Personalized Diagnostics

What can we learn from previous pandemics to apply to the current situation? What do we actually know to be true about the novel coronavirus? Jeffrey Taubenberger, MD, PhD, a physician-scientist and investigator at the National Institutes of Health, joins us to discuss his landmark work in sequencing the 1918 Spanish flu virus and to provide insights into the current novel coronavirus global pandemic.

Change can be slow - particularly in #healthcare. Establishing clinical validity and clinical utility can be slow. Getting regulatory approvals can be slow. Gaining payor acceptance can be slow.

Where are we in this megatrend of precision #medicine?

Since the human genome has been sequenced, it has become clear that the technology to sequence has far outstripped our capabilities to accurately classify and interpret genetic variants. It turns out that genetic variants are much more common than we ever suspected and many - in some cases most - variants are of uncertain significance. But is the attempt to accurately classify Variants of Uncertain Significance (VUS) a losing strategy?

We have seen tremendous advances in sequencing technology. And the cost to sequence is going to zero, according to Moore's Law. More and more genes and gene sets are being correlated with clinical outcome and response to therapy. Is bioinformatics intelligence the missing link to realizing the promise of precision medicine? Will a company emerge as the Google or Amazon of cancer informatics? Our guest is Bruno Larvol, of the eponymous healthcare data company, Larvol.

"We have to evolve." Establishing a "gold standard" for real world evidence will allow us to move beyond what we can learn from the 4% of patients enrolled in clinical trials and allow #innovation to flourish.

Fewer than 4% of oncology patients ever make it onto a clinical trial. And these 4% may not even reflect the real-world patient experience. How can we use real world data in a rigorous and thoughtful way to come up with new standards of evidence to help move innovation forward?

There’s no question that we are awash in promising new technologies with the potential to advance precision medicine. But is the existing infrastructure adequate to bring innovation into patient care? It's generally recognized that the highest levels of evidence are generated via the prospective randomized trial. These trials, however, are extremely costly and time-consuming and generate only a limited number of conclusions from a small subset of patients which may not be truly reflective of the real-world patient experience. Will we be able to evolve and find new ways to generate high levels of evidence to move precision medicine forward?

There’s no question that we are awash in promising new technologies with the potential to advance precision medicine. But is the existing infrastructure adequate to bring innovation into patient care? It's generally recognized that the highest levels of evidence are generated via the prospective randomized trial. These trials, however, are extremely costly and time-consuming and generate only limited conclusions from a small subset of patients which may not be truly reflective of the real-world patient experience. Will we be able to evolve and find new ways to generate high levels of evidence to move precision medicine forward? Dane Dixon, MD, of Taproot Health joins us in one of our most important episodes to date.

The diagnostics #industry is very fragmented, in terms of testing laboratories, test developers, and testing methodologies used. Companion diagnostics testing for targeted therapies is still done by a variety of methodologies, including immunohistochemistry, FISH, RT-PCR, RNA expression analysis as well as next-generation sequencing, and others. The advent of next-generation #sequencing, as many predicted, has not - as of yet - led to a more unified approach to testing. Why is this?

With the advent of next generation sequencing, we've gained the ability to test for nearly any and all genomic alterations – many or most of which are benign or of uncertain significance. And, believe it or not, we encounter many benign or uncertain alterations in tumor related genes. Targeted therapies have historically been developed with a relatively small number of alterations in mind. For example, KRAS testing focused originally only on codon 12 and 13 mutations. While, 90% of deleterious EGFR alterations in lung #cancer are either chromosome 19 deletion or the L858R mutation. Are we in danger of watering down the size of the effect in clinical trials for targeted therapies by trying to incorporate too many genomic alterations in their #design?

Will this be a golden #era for #diagnostics? Are we moving away from a model based on high-value #therapeutics and towards one based more on high-value diagnostics?

