News & Views in ... Biomarkers in Medicine

Researchers at the University of Michigan Medical School (MI, USA) have recently analyzed the cost of peripheral neuropathy diagnosis. The results of the study, published in Archives of Internal Medicine, reveal that less expensive, more effective tests are less likely to be used in diagnosis. As part of the study, the researchers sought to identify opportunities to improve efficiency of care for peripheral neuropathy at the diagnostic stage.

Brian Callaghan (University of Michigan Medical School) and colleagues used the 1996–2007 Health and Retirement Study Medicare claims-linked database to identify 1031 individuals with an incident diagnosis of peripheral neuropathy using International Classification of Diseases, Ninth Revision codes. The study focused on Medicare expenditures and the number and patterns of 15 relevant tests, 6 months before and after neuropathy diagnosis. It was found that 23.2% of neuropathy patients underwent high-cost, low-yield MRIs, while 1% received low-cost, high-yield glucose tolerance tests. Furthermore, expenditures increased substantially in the diagnostic period. Speaking to Future Medicine, Callaghan explains, “Our results indicate that there is a high degree of variability in which tests physicians order and physicians are not always focused on the tests with the highest levels of evidence.”

Peripheral neuropathy is most commonly caused by diabetes, of which rates are increasing in the USA. The study highlights the need for more efficient strategies to be in place for diagnosing peripheral neuropathy. Callaghan explains further, “Part of the problem is that there is little information on which tests to order,” adding that, “this work is just a first step in determining which tests should be ordered.” These results highlight the need for further studies of this kind amongst other areas of disease diagnosis; Callaghan elaborates, “I think there are many areas where you would find the same pattern of high variability in testing and little evidence to support the use of these tests. Unfortunately, we do not often study whether certain testing is appropriate.”

– By Jenaid Rees

Sources: Callaghan B, McCammon R, Kerber K et al. Tests and expenditures in the initial evaluation of peripheral neuropathy. Arch. Intern. Med. 172(2), 127–132 (2012); University of Michigan news release: www.uofmhealth.org/news/neuropathy-patients-receive-expensive-testing

Researchers at the University of Texas Medical branch at Galveston (TX, USA), have recently published two papers detailing improved methods to detect dengue hemorrhagic fever (DHF). The papers, recently published in The American Journal of Tropical Medicine and Hygiene and in Clinical and Translational Science, detail the efforts by the group to improve early detection systems of DHF using modeling and proteomics. At present, patient outcomes when treated early for DHF are considerably more favorable than late-stage treatment.

Lead author Allan Brasier, Director of the University of Texas Medical Branch Institute for Translational Sciences, explained the background of the research: “We have long known that dengue has many manifestations, from asymptomatic to a flu-like state to a life-threatening condition. If we could figure out early a patient’s susceptibility to the deadly form, we could save thousands of lives.” The group used modeling and proteomics to achieve this goal. Brasier commented: “Until now, biomarkers of the disease have proved elusive. But proteomics technologies are changing the landscape and these studies are the first step toward a personalized approach to treating dengue infection.”

Speaking to Future Medicine, Brasier neatly encapsulated the main thrust of the work and hinted at further possible applications: “These two studies demonstrate the feasibility of using combinations of laboratory measurements, blood counts and proteins, to develop a personalized medicine approach for risk assessment of acute infectious disease outcome. Our findings further show how best to combine proteomics measurements into predictive modeling using nonparametric modeling. The NIAID Clinical Proteomics Center is using these same approaches for multivariate identification of risk for other infectious diseases, including Helicobacter pylori infection, invasive aspergillosis and chagas disease.”

Brasier summarized the future potential of the published work: “We have proved it is feasible to identify predictive proteins associated with DHF. If future research bears out these candidate proteins as firm predictors of DHF, doctors can act early to save lives – the highest hope for personalized medicine.” Further detail on ongoing efforts can be found at the Clinical Proteomics Center for Infectious Disease and Biodefense website.

– By Andreas Hadjivasiliou

Sources: Brasier AR, Ju H, Garcia J et al. A three-component biomarker panel for prediction of dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 86(2), 341–348 (2012); Brasier AR, Garcia J, Wiktorowicz JE et al. Discovery proteomics and nonparametric modeling pipeline in the development of a candidate biomarker panel for dengue hemorrhagic fever. Clin. Transl. Sci. doi: 10.1111/j.1752–8062.2011.00377.x (2012) (Epub ahead of print); CPC Overview: https://bioinfo.utmb.edu/CPC

ColonSentry^®, a blood-based biomarker test for assessing an individual’s current risk for colorectal cancer, has recently been approved by the New York State’s Department of Health (NY, USA) to be marketed in the US states of New York and New Jersey. ColonSentry will be marketed exclusively by Enzo Biochem Inc. (NY, USA), the US partners of Canadian molecular diagnostics company GeneNews Ltd (ON, USA), who developed the test. ColonSentry was previously only available in Canada, China and Malaysia.

Colorectal cancer, the second leading cause of cancer mortality in the USA, accounts for approximately 52,000 deaths per year. One-third of colorectal cancer-related deaths could be prevented by early detection. Compliance with colorectal cancer screening is currently low due to the invasive nature of the common screening techniques (colonoscopy and stool-based methods). It is hoped that more patients will be encouraged to undergo colonoscopy if the ColonSentry blood test suggests an increased risk of developing colorectal cancer, allowing more cases to be detected early.

