Volume 3, July 2015

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Diagnostics Today – A Foundation for Improved Health Outcomes
Rick L. Pesano, MD, PhD
Vice President Development, Science and Innovation
Medical Director, Infectious Diseases/Immunology
Quest Diagnostics

Improve health outcomes with limited resources - that’s the perennial challenge for the healthcare system. Dr. Rick Pesano explains how diagnostics is helping meet that challenge by enabling timely interventions and guiding therapies to improve long-term outcomes and costs.

“Healthcare is increasingly subject to multiple demands – to improve health and quality of life, and to deliver those improvements within ever tighter spending constraints,” says Dr. Pesano. “Diagnostics responds to those demands by enabling accurate detection of health risk and early identification of disease. This provides the foundation for more effective treatment and disease management, which in turn reduce down-stream health problems and their associated costs. So, in many ways, diagnostics plays a pivotal role in the ‘health value chain’ by positively influencing the quality of patient care, health outcomes, and long-term resource requirements.”

Examples of how Quest Diagnostics is influencing outcomes along the health continuum are discussed in this newsletter. 14.3.3η is a novel biomarker for rheumatoid arthritis, which enables more sensitive diagnosis of the disease, providing a basis for early intervention to minimize the potential for joint-destruction and co-morbidities. In cardiology, managing residual risk for patients on statin therapy, after accounting for traditional risk factors, is a particular challenge. A study recently conducted by researchers at Skåne University Hospital and Quest Diagnostics demonstrated that LDL particle number identifies patients at elevated risk of atherosclerotic cardiovascular disease (ASCVD) events, independently of traditional risk factors.

Identifying risk and enabling early intervention are the goals of cervical cancer screening. A recently published study of extensive test data for cervical cancer screening, conducted by researchers at University of Pittsburgh Medical Center and Quest Diagnostics, demonstrates that co-testing with Pap smear and HPV-test is more effective at detecting cervical cancer than either test alone. This reinforces current guidelines recommending co-testing as the preferred screening method.

“Diagnostics has been evolving in line with our growing understanding of biological systems and disease, which in turn have led to advances in testing technologies,” continues Dr. Pesano. “As a result, specific categories of diagnostics relative to patient care are moving into new areas, which is fundamentally changing clinical practice. We are moving in the direction of more personalized medicine, or precision medicine, often defined as ‘providing the right patient with the right treatment at the right time.’ One of our goals for clinicians and patients is to be able to assess the risks and the benefits of specific options, which may be customized to their particular health status and quality of life.” This is why Quest Diagnostics has introduced a new approach for reporting test results – Interactive Insights™ – which combines a clear, graphic presentation of results with information to support clinical decision-making and physician-patient dialogue.

“The field is clearly moving toward a more individualized approach to patient care,” summarizes Dr. Pesano. “Quest Diagnostics is both embracing that change and playing a part in making that change a reality.”

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Cervical Cancer Screening – National Study Finds that Co-Testing Detects More Cancers than HPV Primary Testing
Douglas Rabin, MD
Medical Director, Women’s Health
Quest Diagnostics

HPV (human papillomavirus)-only screening is less likely to accurately detect cervical pre-cancer and cancer than co-testing with a Pap test and HPV test in women 30-65 years of age, according to a new study conducted by researchers at the University of Pittsburgh Medical Center (UPMC) and Quest Diagnostics.1 The findings reinforce current guidelines, that recommend co-testing for cervical cancer screening,2-4 and raise questions about the use of an HPV test alone as a primary cervical cancer screen.

Dr. Rabin reviews the guidelines for cervical cancer screening and discusses the findings from the study published in April 2015 in Cancer Cytopathology, a peer-reviewed journal of the American Cancer Society.

