The Stago group, Asnières, France, recently completed the acquisition of HemoSonics LLC, Charlottesvilla, Va, a company specialized in the development of point-of-care testing systems.

With the acquisition of Hemosonics’ patented sonic estimation of elasticity via resonance (SEER) technology and its associated Quantra hemostasis analyzer, Stago seeks to expand opportunities for future growth. The acquisition is part of the company’s ongoing efforts to diversify its portfolio of medical devices.

“This significant step makes us very proud to contribute to the management of healthcare costs and to the improvement of patient outcomes worldwide,” says Lionel Viret, chairman of the board at Diagnostica Stago.

“Stago brings exceptional expertise in the field of thrombosis and hemostasis that will greatly advance our efforts to rapidly and effectively deliver a new standard of care for the management of bleeding in the critical care setting,” says Timothy Fischer, president and CEO of HemoSonics.

Ferghana Partners acted as exclusive financial advisor to HemoSonics for this transaction. For more information, visit Diagnostica Stago and HemoSonics.

Eppendorf, Hauppauge, NY, has introduced the BioFlo 120, a benchscale fermentor and bioreactor system capable of microbial fermentation as well as mammalian cell culture applications. It features an extensive range of glass and BioBlu single-use vessel options, from 250 mL to 40 L. Embedded software offers real-time local process control through an integrated touchscreen. Newly developed auto culture modes for push-button control of microbial and cell culture applications aim to reduce the learning curve associated with new equipment. For additional process control capabilities and secure database management the instrument can also be connected to Eppendorf supervisory control and data acquisition platforms DaSware and BioCommand. For more information, visit Eppendorf.

A high-sensitivity troponin T assay has been shown to improve evaluation of patients complaining of chest pain.

At the Karolinska Institute, Sweden, researchers studying patients discharged from an emergency clinic found that their risk of suffering a serious cardiovascular event within 30 days of returning home was much lower when the new method was in use than when examinations used older versions of the test. The percentage of those subsequently suffering a heart attack, dying, or undergoing unplanned revascularization dropped from 0.9% to 0.6%.

To rule out myocardial infarction, doctors normally check the patient’s electrocardiogram (ECG) and perform a blood test for the cardiac biomarkers troponin I or troponin T. In recent years, however, a new and more sensitive assay has been introduced at Swedish hospitals. Previous studies have shown this high-sensitivity troponin T assay to be more diagnostically accurate, but it has not been previously known whether this accuracy applies to clinical procedures.

The large-scale registry study examined 65,000 patients with unspecified chest pain who had been discharged from 16 Swedish emergency clinics between 2006 and 2013.

Per Svensson, Karolinska Institute.

“Our results are of interest to other countries such as the United States, which is about to change its methods,” says Per Svensson, associate professor and senior lecturer at the Karolinska Institute’s department of medicine.

However, among patients who had been discharged from hospital after being admitted for an unspecified chest pain diagnosis, the risk of suffering serious events increased after the change in method. In this group, 7.2% of patients examined with the new method were affected, compared to 3.4% of patients who were examined in the former way. These particular patients also had a higher risk profile after the change in method.

“We may conclude from the results of our study that examination using high-sensitivity troponin is associated with fewer serious cardiac events and an improvement in risk profile for patients released from emergency clinics with unspecified chest pain,” says Svensson. “The opposite was observed in patients sent home after admission to hospital, which suggests that high-risk patients are identified and hospitalized more frequently. We therefore conclude that high-sensitivity troponin has helped to improve the evaluation of emergency patients with unspecified chest pain.”

The study was financed by the Karolinska Institute.

REFERENCES

1. Nejatian A, Omstedt Å, Höijer J, et al. Outcomes in patients with chest pain discharged after evaluation using a high-sensitivity troponin T assay. J Am Coll Cardiol. 2017;69(21):2622–2630; doi:10.1016/j.jacc.2017.03.586.

VAP Diagnostics Lab, Birmingham, Ala, has relaunched the Vertical Auto Profile+ (VAP+) lipid panel, a heart disease risk assessment and management tool.

The VAP+ lipid panel was taken off the market in early 2016 after investors pulled support for Atherotech Diagnostics Lab, and the company was forced into Chapter 7 bankruptcy. In order to resurrect the VAP+ lipid panel, VAP Diagnostics Lab acquired rights to the VAP+ technology and assumed all of Atherotech’s debt, halting patient billing and collections.

“A dedicated team of people fought very hard to bring back the VAP+ lipid panel, and their efforts have paid off,” says Kenneth French, director of clinical operations for VAP Diagnostics Lab. “We have overcome major challenges and enter the market as a new company that has international corporate backing and global distribution capabilities focused on long-term sustainable growth.”

French says the company has emerged as a stronger organization with a renewed mission to advance heart disease research, improve treatment, and put the patient and doctor first.

“Clinicians who used VAP+ lipid panel in the past and were accustomed to great service and 24-hour turnaround now have access to the same technology and service, but with solid corporate, financial, and organizational support,” explains French.

Unlike the basic cholesterol test, the VAP+ lipid panel directly measures low-density lipoprotein (LDL). Accurate LDL measurement is critical for reducing disease burden and risk. In addition to providing accurate LDL measurements, the VAP+ lipid panel reports three categories of risk: cholesterol-rich; triglyceride-rich; and hereditary, which includes lipoprotein(a).

VAP+ adheres to all major guidelines calling for accurate LDL and additional measures of cholesterol, including LDL particle number (LDL-P). This increase in accuracy and comprehensive information seeks to provide doctors and their patients with a more precise picture of heart disease risk, leading to better treatment and ultimately saving lives. The VAP+ lipid panel is covered by most insurance plans. For more information, visit VAP Diagnostics Lab.

Sciex Diagnostics, Framingham, Mass, has received FDA de novo clearance for its liquid chromatography–mass spectrometry (LC-MS) based vitamin D 200M assay, exclusively for the Sciex Topaz system. The Topaz system is a fully integrated LC-MS platform driven by ClearCore MD, intuitive software designed specifically for use in clinical labs. While individually quantitating D2 and D3 isomers, the Topaz system also automatically differentiates between D3 epimers, providing the specificity to deliver highly accurate diagnostic results in a single analysis. The system is intended for in vitro diagnostic use in the quantitative determination of total 25-hydroxyvitamin D through the measurement of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human serum using LC-MS/MS technology by a trained laboratory professional in a clinical laboratory. For more information, visit Sciex.

In an effort to find new strategies to personalize treatment for pediatric patients, Seattle Children’s Research Institute has opened the first clinical trial applying next-generation T-cell receptor (TCR) sequencing and single-cell gene expression analysis to better understand how the immune system drives both inflammatory bowel disease (IBD) in pediatric autoimmunity patients and graft-versus host disease (GVHD) in pediatric bone marrow transplant (BMT) patients.

The Precision Diagnostics in Inflammatory Bowel Disease, Cellular Therapy, and Transplantation (PREDICT) trial is expected to provide clinicians new information about why IBD arises in children, allowing them to tailor treatment plans to each patient. The trial will later expand to include BMT patients with the goal of identifying the immunologic changes that occur when a patient develops GVHD, the deadliest complication associated with BMT. BMT is used to treat a range of pediatric conditions from leukemia to inherited bone marrow failure syndromes, congenital metabolic disorders, and other metabolic diseases.

Leslie Kean, MD, PhD, Seattle Children’s Research Institute.

“PREDICT seeks to change the paradigm of treatment by first changing the paradigm of diagnosis,” says principal investigator Leslie Kean, MD, PhD, who leads a lab focused on T-cell immunology and is the associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute. “By gaining foundational molecular diagnostic knowledge about a patient’s T cells, we hope to ultimately discover better treatment approaches for IBD and GVHD.”

As part of the trial, Kean and her team will perform TCR sequencing and gene expression analysis on samples collected from 100 IBD and 250 BMT patients. The data resulting from the initial and follow-up analyses will help researchers pinpoint molecular pathways active within a patient’s T cells that could serve as therapeutic targets in future studies. The researchers will collaborate with Adaptive Biotechnologies, Seattle, by implementing the company’s ImmunoSeq platform for high-throughput TCR sequencing and conducting TCR repertoire analyses. The single-cell gene expression analysis will be performed using the Chromium Single Cell 3′ Solution supplied by 10x Genomics, Pleasanton, Calif, which will enable gene expression patterns to be discovered in each patient’s individual T cells.

Over the next 2 years, Kean will work in partnership with transplant, gastroenterology, and immunology physicians to first enroll IBD patients who are undergoing their diagnostic evaluation and treatment at Seattle Children’s, with plans to open the BMT cohort later this year.

