Clinical Chemistry Podcast

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.