Current Guidelines
“Professional guidelines for cervical cancer screening of women 30 to 65 recommend Pap smear/HPV co-testing every 5 years as the preferred method, with Pap smear alone every 3 years as an alternative,” says Dr. Rabin. However, following last year’s FDA approval of the cobas® HPV test for use alone as a primary cervical cancer screen, some professional bodies have issued interim guidance that primary HPV testing can be considered as an alternative to Pap-HPV co-testing or Pap alone.”5-6

Dr. Rabin cautions that it is important to consider the approval of the HPV test in the context of actual practice and current guidelines. “Firstly, it should be noted that the FDA approval was based on a clinical trial that compared HPV testing to Pap testing and involved eight confirmed cervical cancer cases. Given that patients are getting co-tested, one could argue that the comparator used in this study was not the most appropriate in relation to practice in the United States. Additionally, all guidelines remain unchanged and, in fact were reinforced in April in “Best Practice Advice” from the Clinical Guidelines Committee of the American College of Physicians.7

National Study Validates Co-Testing
Researchers at UPMC and Quest Diagnostics recently completed a study comparing cervical cancer screening methods in actual clinical practice.1 The study investigated the sensitivity of 3 testing options for biopsy-proven cervical intraepithelial neoplasia grade 3 or worse (CIN3) and cancer by reviewing 256,648 deidentified results from tests performed in women ages 30 to 65 years who had a cervical biopsy specimen obtained within 1 year of the cotest. The 3 testing options assessed were the Pap-only test, the HPV-only test, and the Pap/HPV cotest. The study is believed to be one of the largest to examine the effectiveness of HPV and Pap screening for cervical pre-cancer and existing cervical cancer, based on approximately 8.6 million women who had tests performed by Quest Diagnostics laboratories in the United States.

“The goal of the study was to demonstrate what the impact of Pap only or HPV only testing would be in women who were co-tested and had a follow-up biopsy,” says Dr. Rabin. “First of all, we were able to demonstrate that the sensitivity of the co-test for intraepithelial neoplasia stage 3 (CIN3) or more sever lesions (including cancer) was significantly better than the sensitivity of HPV only or Pap test only. Sensitivity of HPV-only testing was 94%, and for Pap-only it was 91.3%, while the positive co-test had a sensitivity of 98.8%.”

Cancer Prevention
“Another critical finding concerned the prevention of cancer in the long run,” notes Dr. Rabin. “We found that if patients were only provided HPV testing, almost 19% of their cancers would have been missed. With Pap-only testing, it would be 12% and with co-testing it would be 5.5%. We also found that 26.6% of women who had an adenocarcinoma, verified as cervical in origin, had a negative HPV test, while only 8.3% had a negative co-test. We set out to investigate whether the co-test is a better way to screen women to prevent against the development of cancer, and this was borne out by the data from the large real world population that we studied.”

“This is consistent with what has been shown in the literature - that HPV and Pap co-testing provides the best long-term protection against cancer development,” continues Dr. Rabin. “In other words, if you have a negative co-test, your chance of developing significant disease is limited and while it may double at five years, it is still only 0.011%. This compares to a chance of 0.014% with HPV alone – nearly a 30% difference.”8

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cobas® is a registered trademark of F. Hoffman-La Roche Ltd.

LDL Particle Number - An Independent Measure Of Cardiovascular Risk - New Evidence
Gerard Abate, MD
Medical Director, Cardiovascular
Quest Diagnostics

LDL particle number identifies patients at elevated risk of atherosclerotic cardiovascular disease (ASCVD) events independently of traditional risk factors, including standard lipid measurements. Those were the findings of recent research based on data from the Malmö Diet and Cancer Study.1 Dr. Abate discusses the significance of LDL particle number and the implications of results from this study and related research.

Shortcomings of Standard Lipid Measurement
One of the issues for physicians assessing and managing cardiovascular risk is that in some cases standard measures may not be a reliable indicator of risk. “A basic lipid panel is a reliable measure if a patient has normal triglycerides,” says Dr. Abate, “but as triglycerides increase over 200 mg/dL, the measurement of LDL-C measurement becomes less accurate. In fact, as triglycerides reach the 250 mg/dL to 300 mg/dL range, there can be a 50% to 60% variance in measurement accuracy.”

