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Oasis Diagnostics in AGD Dental ArticleThursday, October 01, 2009 | By: AGD Like any researcher in his field, David T. Wong, DMD, DMSc, practically salivates over what’s to come. Focused and impassioned, Dr. Wong typifies a current generation of scientists who not only champion the power of saliva, but are moving it ever closer to a sea change that could revolutionize health care, including dentistry. Dr. Wong, a professor and associate dean of research in the division of oral biology and medicine at the University of California, Los Angeles (UCLA) and whose research is funded by the National Institute of Dental and Craniofacial Research (NIDCR), is hoping that within the next two years scientists will be able to demonstrate conclusively to the U.S. Food and Drug Administration (FDA) that saliva can be used to detect and monitor at least one systemic disease—in this case, pancreatic cancer, the fourth leading cause of cancer deaths. In June 2009, Dr. Wong and his collaborators at UCLA announced that they had identified 12 genes from collected saliva that appear in patients with pancreatic cancer and can be differentiated from those in control patients without the disease. In other words, clinicians soon may be able to “find out whether patients have pancreatic cancer by having them spit into a cup,” according to a June 2009 report in MedPage Today. Dr. Wong sees this discovery as a turning point in salivary diagnostics. “My quest has been to truly unravel and harness the heart and soul of diagnostic utility in [saliva] and then apply it in a way that has the highest clinical impact,” he proclaims. “Within the next two years, we want to deliver the true marker for pancreatic cancer, and I think that when our physician colleagues look at that they will say, ‘These folks at dental schools have come up with something incredible and irrefutable.’ Basic science findings are now in place to substantiate these clinical claims.” Innovative approaches are also being applied to improve the diagnosis of conditions such as periodontal diseases that are of particular concern to dentists. Researcher William Giannobile, DDS, MS, DMSc, at the University of Michigan has led groundbreaking work also supported by the NIDCR on diagnostic testing. Innovations in recent years have included the development of a portable test that within minutes can measure proteins in saliva that may identify incipient disease in the mouth—and potentially identify systemic diseases as well. This point-of-care (POC) test is indicative of the race to develop practical tests that fully support the preventive foundation of modern dentistry and make them available to clinicians. Engineered by Dr. Giannobile in collaboration with scientists at Sandia National Laboratories, the Integrated Microfluidic Platform for Oral Diagnostics (IMPOD) can reliably measure concentrations of MMP-8, an enzyme associated with periodontitis. According to the March 2009 Journal of Periodontology, Dr. Giannobile and his team also have identified other pathogen and host-response markers that correlate with periodontal disease. “The concept of the IMPOD and the validation of the biomarker results suggest that the detection of single biomarkers—such as MMP-8—offers great utility,” explains Dr. Giannobile. “However, the analysis of multiple markers of periodontal disease may offer good ‘signatures’ of disease severity for different types of periodontal diseases.” As Dr. Giannobile notes, the POC tests can measure host-response markers, markers of inflammation and bone resorption, and periodontal pathogens that predispose patients to periodontal breakdown. “The [March 2009] paper shows how the use of three different biomarkers of disease can be highly accurate for disease detection,” he says. “The IMPOD device can use small volumes of saliva and can run the assays in four to 10 minutes. Thus, these POC diagnostics offer good potential for disease identification.” Researcher Charles Streckfus, DDS, a professor of diagnostic sciences at the University of Texas Health Science Center at Houston with a lengthy background in salivary function, advocates in the March 2008 Journal of the Greater Houston Dental Society that dentists should be the ones to deliver these tests. “Most people, especially women and children, visit the dental office far more often than they ever see a physician. Saliva is a noninvasive, quicker way for detection.” Dr. Streckfus was the lead researcher of a study published in the February 2008 issue of Cancer Investigation that identified and quantified specific proteins in saliva that can provide an early diagnosis of breast cancer. “What’s exciting is that the test may render access to cancer screening to those that may not currently have it,” says Dr. Streckfus. The history of saliva testing It’s impossible to address saliva in depth and without acknowledging the contributions of Irwin Mandel, DDS, who, along with a few others, began to identify the incredible vitality and importance of saliva in the 1960s. Its complexity began to emerge protein by protein. Dr. Streckfus recalls that when he was in dental school, only 70 or so salivary proteins had been identified. “In the last couple of years, it’s over 1,000, and we’re all wondering ‘what are all those things doing in there?’” From the 1960s