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Toward Precision Medicine: Combining Next-Generation Sequencing with Bioinformatics to Help Personalize Therapy
Jay G. Wohlgemuth, M.D.
Senior Vice President, Research and Development, Medical and Chief Scientific Officer
Quest Diagnostics

In this year’s State of the Union address President Obama highlighted the promise of precision medicine to provide the “right treatments, at the right time…to the right person.”1 This has been followed by the launch of the Precision Medicine Initiative, which will provide $215 million to fund a “new model of patient-powered research.” 2 The dramatic advance in DNA sequencing technology is providing a basis for precision medicine in an increasing number of specialties. Dr. Wohlgemuth describes how Quest Diagnostics is combining the power of next-generation sequencing (NGS) with extensive bioinformatics capabilities to help clinicians identify risk and guide therapy in multiple clinical areas, including:

From Data to Relevant Information
“Because of significant improvements in efficiency over recent years, DNA sequencing is allowing us to generate large amounts of data, covering many genes, with a single assay,” says Dr. Wohlgemuth. “It also enables us to sequence a smaller number of genes very thoroughly, with very high sensitivity. But the data generated by this technology only have value if accurately interpreted and linked to clinical decision-making. For this reason we have been developing significant bioinformatics capabilities, which enable us to process and interpret the data to make it clinically meaningful.”

Quest Diagnostics has built a world-class sequencing and bioinformatics capability based on Quest Diagnostics Nichols Institute Genetics Laboratories - Celera Diagnostics and Athena Diagnostics, both acquired in 2011. Celera was the first corporation to sequence the human genome. Athena has been a leader in neurology genetics for over 15 years and has recently moved into a state-of-the-art facility, a “lab of the future,” in Marlborough, Massachusetts.

HIV Tropism
Quest’s first application of NGS was in HIV coreceptor tropism testing. “The original, phenotypic, test for this is very expensive and takes a long time to perform,” notes Dr. Wohlgemuth. “With NGS we’re able to deliver a result in half the time at about half the cost. Following validation of the test in pivotal pharmaceutical trials, guidelines from the Department of Health and Human Services panel on the use of antiretroviral agents were updated to note that genotypic tropism testing should be considered as an alternative to phenotypic tropism testing.3 This was a first for us in the field, as well as for the national laboratory industry as a whole.”

Reproductive Genetics
DNA sequencing has also had an impact in the reproductive genetics field. The availability of non-invasive prenatal testing offers significant benefits over traditional methods, enabling prenatal testing to be performed from a blood sample instead of by amniocentesis or a chorionic villus sampling. “In a very short period of time, testing based on this technology has become a standard of care in high-risk women to determine if there are any abnormalities that warrant further follow up.4 The test is highly accurate - in the 99% plus range for detection of Down syndrome and other major chromosomal abnormalities – and has a rapid turnaround. This is allowing many patients to avoid an amniocentesis, which is now mainly preformed only to confirm a positive non-invasive test.”

In addition, Quest Diagnostics recently released the CFvantageTM assay, which uses NGS to test for cystic fibrosis mutations. “With a low-cost, rapidly performed assay, we can now generate information on over 160 different clinically meaningful cystic fibrosis mutations, whereas we used to look at only 23,” explains Dr. Wohlgemuth. “We anticipate that testing in reproductive genetics will continue to move to this technology, given its efficiency and ability to sequence so many genes.”

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Cancer
In oncology, NGS is used both to determine risk and guide therapy. “In the field of predisposition testing we can determine whether a person has a mutation that confers significant risk for a certain cancer type, the best example being BRCA. As the field evolves we can assess more and more genes: at the end of last year we added five non-BRCA genes to our BRCAvantage™ test, in what is now called BRCAvantage Plus™. We also do genetic testing for hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, and intend to continue expanding the number of genes and cancer types for which we provide this testing.”

If an individual has a solid tumor, a tissue sample can be subjected to NGS, using the OncoVantageTM multiplex panel, to help determine therapy. “We’ve gone from a situation where we used to identify a single mutation in a single gene to determine whether a therapy will work, to one where we're looking for thousands of mutations in 34 genes to enable physicians to choose the most appropriate therapy or identify clinical trials that are appropriate for the patient,” says Dr. Wohlgemuth. “It's really enabling what we call precision or personalized medicine on a much larger scale.”

The ability to determine which targeted therapies might work in a cancer or, if there's not an approved therapy, what clinical trials are available for a particular patient, is largely dependent on bioinformatics capabilities. To extend those capabilities Quest Diagnostics has established a joint collaboration with Memorial Sloan Kettering Cancer Center (MSK), which will utilize MSK’s clinical and research insights into gene mutations associated with solid tumors. “Their oncologists and scientific staff develop the clinical annotation and we use that information to interpret our sequencing and provide a report for our patients,” explains Dr. Wohlgemuth. “The more the database grows, fed by the data generated by our two organizations, the more valuable it will become for interpretation.”