“Another issue is that we now know that LDL-C alone is not the only cardiovascular risk factor,” continues Dr. Abate. “We know that statins can decrease risk by 30% to 45%, but there's still significant residual risk that remains for these patients - that's residual risk, which is not identified or managed by focusing on the LDL-C number alone.2-5 We know that many patients who have LDL-C below 100 mg/dL, and do not qualify for statin therapy based on current AHA/ACC guidelines,6 nevertheless have coronary events. So there need to be improvements in how we assess risk beyond our standard approach for measuring statins.”

LDL Particle Measurement – Subfractionation
A more precise measure of LDL-C than a standard lipid panel is the measurement of LDL particle number using ion mobility subfractionation. This method enables the measurement of 8 subclasses of LDL, 2 subclasses of HDL, as well as subclasses of IDL and VLDL content in addition to the mass of cholesterol. Subfractions are based on the size and density of the particles. LDL particles are divided into subfractions ranging from smaller, more dense particles up to larger, less dense particles, while HDL particles can also be divided into smaller and larger subfractions. It has been shown that residual risk is associated with particle size, as well as concentration. High levels of LDL particles and low levels of HDL particles are associated with CVD events. The increase in CVD risk (from the lowest-risk tertile to the highest-risk tertile) is about 40% for LDL particles, 30% for small LDL subclass particles, 40% for medium LDL particles, and 80% for large HDL particles.7

Smaller LDL particles are associated with a higher incidence of ASCVD, as is a high number of LDL particles.8,9 The concentration of HDL particles is also an important factor, with large HDL particles thought to offer the most protection against ASCVD.10,11

LDL Particle Number as an Independent Risk Factor – Evidence from Analysis of the Malmö Diet and Cancer Study Cardiovascular Cohort
Research was recently conducted by investigators from Skåne University Hospital and Quest Diagnostics to determine whether LDL particle number is associated with ASCVD events among those whose 10-year risk does not exceed the 7.5% threshold for statin therapy, based on the 2013 AHA/ACC guidelines. “2,591 patients of the 4,755 that had previously been assessed in the Malmö Diet and Cancer Study Cardiovascular Cohort in 2013 were classified based on ion mobility sub-fractionation,” explains Dr. Abate. “Based on this, one group of 1,919 patients, with an LDL-C less than 190 mg/dL, would not have been treated with statins per AHA/ACC guidelines – their 10-year ASCVD risk was below 7.5%. When we assessed those patients, we showed that LDL particle had a positive predictive value for risk above and beyond other factors (with a P-value of 0.003). This was consistent with the small and medium particles - the small particle had a P-value of .03 and medium particle of .0007 versus those at baseline. This elevated risk was independent of traditional risk factors, including standard lipid measurements.”1

“The study shows that patients who would not have been eligible for statin treatment could be reclassified based on particle size. Ion mobility subfractionation assists in reclassifying patients with seemingly moderate risk into a higher risk category that would benefit from treatment.”

The Case for Individualized Patient Care
“Combined with other research relating to residual risk, the study confirms that effective treatment of patients goes beyond population management to more individualized personalized medicine,” concludes Dr. Abate. “Every patient's care should be individualized, as no two patients are the same. An assessment should be made based on the patient's history and risk factors - sex, age, smoking history, diabetes, hypertension, history of coronary disease, and family history– and a determination then made whether or not there's a need to go beyond a basic lipid panel.

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14.3.3η – A Biomarker to Enable Early, Accurate Diagnosis of Rheumatoid Arthritis
Stanley J. Naides, M.D., F.A.C.P., F.A.C.R.
Medical Director, Immunology R&D
Quest Diagnostics

The window of opportunity for early diagnosis and treatment of rheumatoid arthritis (RA) to prevent joint destruction is a narrow one. Dr. Naides explains how a novel biomarker, serum 14.3.3η, could play a valuable role in early diagnosis of RA to enable timely intervention. He discusses findings from a recent study published in the Journal of Rheumatology, which indicate that serum 14.3.3η is a “mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA”.