September 25, 1998 - trastuzumab, one of the first targeted therapies with a companion diagnostic, received #FDA approval in breast #cancer. The commercially available IHC and FISH companion #diagnostics were not incorporated into the pivotal clinical trial. They had to be subsequently "developed" and validated by way of concordance studies (which were not stellar). Does this still happen today? Have we begun to appreciate the importance of embedding companion diagnostics directly into clinical trials?

Over the past 20 years we've seen the development of approximately 40 indications for targeted therapies with a companion diagnostic. How can we continue to build on these successes and develop even more effective strategies for developing targeted therapies with companion diagnostics and incorporating diagnostics into clinical trials? Our guest is Tracy George, MD, Professor of Pathology at the University of Utah and the Executive Director of clinical trials and pharma DX at ARUP Laboratories.

We’ve all heard the term “epigenetics.” But what does it actually mean? #Epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself. It is somewhat of a catch-all term and does not apply to any one type of change or any one methodology for measuring these changes.

There appears to be a clear association between age and underlying chronic conditions such as #diabetes and #hypertension and the severity of a #covid19 illness. Can epigenetics inform us of our risk of acquiring acute or infectious illnesses such as Covid-19 and their severity?

How do we age?

We've all heard the term biological age. But what does it mean exactly? How is it measured? And is it possible to "turn back the hands of time?" Does the key to health, wellness and longevity lie in epigenetics? We are joined by Dr. Tom Stubbs, Co- founder and CEO of Chronomics

Slow down - testing for SARS-CoV-2 is not as simple as it may seem. “What I really want to know is: if this test result is positive, what are the chances that my patient actually has the condition. “Sensitivity and specificity really have no utility in a practical everyday clinical setting. “You really want to know the positive predictive value and the negative predictive value.”

Slow down - testing for SARS-CoV-2 is complicated. Jill Hagenkord, MD, FCAP is co-founder and CMO of MDisrupt, as well as previously serving as CMO at Invitae, Complete Genomics Inc., Color, and 23andMe. She joins us for this first installment of "Hagenkord's Korner."

Entrectinib and larotrectinib have been approved to treat tumors with fusions in the neurotrophic tropomyosin receptor kinase (NTRK) gene – irrespective of the tumor’s site of origin. These drugs are the second and third agents, overall, to have a tissue-agnostic indication approved by the FDA. The first was pembrolizumab, an immunotherapy agent, indicated for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017. Have we finally reached the point where tumor biology has become a more important consideration than site of origin?

Microsatellite instability testing in #colon #cancer has evolved considerably over the past several years. It began as a way to screen for Lynch #Syndrome, a heritable condition, which accounts for about 5% of colon cancers. MSI subsequently has been shown to be a prognostic factor in colon cancer. And in its most recent incarnation as a biomarker, it has been shown to be predictive for response to immunotherapy. Pembrolizumab has been approved for patients with microsatellite instability-high tumors. Interestingly, or perhaps counter-intuitively, patients with microsatellite unstable tumors actually have a better prognosis. Why is this?

Diagnostic Testing can be thought of as occurring in three phases: 1. Pre-analytic phase - everything leading up to the actual testing, including properly filling out a requisition, blood draw, specimen handling, gross examination and tissue fixation 2. Analytic phase - the actual testing itself, which is “flashy” and most people understand 3. Post-analytic phase - results interpretation, report generation, communication with the ordering physician and planning for future testing If the pre-analytic phase is suboptimal, everything that follows may be unreliable or uninformative. Colloquially, this is known as “Garbage in, garbage out.”

It is not often we have a major paradigm shift in medicine. Albert Broders, MD, was a pathologist at the Mayo Clinic. Early in his career, he described tumor grading, showing for the first time that features in cancer specimens observed under the microscope could predict outcomes. This discovery was a massive paradigm shift, that quickly begat tumor staging and eventually the whole predictive biomarker field. Rondell Graham, Head of GI and Liver Pathology at the Mayo Clinic, joins us this week on The Personalized Diagnostics Podcast, where we discuss predictive and prognostic markers in colon cancer, molecular diagnostics, digital pathology, the future of targeted therapies and much more.