GVHD occurs when the T cells of newly transplanted bone marrow begin to attack a patient’s tissues, including those of the skin, liver, and intestine. The impact to the gastrointestinal tract can be extremely difficult to overcome and is the most deadly complication of BMT. In patients with IBD, a similar pathogenesis is observed where components of the immune system, including T cells, react abnormally over time, causing chronic inflammation in the digestive system.

“IBD and GVHD have a lot more in common than meets the eye when it comes to the underlying immune response they trigger,” says Kean. “PREDICT aims to bridge IBD and GVHD, shedding new light on the immunologic similarities they share and identifying the molecular causes of each patient’s disease. This will create a unique opportunity to make significant headway in the treatment of both diseases, with the focus on each child and their unique disease signature.”

Initial funding for the PREDICT trial was provided through a Seattle Children’s Research Institute pilot grant and made possible with support from biopharmaceutical collaborators.

The ZE5 Cell Analyzer from Bio-Rad Laboratories, Hercules, Calif, is a new flow cytometer with flexible configurations to meet a broad range of experimental complexities and throughput needs. Whether for low-complexity, two-parameter experiments or high-complexity, 28-parameter experiments, the ZE5 is expandable and flexible, accessible for novice users yet powerful enough for experienced flow cytometry professionals. A fully integrated sample loader with the ability to handle tubes or plates without an instrument hardware change enables true walkaway functionality. Features such as a stat tube station, onboard fluidics that are hot-swappable, and automated startup and quality control support continuous operation and maximization of instrument runtime for core labs. For more information, visit Bio-Rad Laboratories.

This is a companion article to the feature, “HEOR for Diagnostics.”

It would be a mistake to draw the conclusion, based on the Quest Diagnostics research, that more genes tested correlates necessarily with greater value. While multigene test panels have value, having too many genes in a multigene panel may provide information that is not clinically meaningful, or is potentially confusing for the physician and patient.

The test should strive to achieve the right balance between too many and too few genes. Testing that provides well-characterized, guideline-supported, evidence-based, and actionable information may provide greater value.

This is a companion article to the feature, “HEOR for Diagnostics.”

To help make value determinations, health plans may consider health economics and outcomes research (HEOR) that examines the demonstrated or theoretical impact of a service on the increased life years and cost-effectiveness resulting from the use of a specific intervention. The key metrics used to quantify and compare the results of HEOR studies are quality-adjusted life years (QALYs), which measure the benefit of the service, and incremental cost-effectiveness ratios (ICERs), which assess the incremental cost of that benefit.

One could simply estimate the number of life years a treatment strategy adds to a person’s life. But a QALY assumes that not all years of added life should be treated equally. Thus, if a patient gains an additional year of life that they live in complete health, that year would be counted as a full quality-adjusted year of added life. However, if someone lives an additional year but is in a coma, that year would be counted as much less than a full quality-adjusted life year.

Because healthcare resources are by nature limited, some consideration must be given as to whether interventions are reasonable from a cost perspective. To better understand this, some payors use ICERs, a measure of how much a new treatment strategy costs per QALY gained, compared with usual care.

Whether the payor (or patient) is willing to pay for these additional QALYs depends on the willingness to pay threshold, which can differ from patient to patient, payor to payor, and society to society. In the United States, a typical willingness-to-pay threshold is about $100,000 for each QALY gained. To account for societal differences, the World Health Organization has suggested that the willingness to pay threshold be based on GDP.¹

Reference

1. Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost-effectiveness of interventions: alternative approaches. Bull World Health Organ. 2015;93:118–124; doi: 10.2471/blt.14.138206.

The clinical lab community needs a shared vision for calculating the value of diagnostic testing.

By James J. Devlin, PhD

With the acceleration of new diagnostic and therapeutic innovations, healthcare stakeholders are increasingly using the methods of health economics and outcomes research (HEOR) to quantify the value of new products as they relate to clinical practice and reimbursement strategies. This trend is particularly evident in the area of precision medicine. Some new tests and therapies offer clearly evident value, potentially improving a clinical outcome at a low cost. For others, demonstrating value may require large-scale prospective trials or cost-effectiveness modeling.

Cost-effectiveness modeling is usually based on peer-reviewed publications that demonstrate the clinical effectiveness of a new test or therapy. To assess the cost of obtaining improved clinical effectiveness, the cost-effectiveness model evaluates both the improvement in effectiveness (often measured in life years gained) and the cost of obtaining these benefits. The cost of obtaining one additional year of life is referred to as the incremental cost-effectiveness ratio (ICER).

The use of such HEOR concepts has grown rapidly in recent years. When HEOR studies are carefully conducted, they can drive important decisions about access and coverage. To realize the promise of precision medicine, healthcare stakeholders must collaborate on an improved value assessment process that rewards innovation, improves efficiencies, accelerates clinical adoption, and facilitates use in patient care.

Researchers at Quest Diagnostics recently assessed the health and economic value of testing for seven genes known to confer increased risk of hereditary breast cancer. We found that testing for five additional genes, along with BRCA1/2 testing, provides health benefits at an acceptable economic cost, compared with BRCA1/2 testing alone.

Quantifying Value

Arguably, the most important word in healthcare right now is ‘value’—both clinical and economic. Healthcare innovations—diagnostic tests, therapies, and tests that guide the use of therapies—are coming to market rapidly, but across the spectrum of healthcare stakeholders, it is a challenge to quantify value as it applies to real-world clinical practice. And incomplete information about the value of such products has significant effects on their clinical adoption and reimbursement.

Figure 1. In the model used by Quest researchers to compare the seven-gene test strategy to the BRCA1/2 only test strategy, the number of life years gained and the incremental cost of each life year gained depend on the values assigned to multiple input parameters. To explore how changes in the testing assumptions might affect the results, a probabilistic sensitivity analysis was performed, recalculating the model 10,000 times, with different values for each of the input parameters being simultaneously and randomly drawn from reasonable probability distributions for each parameter. The figure shows that 95.7% of the 10,000 model results were under the diagonal line, indicating that 95.7% of the time, the life years gained cost less than $100,000 per life year.

In the diagnostic information services community, value is seen through two lenses. For clinicians, the value of a diagnostic is defined by its ability to provide actionable information associated with improved clinical outcomes, as measured by improved rates for curing disease, preventing adverse health-related events, or extending life.

But payors view value through a different lens. For them, the value of a diagnostic emphasizes the cost of each benefit it provides—not only in terms of direct costs, but also in terms of costs that will be either incurred or avoided during the episode of care that is delivered downstream of the diagnostic testing.

Within the healthcare ecosystem, these seemingly dichotomous considerations must coexist. For many tests and therapies, costs and outcomes align: if inserting a test into a pathway improves a clinical outcome at a low cost, the test obviously has value. But for many other tests and therapies, ‘value’ is a term that requires context. Payors must establish policies that enable them to assign value to tests that fall into a gray area—for example, a test that can recommend a treatment known to extend life, but by very little; or a test with a comparatively high cost for a condition that is very rare.

Payors’ conundrum extends beyond diagnostics: without utilizing laboratory tools that can dictate whether a particular therapy may be effective, payors can find themselves equally challenged to assign value to the therapy itself.

This article examines how HEOR concepts and methods help to quantify the clinical and economic value of laboratory services and related therapies, so that payors can formulate access and coverage determinations for those products. While HEOR currently offers a framework for making such determinations, analyses that arrive at the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) resulting from the use of a test or therapy are performed from a specific perspective; for example, from that of a payor. As such, they do not necessarily fully integrate the value of certain societal, ethical, and individual factors that would be important to those with a different perspective—for example, patients and caregivers—in precision medicine initiatives. (For more information, see “QALYs and ICERs: An Overview.”)

Precision Medicine Complicates the ‘Value’ Paradigm

One of the barriers to assigning value is the differing criteria by which health plans and payors evaluate new diagnostics or therapies for reimbursement. While they may take their cues based on rate-setting by the Centers for Medicare & Medicaid Services (CMS) or Medicare contractors such as Palmetto GBA, most third-party payors have their own methods for assessing economic value and appropriate reimbursement level. These processes evaluate a myriad of factors, including the guidelines of medical specialty societies, clinical validity, comparative effectiveness and, increasingly, economic benefit.

Similar but ultimately distinct processes that payors may use to assess the value of new products and services may function adequately when only a handful of major FDA-approved drugs or diagnostics are brought to market each year. But in today’s emerging era of precision medicine, diagnostic and drug developers are increasingly focused on companion diagnostics and highly targeted treatments that apply only to niche populations, making their value even more challenging to quantify.