The Importance of Early Diagnosis
“In contrast to the limited options available in the past for treating RA, we now have the opportunity to intervene early with effective drugs to prevent joint destruction, and even put patients into remission,” says Dr. Naides. “The optimum period for intervention may be as early as within 14 weeks of onset of symptoms. So, the sooner we identify individuals who have rheumatoid arthritis, the more likely we are to control the disease and prevent joint destruction.”

Limitations of Current Serological Markers
“It's extremely important to have effective markers to identify RA early,” continues Dr. Naides, “particularly because the clinical signs, by which we can determine whether a patient has RA, are not always present in the early stages.”

The classification criteria established by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) provide the basis for how RA is diagnosed.1-2 Applying these criteria there is a potential total of 10 points, 4 of which are based on laboratory markers. The laboratory markers used are rheumatoid factor (RF), antibodies to cyclic citrullinated peptide (CCP), C reactive protein (CRP), and erythrocyte sedimentation rate (ESR). “The problem,” notes Dr. Naides, “is that for many patients, these laboratory markers are normal especially at first medical encounter early in disease: The sedimentation rate is normal in almost half of patients with RA, C reactive protein is normal in anywhere from 30% to 40%, and rheumatoid factor tests are negative in about a third."3 – 6

“Another limitation of current markers,” continues Dr. Naides, “is that the erythrocyte sedimentation rate and C reactive protein are both markers of systemic inflammation. They do not indicate whether the inflammation is occurring specifically in the joints or whether this is an acute phase reactant due to any number of inflammatory, autoimmune, infectious, or neoplastic diseases. In addition, rheumatoid factor and CCP have low sensitivity, particularly in early RA.”

14-3-3η – A “Mechanistic” Marker
“Given the shortcomings of current markers, there is a need for what has been called a mechanistic marker - not one that represents the downstream effects of a pathogenic event, but, rather, one that is involved in the pathogenesis,” says Dr. Naides. “14-3-3η is such a marker. 14-3-3 proteins are distributed throughout the body, with the η isoform found in the brain and in the synovium. Assuming the blood brain barrier is intact, if 14-3-3η is found in the serum, the likely source is the synovium. It turns out that individuals who have RA, and to some extent patients with erosive psoriatic arthritis, express and excrete 14-3-3η into the synovial fluid, which then passes into the serum. We have found that in inflammation, such as in RA, the serum 14-3-3η level is increased. If you take 14-3-3η and put it on synovial fibroblasts, it induces pro-inflammatory changes within the cell. So it is in itself pathogenic when expressed outside the cell and, therefore, a mechanistic marker. By measuring 14-3-3η we're not only measuring something that is uniquely present in RA and in erosive psoriatic arthritis, but we’re also learning about the underlying pathogenesis.”

14-3-3η – The Growing Evidence
Dr. Naides participated in a study recently published in the Journal of Rheumatology, which assessed the diagnostic utility of 14-3-3η in relation to RA and its association with standard clinical and serological measures. “The study looked at 14-3-3η in a number of different patient cohorts,” says Dr. Naides. “The two largest cohorts were individuals with RA, one with early RA and one with established RA. When we looked at patients in both groups many had markedly elevated levels of 14-3-3η, while in the controls we typically did not see elevations in 14-3-3η.”7

“When you looked at 14-3-3η in relation to other markers, it was an independent marker of RA and did not follow C reactive protein, sedimentation rate, RF, or CCP. The study shows that 14-3-3η is a useful, highly specific marker, which enables a more accurate diagnosis of RA. In addition, there is more data from this study, in press, which further demonstrate that adding 14-3-3η to RF and CCP improves the diagnostic pickup.”8

Clinical Utility
“For a primary care physician, 14-3-3η positivity is really a marker to prompt them to refer to a rheumatologist for further evaluation. In the setting of osteoarthritis, that becomes very important. We presented a poster at EULAR in early June, which looked at 166 individuals with doctor-diagnosed osteoarthritis. Of those, only 11 were positive for 14-3-3η. On further examination, one patient was rediagnosed as having RA, one subsequently developed psoriatic arthritis, and a third had osteoarthritis and RA together. That left 8 of 163, or only 5% of the osteoarthritis patients with 14-3-3η, while 64% of early RA patients have 14-3-3η.8, 9 So we believe that 14-3-3η will help the primary care physician, who may not be as adept as a specialist at the subtleties of joint examination, identify patients who have more than osteoarthritis and need to be referred to a rheumatologist.”

