein B as a diagnostic tool for type III hyperlipoproteinemia.  In the same issue, an accompanying editorial entitled “Type III Hyperlipoproteinemia: The Forgotten, Disregarded, Neglected, Overlooked, Ignored but Highly Atherogenic, and Highly Treatable Dyslipo-proteinemia” was also published.  The author of that article is Dr. Allan Sniderman, the Edwards Professor of Cardiology at McGill University in Montreal, Quebec, Canada, and he is our guest in this podcast. 

High-density lipoproteins, or HDLs, are macromolecular assemblies that play a key role in lipid transport, but also exert effects in endothelial function, thrombosis, and inflammation.  A recent focus by several groups on HDL function rather than HDL cholesterol revealed that efflux capacity was inversely associated with coronary artery disease.  Traditionally, cholesterol efflux is measured using a cell-based assay where cultured microphages are treated with radioactively-labeled cholesterol and subsequently exposed to a cholesterol acceptor. A recent study that appeared in the February 2019 issue of Clinical Chemistry took a completely different approach and assessed the lipoprotein proteome by using liquid chromatography and tandem mass spectrometry to measure 21 lipoprotein associated proteins.

Machine learning involves the study of algorithms and mathematical models so that computer systems can progressively improve their performance on solving a specific task. A recent application of machine learning through the interpretation of urine steroid profiles appears in the November 2018 issue of Clinical Chemistry.

A recent study appears in the September 2018 issue of Clinical Chemistry, an assessment of digital PCR as a primary reference measurement procedure to support advances in precision medicine.

In almost all high-income countries, the U.S. included, women live longer than men.  As we enter a new era in which biomedical data are increasingly ubiquitous, current and future research may help us understand the fundamental issues that drive differences in longevity and other health outcomes between men and women.  Our ability to measure the entire spectrum of information about the human biological, environmental, and behavioral condition will become both routine and relatively inexpensive from genes to genomics.  From clinical data to the electronic health record in insurance claims.  From digital information about behavior and social interaction to geospatial referencing. The January 2019 issue of Clinical Chemistry is devoted to topics of men’s health and in that issue, an article examined differences in health outcomes between men and women and underlying biological, behavioral, and societal factors. 

The unintended pregnancy rate in the United States is approximately 45% despite of variety of contraceptive options available to women.  Today, male condoms and withdrawal are the only reversible contraceptive methods available to men with typical failure rates between 10% and 20%.  But what about a male contraceptive pill?  Studies indicate that more than half of men would be interested in using a reversible method if it was available.  And many women would be willing to rely on their partner to use such a contraceptive.  Unplanned pregnancy rates could improve if both partners use a contraceptive method or if men had more options to control their own fertility. The January 2019 issue of Clinical Chemistry is devoted to topics of men’s health.  And in that issue, an article examined developments in male contraceptives with an update on both novel hormonal and non-hormonal methods.

The January 2019 issue of Clinical Chemistry is devoted to the area of men’s health.  Aside from non-melanoma skin cancer, prostate cancer is the most common cancer among men in the United States.  It is remarkable that even though the introduction of prostate specific antigen, or PSA, into U.S. clinical practice occurred over three decades ago, researchers and clinicians are still debating its value for prostate cancer screening. In that special issue, Dr. Andrew Vickers published an Opinion article titled, “Redesigning Prostate Cancer Screening Strategies to Reduce Overdiagnosis.”

Preeclampsia is a serious disorder of pregnancy that occurs by 24 weeks of gestation or later and can occur in up to 5% of all pregnancies.  Maternal weight, advancing maternal age, nulliparity, a previous pregnancy with preeclampsia, and insulin-dependent diabetes are just some of the predisposing factors for developing preeclampsia.  Over the past few years, development in screening, prevention, and treatment for preeclampsia have occurred and genetic studies are just now providing new insights into the etiology of this disorder. A Q&A feature in the December 2018 issue of Clinical Chemistry asked three experts with different roles in this field to discuss recent advances and ongoing challenges in preeclampsia research and implementation. 

The December 2018 issue of Clinical Chemistry published a Perspective article titled “CRISPR Methods for Nucleic Acid Detection Herald the Future of Molecular Diagnostics,” which discusses the findings of Chen and colleagues who earlier this year were the first to create a diagnostic tool out of a CRISPR-Cas system and demonstrate its clinical utility. 

Coronary artery disease is the most common cause of death and morbidity in developed countries, resulting in substantial healthcare costs.  The early detection of this disease and identification of patients at risk for myocardial infarction has enormous medical and economic value.  The introduction of high-sensitivity cardiac troponin assays has revolutionized early diagnosis of myocardial infarction, but what about their use for identifying patients at risk with stable coronary artery disease?Coronary artery disease is the most common cause of death and morbidity in developed countries, resulting in substantial healthcare costs.  The early detection of this disease and identification of patients at risk for myocardial infarction has enormous medical and economic value.  The introduction of high-sensitivity cardiac troponin assays has revolutionized early diagnosis of myocardial infarction, but what about their use for identifying patients at risk with stable coronary artery disease? A recent study to address that issue as well as a comparison of high-sensitivity cardiac troponin I and troponin T assays appeared in the November 2018 issue of Clinical Chemistry.

Influenza viruses affect millions of people each year, leading to several hundred thousand hospitalizations and thousands of deaths annually in the U.S. Early antiviral therapy reduces the duration of illness, complications and mortality associated with the flu, yet antivirals are often underutilized. However, patients with a positive influenza diagnostic test results are more likely to receive appropriate antiviral therapy and less likely to be prescribed unnecessary antibiotics. Access to reliable influenza testing is critical to facilitate both optimal patient outcomes and antimicrobial stewardship. Recently, the first point-of-care molecular diagnostic test was cleared by the U.S. Food and Drug Administration for detection of the flu. At the same time, concerns about the performance of commonly used rapid antigen tests have surfaced. The landscape of influenza diagnostics is rapidly evolving and clinical laboratories are certain to face pressure regarding new testing modalities. A Q&A feature in the November 2018 issue of Clinical Chemistry asked five experts with different roles in this field to discuss recent advances and ongoing challenges in influenza diagnostics.

A Review appearing in the October 2018 issue of Clinical Chemistry describes the trends and the technologies that have emerged in the past decade and are shaping contemporary point-of-care testing.  We are joined by the Review’s first author, Dr. Ping Wang.  She is Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania, and Director of Clinical Chemistry and Core Laboratory at the Hospital of the University of Pennsylvania. 

Standardization efforts for amylase have been limited by a lack of commutability in the current certified reference material.  New candidate reference materials have been developed to potentially overcome this limitation, facilitating their use for calibration and trueness control of routine measurement systems.  An original article appearing in the August of 2018 issue of Clinical Chemistry describes the commutability assessments of these new candidate reference materials for pancreatic alpha amylase.  The authors investigated if a reference material with an artificial matrix could be commutable for routine methods and compared to different statistical approaches to assess the commutability of the candidate reference materials.