We are introducing a new feature: "Hagenkord's Korner." Jill Hagenkord, MD, FCAP is co-founder and CMO of MDisrupt, as well as previously serving as CMO at Invitae, Complete Genomics Inc., Color, and 23andMe. This week we will be discussing how we have been hearing relatively little from experts such as physicians, epidemiologists, virologists and statisticians during the current pandemic. We will also be discussing the pitfalls of testing and test development for SARS-CoV-2.

2020 marks the one hundredth anniversary of the publication of Albert Broder’s landmark paper on tumor grading. The foundation of what is now called personalized medicine is the idea that not all tumors or all patients are the same. Differences in gene expression and phenotype correlate with outcome and inform how a patient is best treated. Dr. Rondell Graham is head of gastrointestinal and liver pathology at the Mayo Clinic. He joins us to discuss predictive and prognostic markers in colon cancer - where we've been, the implications of new technologies such as artificial intelligence, as well as the future of targeted therapies.

Pharmacogenetics is the study of how people respond differently to drug therapy based on their unique genetic makeup. Genetic variations cause differences in the expression of various enzymes involved in drug metabolism. Health #economic studies have shown that the use of pharmacogenetic testing in clinical practice results in better outcomes - by a variety of metrics. Are payors interested in these data? Of course they are. Better outcomes generally save money as well.

Pharmacogenetics allows us to identify differences in how people respond to drugs based on their unique genetic makeup. Genetic variations can affect the function of enzymes involved in drug metabolism, leading to both adverse drug events and toxicity as well as treatment failure. Routine pharmacogenetic testing has been shown to improve outcomes and save costs but yet it is still underutilized.

Pharmacogenetics allows us to identify differences in how people respond to drugs based on their unique genetic makeup. Genetic variations can affect the function of enzymes involved in drug metabolism, leading to both adverse drug events and toxicity as well as treatment failure. Routine pharmacogenetic testing has been shown to improve outcomes and save costs but yet it is still underutilized.

How has pharmacogenetic testing evolved over the past 20 years? We've moved from a very expensive single-gene testing model focused on drug - gene pairs to a more cost-effective multigene panel approach, which can provide significantly more information. Kristine Ashcraft, CEO of YouScript, which offers a unique combination of pharmacogenetic information and EMR-integrated software, joins us this week on The Personalized Diagnostics Podcast.

Pharmacogenetics allows us to identify differences in how people respond to drugs based on their unique genetic makeup. Genetic variations can affect the function of enzymes involved in drug metabolism, leading to both adverse drug events and toxicity as well as treatment failure. Routine pharmacogenetic testing has been shown to improve outcomes and save costs but yet it is still underutilized. Our guest today is out to change that. Kristine Ashcraft is CEO of YouScript, a company offering unique pharmacogenetic information and an Electronic Medical Record integraed software solution.

Prasun Mishra, Ph.D. President and CEO of the American Association for Precision Medicine (AAPM) and chair of the AAPM Coronavirus Taskforce (ACT) discussing the unique challenges of a fighting a pandemic in this modern era of globalization, frequent travel and porous national borders in which the world has become "one big home"

Of the measures available to us to combat #covid19, what should be our priority?

Rahm Emanuel, Chief of Staff to Barack Obama and Mayor of City of Chicago famously said, "Never let a crisis go wasted." What lessons can we learn from the current Covid-19 crisis? Prasun Mishra, Ph.D. President and CEO of the American Association for Precision Medicine (AAPM) and chair of the AAPM Coronavirus Taskforce (ACT)

Prasun Mishra, Ph.D. President and CEO of the American Association for Precision Medicine (AAPM)- and chair of the AAPM Coronavirus Taskforce (ACT) joins us on the The Personalized Diagnostics Podcast during this global pandemic. - Is the novel coronavirus mutating and has a potential to become more contagious? - Strategies to combat COVID-19? - Will things get better before they get worse? - Therapies in development for the novel coronavirus? - The story behind formation of ACT- AAPMs Coronavirus Taskforce - What lessons we'll be able to learn from this crisis?