through the 1980s, salivary science was somewhat stymied by inconsistent saliva collection and storage methods. Still, it took a big leap forward in 1993 when Dr. Mandel and Lawrence Tabak, DDS, PhD, another salivary stalwart who is now the director of the NIDCR, organized a meeting that established guidelines for saliva collection. “That’s when anecdotal observations were turned into real science” in the eyes of many, says Daniel Malamud, PhD, a professor at the New York University College of Dentistry and a noted authority on salivary diagnostics. Since the early 1990s, researchers have discovered many salivary biomarkers—for oral caries, periodontal disease, HIV, various forms of cancer (including oral cancer), diabetes, arthritis, heart disease, autoimmune disorders, and endocrine levels, as well as those used in drug monitoring for both legal and illegal substances. Recent advances in technology that employ genes and proteins as markers have moved saliva up the diagnostic ladder toward blood, but without the needle and the cringing. In the March 2006 issue of the Journal of the American Dental Association, Dr. Wong states that saliva was long considered to have a functional value that far outweighed its diagnostic possibilities. Today, scientists know there is “much more information contained in saliva than was previously thought,” says Dr. Wong. In December 2008, the American Dental Association (ADA) Council on Scientific Affairs lent further credence to oral fluid diagnostics and POC testing in a statement that emphasized their potential advantages over blood testing, citing “ease of access, noninvasive sample collection, increased acceptance by patients, and reduced risks of infectious disease transmission.” The council added that oral fluids provide “an attractive medium for detecting a range of candidate biomarkers, such as proteins, electrolytes, hormones, antibodies, and DNA/RNA, as well as other substances such as therapeutic and/or recreational drugs.” Dr. Malamud states that recent advances in the field have led to the development of “a number of companies that have [salivary diagnostic] products out there and they do work, but they have never gone through the FDA, so they’re used mostly in research studies or sold over the Internet to individuals.” Dr. Malamud says that the only FDA-approved saliva test is one for HIV detection, along with a saliva collector that is sent to a laboratory for testing. “The next FDA-approved test is likely to be for hepatitis C,” he says. “Within the next five years, there will be tests for other infectious diseases, as well as markers for oral cancer and, perhaps, cardiovascular disease.” Dr. Malamud believes that general dentists need to follow the literature, participate in clinical trials, know enough about the research so that they can answer questions from their patients, and be ready to adopt the tests as they become available. “If general dentists don’t step up, these tests will pass them by and will be carried out by other health professionals,” he warns. “We’re at a crossroads in health care. When I met with a large and diverse group of dentists, old and young, what they kept throwing at me was that this is not within the scope and definition of our field. The fact that [diagnostic] sampling can be done orally is within the scope of the field and is an opportunity for the dental profession.” The Holy Grail of oral health? In June 2009, Paul Denny, PhD, a professor of diagnostic sciences at the University of Southern California (USC), stood before a large audience at the North American Dental Hygiene Research Conference and presented tantalizing data in collaboration with Northeast Delta Dental, based in Concord, N.H. The significance of that new data, presented publicly for the first time, lay in the potential clinical application of a test developed by Proactive Oral Solutions (POS), a company Dr. Denny formed with colleagues at USC to market the Caries Advanced Risk Evaluation (CARE) test. The data, based on claims records from Northeast Delta Dental, helps to validate the results of previous studies that involved much smaller samplings of children and their caries experience. These studies were conducted by Dr. Denny and his research team to assess the potential preventive and cost-benefit impact of the CARE test, which is basically an analysis of genetically-related oligosaccharide (sugar chain) ratios on salivary proteins. Its principles are: • Some sugar chains in saliva promote attachment of pathogens to the pellicle. • Other sugar chains can inactivate pathogens by agglutination, preventing attachment. • The CARE test integrates each individual’s sugar chain matrix into an accurate caries susceptibility ranking. In other words, the USC studies of sugar chain ratios suggested that these ratios are associated with consistent patterns of caries occurrence over time. It follows, then, that a test based on such findings could provide accurate, stratified caries risk assessment in a clinical setting. Since sugar chains are present in saliva even before the teeth erupt, such a test might allow intervention that prevents caries even earlier than is possible with any current tests. And while sugar chains are genetically related—just like blood type or eye color—the CARE test is not a “genetics” test and shouldn’t carry concomitant patient