Previously, carrier screening has been used in at-risk and specific ethnic populations, or for a limited number of diseases.  The broader screening approach, called expanded carrier screening, was endorsed in 2017 by the American College of Obstetricians and Gynecologists as an acceptable strategy for preconception and prenatal carrier screening.  This is expected to have a significant clinical impact, as targeted screening approaches likely have missed a large number of affected pregnancies due to the limited conditions tested, the unknown ethnic ancestry of many individuals, and the fact that the majority of children born with a genetic disease have no family history of the condition. When provided with results that their pregnancy is at-risk for a severe condition, study show approximately 80% of such couples pursue alternative reproductive options.  Given these consequences and the relative rarity of the included diseases, expanded carrier screening panels must have a high detection rate to correctly identify at-risk couples, and to minimize the residual risk when only one partner is tested positive.  Though next generation sequencing has revolutionized genetic testing as a whole, advances in detecting copy number variants by next generation sequencing have been critical to improving the analytical quality of expanded carrier screening panels. An original research article appearing in the July 2018 issue of Clinical Chemistry describes these achievements while establishing the analytical validity of expanded carrier screening and quantifying how many pregnancies could be impacted by this approach in the general U.S. population.

Test standardization is a complex and multifaceted effort that’s remained a major goal for laboratory medicine’s professional societies, including the AACC and IFCC.  Hemoglobin A1c is an example of a test that has undergone global standardization due to its worldwide importance in diabetes screening, diagnosis, and care.  A key part of any standardization effort is aligning all manufacturers’ methods to an accepted reference method.  This was the main aim of the European Hemoglobin A1c trial devised by the IFCC’s Committee on Education and Use of Biomarkers in Diabetes. The August 2018 issue of Clinical Chemistry includes an original research article that describes the European Hemoglobin A1c trial and its results.

Proper handling during the collection and processing of specimens is crucial for producing reliable results.  These pre-analytical steps are highly vulnerable to the introduction of experimental bias and variance, which may drastically degrade specimen quality.  Analytes are affected differently by uncontrolled variations in specimen collection, processing, and storage protocols. The August 2018 issue of Clinical Chemistry includes a Review article from the Precision Medicine and Pharmacometabolomics Task Group of the Metabolomics Society.  The authors summarize the current variability among pre-analytical processing and biobanking procedures for metabolomics research and provide recommendations for best practices.

According to the World Health Organization, type 2 diabetes comprises the majority of the more than 400 million people with diabetes around the world. In efforts to better understand the disease, metabolomics measurements have identified tryptophan metabolites as potential biological mediators in the development of type 2 diabetes.  The PREDIMED trial was a multi-center trial of Mediterranean-style diets where the primary prevention of cardiovascular events that also included type 2 diabetes as a secondary end point. An original research article published in the August 2018 issue of Clinical Chemistry studies whether tryptophan metabolites in PREDIMED participants were associated with development of type 2 diabetes and insulin resistance.

It was once thought that RNA only existed within cells.  However, recent discoveries show that RNA is exported from cells and may be functional in cell to cell communication.  This extracellular RNA can be abundant and stable and is found in bodily fluids such as saliva.  Saliva has long been of interest for biomarker discovery and development, given its noninvasiveness and relative ease of collection. Despite these advantages, use of saliva for understanding more about extracellular RNA and its role in human biology and disease through RNA sequencing has some challenges.  The high bacterial content and low abundance of extracellular RNA in saliva mean that optimization of RNA library construction and isolation protocols are critical to the success of these RNA sequencing experiments. An original research article in the July 2018 issue of Clinical Chemistry compares different RNA isolation methods and library construction kits for long and small RNA sequencing of salivary extracellular RNA.  The authors described which protocols provide the best RNA yield and detection by next generation sequencing.

Liquid biopsy methods are an exciting area in cancer screening, diagnosis, and management.  These methods are aimed at measuring genomic signatures of tumor cells in the blood.  They rely on detection of circulating tumor cells, tumor-derived extracellular vesicles, or exosomes, or cell-free circulating DNA.  Liquid biopsy methods have been proposed to compliment, enhance or perhaps even replace tissue biopsy in some scenarios.  Liquid biopsy methods are an exciting area in cancer screening, diagnosis, and management.  These methods are aimed at measuring genomic signatures of tumor cells in the blood.  They rely on detection of circulating tumor cells, tumor-derived extracellular vesicles, or exosomes, or cell-free circulating DNA.  Liquid biopsy methods have been proposed to compliment, enhance or perhaps even replace tissue biopsy in some scenarios.   Beyond the minimal invasiveness, performing liquid biopsy may overcome some other weaknesses of tissue biopsy that are related to a single site’s inability to capture intratumor heterogeneity or be representative of all the changes within the tumor.  All three approaches to detect a tumor’s genetic material have been applied for therapy stratification and monitoring in breast cancer.  However, knowledge about the differences between these methods in the same patient cohort is limited. An original article in the July 2018 issue of Clinical Chemistry compared messenger RNA profiles of circulating tumor cells and extracellular vesicles in patients with metastatic breast cancer to estimate the utility of each in therapy management.

Laboratory testing is a key component of models of care for all types of lipid disorders.  New therapies demand accuracy of dyslipidemia testing at very low LDL cholesterol concentration ranges.  Inaccurate results lead to incorrect diagnosis and therapeutic management, both of which are costly to society and harmful to patients. To address these key issues of lipoprotein and apolipoprotein markers and reach consensus on contemporary lipid testing, a multidisciplinary panel was established by the European Federation of Clinical Chemistry and Laboratory Medicine and the European Atherosclerosis Society.       The July 2018 issue of Clinical Chemistry includes a special report from this joint consensus initiative.  It provides recommendations for improving the use of the lipid profile to assess cardiovascular disease risk conferred by atherogenic lipoproteins.  

Cardiac troponins are recognized as the primary biomarkers used in the diagnosis of acute myocardial infarction.  These are commonly detected by immunoassays, which offer the wide availability and rapid results needed in clinical care scenarios to rule out myocardial infarction.  However, immunodetection methods can be limited when there is degradation of the target analyte, as is the case with cardiac troponin I. Early studies suggested that the central region, located between amino acid residues 30 and 110, was the most stable part of the molecule.  This was a driver for the majority of current diagnostic systems to utilize antibodies with epitopes located within the central region.  A down side to this approach is that auto antibodies also bind to this region, potentially causing interference and erroneous results. As more recent studies have identified additional cardiac troponin I proteolytic fragments, it is important to understand their composition and prevalence in the blood of patients with acute myocardial infarction.  Furthermore, there is a need to evaluate whether monoclonal antibodies specific to the regions beyond the central section of the molecule can be used to develop cardiac troponin I assays with improved performance over those currently available.  An original article appearing in the July 2018 issue of Clinical Chemistry describes a study investigating these concepts. 

The June 2018 issue of Clinical Chemistry published a Perspective article titled, “Clinical Utility of Transcriptome Sequencing: Towards a Better Diagnosis for Mendelian Disorders.”  In it, the authors Drs. Sumant Chakravorty and Madhuri Hegde discussed the impact of findings by Cummings and colleagues, who have shown for the first time in 2017 the clinical utility of next generation sequencing based transcriptome sequencing to increase molecular diagnostic yield by sequencing RNA.