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Neurology
Another field benefiting from advances in NGS is neurology, where Athena has been a leader for over 15 years. “There are many rare diseases in neurology that require genetic diagnosis,” says Dr. Wohlgemuth. “Our offering represents a continuum ranging from the testing of individual genes to what we call a “whole neurome” analysis – or an analysis of all genes known to be involved in neurological disorders. For a child with a specific neurologic syndrome, we might recommend a small panel of genes that are more likely involved with the patient’s disorder. In other cases - if the patient's presentation is broad or nothing has been identified by previous genetic tests - we sequence all genes involved in neurology genetics and provide a whole neurome analysis. Because of Athena’s extensive experience in this field, they have one of the best, if not the best, databases related to the rates of mutation of different genes.”

“We feel that in neurology it's highly important to integrate the genetic information with other clinical information, such as clinical history, MRI findings, and EEG results. We are devoting a lot of effort to this area, and in particular are working with the University of California, San Francisco (UCSF), to develop a more integrated approach to the analysis of neurology biomarkers and genetics, which takes into account other findings and clinical data.”

1. President Obama’s Precision Medicine Initiative. The WhiteHouse. http://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative Accessed February 26, 2015

2. President Barack Obama's State of the Union Address. The White House. http://www.whitehouse.gov/the-press-office/2014/01/28/president-barack-obamas-state-union-address. Accessed January 23, 2015

3. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1–infected adults and adolescents. Department of Health and Human Services. February 12, 2013. Available at: http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Accessed January 29, 2015.

4. The American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. Obstet Gynecol. 2012;120(6):1532-1534.

Prescription Drug Monitoring: How Oral Fluid Testing Is Helping to Verify Compliance
Les Edinboro, MS, PhD, F-ABFT
Science Director, Toxicology
Quest Diagnostics Nichols Institute

The abuse of prescription painkillers and narcotics constitutes a public health crisis in the United States,1 with 55% of Americans potentially at risk through misuse of medications.2-3 Dr. Les Edinboro discusses the critical role of prescription drug monitoring (PDM) to limit this abuse. He explains why oral fluid testing is a valuable tool for obtaining samples in high-risk areas and for reducing the possibility of obtaining false-negative results for those on low medication dosages.

“The reason for prescription drug monitoring, which is essentially compliance testing, is simply to determine if a patient is taking their medication,” says Dr. Edinboro. “If a test is negative we can’t say whether the patient is diverting it – it’s up to the physician to determine reasons for any inconsistency.”

“A key principle of our program,” continues Dr. Edinboro, “is to ensure the cutoffs for our assays are as low as possible. This allows us to detect the lowest possible amount of drug in line with the range of dosing scenarios for a controlled substance. We try to achieve the lowest possible number of false-negative results, since that's the adverse outcome. Because there are so many possible dosing intervals and because lower doses are now being prescribed for pain medications, particularly by primary care.”

Observed Collection
The challenge of detecting very low levels of a drug is being met by oral fluid testing. This method was introduced as an alternative method for situations where urine testing may not be appropriate. It’s a solution when there would be difficulty obtaining a urine sample because a patient is not ambulatory, is morbidly obese, or is unable to give a urine sample. Also, because it provides a means of observed collection, it’s very useful in a high-risk environment where the risk of diversion and abuse is high.

Low Cutoffs
Characteristics of the oral fluid test are clinically driven: cutoffs mirror the level in the blood, which in turn reflects the dose taken by the patient. While the window of detection is much shorter than with urine tests, this is countered by using a more clinically relevant cutoff. “This has been a real priority for us,” stresses Dr. Edinboro. ”Our cutoff may be fivefold, tenfold, or even a hundred fold lower than other tests that are available. A good example of this is the test we are providing for use in Suboxone clinics. While the typical cutoff for buprenorphine is 2.0 - 2.5 ng/mL, one of our providers asked us to go to 0.025 ng/mL - a hundred fold lower. This has resulted in 10% fewer patients getting negative results and being suspected of not complying with their prescription. Because patients in these clinics are taking such small doses, this is an essential tool for providers to have available.”

Potential of Pharmacogenomics
As the PDM field evolves, one promising area of development is that of pharmacogenomics, which enables DNA analysis to determine how a patient will metabolize a drug. “The application of pharmacogenomics could help us identify the right drug for a particular patient and so shorten the cycle of drugs prescribed before selecting the appropriate one,” explains Dr. Edinboro. “In relation to PDM, if you identify that someone is a very rapid metabolizer, you can feel more comfortable giving a particular drug knowing that their body can handle the higher doses. Such a patient may have all the hallmarks of a drug diverter, asking for increasing doses because the drug’s not effective, but if the provider knows that patient is a rapid metabolizer they needn’t be overly concerned that they’re dealing with a diverter. Conversely, by identifying a low metabolizer, a provider would look to use a lower dose or explore other approaches to manage that patient.”