Will people lose their jobs due to increased #automation and artificial intelligence applications? "There's a difference between your 'work' and your 'job.' " The tasks you perform or the #work you do may not be the essence of your job. "There is a well-known 'Amazon paradox,' which is that as Amazon was increasing the amount of automation in their warehouses and distribution facilities, they were actually increasing their hiring rate."

What are some of the misconceptions surrounding #AI? A focus on “artificial general intelligence” – the stuff of 1950’s science fiction and concerns of robots taking over the world - “What could you do if you had a machine that is able to act and think and be just like a human,” seems to be going away somewhat. This #focus is being replaced by realistic concerns and a focus on what it is possible to achieve with specific narrow applications that can solve real problems today - not at some point in the future.

There’s still a lot of misunderstanding surrounding Artificial #Intelligence. When two people talk about #AI, they are quite likely not even talking about the same thing. To eliminate confusion and facilitate understanding, Cognilytica focuses on the 7 Patterns of AI: Conversation and Human Interaction Recognition Patterns and Anomalies Predictive Analytics Autonomous Systems Hyperpersonalization Goal Directed Systems

Kathleen Walch and Ron Schmelzer, managing partners of the Artificial Intelligence-focused advisory firm Cognilytica The 7 patterns of #AI "How can we regulate something that is continuously evolving?" "Are we focusing on the wrong thing?" "Where's my flying car?" and much more... That's this week on the Personalized Diagnostics Podcast

One of the promises of precision #medicine is the ability to iterate and incorporate new #information in real-time, rather than having to wait months or years to incorporate new findings into patient treatment decisions. Have we reached the point where information or data that we observe in patients this week can be used to enhance our ability to treat patients next week?

"We're helping customers internalize next generation #sequencing for clinical use... in virtually every market segment." PierianDx is on a mission to democratize next generation sequencing and #genomics in medicine worldwide.

In Greek mythology, the Pierian Spring of Macedonia was sacred to the Muses. It was believed that drinking from it would bring you great knowledge and #inspiration. As the metaphorical source of knowledge of art and #science, it was popularized in Alexander Pope's poem "An Essay on Criticism" (1711): "A little learning is a dang'rous thing; Drink deep, or taste not the Pierian spring."

Despite tremendous advances in #sequencing technologies, informatics and computational power, there still remains a fair degree of subjectivity in genomics and personalized medicine. It takes a team of laboratory scientists, informaticians, variant scientists and physicians to develop and perform assays and formulate treatment decisions for patients.

In Greek mythology, the Pierian Spring of Macedonia was sacred to the Muses. It was believed that drinking from it would bring you great knowledge and inspiration. As the metaphorical source of knowledge of art and science, it was popularized in Alexander Pope's poem "An Essay on Criticism" (1711): "A little learning is a dang'rous thing; Drink deep, or taste not the Pierian spring: It takes a team of laboratory scientists, informaticians, variant scientists and physicians to develop and perform assays and formulate treatment decisions for patients. Rakesh Nagarajan, MD, PhD, of PierianDx joins us to discuss their mission to democratize next generation sequencing.

Will AI applications be limited to research and discovery and development of drugs and diagnostics? What about post-launch and real-world experience? "The observational study space is fairly disorganized and could greatly benefit from digitization and machine learning."

What are patient avatars? Imagine being able to understand drug efficacy and toxicities without having to involve actual patients.

All of this talk about #AI can be confusing and intimidating. What is it? How does it work? What are applications in #healthcare going to look like? Is it going to take away my job?

All of this talk about Artificial Intelligence can be confusing and intimidating. What is it? How does it work? What are applications in healthcare going to look like? Is it going to take away my job? Finally, AI for the Rest of Us. Sunandini Chopra, PhD, joins us this week.

"It doesn't give you a diagnosis, but it gives you additional information... and the hope is that all pathologists will have the same information."

"In the same way that when you listen to Pandora, it knows what song you're going to like..."

A confluence of factors will drive the shift to digital pathology.