Dementia is a devastating disease with a huge global impact. Today, over 46 million people live with dementia worldwide. It is possible that promising treatments for Alzheimer’s disease have failed thus far because treatment was started at a late stage of the disease process. So, early treatment could be beneficial, but how do you recognize a patient with Alzheimer’s disease if he or she does not present with clinical symptoms? This is a key question, and presents an enormous opportunity for laboratory test based on biological markers of ongoing brain pathology. One example is measurement of neurogranin, a protein in cerebrospinal fluid that correlates with cognitive decline and is a potential novel biomarker for Alzheimer’s disease dementia. There are multiple antibody-based neurogranin assays, which all target different segments of the protein. An original article in the June 2018 issue of Clinical Chemistry compared the analytical and the diagnostic performance of three commonly used neurogranin assays on the same cohort of patients.

Tuberculosis is a prevalent and potentially deadly infectious disease with a worldwide incidence of more than 10 million new cases each year, and in 2015 alone, 1.4 million deaths were attributed to TB.  Much of the world relies on microbiologic techniques to detect tuberculosis including smear microscopy and mycobacterial culture which has a very long sample to answer timeframe. Both methods also have low clinical sensitivity for paucibacillary TB cases which account for more than 60% of new TB cases each year in emerging endemic areas such as China.  PCR-based methods are faster but also have limitations.  In the May 2018 issue of Clinical Chemistry, Dr. Tony Hu and his colleagues described a new peptide-based approach to detecting TB that overcomes those issues by using antibody conjugated nanoparticles, or nanodiscs, to bind specific peptides present in digested serum samples from cases of tuberculosis.  These are then detected by benchtop matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, or MALDI-TOF MS.

Metastatic or recurrent cancers are a common cause of death among cancer patients.  Genomic investigations of cancer over the past 10 years have led to tremendous advancement in the understanding of the underlying biology and in the development of targeted treatment options.  Much of the discovery has been focused on primary treatment-naive cancers, since biological specimens for genomic analysis are more abundant in these cases that are available from patients with metastatic cancers. The lack of specimens has provided a significant obstacle in the genomic study of metastatic cancers.  Therefore, a recent study by Dr. Dan Robinson and colleagues reported in the journal Nature has raised excitement.  The investigators performed integrative analysis of DNA and RNA data for 500 metastatic lesions obtained from cancer patients with over 30 different primary cancer diagnoses to derive several types of molecular characterizations.  Though further studies are needed, applying these approaches to individual patients in the clinical setting of metastasis may lead to more precisely tailored therapeutic treatments with higher effectiveness. The May 2018 issue of Clinical Chemistry includes an expert commentary on this noteworthy study. 

Surgery is a common form of treatment in patients with solid tumors.  Depending on the cancer, surgery may be used to remove cancer that is contained within a specific area, to debulk a tumor, or to ease symptoms caused by a tumor.  In each case, it is critical to distinguish cancerous from noncancerous tissue during the operation. Today, pathologists perform rapid microscopic investigations of biopsied tissue and make the diagnosis.  In the future, this may be conducted using mass spectrometry based measurements.  Ambient ionization mass spectrometry methods make localized molecular level chemical analysis of tissue samples possible at atmospheric pressure and without prior sample purification and pre-treatment.  Over the past decades, scientific advances have extended the role of these methods from the research laboratory to the operating room.  The April 2018 issue of Clinical Chemistry includes a commentary on the different technologies and their potential in cancer diagnosis.

Cardiac troponin measured with newer generations of analytically highly sensitive assays have been investigated in accelerated discharge protocols on the assumption that they have an improved ability to detect and quantify cardiomyocyte injury more quickly than previous generation’s assays. In the May 2018 issue of Clinical Chemistry, Dr. Jaimi Greenslade from the Royal Brisbane and Women’s Hospital in Herston, Australia, and her colleagues investigated a high sensitivity cardiac troponin I assay to see if a single test threshold can safely rule out acute MI.

Amniocentesis is a common procedure usually performed to collect cells from the fetus to allow testing for abnormal chromosomes.  Cells from the amniotic fluid are collected through centrifugation, cultured, and after about two weeks, analyzed by fluorescent in situ hybridization, or FISH, or with a microarray to detect abnormal chromosome copy number changes or large chromosomal structural rearrangements.  These tests have become the gold standard for detecting Down Syndrome and several other serious birth defects because they have a low false positive rate.  However, they are unable to detect the majority of birth defects.Amniocentesis is a common procedure usually performed to collect cells from the fetus to allow testing for abnormal chromosomes.  Cells from the amniotic fluid are collected through centrifugation, cultured, and after about two weeks, analyzed by fluorescent in situ hybridization, or FISH, or with a microarray to detect abnormal chromosome copy number changes or large chromosomal structural rearrangements.  These tests have become the gold standard for detecting Down Syndrome and several other serious birth defects because they have a low false positive rate.  However, they are unable to detect the majority of birth defects. In the April 2018 issue of Clinical Chemistry, a paper demonstrated the feasibility of generating an accurate whole genome sequence of a fetus from either the cellular or cell-free DNA of an amniotic sample. 

High-density lipoprotein, or HDL, cholesterol is often referred to as the “good” cholesterol due to its involvement in transport of cholesterol from peripheral tissues back to the liver during reverse cholesterol transport.  However, some studies have demonstrated that the size and composition of HTL particles may influence the mechanism and capacity for this cholesterol efflux and other possible protective activities.  So, some researchers believe that measurement of HTL particles, size, and composition may provide an indication of HTL protective activity. The March 2018 issue of Clinical Chemistry published a report comparing five different procedures for HDL particle measurement.  In the same issue an editorial by Dr. Jeffrey Meeusen appeared titled “Comparing Measures of HDL: On the Right Path with the Wrong Map.”

Data on biological variation can be used in many ways, most notably for the diagnosis and monitoring of disease and also for setting analytical performance specifications.  In 2014, after the first strategic conference of the European Federation of Clinical Chemistry and Laboratory Medicine, a task force was established to develop criteria for evaluation of the literature on biological variation. A report from this group appears in the March 2018 issue of Clinical Chemistry.

Studies have found that drugs are now so prevalent that over 10% of a population were found to have traces of Class A drugs on their fingerprints despite never using any of those drugs.  While fingerprints have been suggested as a possible sample to rapidly and noninvasively carry out drug testing, identifying drug users and not those who may have passively encountered a drug can be complex. In a study published in the June 2018 issue of Clinical Chemistry and available online now, researchers from the University of Surrey together with Dutch scientists may have found a solution.  They present evidence that their techniques give a zero false positive rate in the fingerprints from drug-free volunteers.  Yet, they were able to detect 87.5% of the cocaine users and 100% of heroin users.

