Jill Hagenkord

Are physicians ready for the tsunami of genetic information that is headed towards the medical community?

Jill Hagenkord on the upcoming impact of genetic data on patient care

Adapt or Perish: Why All Doctors Will Need To Be Geneticists

Earlier this month our Co-founder Randy Scott, posted a blog where he talks about moving from a world of Genetic Scarcity to a world of Genetic abundance.  What are the implications for medical community?

Lets face it, doctors don’t really know much genetics.  Yes, we all have science undergrad degrees and yes, a lifetime ago we all took genetics and biochemistry classes and got A+’s. Then we went to med school and had a 2 week course in genetics that was kind of a “throw away class” wedged into first semester while we were getting our butts kicked in gross anatomy and histology. I remember my genetics class being all math and very little medicine. I took it pass/fail just to get it over with so I could focus on the courses that seemed more relevant. There are always a few genetics questions on every certification exam that we have to take along the way, but most doctors are willing to just get those questions wrong and focus on the topics that are more relevant to the daily practice of their specialty.

After you are done with the examination gauntlet, you never needed to know much genetics again…and so what little you retained simply atrophies. Now you have to try hard to remember the difference between DNA and RNA.  I get it. But, with the plummeting cost of DNA sequencing there is a tsunami of genetics headed toward the medical community. Resistance is futile. Adapt or perish.

This blog is my attempt to alert doctors that in the new world of genetic abundance, we will all need to be geneticists. Here’s my prediction at how it will evolve.

Step 1: An Increase in Multi-gene, Disorder-Specific Testing Panels

In the era of genetic scarcity, we couldn’t test for all possible causative genes or variants. We know that often times there are multiple genes that can cause a genetic disorder (eg, Long QT syndrome, hereditary cardiomyopathy) or thousands of possible disease causing variants in a single gene (eg, cystic fibrosis, Marfan syndrome). It was not feasible to use Sanger sequencing in these disorders to get a “complete” answer, so we were forced to either just test the genes that are most often implicated in the disease or just target common variants in a gene. We were using population statistics to make the best guess we could for the patient sitting in front of us.

Often times we got a negative result and we never knew if it was because the patient’s disease truly wasn’t genetic or if our test simply didn’t detect the causative variant. For patients with the financial bandwidth, many went on a “diagnostic odyssey” of iterative testing.

Let’s take Bardet-Biedl syndrome. What? It’s a rare pediatric genetic disorder that has fairly non-specific symptoms. Stay with me, it makes a nice point. Diagnosis is often delayed for years as the phenotype slowly declares itself and a clinical diagnosis is possible. Even when you are pretty sure that it is indeed BBS, there are 14 genes known to cause BBS. Historically, you would first test the gene that caused the most cases of BBS most of the time. It cost about $1000 and took about 2 months to get a result. If it was negative, you continued down the gene list until you either 1) got a positive result, or 2) the family ran out of money.

For a gene that accounts for only a few percent of BBS, it could take several years and close to $20,000 to get an answer.

At Invitae, we can now assess all 14 genes in a single test for only $1500 with a turn around time of 3 weeks on average. This means that more patients have access to a correct diagnosis faster.  The families can understand the risk to future pregnancies and the physicians can now confidently anticipate the likely course of the disease for the proband and make appropriate management decisions.

Step 2: Genetic Testing Will Go Mainstream

How many of you deal with hypercholesterolemia in your daily practice? Did you know that 5% of high cholesterol is due to Familial Hypercholesterolemia (FH)?  I’m going to guess no because 85% of FH goes undiagnosed (BMJ. 2012 May 11;344:e3228).

Did you know that medication dosages and risk estimation tools used for other patients are not appropriate for people with FH? Did you know that untreated FH heterozygotes have a 100-fold greater mortality risk from coronary disease in early adulthood? Did you know that their children would have high cholesterol at birth? The first time I got my cholesterol tested I was in my 30s. How old were you the first time you got your cholesterol tested? These children can go for decades with without the benefit of life style changes or appropriate medication.

In the Era of Genetic Scarcity, we had to use genetic testing judiciously since it was so expensive and laborious. We’ve long known that dyslipidemias can be genetic, but it just wasn’t practical to test for them. Historically, if we diagnosed FH at all, we did it based on clinical features– if we thought to look for xanthomas on someone’s Achilles tendon. It was the best we could do. Now we can do better. In the Era of Genetic Abundance, it becomes cost-effective to do a genetic test on every person with newly diagnosed hypercholesterolemia.