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Hepatitis C: Improving Outcomes through Guideline-Driven Testing and Patient Management
Rick L. Pesano, MD, PhD
Vice President, Research and Development
Medical Director, Infectious Diseases
Quest Diagnostics

The field of hepatitis C is evolving rapidly. The introduction of new antiviral drugs is transforming treatment, while the adoption of birth-cohort screening guidelines could dramatically increase the number of patients diagnosed with the disease. Dr. Pesano reviews current approaches to screening and patient management, and discusses how a new partnership with the Centers for Disease Control and Prevention (CDC) to analyze hepatitis trends provides a basis for enhancing outcomes through earlier diagnosis and treatment.

Identifying the Undiagnosed
Approximately 3 million people in the United States have chronic hepatitis C virus (HCV) infection,1-3 yet less than half of those have been diagnosed and 60% to 70% will develop chronic liver disease due to their infection.4 To address the impact of the hepatitis C epidemic the CDC and the United States Preventive Services Task Force, together with several professional organizations, have issued recommendations to screen for HCV infection in adults born between 1945 and1965, in addition to those at high risk of infection.5, 6 This group, “the baby-boomers,” is five times more likely than other adults to be infected with HCV.

Implementing Screening Guidelines
To implement screening effectively, there are some important points to consider. “Many physicians screen for HCV based on the detection of antibodies alone,” notes Dr. Pesano, “yet it has been well established that an antibody screen on its own is not sufficient to screen for HCV infection. Guidelines indicate that every antibody-positive test requires confirmation with a nucleic acid test to determine if there is an active infection – an infection that needs treatment.7 To facilitate compliance with these guidelines, Quest Diagnostics links an antibody test with a nucleic acid test in a reflex. If a doctor orders the reflex test code and the antibody test result is positive, it automatically reflexes to the nucleic acid test.”

A Continuum of Care
“We view hepatitis C management as a continuum of care – from diagnosis through treatment and monitoring, until eradication of infection is documented,” continues Dr. Pesano. If active infection is confirmed, physicians should also order a HCV genotype test to indicate how well someone may respond to treatment. In addition, as some treatments are only active against specific genotypes, it also helps direct therapy.”

Before initiating treatment, it is also important to account for the potential consequences of having HCV infection by looking at the extent of liver disease—specifically cirrhosis and/or fibrosis. A liver fibrosis panel can be ordered to predict the extent of liver fibrosis in individuals infected with HCV. “We need to make sure that we test for baseline liver disease because the treatment duration and the drug combinations you use are also based on the status of the liver,” says Dr. Pesano. “With severe fibrosis or cirrhosis, a different set of guidelines applies. Based on the American Association for the Study of Liver Diseases (AASLD) guidelines8 for tests to perform at screening, at baseline, and for monitoring patients on therapy, we’ve combined the appropriate tests into panels. So, a doctor can now order a single test code to cover all the tests needed at each stage of care, instead of selecting each individual test. (This doesn’t include the liver fibrosis panel, which is ordered separately). ”

Partnering With the CDC to Enhance Outcomes
Quest Diagnostics’ commitment to advance public health in relation to hepatitis C is illustrated by a partnership with the CDC to access and analyze data to further understanding of hepatitis trends. The partnership was established in July 2013 and provided a basis for the two organizations to jointly analyze de-identified hepatitis C testing data in the Quest Diagnostics Health Trends™ database for individuals born between 1945 and 1965. This analysis provided information on clinical behavior to help the CDC determine the impact of the birth-cohort screening guidelines. This included information on screening rates and number of patients being diagnosed. The initiative was subsequently broadened to identify ordering patterns, track patients longitudinally, and assess the burden of disease through liver function data.

Building on this joint-approach to enhance management of hepatitis, Quest Diagnostics and the CDC announced in February 2015 that they will collaborate to identify trends in screening, diagnosis, and treatment for four hepatitis viruses in the United States. Under the new agreement, medical and bioinformatics experts from Quest Diagnostics and CDC's Division of Viral Hepatitis will analyze de-identified test results from the Quest Diagnostics Health Trends national database for hepatitis A, B, C, and E viral infection in adults age 18 years and over. Analysis will include results of screening and confirmatory diagnostic tests as well as treatment-guiding genotyping and viral load tests by gender, age group, geography, and type of physician. The teams will jointly develop study designs and protocols based on Quest Diagnostics’ proprietary data-mining techniques to identify patterns in prevalence and clinical management of patients.