Familial hypercholesterolemia is a frequent genetic disorder encountered in clinical practice and is associated with high levels of serum LDL cholesterol known as the “bad cholesterol.” A diagnosis of familial hypercholesterolemia has important clinical implications with respect to risk of cardiovascular disease and a requirement for intensive pharmacological therapy. Often, the baseline LDL cholesterol before treatment is not available because the patient has initiated and continues on lipid lowering therapy, especially statins. Furthermore, the original baseline LDL cholesterol may predate the current status by many years and cannot be easily retrieved. The February 2018 issue of Clinical Chemistry published a paper describing a method to obtain an imputed, or estimated, baseline LDL cholesterol concentration in these patients who are already taking cholesterol lowering drugs. Both a computer program and a smartphone app are available from links in the paper. We are pleased to have the lead author of that paper as a guest on this podcast. Isabelle Ruel is a Clinical Biochemist at the Research Institute of the McGill University Health Center Royal Victoria Hospital in Montreal, Quebec, and is currently the national coordinator of the Canadian Registry on Familial Hypercholesterolemia.

A paper in the March 2018 issue of Clinical Chemistry describes a liquid chromatography tandem mass spectrometry procedure for multi-steroid profiling in Cushing syndrome and other disorders.  The lead author of that study is Dr. Graeme Eisenhofer, who is professor and the Chief of the Division of Clinical Neurochemistry at the Institute for Clinical Chemistry and Laboratory Medicine at the Technical University in Dresden, Germany.  He is our guest in this podcast.

Commutability is an important concept in determining traceability and the relationship among different methods that are used to measure the same analyte but just how to describe and classify commutable materials is not always straightforward.  The March 2018 issue of Clinical Chemistry published a series of three reports from the Working Group on Commutability of the International Federation of Clinical Chemistry and Laboratory Medicine, or IFCC, that describe recommendations for assessing commutability.

Normal pregnancy is associated with profound hormonal and metabolic changes in the mother, including changes in thyroid hormones.  These normal changes include increased thyroid binding globulin, increased total T3 and total T4, transient decrease in TSH, and in some patients, a transient increase in serum FT4 during the first trimester. In 2017, the American Thyroid Association issued new guidelines for the diagnosis and management of thyroid diseases during pregnancy, which can be difficult due to the numerous normal physiological changes.  Most would agree that the document is an excellent review of current literature relating to the assessment of thyroid status during pregnancy.  However, one researcher wonders if a particular recommendation of the document is misguided.

Expert Q&A 

In the era of precision medicine, it is no surprise that there is an emerging interest in personalizing one’s diet based on their genetic make-up.  This concept called, “precision nutrition,” refers to the application of -omics techniques such as genomics and metabolomics, to achieve better prevention or treatment of disease to optimize nutrition. The January 2017 Clinical Chemistry special issue on obesity includes a review article that summarizes the current and future roles of nutritional metabolomics.

Although bariatric surgery techniques were originally developed to treat morbid obesity, the indications for their use have expanded as a consequence of the emerging evidence of their wider metabolic benefits.  Now described as metabolic surgeries, these treatment methods derive as much benefit from their metabolic and cardiovascular effects as from the resulting weight reduction. Though promising evidence is emerging, there is a need for further mechanistic studies to assess the true potential of metabolic surgery to treat the myriad other disorders of metabolism and to better understand their consequences in terms of cardiovascular disease and cancer risk reduction.  Additionally, there may be unintended consequences of bariatric surgery that are related to long term adverse skeletal effects and nutritional deficiencies.  

Hepatitis C virus or HCV infection affects close to 150 million people worldwide.  In the U.S., it is estimated that as many as five million people have been infected with the Hepatitis C virus, many of whom are unaware of their infection.  HCV is now the most common indication for liver transplantation, and it accounts for more deaths each year than all other reportable infectious diseases combined including HIV. Advances in testing methods and antiviral therapies with increased development of infrastructures that improve access care now make eradication of HCV infection in well-resourced countries a realistic goal.  However, challenges in implementing screening programs and continues evolution of assay methods and screening protocols raise several issues for how clinicians and laboratories respond to the changing landscape for HCV diagnosis and treatment.  The December 2017 issue of Clinical Chemistry includes a Q&A article with several experts who offer their insights and opinions on this topic.

Adrenal steroid analysis plays an important role in the diagnosis of Cushing's syndrome, disorders of steroidogenesis, and adrenal tumors.  The analytical sensitivity and specificity for steroid assays have evolved over time from individual immunoassays to multiplexed mass spectrometry-based methods.  This transition has highlighted a need for simultaneous measurement of multiple steroids and their various metabolites to achieve the best diagnostic accuracy.  Therefore, metabolomic profiling performed by liquid chromatography, high-resolution accurate-mass mass spectrometry might be poised to make a substantial impact on endocrine laboratory testing.  The December 2017 Issue of Clinical Chemistry describes such a method used to determine sex- and age-based reference intervals and to perform a limited assay evaluation in patients with different adrenal diseases.

Exposure to lead in adults is typically via occupational or environmental exposures. The incidence of lead poisoning have declined worldwide due to improved industrial safety measures and the limited use of lead in paint, pipes, and canned goods. Though an increasing number of lead intoxications have been caused by the use of contaminated illicit drugs, including opium, marijuana and amphetamine, this may be due to impurities introduced during manufacturing or from deliberate addition to increase the weight for a higher selling price. A Clinical Case Study in the December 2017 issue of Clinical Chemistry discusses a series of adult patients who presented with similar symptoms and were discovered to have extremely elevated blood lead concentrations.

Sepsis is a life-threatening condition associated with significant mortality and healthcare cost.  There is increasing evidence supporting the use procalcitonin as a biomarker for diagnosis of bacterial sepsis and as a guide to discontinue antibiotic therapy.  However, concerns about the efficacy, safety, and availability of procalcitonin exist.  A Q&A article in the September 2017 issue of Clinical Chemistry asked experts with different roles in this field to share their thoughts on the challenges of procalcitonin-guided diagnosis and antibiotic therapy. 

Richard Body

Randie Little

Matthew McInnes

Jason Park

Dina Greene

Daniel Korevaar

Greg Miller

Mark Chan

 Asthma is a chronic inflammatory lung disease that affects an estimated 300 million people worldwide, including 25 million in the United States. There are currently no definitive diagnostic tests for asthma. Diagnosis is based on history and tests of respiratory function.

Circulating tumor cells are fundamental to the concept of a liquid biopsy for cancer.  These cells are shed from the primary tumor and are carried in the blood to remote sites, potentially leading to metastasis formation.  Understanding more about this process is critical as tumor metastasis is a leading cause of cancer death.  Yet this is challenging as the number of circulating tumor cells in an individual is very small, making them difficult to study in detail. Cell lines derived from circulating tumor cells can be created to overcome this problem.  This has been done in colon cancer, for example, and enables researchers to examine molecular and functional differences between the circulating tumor cells and those from the primary tumor.  In this way, researchers may further our ability to identify and characterize cells that initiate metastasis and to ultimately develop new therapies to stop them. An original report in the January 2017 issue of Clinical Chemistry describes the differential gene expression between colon cancer cell lines derived from circulating tumor cells and the primary tumor.  Dr. Catherine Alix-Panabières is the primary author of this article and joins us for this podcast.