Before we leave this step, just a few more thoughts. In 2012, the FDA approved two drugs for FH that are only appropriate for FH homozygotes. The drugs cost around $200,000 per year. You will need to think about genetics before prescribing these drugs. Secondly, as you know, statins are the drug of choice for many people with high cholesterol. When you prescribe statins, you warn the patients of the possible side effect of myopathy. The risk of statin-induced myopathy is genetically determined. In the Era of Genetic Abundance, you can determine if the patient has FH and simultaneously find out if they are at increased risk for statin-induced myopathy. Medicine starts to become preventative rather than reactive.

Eventually, many FH patients end up getting cardiac surgery. Would you also like to know if they have a genetic predisposition to bleeding before you took them to the operating room? Or clotting? Or cardiac arrhythmia? Or adverse anesthesia reaction? We can provide that information, too, when you need it. All in one test. No need to guess anymore. That takes us to Step 3.

Step 3: Genetic Information Will ‘Just Exist’ for Everyone. 

Within 10 years, DNA sequence information will exist for everyone and you won’t have to order it any more. There are many ways that it could just exist. Maybe the hospital systems do whole genome sequencing on every newborn and each newly admitted patient. Maybe the patients come in with their genomes on their mobile devices and can instantly download into the EHR. Maybe whole genome sequencing is done as point of care testing at the bedside whenever it is needed and the information is not stored long term anywhere other than in the patient’s cells.

I have my whole genome on my laptop and I bring it with me to the doctor’s office. It’s also available for anyone to access for teaching or research via George Church’s Personal Genome Project http://www.personalgenomes.org/. It is cryptically named, Jill’s Genome. See if you can find my Factor V Leiden variant.

My hypothesis is that when genetic information just exists, it will:

1) reduce complexity and uncertainty of current diagnostic algorithms,

2) result in faster turn around time and treatment,

3) lower overall cost of all clinical laboratory testing,

4) provide preventative information that would not have otherwise been ascertained. 

Are there any insurance providers or hospital administrators out there following along? I’m happy to have a longer conversation with you about my hypothesis.

Step 4: “Just Look at the DNA” Will be the Answer to Many Questions Across Multiple Medical Disciplines

The example I am going to use here is coagulation (coag) testing.  Almost all physicians have to order basic coag tests to assess possible disorders of hemostatis. Over 200 million basic coagulation studies are performed annually in the US (Thromb Res. 2010 March; 125(3): 210–215). Once ordered, we have to chase down every abnormal PT, PTT, and platelet count that comes down the pipe. In the coag lab, we have an elaborate testing algorithm that pivots off one major question: Is the defect genetic or acquired. We know so much about the genetic of hemostasis, but it has never been feasible to incorporate genetic testing into routine coag labs. So we do a series of functional assays to try to make a guess at what the DNA is doing. It was the best we could do. But in the era of genetic abundance, we can do better.

We currently do dozens of functional tests trying to rule out genetic causes of abnormal coag values. What does the testing algorithm look like when you can just click a mouse and rule out genetic causes of clotting factors and platelet disorders up front? How much time and money will this save?

It doesn’t stop with the coag lab. What does the blood bank look like in 10 years? Are they still relying on agglutination-based assays that were developed in the 1950s? Or are they simply looking at the DNA? What does the immunology lab look like? The microbiology lab? I’ve been studying for my pathology recertification exam and it struck how much the answers to the test questions are going to change before I have to re-cert again in 2026. The answer is often going to be, “Just look at the DNA.”

A Stepping-Stone into the World of Genetic Abundance.

At Invitae, we understand that many physicians aren’t prepared for the tsunami of genetic information that is coming toward them.

We believe that our approach today provides a stepping-stone towards the world of genetic abundance. Today we can do so much better than the single gene tests that we relied on in the world of genetic scarcity.  A common criticism of broad based genetic testing like exomes and whole genomes is that it provides us with too much information, most of which we don’t understand yet.

The Invitae approach is a good midway point between the two extremes.  Our first step was to lock a bunch of brilliant geneticists in a room and have them make a list of all the variants in the human genome that we know are important.  Then we rationally designed and optimized an assay that detects those genetic variants very reliably. In this way, we reduce the amount of genetic “noise” or uncertainty we might pick up with a broader swath of the genome.

Having one technical assay gives us the benefits of an economy of scale. As doctors become more comfortable with genetic information, they can request broader diagnostic panels and order the genes they would like to test a la carte. They set the pace.

Genetic Testing for a Billion People on the Planet 

Here at Invitae, we have a longterm mission and ambitious goal – we want to bring comprehensive genetic testing to a billion people on the planet – meaning everyone in developed healthcare systems and hopefully those in emerging healthcare systems, too.  We would like to partner with physicians to make genetic testing more accessible to those who could benefit from it and together move toward more preventative, and less reactive, medical care.

Join our Invitae community at http://www.invitae.com

-Jill Hagenkord, Invitae