concerns. Initial data was generated by POS based on decayed and missing teeth (DMT) caries assessments and self-reported history in two southern California elementary schools. The results showed that 15 to 20 percent of 7- to 10-year-old children who had regular professional oral care and continuous dental insurance coverage still had caries in six-year molars. “These results showed us that there is a lot of caries out there that is attributable to an individual’s predisposition to the disease, apart from diet and oral care,” Dr. Denny says. A frequently referenced and respected study by Max Anderson, DDS, completed in 2002 and involving more than half a million children with and without sealants, indicated that sealant and fluoride together may reduce incidence of caries by up to 93 percent. The usefulness of the CARE test stems from its promise to indicate which children, and which teeth, require preventive treatment, and which ones do not. Shannon Mills, DDS, FAGD, vice president of professional relations for Northeast Delta Dental, says that without access to dental records or claims data, it was difficult to “state with certainty that the preventive benefits of sealant application had not affected the [POS] results.” Dr. Mills and Dr. Denny believe that the Northeast Dental data provide an objective longitudinal history of restoration placement and sealant application in continuously insured individuals. “We saw a clear opportunity to leverage the power of our claims data to help bring technology to market that could have a significant impact on the management of caries in both children and adults,” Dr. Mills says. This joint research effort, which has involved analysis of thousands of patient records, is being conducted under supervision of the USC Institutional Review Board (IRB). Dr. Denny expects the insurance data, together with hundreds of de-identified saliva samples from patient volunteers, to help refine and validate the CARE test, thereby accelerating the timeframe to make the test commercially available. The bottom line: “It is clear that there has been a dramatic change in occlusal surface caries over the U.S. population of young patients, with pits and fissures accounting for 88 percent of caries in children while making up only 13 percent of total tooth surfaces. Therefore, the economic and health benefit for sealant treatment has undergone a redefinition based on the newer caries risk figures. A more contemporary perspective is that sealants should be directed to those teeth judged at risk for caries, not directed to all teeth with pits and fissures” (Pediatric Dentistry: Conference Paper, 28: 143-150 2006). Since the CARE test is based on an algorithm that uses the record of number and location of first-time caries in young adults (ages 24 to 35), susceptibility levels can be established in children before caries occurs and the test can identify which groups of permanent teeth are most susceptible. That data applies to corresponding preventive treatment levels: • Susceptibility level 1 (no caries): fluoride treatments only • Susceptibility level 2 (one or two molars only after age 14): fluoride treatments; increased monitoring to detect lesions early • Susceptibility level 3 (molars only): seal eight teeth; fluoride treatments • Susceptibility level 4 (molars and premolars): seal 16 teeth; fluoride treatments “If you can decide that not every patient needs a prophy every six months, or every three months, it can individualize screening and treatment,” explains Dr. Malamud. “Moreover, it can individualize the use of sealants and other preventive approaches, saving a lot of teeth and money in the long run.” When the test is commercially available, Northeast Delta Dental anticipates that it can be used to ensure that high-risk individuals are provided with the latest evidence-based modalities to prevent and conservatively treat dental caries, says Dr. Mills. “From a dental benefit planner’s perspective, the ability to identify high-risk individuals early and provide targeted benefits to those identified to be at the highest risk offers an opportunity to improve outcomes and lower claims expenses for both purchasers and subscribers.” As if reading clinicians’ minds, Dr. Denny acknowledges that the new technology could meet pockets of resistance. “Some dentists might worry that this type of prevention is a threat to their business model,” he says. “That needn’t be the case. For one thing, the CARE test should bring at-risk kids into the dental office at younger ages, and perhaps more frequently. It will encourage the use and acceptance of measures such as sealants and fluoride, both of which are underutilized by many practices and unfamiliar to many families.” By emphasizing objective, evidence-based prevention, actual dental chair time will focus on high-value treatment and procedures for patients who need it most. The forefront of salivary diagnostics Paul Slowey, PhD, the founder and CEO of Oasis Diagnostics Corp. in Vancouver, Wash., was elated by a recent award his company received. The ZINO Society, a membership, business, and social network that connects accredited investors with entrepreneurs seeking funding, selected Oasis from 12 candidates whose commitment to new technology stands out in the crowd. Beyond the money the company received, Dr. Slowey says that Oasis is now