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Interactive Insights™ by Care360® - Transforming Diagnostic Laboratory Reporting
Katie M. Wietmarschen
Product Manager, Healthcare Technology and Analytics Solutions

Sound clinical decision-making is dependent on comprehensive, relevant information that’s easily accessible. That’s why Quest Diagnostics has launched Interactive Insights by Care360®, a web-based reporting solution, designed to provide physicians and patients with the right information, at the right time, in the right format.

Ms. Wietmarschen explains how Interactive Insights™ is transforming the communication of laboratory and diagnostic results to support clinical decision-making and facilitate physician-patient dialogue.

Supporting Clinical Decision-Making
Interactive Insights provides diagnostic insights based on a patient’s laboratory data to enable more informed decision making by both the physician and patient,” notes Ms. Wietmarschen. “We have converted traditional paper-based results into a web-based interactive format, that provides diagnostic content relevant to the result in context.”

Interactive Insights results are displayed in three views: Current, within a reference Range, and longitudinally Over Time. Results are shown in order of priority, with historical trends displayed in the context of a patient’s continuum of care. Physicians can see up to two years of patient-specific history for that test, no matter where previous Quest Diagnostics tests were ordered or who ordered them. Out-of-range results are clearly displayed and can be flagged for further attention.

“A key aspect of Interactive Insights is the access it provides to information in addition to the test results,” says Ms. Wietmarschen. “The product supplements traditional test result data with additional information, such as FAQs, clinical algorithms, videos, publications, and more to help with clinical decision-making.”

Facilitating Physician-Patient Dialogue
“Interactive Insights enhances physician and patient communication by presenting test results in a clear, simplified format tailored to patients. Result reporting is combined with trusted educational content to enhance patient understanding of their results and help the clinician engage patients in medical discussions. Results and educational content can be shared with patients in the office or can be emailed to them. It is also available to patients through the MyQuest™ by Care360®, patient portal application,” says Ms. Wietmarschen.

Initial feedback from healthcare providers and patients indicates that Interactive Insights is a valuable tool to facilitate ease of access to results and understanding of diagnostic data.

Accessible Anywhere
Interactive Insights has been designed to bring insights closer to the point of care. For this reason it can be accessed by providers from anywhere – in or out of the office, from a desktop, tablet or mobile device. It can be viewed as a standalone application, or integrated with an EMR/EHR system and is automatically available on Care360 and to patients in MyQuest.

“Essentially, Interactive Insights enhances the presentation of diagnostic test results and provides context based content tailored by audience, providing a basis for meaningful conversations between clinicians and patients,” says Ms. Wietmarschen. By providing timely access to the vital information clinicians need, Interactive Insights exemplifies the commitment by Quest Diagnostics to transform knowledge into insights, and insights into solutions, which allow physicians to focus on bettering the health of their patients.

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Upcoming Events

Thurs., July 30, 20155
3:00 pm ET/12:00 pm PT
ICD-10 Readiness & Preventive Lab Services
Presenter: Kathy A. Montoya
Overview: Provider Outreach and Education Representative
Noridian Healthcare Solutions
A/B Medicare Administrative Contractor
Jurisdiction E, California and Nevada.

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Tues., Aug 4, 20155
11:00 am ET/8:00 am PT
ICD-10 Readiness & Preventive Lab Services
Presenter: Kathy A. Montoya
Overview: Provider Outreach and Education Representative
Noridian Healthcare Solutions
A/B Medicare Administrative Contractor
Jurisdiction E, California and Nevada.

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