Without large-scale biomedical information datasets that further our understanding of disease and the outcomes of targeted interventions—data that are aggregated by the diagnostic information services community—individual payors may lack the information they need to make informed value assessments and coverage decisions, let alone to align those determinations with those of others in the healthcare payor community. Such systemic weaknesses contribute to a fragmented system in which value remains unquantified and innovation unrewarded. And without adequate reimbursement, clinical uptake may be stymied.

Multiplexing for Value

A recently published study offers the opportunity to explore how the ‘value factors’ of QALYs and ICERs relate to testing and outcomes determinations.¹

Table 1. Incremental cost-effectiveness ratios per QALY gained, seven-gene panel versus BRCA1/2 testing alone. Click to expand.

As a leader in oncology and women’s health, Quest Diagnostics sought to better understand the potential health and economic value of genetic testing for women at increased risk of hereditary breast cancer. Specifically, we investigated whether testing for five genes beyond the well-established BRCA1 and BRCA2 genes associated with heightened risk of breast cancer would confer health or economic value.

Our team of researchers developed a decision analytic (Markov) model for two hypothetical cohorts of 40-year-old and 50-year-old asymptomatic women with a family history of breast or ovarian cancer or other hereditary syndromes. The model compared two strategies for detecting pathogenic genetic variants and using the test results to select appropriate breast cancer risk reduction: the usual care strategy, which tests for variants in the BRCA1 and BRCA2 genes (BRCA1/2 testing); and a multigene strategy, which tests for variants in the BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53 genes (seven-gene testing).

We found that the hypothetical cohorts of 40- and 50-year-old women who underwent genetic testing with the seven-gene panel—followed by risk-reduction procedures as recommended by National Comprehensive Cancer Network guidelines—would see incremental cost-effectiveness ratios (ICERs) of $23,734 and $42,067 per life-year gained, respectively, when compared to BRCA1/2 testing alone (see Table 1).

To explore how changes in the testing assumptions might affect the results, a probabilistic sensitivity analysis found that the seven-gene test strategy cost less than $100,000 per QALY gained in 95.7% of the trials for the 50-year-old cohort (see Figure 1). This calculation suggests that the seven-gene test strategy would be cost-effective according to World Health Organization thresholds for the cost-effectiveness of interventions. It also compares favorably with annual screening for high-risk women via magnetic resonance imaging (MRI), which has an estimated ICER of $179,600.

In sum, the seven-gene strategy provides greater health and economic benefits than BRCA1/2 testing alone.

Our team at Quest Diagnostics has also conducted research that examined the cost-effectiveness of laboratory testing to aid oncology treatment selection.² In this work, we sought to determine whether a next-generation sequencing (NGS) panel of 34 cancer-associated genes would cost-effectively aid in treatment selection for patients with metastatic melanoma, compared with a single-site BRAF V600 mutation test (see Figure 2).

Table 2. Incremental cost-effectiveness ratios per QALY gained, single-site mutation test versus gene sequencing panel. Click to expand.

In that study, we found that the gene sequencing panel strategy resulted in a cost of $120,022 and an increase of 0.721 QALYs per patient, while the single-site mutation test strategy resulted in a cost of $128,965 and an increase of 0.704 QALYs (see Table 2). Thus the key finding, from a US payor perspective, was that using an NGS panel of 34 cancer-associated genes to guide selection of first-line targeted treatment for metastatic melanoma could reduce medical costs and increase the patient’s quality and length of life, when compared with using a single-site mutation test.

Limitations of QALYs and ICERs

QALYs and ICERs are broadly accepted metrics that can be used to compare the relative value of healthcare interventions. Nevertheless, many factors that influence the value of such interventions cannot be adequately reflected by QALYs and ICERs alone. (For more information, see “More is not Necessarily Better.”)

For instance, HEOR studies are not intended to account for or assign a value metric to psychological or societal factors that may affect patients, such as their anguish or relief over knowing whether an effective treatment may be available for their disease—however remote its chances of success. Nor do such studies attempt to negotiate the ethical conundrums involved in impartially assigning value to the life and health of an individual, without considering any factors specific to that individual. While the selection and effectiveness of a particular cancer therapy often depend on the type of gene mutations occurring in the cancer tumor, for example, mutations vary for each individual and can even change during the course of treatment, which complicates the development of cost-effectiveness models.

Additionally, regulatory considerations, market competition (or lack thereof), and related cost considerations can make it difficult to include correct future pricing in the model.

Improving the HEOR Model in Diagnostics

On the whole, the healthcare community is just beginning to do the work that will be needed to realize the promise of precision medicine in clinical practice. To improve on the current HEOR model for determining the value of diagnostics, the diagnostic information services and health plan communities should work together more closely—and much earlier—to develop a standardized, evidence-based approach.

As a first step, test developers and payors should find ways to collaborate earlier on a shared vision of methods for calculating the value of diagnostic testing. In most other sectors of the economy, companies that are introducing products to the market usually begin with some understanding of what financial value the market will place on those products. In a similar fashion, diagnostic service providers should work with their prospective buyers to understand how to value their offerings before introducing them to the market. However, such early collaboration is often complicated by the fact that the buyer (the payor) is not the person (the patient) who receives the benefit.

Figure 2. A Quest Diagnostics scientist conducts next-generation sequencing (NGS) at the company’s San Juan Capistrano, Calif, high-complexity laboratory. Quest’s broad NGS offerings include IBM Watson Genomics from Quest Diagnostics, OncoVantage, and other diagnostic tests.

The same need for early collaboration applies to the relations between test developers and regulators, including the Clinical Laboratory Improvement Advisory Committee of the US Centers for Disease Control and Prevention, FDA, and bodies that certify product compliance with the European Union’s directive for in vitro diagnostics. Separately and together, such agencies are responsible for reviewing new diagnostic products, authorizing their entry to market, and ensuring that testing is carried out in accord with the regulations that apply to clinical laboratories.

While consistency in reimbursement evaluation and coverage decisions reduces inefficiency and uncertainty, there is a downside. Sometimes the successful introduction of a beneficial new diagnostic or therapy is based on a single payor deciding to offer coverage, which gives the innovation the chance it needs to fully demonstrate that it fills an unmet need. Therefore, modifications to the value assessment models should seek to avoid rigidity that could dissuade coverage by a single actor.

The lack of consistency and standardization has led to the emergence of differing approaches for making reimbursement and coverage determinations.

One such approach that has become a health plan mainstay is the ACCE model process for evaluating genetic tests, which is named for its key criteria—analytic validity; clinical validity; clinical utility; and associated ethical, legal, and social implications.³ While widely used, the process has not been revised to keep pace with innovations in test development, including the emergence of high-complexity genomic tests used for predictive testing.

More-promising models incorporate a collaborative approach. The Evidence Street pilot program of the Blue Cross Blue Shield Association is designed to create uniformity in the exchange of clinical evidence. It provides a route for companies to submit test data and see the information used to evaluate a device.⁴

Under an ideal approach, healthcare stakeholders—including the clinical laboratory community—will reach agreement on the baseline principles that are the underpinnings of value assessments, then use those principles to facilitate consistency across multiple organizations. Organizations such as the Personalized Medicine Coalition and, more recently, AdvaMedDx have proposed such cross-stakeholder approaches.^5,6 Lessons from these approaches may support the development of future HEOR studies.

Conclusion

HEOR studies that measure the value of diagnostics and therapies in terms of QALYs gained and their associated ICERs imperfectly represent the totality of factors that contribute to the value of a healthcare intervention. Nevertheless, they remain a credible and widely used means of measuring the ‘value’ of new diagnostic services.

Greater engagement by diagnostic information service providers and other stakeholders—from health plans, to patients, to biopharmaceutical companies—in the task of defining and recognizing value will hasten innovation, improve efficiencies and, ultimately, help patients access the healthcare services they need.

James J. Devlin, PhD, is a senior science director and leads a chief medical officer analytics group at Quest Diagnostics. For further information, contact CLP chief editor Steve Halasey via shalasey@nullmedqor.com.

References

1. Li Y, Arellano AR, Bare LA, Bender RA, Strom CM, Devlin JJ. A multigene test could cost-effectively help extend life expectancy for women at risk of hereditary breast cancer. Value Health. 2017;20(4):547–555; doi: 10.1016/j.jval.2017.01.006.

2. Li Y, Bare LA, Bender RA, et al. Cost-effectiveness of sequencing 34 cancer-associated genes as an aid for treatment selection in patients with metastatic melanoma. Mol Diagn Ther. 2015;19(3):169–177; doi: 10.1007/s40291-015-0140-9.

3. ACCE model process of evaluating genetic tests [online]. Atlanta: Centers for Disease Control and Prevention, 2010. Available at: www.cdc.gov/genomics/gtesting/acce. Accessed May 15, 2017.

