Clinical Chemistry Podcast

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.