Cannabis and its products are the most widely used illicit drugs world-wide, with the majority of countries currently harboring consumers and producers. Medicalization and legalization of the drug...

Monitoring of glycemic control with hemoglobin A1c (A1c) in hemodialysis patients may be compromised by anemia and erythropoietin therapy.

Disorders of bone metabolism, most notably osteoporosis, are highly prevalent and predispose to fractures, causing high patient morbidity and mortality.

In addition to focusing on the publication of cutting-edge scientific reports, Clinical Chemistry has shown a genuine commitment to education by devoting a substantial portion of its pages to educational articles since 2008.

Every year, commercial testing labs earn millions of dollars from selling the anonymized results of blood, urine, tissue, and other tests with almost no public scrutiny or debate.2 Few outside the industry know anything about this trade, and lab workers are often in the dark as well.

Researchers have developed approaches for the noninvasive prenatal testing of single gene diseases.

Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point.

Quantifying the variability of biomarkers is important, as high within-person variability can lead to misclassification of individuals. Short-term variability of important markers of vitamin D metabolism is relatively unknown.

Chronic kidney disease (CKD) is common, particularly in those of advanced age.

The development and implementation of sensitive and high-sensitivity cardiac troponin assays has not only expedited the early ruling in and ruling out of acute myocardial infarction, but has also contributed to the identification of patients at risk for myocardial injury with necrosis, as confirmed by the presence of cardiac troponin concentrations above the 99th percentile.

Pulmonary embolism (PE) is associated with high all-cause and PE-related mortality and requires individualized management.

Serial measurements of high-sensitivity troponin are used to rule out acute myocardial infarction (AMI) with an assay specific cutoff at the 99th percentile.

Risk stratification in acute myocardial infarction (MI) remains a clinical challenge.

Patients with chest pain comprise a large proportion of emergency presentations and place a major burden on healthcare resources.

The role of alcohol in the development of subclinical cardiovascular disease is unclear. We examined the association between alcohol consumption and markers of subclinical cardiac damage and wall stress.

The substantial technological advancements in next-generation sequencing (NGS), combined with dropping costs, have allowed for a swift diffusion of NGS applications in clinical settings.

This is the November2016 issue of Clinical Chemistry, Volume 62, Issue 11.

Measurement of serum cancer antigen 125 (CA125) is the standard approach for epithelial ovarian cancer (EOC) diagnostics and follow-up. However, the clinical specificity is not optimal because increased values are also detected in healthy controls and in benign diseases.

Electrophoretic separation of serum and urine proteins has played a central role in diagnosing and monitoring plasma cell disorders. Despite limitations in resolution and analytical sensitivity, plus the necessity for adjunct methods, protein gel electrophoresis and immunofixation electrophoresis (IFE) remain front-line tests.

Circulating tumor DNA (ctDNA) has emerged as a good candidate for tracking tumor dynamics in different cancer types, potentially avoiding repeated tumor biopsies. Many different genes can be mutated within a tumor, complicating procedures for tumor monitoring, even with highly sensitive next-generation sequencing (NGS) strategies.

Most people perceive pilots who don't fly for the commercial airlines as daredevils who always "fall out of the sky." My acquaintances are genuinely surprised to learn that I, a medical doctor and a clinical chemist, am one of those presumed reckless individuals.

Cardiac troponin is integral in the investigation of acute coronary syndromes. Modern high-sensitivity versions of troponin assays are able to detect very low concentrations and potentially identify disease sooner.

The Ebola outbreak in the fall of 2015 led to emergent responses by hospitals to prepare for potential patients. This included preparedness efforts by laboratories, which was challenging as they was evolving and at times contradicting information about how samples from patients under investigation for Ebola should be handled.

It is no secret that laboratory tests are overordered in the clinical environment; a recent metaanalysis demonstrated that tests are overused by 20.6% on average. The ordering of unnecessary tests on such a massive scale may impact not only direct healthcare costs, but also patient safety, and may lead to unnecessary follow-up investigation and iatrogenic blood loss due to excess phlebotomy. Unfortunately, in large hospitals with high patient volumes, it would be impractical for laboratory directors to evaluate every test individually for appropriateness, and even more difficult to convince providers to change ordering practices. Meeting other evidence-based quality objectives in laboratory ordering is similarly labor-intensive.

Initial detection and reporting by clinical microbiology laboratories is a sentinel marker for foodborne outbreak surveillance systems. Initiation of a public health investigation is reliant on the rapid initial identification of pathogens of interest. Diagnostics for Escherichia coli have evolved to reduce identification turnaround time, incorporating technologies for rapid identification (MALDI-TOF MS) and serogrouping (O157 antiserum or latex agglutination). Reporting of these isolates to a public health agency may initiate further laboratory investigations, such as pulsed-field gel electrophoresis, for confirmation that isolates may be related to a common source (clonal population).

Next generation sequencing is increasingly available in clinical laboratories, enabling the sequencing of more genes for relatively lower costs.

The practice of medicine is not always clear-cut. Healthcare providersare often faced with difficult decisions such as what test to perform on patients, what treatment should be given, and what type of follow-up is needed. Providers have a duty to enhance the wellbeing and minimize harm to their patients.

The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect.

The basic problem shared by many of the biostatistical methods used in marker research is that they relate numbers to other numbers, rather than to anything that we might care about in the real world.

Pneumatic tube systems have become a primary way of automating the transport of clinical specimens in medical centers. These may travel within the floors of a building and also between buildings. Although this provides convenience and speed of transport, the excessive acceleration forces and the prolonged time and distance travelled have been linked to pre-analytical variation including hemolysis of blood specimens. As a result, it has been suggested that users regularly assess the forces encountered in a pneumatic tube system.

Postmarket surveillance is an important monitor of the safety of pharmaceuticals and medical devices after regulatory approval and entry to the market. Although premarket studies are substantial, costs prohibit examination of heterogeneous populations or rare events over long durations.

There are nearly 60,000 community pharmacies in the United States today. In addition to being sources of prescriptions and medications, they're also often a site for wellness visits, vaccinations, acute illness diagnosis and treatment, as well as monitoring of chronic disease. Pharmacies often offer a convenient alternative to physician offices because of their accessible locations and extended service hours. Approximately 18% of pharmacies in the U.S. have CLIA-waived status, which means they can perform any of the approximately 120 CLIA-waived tests. Many pharmacists help patients make drug dosage decisions in specialized centers such as coumadin in diabetes clinics. With pharmacists performing and interpreting more laboratory tests, what does this mean for the clinical laboratory community? Do pharmacists receive the proper training to perform and interpret laboratory tests? And how do we ensure the quality of testing?