4. Blue Cross Blue Shield Evidence Street [online]. Chicago: Blue Cross Blue Shield Association, 2017. Available at: https://app.evidencestreet.com. Accessed May 15, 2017.

5. Pritchard DE, Moeckel F, Villa MS, Housman LT, McCarty CA, McLeod HL. Strategies for integrating personalized medicine into healthcare practice. Personalized Medicine. 2017;14(2):141–152; doi:10.2217/pme-2016-0064.

6. A Framework for Comprehensive Assessment of the Value of Diagnostic Tests. Washington, DC: Deloitte Development, 2017. Available at: www.advamed.org/resource-center/framework-comprehensive-assessment-value-diagnostic-tests. Accessed May 31, 2017.

This is a companion article to the feature, “Tackling Evolving Market Challenges.”

Before the installation of a total lab solution begins, Lean consultants can help establish key performance indicators for the postimplementation assessment of whether the project has been successful. Tailored automation design helps maximize return on investment.

Automation has been proven to improve operational efficiency by delivering on such performance targets as reduced errors and improved turnaround time, which can ultimately save time, reduce waste. and reduce costs. Informatics solutions that provide data and predictive analytics can also improve the bottom line through oversight, compliance management, and statistical reporting capabilities.

Automation using informatics has been shown to produce quality results for clinicians by eliminating manual steps and operator decision points, while also reducing process variations that can lead to errors. Automated labs have enabled valuable professionals to focus on driving better clinical outcomes—and spending less time managing operations—by reducing human errors and eliminating time-consuming, repetitive tasks.

The decision to automate creates a long-term relationship with the products and the people who support this sophisticated equipment. Therefore, having a strategic relationship with a company that has extensive experience with the process is essential for achieving long-term laboratory automation goals.

Expertise in Lean manufacturing principles and Six Sigma process improvements enables manufacturers to work with laboratories to design the optimal workflow for their unique needs. Before the installation begins, Lean consultants can help establish key performance indicators that will demonstrate that the project has been successful.

Consultants can help manage the installation and implementation process according to the project plan. As the installation progresses, consultants can help make adjustments, which may involve dissecting and rebuilding the current workflow processes and removing non-value-added steps.

Once the automation system is up and running, periodic system optimization reviews, or health checks, should be performed annually. Health checks designed to assess newly installed and existing automation processes help evaluate how the entire automation system is working, from the time the sample enters the laboratory until the result is generated and the sample is disposed.

Automation is meant to improve workflow efficiency, to improve turnaround time, and to reduce errors; health checks ensure these goals are met. When labs get it right, they realize the payoff in measurable improvements in workflow and clinical excellence from a true multidisciplinary solution.

Manufacturers are leveraging global insights to address the emerging needs of US laboratories 

By Donna Woodall, MT(ASCP)

Donna Woodall, MT(ASCP), Siemens Healthineers.

The clinical laboratory plays a vital role in patient care by delivering to healthcare professionals the diagnostic test results they require to inform critical treatment decisions. However, clinical laboratories are challenged to meet greater testing demands, improve efficiency, and deliver reliable, quality results in the face of labor and budget constraints.

As laboratories focus on reducing cost burdens while meeting increasing testing demands, they are also moving away from buying individual analyzers in the direction of purchasing total solutions that can address both current challenges and long-term needs. Consequently, manufacturers of in vitro diagnostics (IVDs) are leveraging their expertise in global diagnostic trends to bring to market total solutions designed to help meet the needs of the clinical laboratory of the future.

Market trends are forcing adaptation in the clinical laboratory (see Figure 1). The aging population is increasing, and with this rise, the volume of laboratory testing also is increasing. This higher demand on the laboratory, together with test menu expansion, means that today’s labs have to accomplish ever-increasingly more than ever before—but with more stringent budgets. Recognizing that technology can play a critical role in addressing these challenges, manufacturers are introducing comprehensive solutions designed to meet a wide range of laboratories’ needs.

Market Trends Affecting Laboratories

Increased financial pressures and staff shortages are causing labs to rethink their staffing allocations. Relative to the growing volume of tests being performed by laboratories today, there are fewer laboratory technologists processing the ever-growing number of samples. Globally, health worker demand is expected to rise to 80 million by 2030, while the supply of health workers is expected to reach just 65 million over the same period.¹ Regions such as Brazil and China are already struggling to adequately staff positions for laboratory specialists and other medical professionals.

Figure 1. The macro trends driving change in the clinical laboratory are focused around how the decreasing population of trained medical and laboratory technicians will keep pace with the ever-increasing testing workload brought on by a growing general population. Combined with an expanding menu of tests and a growing focus on proactive health management, these macro trends are leading manufacturers to create more automated and optimized technology for the central laboratory.

The US Bureau of Labor Statistics reports that between 2012 and 2022 the nation’s demand for clinical laboratory technologists and technicians will grow by 22%. However, the US programs preparing tomorrow’s laboratory workforce are currently training only about half of what is expected to be needed, while approximately 40% of the current laboratory workforce is within 10 years of retirement.²

In spite of such challenging market dynamics, the global healthcare community recognizes the importance of clinical laboratory testing for improving patient outcomes. But the extent of that contribution is not widely understood, especially among C-level healthcare executives who are responsible for making major investment decisions on behalf of their institutions and the communities they serve. This is evidenced by the widely accepted estimates that roughly 70% of critical clinical decisions are guided by the results of in vitro diagnostic testing, while clinical laboratories account for only about 2% to 3% of overall healthcare costs.

When patient testing is focused on diagnosis after symptoms have already become manifest—as has traditionally been the case—the impact on the overall continuum of care is that money is funneled into expensive therapies and long-term care. Such delayed diagnosis and intervention ultimately drives up costs while diminishing the quality of patient outcomes (see Figure 2).³

Figure 2. In vitro diagnostics accounts for roughly 2% to 3% of the total healthcare costs in the United States, but affects roughly 70% of all critical clinical decisions. Laboratory diagnostics is relevant to the cost structure of every healthcare system across the entire care continuum.

Value-based healthcare policies are driving the healthcare market toward better patient management by shifting its focus in the direction of prevention and early detection. Examples include Europe’s most economic advantageous tender (MEAT) program, which is a public procurement directive using a life-cycle costing approach to arrive at the best price:quality ratio—essentially the best value for money—for purchased goods and services.⁴ And in the United States, there has been a similar rise in the development of bundled payment programs intended to standardize care, eliminate unnecessary variation, and improve quality. In the context of such comprehensive care and bundled payment models, early testing with the right technologies can improve patient outcomes through prevention, earlier diagnosis, and focused therapies—ultimately improving overall patient care at a lower total cost.

Reducing Costs and Maximizing ROI

With the aging of populations resulting in increased clinical laboratory testing, both public and private health systems throughout the world are feeling a corresponding need to reduce costs related to patient testing.

In the United States, laboratories are closely monitoring and preparing for implementation of the Protecting Access to Medicare Act of 2014 (PAMA), which will go into full effect in January 2018. PAMA represents the first significant overhaul of the Centers for Medicare & Medicaid Services (CMS) clinical laboratory fee schedule in more than 30 years, and is intended to create a rate-setting system based on average market prices charged for testing services.

Figure 3 The Atellica Solution comprises sample management, immunoassay, and chemistry analyzer components. It delivers unprecedented flexibility to adapt to growing testing needs and space constraints. The Atellica Solution can combine up to 10 components into more than 300 customizable configurations—including linear, L- and U-shapes. It can also connect to Aptio automation to provide a comprehensive multidisciplinary solution or operate as a standalone system.

In effect, PAMA will create a new baseline for the clinical laboratory fee schedule, which serves as the basis for laboratory reimbursement for the government’s Medicare and Medicaid programs as well as for private insurers. When PAMA is implemented, it is expected that reimbursement for many commodity tests could be reduced by as much as 30%. CMS aims to save $3.93 billion in lab reimbursement over a period of 10 years. Private insurers are expected to follow suit and further decrease their reimbursement rates.⁵

To address these trends, laboratories are moving aggressively toward consolidation, with the expectation that this will enable them to take advantage of economies of scale. Larger hospitals and health systems are pursuing strategic mergers and acquisitions in order to gain market share, achieve cost efficiencies, and wield greater negotiating power over suppliers. Such health systems are also acquiring more pre- and post-acute care facilities and services, as well as physician medical groups, allowing for an expansion of the hospitals’ regional footprint and increased patient engagement through skilled nursing, home healthcare, and rehabilitation services. Meanwhile, small standalone hospitals remain affected by financial pressures, and are gradually dwindling in number as they find that they cannot compete with the large hospital and laboratory networks.

Leveraging Global Best Practices

The fastest-growing and most critical areas of clinical diagnostics are cancer diagnostics, infectious disease tests, and molecular assays and systems. Together, these three areas represent approximately 40% of the IVD market. In the future, they are expected to outpace the growth rate of the overall IVD market.