connected to a network of accredited investors. He was already traveling frequently to spread his message and make connections with researchers, including Drs. Streckfus, Denny, and Wong, who will require salivary tools or platforms for their diagnostic technologies. The ZINO Life Fund investors liked Oasis for several reasons. Among the determining factors were the shorter path to the market and consumers, Dr. Slowey’s passion for the business, and the clear benefit that Oasis brings to a patient, according to Cathi Hatch, ZINO Society CEO and founder. “When looking at a company to invest in, we often ask what problem the company is solving or what is the pain point? Oasis literally takes the pain out of diagnostic testing.” At the first-ever ZINO Life Sciences Investment Forum held in February 2009 for the dozen candidates, Dr. Slowey emphasized the pain-free application of the Oasis technologies by showing a photo of a young girl grimacing while having a blood sample drawn with a needle. This was contrasted with a photo of the same girl smiling while an equally effective saliva sample was taken from her mouth with an Oasis collection swab. Oasis products include a saliva specimen collection device with a built-in sample sufficiency indicator, a rapid diagnostic test platform that serves as a medium for the development of immediate tests using saliva, a novel device for the collection of saliva for subsequent DNA/RNA extraction, and [through a third party] a drug testing system that enables immediate checks at the roadside, in schools, and at other venues. In the company’s pipeline are rapid diagnostic tests for prediabetic screening, breast cancer monitoring, tuberculosis, and immune response to anthrax. The company is now developing a strategy to carry out testing for lead in children. Lead poisoning is a huge problem, particularly in high-density urban environments where old lead paint chips from walls and windowsills can be consumed by young children, leading to many neurological problems and possibly death. Dr. Slowey says that one approach under consideration would have dental offices as the point of collection. “There isn’t any reason that dentists can’t be the point of collection for lead and any other tests right now for that matter,” Dr. Slowey declares. “After all, saliva is a mirror of the body’s health.” The oral-systemic connection New science is abetting the development of salivary diagnostics and POC tests that can be used in dental offices by affirming the oral-systemic connection, which, for instance, ties periodontal disease to the severity of diabetes, heart disease, and even low birth-weight babies. Researchers see the data collected so far as the tip of the iceberg, with far more to come as technology continues to advance. OralDNA Labs in Brentwood, Tenn., has built its growing reputation in part on that systemic connection, emphasizing that oral plaque is actually a complex biofilm that is highly individual from person to person and expresses disease as the result of an overgrowth of microorganisms that are site-specific in the mouth and lead to the chronic inflammation that characterizes periodontitis. For example, in humans, the bacteria that form biofilms colonize the surface of the entire digestive tract from the mouth to the colon. Thomas Nabors, DDS, a longtime clinician and pioneer in molecular diagnostics who founded OralDNA Labs and remains its chief dental officer, says that the company’s testing for periodontal infections serves a dual role for clinicians. On one hand, the testing can identify a genetic susceptibility to overall infection that occurs in 25 to 30 percent of the American population. People with that variation, or polymorphism, tend to have a more aggressive response to a bacterial assault. “If we can determine who these patients are early in their lives, we can help them before they develop a more aggressive form of the disease,” Dr. Nabors says. “Knowledge gives us control.” The testing also indicates the quantity and type of microorganisms in a particular mouth and, in turn, helps dictate the type and duration of personalized antimicrobial therapy, which can include locally applied sustained release medications to reduce the virulence of the biofilm and a product that modifies the environment in the host to slow the breakdown of oral tissues. “These tests are game changers in our ability to detect real causation and real genetic traits at the earliest time and not wait until patients have 5 millimeter pockets to begin treatment,” says Dr. Nabors. “Clinicians can diagnose the disease more accurately and build the diagnostic concept into their protocol.” Dr. Nabors believes that the use of such testing will reach a critical mass based on the oral-systemic relationship. “The literature supports this connection, and we have the opportunity as a profession to communicate with our patients and other doctors through clinical lab messages. That’s how physicians already communicate.” “The most important message to clinicians and to patients,” says Dr. Nabors, “is that adding more accurate diagnostics such as those that we provide, at earlier time intervals, equals more healthy patients: both orally and systemically.” One dentist’s approach Brian Novy, DDS, a clinician and assistant professor at Loma Linda University, offers a glimmer of the possibilities