The test measures the expression levels of six genes associated with the response in the circulating blood to the presence of a tumor (ANXA3, CLEC4D, LMNB1, PRRG4, TNFAIP6 and VNN1) relative to a reference gene (IL2RB). “The genes are known to be involved in pathways related to anti-apoptosis, inflammatory response, cellular signaling and response to stimulus,” explained Gailina Liew, President and Chief Operating Officer of GeneNews, when speaking to Biomarkers in Medicine.

In addition to improving early detection of colorectal cancer, the approval of ColonSentry for marketing in the USA also has wider implications: “Approval of blood tests that measure the mRNA expression of defined genes as biomarkers for specific clinical applications will encourage the development of more noninvasive tests that can accelerate the move towards personalized medicine and more efficient use of healthcare resources,” concluded Liew.

– By Sarah Miller

Source: GeneNews Ltd. News Release: www.genenews.com/node/304

A free, web-based software program to assist in interpreting DNA sequencing results has been developed by scientists at the Johns Hopkins University School of Medicine (MD, USA). The program, termed Pyromaker, was generated to aid the identification of complex genetic mutations from the results of the pyrosequencing DNA-sequencing method. Once identified, the knowledge of these genetic mutations could be useful in both cancer diagnosis and treatment selection. The researchers demonstrated the validity of the new tool in a study recently published in the Journal of Molecular Diagnostics.

Current methods of interpretation for DNA sequencing, such as TA cloning^® and sequencing, are labor intensive and are not often used despite the potential complexity of results generated by DNA sequencing. Pyromaker aims to simplify this process by generating virtual traces for DNA sequencing results based on user inputs.

In testing the tool, researchers at the Johns Hopkins University School of Medicine compared actual pyrograms containing common KRAS gene mutations, and several mutations in the BRAF, GNAS and p53 genes, to virtual pyrograms produced by the Pyromaker tool. Pyromaker was used to identify the complex mutations in two modes, one mode matched hypothesis-based simulated pyrograms to the actual pyrogram, another reconstructed the pyrogram to identify the underlying mutation. Both methods successfully identified the complex mutations, which were confirmed by cloning and sequencing.

James Eshleman of Johns Hopkins University School of Medicine comments, “Although pyrosequencing and Sanger sequencing are both powerful tools to resolve most mutations, for certain complex cases, neither of them alone is enough to provide a definitive interpretation. Additional methods, such as Pyromaker analysis or TA cloning and sequencing, allow one to definitively diagnose the variant allele. Pyromaker is available free online and can be accessed from any computer with internet access. Iterative Pyromaker analysis is the least expensive and fastest method to resolve these cases.”

– By Jenaid Rees

Source: Chen G, Olson MT, O’Neill A et al. A virtual pyrogram generator to resolve complex pyrosequencing results. J. Mol. Diagn. 14(2), 149–159 (2012).

A novel blood test for analyzing and detecting circulating tumor cells (CTCs), termed the ‘high-definition (HD)-CTC assay’, has been developed by scientists at The Scripps Research Institute (CA, USA). The new device was demonstrated to be effective by a collaboration of cancer researchers from a range of institutes and the results are published in the journal Physical Biology, spanning five papers. The new assay has strong prognostic potential, as CTCs are established prognostic markers in prostate, breast and lung cancer. Previous tests designed to capture CTCs have used ‘enrichment’ steps known to exclude some types of CTCs. The new HD-CTC assay is, however, reported to enable a more complete analysis of CTCs, generating such highly sensitive blood analysis as to be comparable to some surgical biopsies.

The HD-CTC assay is a fluid-phase biopsy that identifies and presents CTCs; the assay distinguishes CTCs through labeling, then isolates and images suspect cells, providing sufficiently HD quality images to allow for diagnostic pathology.

In the first study, the researchers at The Scripps Research Institute analyzed blood samples for CTCs from prostate, breast and pancreatic metastatic cancer patients. The HD-CTC assay was reported to have detected more than five HD-CTCs per milliliter of blood in over 50% of all the cancer patients and identified CTC clusters, of 2–30 CTCs, in the majority of the cancer patients. These results confirmed the ability of the HD-CTC assay to identify significant numbers of CTCs in prostate, breast and pancreatic cancer patients.

Primary inventor of the HD-CTC assay Peter Kuhn (The Scripps Research Institute) remarked, “It is a next-generation technology. It significantly boosts our ability to monitor, predict, and understand cancer progression, including metastasis, which is the major cause of death for cancer patients.” Kuhn and colleagues now look to progress the assay further for clinical monitoring and cancer research and to study the potential of HD-CTC as a screening test, with the aim to also develop the assay as a diagnostic tool.

– By Jenaid Rees

Sources: Marrinucci D, Bethel K, Kolatkar A et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys. Biol. doi:10.1088/1478–3975/9/1/016003 (2012) (Epub ahead of print); The Scripps Research Institute news release: www.scripps.edu/news/press/20120202kuhn.html