Protease neprilysin is known to be responsible for the degradation of natriuretic peptides. A recent heart failure (HF) drug, LCZ696 (EntrestoTM), that combines a neprilysin inhibitor and an angiotensin II receptor inhibitor was suggested to augment circulating B-type natriuretic peptide (BNP) concentrations, making the results of BNP measurements diagnostically ambiguous. Because the main form of measured BNP in HF patients is represented by its uncleaved precursor, proBNP, it is important to know the susceptibility of proBNP to cleavage by neprilysin.

CREB-regulated transcription coactivator 3 (CRTC3) is found in adipocytes, where it may promote obesity through disruption of catecholamine signaling. We wished to assess whether CRTC3 is a soluble protein secreted by adipose tissue, explore whether CRTC3 is detectable and quantifiable in the circulation, and ascertain whether CRTC3 serum concentrations are related to metabolic markers in children.

The analysis of dried blood spots has been used routinely for newborn screening since the early 1970s, and the number of disorders screened has expanded substantially in recent years. However, there is a lack of evidence regarding minimum blood spot quality acceptance criteria for sample analysis.

For many years the determination of a routine lipid profile (total, LDL, and HDL cholesterol and triglycerides) has been done routinely in the clinical laboratory using a blood specimen that is collected in the fasting state.

Primary aldosteronism,also known as Conn's syndrome,is a form of endocrine hypertension that results from excess product of aldosterone by the adrenal glands.

More than 70 million couples worldwide are affected by infertility, with male-factor infertility accounting for about half of the cases. Semen analysis is critical for determining male fertility potential, but conventional testing is costly and complex. Here, we demonstrate a paper-based microfluidic approach to quantify male fertility potential, simultaneously measuring 3 critical semen parameters in 10 min: live and motile sperm concentrations and sperm motility.

Clostridium difficile is the most common cause of healthcare associated infections in the United States and is increasingly recognized as a pathogen in the community. This organism is considered to be one of the most urgent antibiotic resistant threats to public health, and can cause a variety of clinical manifestations ranging from asymptomatic to mild diarrhea, to toxic megacolon, and even death.

More than 70 million couples worldwide are affected by infertility, with male-factor infertility accounting for about half of the cases. Semen analysis is critical for determining male fertility potential, but conventional testing is costly and complex. Here, we demonstrate a paper-based microfluidic approach to quantify male fertility potential, simultaneously measuring 3 critical semen parameters in 10 min: live and motile sperm concentrations and sperm motility.

Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes, but risk is reduced with identification and early treatment. Glucose measurements are affected by preanalytical sample handling, such as temperature of storage, phlebotomy–analysis interval, and use of a glycolysis inhibitor. We evaluated glucose concentrations and the incidence of GDM after strict implementation of the American Diabetes Association (ADA) preanalytical guidelines, compared with usual hospital conditions.

Evidence is accumulating that circulating 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations are inversely related to overall mortality.

Limited information is available about testosterone concentrations representative of the general US population, especially children, women, and non-Hispanic Asians.

Mass spectrometry–based in vitro diagnostic devices that measure proteins and peptides are underutilized in clinical practice, and none has been cleared or approved by the Food and Drug Administration (FDA) for marketing or for use in clinical trials. One way to increase their utilization is through enhanced interactions between the FDA and the clinical mass spectrometry community to improve the validation and regulatory review of these devices.

There are now numerous epidemiological studies that have demonstrated that low plasma concentrations of vitamin D are associated with not only bone related disorders, but with a wide variety of adverse health outcomes.

A driving force in the development of point-of-care diagnostics is to conveniently provide information without delay so that healthcare decisions can be made while the patient is on-site. Most point-of-care devices are based on immunochemical, electrochemicalor colorimetric techniques that can be miniaturized and made portable.

A mass spectrometer is a sensitive and specific instrument." In some form or another, this is often the label applied to the platform by all manner of professions (chemists, physicists, biologists, physicians, clinicians, and laboratorians, novice and expert alike). This is a view of mass spectrometry (MS) through rose-colored glasses. It should be properly said that MS can be sensitive and specific, but not without due consideration for the measurement to be performed. In clinical laboratories, this measurement is the extraction, detection, and often, quantification of a compound of interest from a biological matrix.

Despite increasing prevalence of novel psychoactive substances, no human metabolism data are currently available, complicating laboratory documentation of intake in urine samples and assessment of the drugs' pharmacodynamic, pharmacokinetic, and toxicological properties. In 2014, THJ-018 and THJ-2201, synthetic cannabinoid indazole analogs of JWH-018 and AM-2201, were identified, with the National Forensic Laboratory Information System containing 220 THJ-2201 reports. Because of numerous adverse events, the Drug Enforcement Administration listed THJ-2201 as Schedule I in January 2015.

Protein glycosylation is increasingly recognized as a crucial modulator of protein function, offering a third layer of biological information over genomics and proteomics. Modern tools for analyzing released N-glycans from cells and body fluids, i.e., the glycome, have shown abnormal protein glycosylation in numerous human diseases. These include both genetic and acquired diseases, ranging from diabetes, cancer, and inflammatory disease to neurodegenerative and neuromuscular disease. Insights from this novel field in human medicine provide exciting perspectives toward understanding disease processes, identifying therapeutic targets, and designing individualized diagnostics based on protein concentrations and glycosylation status. However, the main question is how we can translate this information into concrete biomarkers in a clinical diagnostic setting, with high demands on technical robustness and the ability to interpret results within specific patient groups.

Analytically sensitive techniques for measuring minimal residual disease (MRD) in multiple myeloma (MM) currently require invasive and costly bone marrow aspiration. These methods include immunohistochemistry (IHC), flow cytometry, quantitative PCR, and next-generation sequencing. An ideal MM MRD test would be a serum-based test sensitive enough to detect low concentrations of Ig secreted from multifocal lesions.

The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends use of a cystatin C–based estimated glomerular filtration rate (eGFR) to confirm creatinine-based eGFR between 45 and 59 mL · min−1 · (1.73 m2)−1. Prior studies have demonstrated that comorbidities such as solid-organ transplant strongly influence the relationship between measured GFR, creatinine, and cystatin C. Our objective was to evaluate the performance of cystatin C–based eGFR equations compared with creatinine-based eGFR and measured GFR across different clinical presentations.

Informatics is changing the processes behind laboratory medicine. With ever-growing demands on laboratory medicine professionals not only to collect and interpret omics data in the era of the Precision Medicine Initiative, but also to ensure high-quality, low-cost patient management in the structure of accountable care organizations, we have invited several experts to discuss their take on "big data."

Combined testing of high-sensitivity cardiac troponin T (hs-cTnT) and copeptin at presentation provides a very high—although still imperfect—negative predictive value (NPV) for the early rule-out of acute myocardial infarction (AMI). We hypothesized that a second copeptin measurement at 1 h might further increase the NPV.

We investigated whether obese pregnant women negative for gestational diabetes (GDM) still experience dysglycemia, as indicated by high glycated hemoglobin (Hb A1c) at delivery, and whether this impacts offspring and long-term maternal outcomes.