Globally, specialty testing for the management of critical diseases such as cancer, cardiovascular disease, infectious diseases, and kidney disease accounts for approximately 38% of clinical laboratory revenue. While routine testing boasts a much higher volume of activity, specialty testing is expected to experience double the growth of routine testing over similar periods. The largest areas of specialty testing are esoteric and genetic testing, followed by pathology testing. As the volume of specialty testing increases, laboratories will need to acquire the capital equipment, menu, and experienced personnel needed to conduct such testing.⁶

Figure 4. The Atellica Solution simplifies laboratory operations through intelligent sample handling. It can process more than 30 different sample container types, including pediatric and tube-top sample cups that can be aspirated from the primary tube. By using the same reagents and consumables across different analyzer configurations, laboratories can streamline inventory and deliver consistent patient results no matter where patients are tested.

To meet their equipment needs for this changing marketplace, labs are transitioning from buying individual analyzers to purchasing total solutions from a single trusted partner. Total solutions encompass a variety of offerings, including equipment for sample management, a broad menu of assays, IVD analyzers, automation systems, and informatics. Taken together, such total solutions are designed to anticipate and address the emerging needs of clinical laboratories.

The shape of such total solutions often originates with the pooled experience and information about diagnostic market trends that IVD manufacturers gather from the global markets in which they operate. Closely observing laboratory trends and collecting information about customer pain points enables manufacturers to respond through continuous investment in technology and innovation. The result is a wide range of options available to laboratories. (For more information, see “Proven Practices for Optimizing a Laboratory with Automation.”)

US laboratorians seeking to adopt a total solutions approach can learn a great deal from their early adopter counterparts globally. In Europe, for example, automated laboratories have become more multidisciplinary, often incorporating hematology, hemostasis, proteins, and urinalysis. And as automated systems become more open—not bound by the limits of proprietary interoperability—other specialty disciplines, such as molecular diagnostics, are also being automated.

Such laboratories capitalize on the benefits delivered by customized automation solutions, such as vertical transport modules that allow samples to travel between different floors, and open systems connecting third-party analyzers to provide integrated and efficient operations. All of these options are brought together through the application of comprehensive information technologies that integrate the entire solution.

Powerful analytical solutions that are fast, flexible, reliable and automation-ready will be key to meeting increasing testing demands and expediting patient results. Siemens Healthineers, Tarrytown, NY, recently unveiled the Atellica Solution, next-generation immunoassay and clinical chemistry analyzers (see Figure 3).⁷ The Atellica Solution is highly flexible, with more than 300 customizable configurations, and can be connected to Aptio automation for a comprehensive multidisciplinary solution.

Figure 5. One key feature of the Atellica Solution is the Atellica Magline transport, a patented bidirectional, magnetic transport technology that is 10x faster than conventional sample conveyors. It connects the different analytical components and independently transports samples within their analytical testing environment. The transport technology, together with a multicamera vision system, intelligent sample routing, and automatic quality control (QC) and calibration capabilities, give laboratories independent control over every sample—from routine to stat—to speed patient results to clinicians.

The innovative design features of the Atellica Solution include its high level of automation; a sophisticated vision system; automated QC and calibration; and efficient, intelligent sample management and test scheduling (see Figure 4). These features, along with a unique bidirectional magnetic sample transport technology, were purposefully engineered to better utilize the diminishing labor available and to reduce the need for multiple highly skilled operators (see Figure 5).

With increasing test volume and consolidation, analyzers are expected to produce higher throughput and be able to connect to automation tracks in high volume ‘hub’ laboratories, while also providing efficiency and standardization across the laboratory network, including the ‘spokes.’ Prompt turnaround time for test results has high value to physicians, as results may lead to diagnostic decisionmaking that can reduce treatment costs, reduce the length of hospital stays, and improve patient care—all while reducing overall costs.

The Atellica Solution was developed based on an understanding of a number of market trends that are driving the emerging needs of clinical laboratories on a global scale. Mainly, the Atellica Solution is a contribution to helping laboratorians focus on driving better business and clinical outcomes, and spending less time managing their operations.

Conclusion

The clinical laboratory plays a vital role by delivering to healthcare professionals diagnostic test results that are used to inform critical treatment decisions. However, clinical laboratories are often challenged to meet greater testing demands while also improving efficiency and delivering reliable, quality results—even in the face of labor and budget constraints.

As laboratories focus on reducing cost burdens while meeting increasing testing demands such as specialty diagnostic testing, they are moving away from buying individual analyzers to purchasing total solutions that can address both current challenges and long-term laboratory needs. Laboratory diagnostics manufacturers are leveraging their expertise in global diagnostic trends to produce total laboratory solutions designed to help meet the emerging needs of the clinical laboratory of the future.

Donna Woodall, MT(ASCP), is senior director of global marketing for next-generation products at Siemens Healthineers, Tarrytown, NY. For further information contact CLP chief editor Steve Halasey via shalasey@nullmedqor.com.

References

1. Liu JX, Goryakin Y, Maeda A, Bruckner T, Scheffler R. Global health workforce labor market projections for 2030. Hum Resour Health. 2017;15(1):11; doi: 10.1186/s12960-017-0187-2.

2. Lingo A. US demand for medical technologists reaches boiling point [online]. Cincinnati, Ohio: PassportUSA by Health Carousel, 2016. Available at: https://passportusa.com/med-tech-jobs-in-usa. Accessed June 13, 2017.

3. Wolcott J, Schwartz A, Goodman C. Laboratory Medicine: A National Status Report. Columbus, Ohio: Battelle Memorial Institute, 2008. Available at: https://wwwn.cdc.gov/futurelabmedicine/pdfs/2007%20status%20report%20laboratory_medicine_-_a_national_status_report_from_the_lewin_group_updated_2008-9.pdf. Accessed June 13, 2017.

4. Most economically advantageous tender (MEAT) [online]. Salford, UK: Crescent Purchasing Consortium, 2015. Available at: http://www.felp.ac.uk/content/most-economically-advantageous-tender-meat. Accessed June 13, 2017.

5. Burns J. CMS issues PAMA final rule that aims to cut Medicare’s clinical laboratory test price schedule sharply beginning in 2018 [online]. Dark Daily. July 18, 2016. Available at: www.darkdaily.com/cms-issues-pama-final-rule-that-aims-to-cut-medicares-clinical-laboratory-test-price-schedule-sharply-beginning-in-2018. Accessed June 19, 2017.

6. Clinical Laboratory Services Market: Forecasts to 2020. Rockville, Md: Kalorama Information, 2015. Available at: www.kaloramainformation.com/clinical-laboratory-services-9305161. Accessed June 13, 2017.

7. Siemens Healthineers unveils game-changing Atellica Solution at AACC 2016 [press release]. Erlangen, Germany: Siemens Healthineers, 2016. Available at: www.siemens.com/press/en/pressrelease/?press=/en/pressrelease/2016/healthcare/pr2016080357hcen.htm&content[]=HC. Accessed June 13, 2017.

Personalized treatments for cancer are multiplying. As they multiply, so do clinical questions, such as: Which targeted therapies will be most effective? Have the first signs of a relapse begun? When does a tumor become resistant to the current protocol?

Decisive moments in care begin at the point of diagnosis and extend through time. They hinge on subtle genetic differences and bring together the lab, the clinician, and the patient. Your first decisive moment is deciding which technology platforms to bring into your lab. As clinicians’ options increase, so does their need for guidance. If you can give them clear genotyping information, you help them identify which tumors are susceptible to targeted agents.

With plasma genotyping, also known as liquid biopsy, you can offer a noninvasive method that evaluates tumor-derived cell-free DNA in a patient’s blood. Your ability to monitor genetic biomarkers may soon make important clinical decisions possible in near real time. Liquid biopsy is beginning to bring the power of noninvasive, highly sensitive, near real-time monitoring of treatment response to solid tumors as well. Early detection of resistance facilitates early adjustment of treatment. By providing this information to the clinical team, you can help them make treatment changes that may ultimately lead to better patient outcomes. How will your lab develop the tests and practices that will help clinicians and patients with today’s and tomorrow’s decisive moments? Where will you make a difference? Learn more about Decisive Moments in Personalized Cancer Treatment by watching this video.

Sir Bruce Ponder, FRCP, FMedSci, FRS.

Owlstone Medical, Cambridge, UK, recently appointed Sir Bruce Ponder, FRCP, FMedSci, FRS, to its newly established scientific advisory board. The board will form a key strategic resource, providing unique research perspectives and clinical expertise as the company introduces a new noninvasive diagnostic modality focused on cancer, inflammatory disease, and infectious disease.