that salivary diagnostics can bring to chairside prevention. Much like the frustration Dr. Nabors experienced as patients treated for periodontal disease returned again and again with chronic problems despite cutting-edge treatment, Dr. Novy’s disappointment came in the form of recurring caries even in patients who were diligent about brushing, flossing, and using fluoride. Dr. Novy believes that while caries has long been considered a bacterial infection, it actually is a “pH disease.” The underlying premise is that oral microorganisms like nothing better than swimming in an acid bath, which encourages their growth and invites more free-floating (planktonic) bacteria to join the biofilm party. Those bacteria, in turn, produce more acid, which keeps the pH low and demineralizes the enamel. When a “healthy” pH is re-established, tooth repair can begin, says Dr. Novy. “Repairing the teeth without addressing the pH level of the mouth is a recipe for disaster,” states Dr. Novy in the April 2009 issue of Dentaltown. “Demineralization will continue and each time the patient returns there will be new cavities.” Dr. Novy’s salivary diagnostics prior to treatment include the use of pH test strips to gauge the acid level in the saliva. He notes that kits are available to measure salivary consistency, stimulated saliva flow, and saliva buffering capacity as well. Dr. Novy agrees that DNA testing can provide a useful bacterial analysis and says that some products even allow dentists to measure adenosine triphosphate (ATP) levels in the biofilm bacteria. A unit of energy used by all living cells, ATP can shed light on the metabolic processes going on in specific oral biofilm bacteria. The higher the ATP level, the more “food” there is for bacteria to metabolize, grow, and produce acid as a byproduct. “Some will say that you can’t really change pH long term,” says Dr. Novy, “but studying renal physiology shows that you can. People with chronic renal failure don’t get tooth decay because their mouths are alkaline due to the high level of urea excreted through the salivary glands. This is true even though these patients crave sugar as a side effect of the alkaline oral environment.” Dr. Novy has sent patients home with test strips to monitor their pH levels on a day-to-day basis, and some patients have returned with computer graphs compiled over a series of weeks. He says that this level of awareness is “kind of like a diabetic who monitors his blood glucose level to catch a problem before it becomes a diabetic emergency.” Dr. Novy believes that the increasing utility of salivary diagnostics dovetails with his preventive philosophy because there is relatively little research on the salivary glands. He also believes that a better understanding of the salivary glands might reveal a simple, biologically mediated way to prevent and control caries. “I think we’re just scratching the surface now in terms of what we can actually measure [in the saliva],” he proclaims. “We can already measure at a reasonable cost how cariogenic the bacteria are in the mouth using saliva, and easily understand the pH in different areas of the mouth and how it fluctuates during the day. In an ideal world, I would have a chairside test, hook the patient up to a machine, and measure phosphate, calcium, and fluoride in the mouth, and do it quickly.”
Rick Asa regularly contributes to AGD Impact. Rick lives in Westmont, Ill., and has been a full-time freelancer for the past 13 years. Prior to that, he was the national media manager for the American Dental Association (ADA) for five years, a science editor for the University of Illinois at Chicago News Bureau, and a newspaper reporter. To comment on this article, e-mail impact@agd.org.
Diagnostic Disclosure Debate Salivary diagnostics provides the unique ability to monitor health status, disease onset and progression, and treatment outcome. However, despite the utility, many patient and health care advocates caution the implications of such configured analyses. The advent of diagnostic testing is increasing patients’ concerns about the disclosure of enzymes, proteins, biomarkers, and gene variants that indicate predispositions for various cancers, diseases, and conditions because the information could be used by insurers to deny, limit, or cancel health insurance and by employers to discriminate in the workplace. For example, if a patient’s salivary diagnostics indicates a high concentration of IL-8, a protein in saliva linked to oral cancer, his or her insurance company could argue that this represents a pre-existing condition. However, numerous pieces of legislation—such as the Rehabilitation Act of 1973, the 1990 Americans with Disabilities Act (ADA), the Health Insurance Portability and Accountability Act (HIPAA), and the Genetic Information Nondiscrimination Act (GINA)—outlaw this kind of discrimination.
Have Your Say... AGD Impact wants to hear from you! What are your thoughts about diagnostic testing? Should a patient be judged in terms of coverage and employment if his or her diagnostic test indicates a predisposition for a certain cancer, disease, or condition? How would you address the privacy and discrimination concerns of your patients? E-mail impact@agd.org and your two cents might appear in an upcoming issue of AGD Impact!
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