STARD 2015: An updated list of essential items for reporting diagnostic accuracy studies

Increased concentrations of non-fasting remnant cholesterol are thought to be atherogenic in thesame way as LDL cholesterol,by transport into andaccumulationof lipid into the arterial wall.

For patients with acute coronary syndrome who have undergone interventions such as placement of a stent, it has become standard practice to treat them with a combination of aspirin and opidogrel to prevent subsequent thrombotic events; however, clopidogrel is a drug that requires activation by a liver enzyme, CYP2C19.

Most of us are familiar with the link between elevated concentrations of lipids in our blood and an increased risk for cardiovascular disease which is responsible for about 500,000 deaths each year in the United States. It has been common practice to measure those lipids only after a period of fasting. This practice was put in place because of the known increases in triglycerides that can occur after eating; however, fasting lipid profiles have not actually been shown to be superior to nonfasting lipid profiles in assessing the risk for cardiovascular disease.

Microfluidics has attracted a lot of attention across a wide range of disciplines because of the potential for using it to analyze tiny samples and to integrate processes onto handheld Labs-on-a-Chip. So instead of sending vials of blood to a central laboratory and getting results back days later, you can imagine a Microfluidic device that can give you the same performance, but with a finger prick of blood right on the spot, in minutes.

Commutability is an important concept in determining traceability and relationship among different methods used to measure the same analyte, but how to delineate commutable materials is not straightforward and a number of techniques have been proposed.

Several studies have suggested that prevention of atherosclerosis should begin in childhood as dyslipidemia in children is associated with severity of atherosclerotic lesions later in life. Pediatric lipid screening aims to identify children and adolescents with dyslipidemia, including both those with more severe genetic cases and those cases with mild to moderate lipid elevation due to secondary causes.

Advances in clinical laboratory testing have had a profound impact in improving the quality of medical care. Today laboratory diagnostic tests inform physicians and patients of the exact causes of a number of diseases and disorders, including cancer, chronic diseases, infectious diseases, sexually transmitted diseases, and genetic disorders.

In the past decade there has been a rapid increase in the number of individuals who have had their entire genome sequenced. Over the next decade that number will go from the thousands to the millions. These people are having their genomes sequenced for research, recreational interest, and clinical testing.

Vitamin D insufficiency has been widely associated with numerous negative health outcomes, including higher all-cause mortality, although no mechanism has been formally established for such observations.

Clinical trials, epidemiologic and most types of clinical research, include the acquisition of biological samples to be analyzed either immediately after collection, or in the future for biomarkers related to the study hypotheses. Tested biomarkers include those used to monitor subjects' health and to detect harmful side effects or to follow impact of therapeutic interventions.

Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use.

Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use.

A major objective of the International Federation of Clinical Chemistry and Laboratory Medicine, or IFCC, Task Force on implementation of Hemoglobin A1c Standardization is to develop quality targets with the measurement of Hemoglobin A1c.

Medical laboratories provide valuable services to aid in patient diagnosis and management, but systematic evidence of laboratory medicine's specific contribution to the overall process of healthcare is not easy to come by. Even the widely quoted claim that laboratory medicine results are responsible for a 70% of all clinical decisions seems to elude objective verification.

Over the past 20 years or so there have been several studies published showing an association between decreased concentrations of vitamin D in blood and the risks of cardiovascular disease, stroke, cancer, fractures, even overall mortality.

Rapid urine pregnancy tests have been available for over 30 years. They can be performed in minutes and are used at home, in doctors' offices and in emergency rooms. Doctors in particular rely on these tests to rule out pregnancy in order to prevent fetal injury or death that could be caused by certain medical procedures or drugs.

Recently, the New England Journal of Medicine partnered with Area9 Learning, a physician-led pioneer in adaptive learning, to create a platform with smart technology that adapts to clinicians' learning goals and knowledge gaps to deliver the information they need to know.

Aggressive strategies to lower Low Density Lipoprotein cholesterol in circulation are recommended for prevention of cardiovascular events. Most often laboratories report LDL-cholesterol based on an equation using measured values of total cholesterol, HDL - cholesterol and triglycerides, the so called Friedewald calculation named after the first author who published that work in Clinical Chemistry back in 1972.

Medical laboratories frequently encounter clinically unexpected results that require timely clinical evaluation because they may indicate an imminent life-threatening condition or a major clinical deterioration. Laboratories, therefore, need to identify and report such results sooner than they normally would, and have policies and procedures that minimize the possibility of patient harm due to delayed clinical attention. The concept of these so-called "panic values" was raised by George Lundberg in 1970, but a variety of other terms have since appeared in the literature. For example, urgent, critical, acute, alert, abnormal, markedly or significantly abnormal, clinically significant, vital, red or orange or yellow zone values, and various combinations of terms.

In December 2013 the genetics laboratory 23andMe stopped marketing direct-to-consumer disease predictive genetic testing in order to comply with a directive from the US Food and Drug Administration. The FDA's action was intended to protect the American public from questionable disease risk predictions.

Big data now seems to be everywhere. Google search queries are used to predict flu outbreaks and airline statistics or mined to determine the best hour of which day to book plane tickets. Clinical laboratories can also benefit from these trends. Given the emerging importance of reproducible data analysis pipelines, one could think of a special group of trained big data experts that could be available to regulatory agencies and to clinical laboratories for review and auditing of their processes and practices, and who may be able to offer suggestions for improvements.

Hemoglobin A1c is widely used to monitor glycemic control and is now recommended for use in the diagnosis of diabetes. Although hemoglobin A1c has high reliability compared to the oral glucose tolerance test, there are certain settings in which such testing may be problematic and there is a growing interest in alternative markers of hyperglycemia.

Although hemoglobin A 1 C has high reliability , there a re certain settings in which hemoglobin A1C testing is thought to be problematic. 1 , 5 - anhydroglucitol or 1,5 - deoxyglucose is a monosaccharide originating mainly fr om foods and closely resembles glucose in structure , but is usually excreted by the kidneys.

Human saliva has been increasingly used for biomarker development to allow noninvasive detection of diseases. Extracellular RNA was discovered in saliva about 10 years ago, and since then the nature, origin , and characterization of salivary RNA have been actively pursued.

Prenatal testing using blood specimens rather than more invasive sampling has been successfully used for common chromosome disorders and for clinically significant copy number variations . H owever , detecting single gene disorders which are caused by mutations remains an analytical challenge.

In the last year, multiple clinical studies have shown the diagnosti c power of testing a patient's exome. Clinical exome testing is now available at over a dozen clinical laboratories in the US , and has been performed for thousands of patients.

Next generation sequencing (NGS)13 technology, also known as massively parallel sequencing (MPS), is being incorporated rapidly to clinical laboratory testing. Current applications include detection of germline variants in inherited diseases, somatic variants in cancers, subpopulations of circulating cell-free DNA, and single viral or microbial genomes in infections or metamicrobial genomes in normal or altered human flora. Each application is unique and has its advantages and disadvantages.

Extreme sports, extreme eating, extreme weight loss, extreme makeovers, just when you think you've heard it all, how about Extreme PCR?