Ponder is emeritus professor of oncology at the University of Cambridge and was the inaugural director of the Cancer Research UK Cambridge Institute (CRUKCI). He was knighted for services to medicine in 2008, and was awarded the Cancer Research UK lifetime achievement prize in 2013.

Ponder has made significant contributions to the field of oncology, including setting up one of the first specialist clinics for families with cancer, being involved in the discovery of several genes predisposing to cancer, and helping to advance the understanding of how cancer develops. His group at CRUKCI is investigating how variations in multiple genes combine to contribute to susceptibility to breast and lung cancer, with the aim to identify high-risk groups for targeted cancer screening and prevention.

Billy Boyle, Owlstone Medical.

“With over 4 decades’ work in cancer research, we are honored that Professor Sir Bruce Ponder is joining our scientific advisory board,” says Billy Boyle, cofounder and CEO at Owlstone Medical. “His tremendous depth of experience and knowledge will be hugely valuable to Owlstone Medical as we develop our breath biopsy platform for early detection of cancer and realize our ambition to save 100,000 lives and $1.5 billion in healthcare costs.”

“There is a great need to detect cancer earlier, and I strongly believe that Owlstone Medical’s technology enabling noninvasive diagnosis through breath can make a big difference in our approach to cancer screening,” Ponder adds. “I am excited to be contributing to the growth and future direction of Owlstone Medical.”

For more information, visit Owlstone Medical.

Micronic, Lelystad, the Netherlands, has launched a 0.30 mL tube with external thread that enables miniaturization of reaction volumes required in genomic applications. The tube eliminates the need for intermediate screening plates and is designed to be more accessible for low-volume liquid handlers. In addition, an automation-friendly 0.30 mL tube, with a working volume of 210 µL, is ideal for RNA/DNA libraries, offering unique aliquoting and storage capacity with multi-access. After the company’s 1.40 mL and 0.75 mL tubes, the 0.30 mL tube is the next size in a range of new designs featuring an external thread. Using externally threaded tubes for sample storage eliminates the possibility of the sample coming into contact with the screw thread, reducing the chance of cross-contamination while improving sample integrity. Due to thick tube walls, the tube has a sturdy design and excellent properties for ultra-low temperature storage. For more information, visit Micronic.

Calibrated electronic verification Lollipop Stem thermometers from Bel-Art–SP Scienceware, Wayne, NJ, are compact, all-in-one units with the display attached directly to the probe rather than with a cable. The entire digital unit can be placed inside a refrigerator, incubator, or room to verify sample temperatures. Available with general calibration, or with calibration specific to refrigerators, incubators, or ambient temperatures, the Lollipop Stem thermometers are supplied with calibration documents that meet the requirements of ISO 17025. For more information, visit Bel-Art–SP Scienceware.

The Avisio FOXC1 immunohistochemistry (IHC) test for basal-like breast cancer (BLBC) from 3N Diagnostics (3NDx), Belfast, UK, has obtained the CE mark. A pilot launch is currently taking place in 10 oncology centers in Europe.

On microscopic examination of breast tissue, BLBC cells may appear identical to less aggressive cancer cells. In breast tumor samples, 3N Diagnostics has identified and characterized expression of the forkhead box C1 (FOXC1) gene as a specific biomarker unique to the BLBC molecular subtype.

According to the company, evaluating FOXC1 expression enables accurate detection of BLBC in both estrogen-receptor-positive (ER+) and estrogen-receptor-negative (ER–) breast tumors. The Avisio test is designed to identify previously undetectable BLBC cells positively using standard IHC methods.

Partha S. Ray, MD, 3N Diagnostics.

“With the new, easy-to-use Avisio test, it is now possible to detect the lethal BLBC subtype early in the disease process, even in resource-challenged regions of the world,” says Partha S. Ray, MD, chief scientific officer at 3N Diagnostics and inventor of the Avisio test. “This is key to providing the most effective treatment possible, as early as possible, to any patient diagnosed with this aggressive cancer.”

Pathologists will have access to the Avisio FOXC1 test without the need to purchase additional processing or specialized staining equipment. Use of the test seeks to enable early identification of BLBC upon initial patient presentation, allowing multidisciplinary cancer treatment teams to formulate the most appropriate plan for each individual patient. Early detection and early initiation of best available therapy can improve the prognosis and survival of those diagnosed with this cancer.

Roberto Fagnani, PhD, 3N Diagnostics.

“Obtaining CE marking for Avisio FOXC1 culminates a major milestone [that] included the validation of the test in more than 5,000 patients and performing clinical trials in 1,429 patients,” says Roberto Fagnani, PhD, CEO of 3N Diagnostics. “We have also identified several promising strategies for targeted therapy of BLBC and are excited at the prospect of working with our colleagues in pharma and biotech to develop bespoke treatment plans for BLBC guided by use of the Avisio FOXC1 test.”

For more information, visit 3N Diagnostics.

Quanterix Corp, Lexington, Mass, has launched the Simoa Neurology 4-Plex A assay (N4PA). The Simoa N4PA assay can simultaneously measure four protein biomarkers from either cerebrospinal fluid (CSF) or directly from blood samples for the study of traumatic brain injury (TBI) and other neurodegenerative conditions. The four biomarkers used on the panel include neurofilament light (NF-L), tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1).

Recent studies indicate that serum NF-L is a biomarker for mild TBI in amateur boxers and professional hockey players, that plasma tau is related to concussion severity and return-to-play, and that serum GFAP and UCH-L1 can detect mild to moderate TBI.^1–3 The TBI endpoints development initiative has also hosted a 2017 consensus conference, where thought leaders have identified NF-L, tau, GFAP, and UCH-L1 as the top four fluid biomarkers of interest for mild TBI assessment.

Kevin Hrusovsky, Quanterix.

“The Simoa N4PA panel is an essential research tool for assessing head trauma-induced neural damage, particularly mild cases of TBI, which are the hardest to detect,” says Kevin Hrusovsky, executive chairman and CEO at Quanterix. “The assay is the first of its kind to detect all four key neuro biomarkers linked to TBI. This can be done simultaneously in a single well, at 1/1000th of the concentration level required by traditional enzyme-linked immunosorbent assays. As a result of continued product advances, we plan to usher this ultrasensitive multiplex technology into the clinic, and develop the most accurate and predictive tests for neurological disorders.”

The assay’s high degree of sensitivity allows the use of blood serum or blood plasma to detect neurological biomarkers, in place of conventional CSF sampling that is invasive and painful. Similarly, the assay’s ultralow detection level makes it possible to measure the biomarkers from early/mild stages to severe impairment.

“The design of this multiplexed assay will provide researchers with the insights needed to speed the development of a new generation of diagnostic products that will hopefully be useful for early detection of neurological disease,” says Henrik Zetterberg, MD, PhD, professor of neurochemistry and head of the department of psychiatry and neurochemistry at Sahlgrenska Academy of the University of Gothenburg. “Comparing the diagnostic and prognostic utility of tau, NF-L, UCHL-1, and GFAP head-to-head in samples collected at different time points following traumatic brain injury will give us new information on how we could potentially use these markers in clinical practice.”

The assay kit includes Simoa reagents, calibrators, multiplex Simoa beads, detector antibodies, and sample diluent required to run up to 96 tests. It is available for immediate purchase to run on the Simoa HD-1 analyzer or via the Simoa Accelerator Lab, an innovation center for biomarker research, custom assay development, and clinical sample testing.

Quanterix’s research and development in the area of neurological testing, including the Simoa N4PA assay, is a result of two GE and NFL Head Health Challenge grants that have been awarded to the company since 2015. The Simoa N4PA assay is for research use only and not for use in diagnostic procedures.

For more information, visit Quanterix.

REFERENCES

1. Shahim P, Zetterberg H, Tegner Y, et al. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology. 2017;88(19):1788–1794; doi: 10.1212/WNL.0000000000003912.

2. Gill J, Merchant-Borna K, Jeromin A, Livingston W, et al. Acute plasma tau relates to prolonged return to play after concussion. Neurology. 2017;88(6):595–602; doi: 10.1212/WNL.0000000000003587.

3. Papa L, Brophy GM, Welch RD, et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol. 2016;73(5):551–560; doi: 10.1001/jamaneurol.2016.0039.

Olympus, Center Valley, Pa, has expanded its device portfolio for endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) with new ViziShot 2 single-use aspiration needles. EBUS-TBNA is a minimally invasive alternative to a surgical procedure and is considered the gold standard for lung cancer staging.