"The innovative collaboration with Quest Diagnostics will allow us to use data analytics to better monitor the implementation of CDC’s testing guidelines and progress toward reducing deaths from hepatitis,” said John W. Ward, M.D., director of CDC's Division of Viral Hepatitis. “Increased testing is critical to ensure that those who are infected with hepatitis receive life-saving care and treatment."

“Our partnership with CDC reflects the growing value of data analytics in health care to improve decision making, both for population health and in a clinical setting,” says Dr. Pesano. “Transforming data into insights to measure and predict behaviors and outcomes will be increasingly important as the nation’s healthcare system moves to fill gaps in guideline-based care.”

Partnering with Memorial Sloan Kettering Cancer Center to Enable Precision Medicine in Cancer Treatment
Frederic Waldman, MD, PhDD
Medical Director, Cancer Diagnostics
Quest Diagnostics Nichols Institute

Precision medicine is recognized as a highly promising development in healthcare and was highlighted by President Obama in the State of the Union address on January 20, 2015.1 Dr. Waldman discusses how the potential of precision medicine is being fulfilled in oncology through a collaboration between Quest Diagnostics and Memorial Sloan Kettering Cancer Center (MSK), which combines the capabilities of the OncoVantage™ test panel with MSK’s scientific and clinical expertise. This partnership is enabling physicians to personalize treatment by selecting the most appropriate therapy based on the alterations found in an individual's tumor sample DNA.

OncoVantage™ - Providing Clinically Actionable Data on Gene Mutations
“OncoVantage is an assay that enables molecular characterization of solid tumors by testing 34 different genes for mutations,” explains Dr. Waldman. “We selected these 34 genes because they are the most clinically actionable. That is to say, we know that the identification of mutations in those genes will guide the behavior of physicians by helping them identify and choose treatments that target those genes. In one assay we've combined a set of the most relevant molecular alterations, based on medical guidelines for testing and therapeutics.”

Combining Knowledge and Expertise to Guide Therapy
Having developed the OncoVantage test, Quest Diagnostics entered into a partnership with Memorial Sloan Kettering (MSK) Cancer Center to utilize MSK’s clinical and research insights into gene mutations associated with solid tumors. “MSK has extensive databases of gene mutations linked to various types of cancer,” explains Dr. Waldman, “and they have developed approaches for therapy of those cancers based on scientific literature, treatment of patients at their institution, and clinical trials conducted by MSK researchers and scientists.”

“Using their clinical and scientific knowledge, MSK clinicians and clinician scientists are developing clinical annotation to support our assay results,” continues Dr. Waldman. “They look at the assay results we send them and provide us with the clinical implications of the mutations that we have found. We then take that information and include it in the reports we send to our physicians and their patients. These reports are clearly identified as coming from both MSK and Quest Diagnostics. This is particularly exciting because MSK scientists are world experts in developing therapies targeted toward the gene mutations we identify. They are also well informed about all the clinical trials that may be relevant to a particular patient.”

Keeping Pace with Developments in the Field
“Over time, the two organizations intend to further study and extend the mutation data sets to potentially generate improved diagnostics, in addition to research and clinical trials. Quest Diagnostics is continuously working to extend its capabilities in the oncology field. “We are developing a new, larger gene assay with about 400 genes, for which MSK will be providing annotations, as well as a panel for thyroid cancer,” says Dr. Waldman. “In addition we are going to double the genes we test for mutations in the OncoVantage panel. This will allow us to keep pace with the growing understanding of what’s relevant in cancer treatment.”

Upcoming Events

Tuesday, Mar. 10, 2015
12:00 pm ET/9:00 am PT
Familial Hypercholesterolemia from A to Z
Presenter: Seth J. Baum, MD, FACC
Overview: Participants will learn about the genetic nature of familial hypercholesterolemia (FH) including the causal genetic mutations, pathophysiology and how to recognize the typical and atypical features of clinical presentation as well as discuss current treatment options.

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Tues., March 24, 2015
12:00 pm ET/9:00 am PT
Latent TB Testing: Challenges in the 21st Century
Presenter: John A. Leake, MD, MPH
Overview: Dr. Leake will discuss who should be tested for Tuberculosis and why, the risk of progression from LTBI to active infection and help attendees understand indeterminate results.

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Wed., Apr. 1, 2015
3:00 pm ET/12:00 pm PT
Latent TB Testing: Challenges in the 21st Century
Presenter: John A. Leake, MD, MPH
Overview: Dr. Leake will discuss who should be tested for Tuberculosis and why, the risk of progression from LTBI to active infection and help attendees understand indeterminate results.

Register

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