Familial hypercholesterolemia is a genetic disorder characterized by increased plasma concentrations of low density lipoprotein cholesterol and premature symptoms of coronary heart disease. Early identification of at-risk individuals allows changes in lifestyle including dietary intervention and drug treatment. In the January 2015 issue of Clinical Chemistry, a Special Issue devoted to Molecular Diagnostics, a group of researchers in a multi-center study describes a genetic risk score procedure that distinguishes familial hypercholesterolemia patients from healthy subjects.

Extreme sports, extreme eating, extreme weight loss, extreme makeovers, just when you think you've heard it all, how about Extreme PCR?

For decades iron has been thought of as beneficial for the body. Most everyone knows that iron deficiency is harmful and that the condition should be treated by additional iron in the diet. However, too much iron can also be harmful to the body. Ferritin is a protein that stores iron and measurement of ferritin in serum is a measure of the iron deposits in the body.

Biobanking for clinical or research purposes includes the collection, processing, storage and analysis of biological specimens. It is now well-recognized that biobanking involves a complex array of technical, ethical, and regulatory considerations.

Kidney cancer is among the ten most frequently occurring cancers in the Western world and its incidence has been steadily rising each year. In the absence of symptoms, about 30% of patients with renalcell carcinomas are diagnosed with disease already in the metastatic stage.

Over the past decade genomic testing has emerged as a clinical tool available in multiple hospital and independent laboratories across the United States. In the November 2014 issue of Clinical Chemistry, an opinion article titled "Clinical Genomics: When Whole Genome Sequencing Is like a Whole-body CT Scan" framed the clinical utility of genomic testing in the context of another recently transformative test, whole-body computed tomography scanning, more commonly known as a CT scan.

In August 2014, the first patient with the Ebola virus disease arrived in the United States and was transported to Emory Hospital in Atlanta. While hospitals and laboratories knew that it was only a matter of time before this occurred, subsequent experience has shown that not all institutions in the U.S. were equally prepared for this eventuality. In this special podcast from Clinical Chemistry, we're joined by two members of the laboratory team that treated the first healthcare workers arriving from West Africa.

Turnaround times are often long in PCR-based tests because multiple reactions are usually performed in parallel using programmable thermal cyclers. These methods typically use a single protocol, placing constraints on assay design.

Thrombosis and bleeding are among the foremost causes of morbidity and mortality, and the recent introduction of novel anticoagulants, anti-thrombotic, and hemostatic drugs has increased the need for rapid and accurate assessment of their activities. While the usual laboratory assessment of hemostasis, such as prothrombin time and other coagulation tests, are often effective, these methods may not identify all bleeding disorders.

Using prohibited substances to enhance performance in sports, often referred to as doping, is a practice that's been with us all of recorded history. In ancient time, athletes or combatants were often supplied diets and supplements considered beneficial to enhance their performance.

Estimating Glomerular Filtration Rate or GFR is important for the detection and monitoring of impairment of renal function for safety in the use of potentially nephrotoxic pharmaceuticals and radiographic contrast media, and for administration of correct dosage of drugs cleared by the kidneys. Even though it is not ideal, serum creatinine is widely used as a marker for calculating Glomerular Filtration Rates.

Where are all the new omics-based tests? That's the question that Patrick Bossuyt asks in his paper appearing in the October 2014 issue of Clinical Chemistry. After billions of dollars worldwide have been spent upon omics-based research and announcements of many biomarker discoveries, clinical medicine has not gone through a radical change, despite all of the investment of time, money, and the collaboration of thousands of study participants.

Fragile X Syndrome is a severe neurodevelopmental disorder which is both complex and heterogeneous in both clinical phenotype and epigenotype. It is also one of the major inherited conditions co-morbid with autistic behaviors.

Fragile X Syndrome is a severe neurodevelopmental disorder which is both complex and heterogeneous in both clinical phenotype and epigenotype. It is also one of the major inherited conditions co-morbid with autistic behaviors.

In a 2009 study in Clinical Chemistry, Dr. Erna Lenters and Dr. Robbert Slingerland evaluated eight different points of care instruments measuring hemoglobin A1c and came to the conclusion that six of the eight did not meet generally accepted analytical performance criteria.

MicroRNAs measured in blood samples are promising, minimally invasive biomarker candidates that have recently been the target of many case control studies. However, the influence of age and gender is confounding variables and MicroRNAs remain largely unknown.

Analysis of circulating RNA in the plasma of pregnant women can be a powerful tool for noninvasive prenatal testing and research. However, unbiased and high throughput detection of circulating RNA in plasma is a technical challenge.

The cover of the September 2014 issue of Clinical Chemistry tells it all: one million downloads! That's the number of Clinical Chemistry podcasts that have been downloaded since the feature was initiated in 2009. It's a relatively new feature in the 60 years of publication of the journal, and the word podcast itself is only been in the vernacular for about 10 years.

Performing measurements that are comparable over time and location and across assays is essential for insuring appropriate clinical and public health practice. One step toward achieving this goal is using assays that are traceable to a higher-order reference measurement system or harmonized by using internationally recognized procedures.

Analysis of Human Chorionic Gonadotropin or hCG is usually associated with monitoring or detecting pregnancy. It is also a protein tumor marker for some cancers. In males, hCG stimulates testosterone production and has the potential to be abused by athletes in an attempt to enhance performance in sports.

There are few scientific papers that do not include the use of the P value to evaluate the statistical significance of results. However, use of this statistic may be misleading, as noted by a recent paper by Regina Nuzzo in the journal Nature. That paper served as a basis for commentary with additional examples by Drs. Jim Boyd and Tom Annesley in the July 2014 issue of Clinical Chemistry.

Chronic kidney disease is an important risk factor for cardiovascular morbidity and mortality. This risk is all the more important for patients undergoing hemodialysis. In the presence of clinical signs of an acute myocardial infarction, the universal definition includes the finding of a serum cardiac troponin concentration above the 99 percentile as defined by healthy individuals, together with time dependant changes in serum and troponin concentrations. But in contrast to individuals with normal kidney function the troponin concentrations in patients with chronic kidney disease, but no myocardial infarction, may already be at concentrations higher than the 99 percentile of a healthy population.

Central nervous system infections, including diseases like meningitis and encephalitis, are important public heath concerns across the globe, as they occur commonly and/or associated with high rates of mortality and morbidity. Measurement of biomarkers provide objective indicators of normal function or pathology, and can present information that may assist diagnosis, assessment of health condition, and evaluation of treatment safety and efficacy.

Early detection of acute myocardial infarction is crucial for deciding the course of treatment to preserve and prevent further damage to the myocardial tissue. During the last several years there has been a burgeoning interest in circulating microRNAs as potential novel biomarkers for acute myocardial infarction.

The universal definition of myocardial infarction requires both an increase in cardiac troponin concentrations and changes in values over serial measurements. However, exact criteria regarding the magnitude of change in troponin remain elusive. In the June 2014 issue of Clinical Chemistry, two studies on biological variation of serum troponins helped shed further light on the kinetics of this important cardiac marker.!