The new needles were developed to offer improved access, usability, and puncture of difficult-to-access lymph node targets. The ‘backcut’ design of the ViziShot 2 provides a sharper needle, reducing puncture force required to sample even calcified lymph nodes. An ergonomic handle design and improved bronchoscope adapter enable stability and precise puncture control throughout the procedure. The newly designed green-colored sheath provides endoscopic visibility to ensure the needle can be deployed at the exact location required, with minimal sheath movement. Both 21 G and 22 G sizes are available to suit physician needs.

In addition to the ViziShot 2, Olympus recently introduced the ViziShot 2 Flex 19 G needle, featuring a new ergonomic handle. When used with the Olympus BF-UC180F 2.2 mm channel EBUS bronchoscope, the needle provides up to 84° of angulation to help physicians gain access to the most difficult lymph node stations, such as 4L, with ease. According to Olympus, the needle has the largest inner lumen currently available in the United States, ensuring improved sample acquisition for advanced molecular testing and enabling physicians to obtain ample quantities of the high-quality specimens needed for a comprehensive histological analysis, especially when diagnosing sarcoidosis and lymphomas.

“Great strides have been made in diagnosing and staging lung cancer and other diseases of the lung using minimally-invasive approaches, and we are proud of our contributions,” says Kurt Heine, group vice president of the endoscopy division at Olympus America Inc. “Our continued commitment to pulmonologists to advance minimally invasive methods is driven by the evidence that such approaches improve patient outcomes, cost containment, and patient satisfaction.”

For more information, visit Olympus.

Emerging ultrasensitive tests promise a paradigm shift in immunodiagnostics

By John Todd, PhD

Over the past half-century, immunoassays have become important tools in both research and clinical laboratories. An ongoing challenge for such immunoassay technologies has always been their relative lack of the sensitivity needed for accurate diagnosis and rule-out of disease. With single molecule counting technologies now making possible ultrasensitive immunoassays, however, a paradigm shift is under way for the field of immunodiagnostics.

Discovery and Development

The first immunoassay was developed in the 1950s by Solomon Berson, MD, and Rosalyn Yalow, PhD, of the Bronx Veterans Administration Medical Center.^1,2 The immunoassay they created was a radioimmunoassay using radioactive iodine-131. It was initially developed for use in measuring the concentration of insulin in plasma specimens, and was subsequently modified for the measurement of other hormones. In 1977, Yalow received the Nobel Prize in Physiology or Medicine for this work.

John Todd, PhD, Singulex.

During the following decades, the immunoassay technology was further developed and refined, and announcements of multiple new radioimmunoassays were published. In time, the use of radioisotopes was replaced by the use of enzymes, leading to the development of the enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA) technologies.^3,4 The discovery of the enzyme-multiplied immunoassay technique (EMIT) and other homogeneous immunoassays simplified the technology and allowed for automation.⁵ The application of chemiluminescent labels further improved analytical sensitivity.⁶

While early immunoassays relied upon antibodies purified from animals, the development of techniques for producing monoclonal antibodies from cell cultures enabled the manufacturing of larger quantities, and was awarded the Nobel Prize in Physiology or Medicine in 1984.⁷ In turn, this achievement allowed for the development of noncompetitive sandwich immunoassays, an approach that enhanced analytical sensitivity but required larger quantities of antibodies.

Today, immunoassay platforms capable of automatized analysis allow for high-throughput testing and are a mainstay in clinical laboratories. In addition, the development of lateral-flow tests has brought the technology from healthcare facilities to decentralized settings.

Although a mainstay of clinical diagnostic laboratories, the utility of such automated immunoassays has been limited by their relatively poor sensitivity and precision at low concentrations of analytes. The limits of sensitivity have been mainly the result of high background noise blocking the measurement of analyte signals at low concentrations. Thus, the holy grail of immunoassay development has been to enhance analyte signal while decreasing the background noise, commonly measured as the signal-to-noise (S/N) ratio.

Dawn of Ultrasensitive Immunoassays

The recent development of high-sensitivity immunoassays ushers in a new era for immunodiagnostics. Single molecule counting or detection technology, linked with traditional immunoassay technology, has made it possible to realize the holy grail of immunoassay development—specifically, improving the signal-to-noise ratio of an assay by up to a thousand-fold.

When polymerase chain reaction (PCR) technology was introduced to clinical laboratories, it led to significant improvements in the analytical sensitivity of molecular diagnostics. However, PCR-based tests can be hampered by high costs and poor precision. The evolution of high-sensitivity immunoassays has enabled detection of low-abundance molecules, approaching the clinical sensitivity accomplished with PCR.

Newly developed capabilities for detecting and quantifying biomarkers at low concentrations are changing clinical practice and patient management. Biomarker measurement has many applications, including risk stratification, disease detection, staging, prognosis determination, and monitoring. With a wide range of diagnostic opportunities, high-sensitivity immunoassays have the potential for a great and growing clinical impact.

The ability to rule-out disease is critical for an accurate, safe, and cost-effective diagnostic workup. High-sensitivity immunoassays may allow for such a paradigm shift, not only in detecting and diagnosing disease, but also in ruling-out disease, thereby eliminating unnecessary testing, and ultimately improving patient care.

Figure 1. The Sgx Clarity by Singulex, a fully automated in vitro diagnostic platform employing single molecule counting technology to detect analytes down to femtogram-per-milliliter levels.

A proprietary single molecule counting technology by Singulex, Alameda, Calif, aims to take immunodiagnostics to the next level by offering sensitivity up to a thousand times greater than contemporary immunoassay platforms. The company’s ultrasensitive, fully automated, quantitative, fluorescent, sandwich immunoassay allows for detection of analytes down to femtogram-per-milliliter levels. The single molecule counting digital detection technology has been developed for a fully automated in vitro diagnostic platform, the Sgx Clarity system (see Figure 1).

Singulex was founded in 2004, with the mission of bringing ultrasensitive immunodiagnostics to scientists and clinicians. In 2015, Singulex’s Erenna system, a research use only (RUO) platform, was acquired by EMD Millipore, the life science research business of Merck KGaA. In 2016, Grifols acquired a license to Singulex’s single molecule counting technology for pathogen detection in blood-screening applications. Today, Singulex is developing a broad analyte menu for the Sgx Clarity system, which is expected to be available in the European Union following CE marking of the instrument earlier this year. Singulex further plans to launch the Clarity system in the United States, subsequent to FDA clearance.

Single Molecule Counting

The Sgx Clarity system is based on a microparticle immunoassay powered by single molecule counting technology. During the capture step, microparticles are coated with specific antibodies. The surface chemistry of the microparticles improves binding efficiency while minimizing nonspecific binding. After capture, the microparticles are magnetically separated and washed to remove unbound proteins and any remnants of nonspecific binding.

Figure 2. Ultrasensitive single molecule counting technology used in the Sgx Clarity system from Singulex. A bright dye and optimized confocal optic system increase the signal, and low nonspecific binding and a very small interrogation space minimize background fluorescence.

Specific fluorescent dye-labeled detection antibodies translate each captured analyte into a signal. After isolation, each signal corresponds to a single analyte molecule. Elution volume is reduced to concentrate the signal and enhance the single molecule counting process. The eluate is then transferred to a microwell plate and loaded into the fully automated Sgx Clarity instrument for reading.

Single molecule counting is performed directly inside individual plate wells. Inside the well, a very small interrogation space is illuminated by a laser, which scans along a helical path, ensuring efficient signal capture. Single fluorescent-labeled molecules generate intense flashes of light as they are scanned (see Figure 2).

During counting, the intensity of the fluorescence encountered in the interrogation space is captured as a function of time. The measured fluorescence is sequestered in 100 microsecond time bins. Detected signals with peak intensity above the threshold of background fluorescence are counted as digital events, and the instrument records the sum of all digital events counted. At high concentrations, a proprietary algorithm computes the sum of all photons recorded; thus, a dynamic range of over six logs is achieved. Singulex’s single molecule counting technology allows for ultrasensitivity and broader dynamic range than contemporary assays.⁸

First Application: Cardiac Troponin  

Now commercially available in the European Union, and available as an RUO instrument in the United States, Singulex’s single molecule counting technology has been validated in more than 130 peer-reviewed publications—predominantly, but not exclusively, for cardiovascular applications. The use of such a precise tool for early detection and rule-out of coronary artery disease (CAD) and acute myocardial infarction (AMI) may avoid unnecessary diagnostic testing, reduce healthcare costs, and improve patient care.

Table 1. Lower limit of detection (LoD) and 99th percentile values in a presumably healthy population measured by high-sensitivity, sensitive-contemporary, and point-of-care cTnI and cTnT assays, including Singulex’s cTnI assay for research use only (reproduced by permission of the American Association for Clinical Chemistry).¹⁵

Cardiac troponins I (cTnI) and T (cTnT) are used in the management of suspected AMI and have been associated with risk of future cardiovascular disease (CVD).^9–11 But until recently, available assays have not been sufficiently sensitive to detect cTnI among healthy people. Singulex was the first research group to measure cTnI, a marker with low biological variability, in 100% of a group of presumably healthy individuals.^12–14 When comparing the lower limit of detection and measurable values greater than the limit of detection among 19 cTnI and cTnT assays, the RUO single molecule counting assay from Singulex showed superior performance compared to contemporary cTnI assays (see Table 1).¹⁵

Plasma- or serum-based cardiac troponin tests have been shown to be capable of differentiating healthy patients from those that either have CVD or are at risk for developing CVD. In individuals without known risks for CVD, cTnI assays using single molecule counting technologies have been shown to predict risk of cardiovascular death, incident congestive heart failure (CHF), major adverse cardiovascular events, and all-cause mortality.^9–11

In a comparison of Singulex’s single molecule counting RUO cTnI assay with two commercially available cTnI assays (Stat troponin I immunoassay and Architect Stat highly sensitive troponin I immunoassay; both performed on the Architect i2000SR immunoassay analyzer by Abbott Diagnostics, Abbott Park, Ill), the Singulex ultrasensitive assay had a stronger association with cardiovascular outcomes.¹⁰

Figure 3. The ultrasensitive cardiac troponin I assay by Singulex is CE marked and developed for use on the Sgx Clarity system.

In patients with stable CAD and recent acute coronary syndrome (ACS), monitoring of single molecule counting cTnI was shown to predict cardiovascular death and CHF. Such results can be used to guide therapy: patients with high cTnI levels 30 days after ACS had a reduction in cardiovascular death and CHF with high-intensity compared with moderate-intensity statin therapy.¹⁶ It has been further demonstrated that cTnI is predictive of CAD and is reduced by statin therapy.¹⁷

Measurement of cTnI is standard in the management of patients with suspected AMI.¹⁸ When evaluating presentation cTnI values in order to rule-in or rule-out AMI, the Singulex RUO cTnI single molecule counting assay has excellent sensitivity and negative predictive value when compared to a contemporary commercially available assay (TnI-Ultra; Siemens Healthineers, Tarrytown, NY).¹⁹ The ability to rule-in and rule-out AMI and non-ST-segment elevation myocardial infarction (NSTEMI) has been further demonstrated using the Singulex RUO cTnI assay for evaluating cTnI at presentation and for evaluating postpresentation changes in cTnI levels.^20,21

Singulex has developed and CE marked a cTnI assay for use on the Sgx Clarity system (see Figure 3). Testing of that assay’s analytical performance characteristics shows that the limits of blank (LoB) and limits of detection (LoD) are 0.02 and 0.08 pg/mL, respectively. The assay’s limit of quantification (LoQ) is estimated to be 0.14 pg/mL at 20% CV, and 0.53 pg/mL at 10% CV, with observed precision in the range from 4.0% to 9.6%. The 99th percentile is 8.67 pg/mL (95% CI, 6.68–29.16).²²

Table 2. Cardiac troponin I measurement using the Sgx Clarity cTnI assay: characteristics of prespecified cutoff values.²²

To reduce the public health burden of CAD, early detection of the disease is critical. Cardiac stress testing is the mainstay of noninvasive CAD diagnostics. Nuclear stress testing with imaging, such as myocardial perfusion imaging single-photon emission computed tomography (MPI-SPECT), has limitations, including a poor diagnostic yield, high costs, limited availability, and exposure to contrast agents and radiation.²³ Consequently, there is a need for developing more cost-effective strategies for the initial work-up of patients who are presently at low risk of manifesting inducible myocardial ischemia during cardiac imaging procedures. In addition to reducing healthcare costs, an alternative rule-out tool would reduce patient time in medical facilities and the number of specialist referrals needed. In a study of 555 patients without previously known CAD referred for stress MPI-SPECT imaging, cTnI measurements using the Sgx Clarity cTnI assay were obtained before stress testing. When cTnI test results were <0.50 pg/mL, the test had a sensitivity of 94% and negative predictive value (NPV) of 91% for ruling-out cardiac ischemia. Combining clinical judgment using visual analog scale (VAS) assessment with a cTnI prestress test increased the ability to rule-out the presence of cardiac ischemia at an NPV of 93% (see Table 2).²² In addition, the single molecule counting RUO cTnI assay has been shown to be predictive of obstructive CAD.²⁴

Advancing Clinical Research

Singulex is expanding clinical evaluation of the Sgx Clarity system at a number of research sites in the European Union. In collaboration with Jordi Ordóñez-Llanos, MD, PhD, professor of clinical biochemistry at Hospital de la Santa Creu i Sant Pau, Barcelona, clinical research studies evaluating the value of single molecule counting technology for cTnI assessment in patients suspected of having ACS, including AMI, are currently underway.

According to Ordóñez-Llanos, “Singulex’s proprietary single molecule counting technology is already proven to have improved cTnI detection and clinical sensitivity, thus increasing the performance of the biomarker to evaluate ACS and, particularly, AMI.

“With that clinically proven power now available in an in vitro diagnostics platform, researchers like me can have direct access and explore the potential for clinical use,” he adds. “At my site in Barcelona, we’ve already demonstrated precision and functional sensitivity and are expanding clinical research studies to explore applications of the cTnI to better understand heart disease status.”

At St. George’s University, London, Paul O. Collinson, MBBChir, MD, FRCPath, FACB, FRCP, professor of cardiovascular biomarkers, has completed analytical evaluation of the Sgx Clarity system’s performance. Collinson will go on to test the Westcor study to investigate the ability of hs-cTnI assays to rule out the presence of AMI.

“We have observed performance of the Sgx Clarity cTnl assay at the level which we believe meets the European Society of Cardiology guidelines for the management of acute coronary syndromes, specifically to rule-in and rule-out patients,” says Collinson. “In our view, this validates the utility of Singulex’s in vitro diagnostics platform and reinforces the opportunity it may present to our understanding of heart and total health status.”

Anthony Freemont, MD, FRCP, FRCPath, director of the molecular pathology innovation center at the University of Manchester, and Richard Body, MBChB, PhD, MRCSEd(A&E), FCEM, professor of the Royal College of Emergency Medicine, are testing the Sgx Clarity cTnI assay in the supersensitive troponin admission reduction (STAR) study. The study is an evaluation of patients across the UK with cardiac chest pain to determine whether use of the ultrasensitive Sgx Clarity cTnI assay can rule-out ACS, lead to lower readmission rates, and bring cost savings to the UK’s National Health Service.

Future Directions

In April of this year, the Sgx Clarity system achieved the CE mark, making it eligible for marketing in Europe and other countries that accept the mark. Singulex plans to submit the system for FDA premarket notification (510(k)) clearance during the second half of this year.

To expand the future Sgx Clarity test menu beyond cTnI, Singulex is currently developing additional assays, including assays for procalcitonin and Clostridium difficile toxins A and B. Procalcitonin has been shown to aid in the diagnosis of severe sepsis.²⁵ Testing for procalcitonin on the Sgx Clarity system may allow for rule-out of sepsis and subsequently guide antibiotic stewardship.

Diagnosis of C. difficile infection is challenging, in part because the currently available arsenal is dominated by immunoassays with relatively low sensitivity and molecular tests with low clinical specificity. It is intended that the Sgx Clarity C. difficile assay will achieve improved accuracy, making it a critical diagnostic tool for patients with suspected C. difficile infection.

Singulex is also in the process of developing a point-of-care instrument. The company’s goal is to have a prototype device ready by the end of 2017. It is expected that such a point-of-care system will facilitate patient-centered care, allow for more rapid turnaround times and immediate decisionmaking, and result in less fragmented healthcare.

In an effort to enter strategic collaborations, Singulex has recently partnered with Qiagen, Germantown, Md, to codevelop companion diagnostics. Singulex will contribute immunoassay capacity to Qiagen’s molecular testing services, when offering companion diagnostic capabilities to the pharmaceutical industry.

Conclusion

The evolution from Berson and Yalow’s first radioimmunoassay to today’s ultrasensitive single molecule counting technology spans nearly 6 decades. Immunoassays fundamentally changed clinical practice, and with the advancement of ultrasensitive immunoassays, the next disruption in healthcare will follow.

The Sgx Clarity system offers ultrasensitive biomarker detection that has the potential to support a paradigm shift in patient management. With unprecedented sensitivity, the single molecule counting technology will transform immunodiagnostics across multiple disease areas in both acute and chronic disease management, and change patient care from reactive disease treatment to proactive health management.

John Todd, PhD, is chief scientific officer at Singulex. For further information contact CLP chief editor Steve Halasey via shalasey@nullmedqor.com.

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