Congratulations Generation Health. Nice pick up!

Is it any surprise that insurance companies have no clue what the hell is going on with genetic testing?



You see, there are a set of ICD9 codes that can mean 2C19 testing or hepatitis pcr........



The coding system doesn't allow the companies to run their algorithms accurately......



Insurers have no clue which is which and they are getting banged out for these tests.



Don't believe me, just take a look at what United has done with their BRCA testing (which BTW has their own codes)



"By instituting a prior notification policy and placing Myriad in charge of determining which patients get tested, United Healthcare can monitor more closely which of its policy holders are receiving testing on BRACAnalysis."



Add in the SGO guidelines which suggest a 5% BRCA carrier risk may be worthwhile and you can see why the companies are looking to stop the carnage or testing overuse.



Myriad on the other hand would beg to differ. They see years of under utilization as something to combat. And they are very successful at it, just check out MYGN.



The answer is somewhere in the middle. What is a responsible insurance company to do?



Answer: Generation Health.



What happens when genetic testing costs less than 100 bucks? Well, then maybe Generation Health will need to speak with me regarding a diversification company we are working on.....



With other PBM companies actively looking at new automated strategies for GBM (not glioblastoma multiforme) Generation Health is an interesting play.



I remember speaking with a certain player who also was involved with the DTC companies, who agreed with me. DTC is a bull$h!t play, benefits management of real testing, hyperlipids, HCM, etc are where the puck will be......From the Genome Web article (HT Turna Ray)



"The partnership will also “allow the companies to explore future programs in the medical diagnostics arena to encourage appropriate and cost-effective testing for certain hereditary diseases, and eliminate unnecessary testing where evidence for clinical validity and utility is lacking,” the collaboration partners said in a statement. "



We talked about this for some time (unnamed MD and myself) and then.....radio silence.......Only to show up with funding and some small hits.



They chose genetic counselors instead of my band of geneticists......



These guys are moving in the right direction. The industry is shaping up and guess what the killer app for genetic testing is?????



That's right, actual, honest, regulated medical testing........ Go figure.



Now, who gets what, how is it paid for, how is it used?



These are the questions that will need to be solved.



Until of course the accuracy and cost of a genome is less than 500 USD Which could be quite a while.



Meaning, Generation Health has about 10 years of life as the company it is right now. Not bad.



Imagine saving insurers millions per year, then taking 10-20% of those savings......... per year CVS/Caremark is a great partner and now owner/investor.........A very strategic investment.



My guess is that the DTC companies will fall in line or perish. Then labs will have to start marketing better, offer faster turnaround times and there will be "preferred" lab status.....per insurer.



Basically creating a super confusing land mine for physicians and patients. Just like radiology, just like surgery, just like chemo, just like......medicines



The Sherpa Says: Finally, corporations and investors are figuring out what IS important. Staying alive and having your medications work!!

Long QT Syndrome, location matters

I just saw a family who had Long QT with a KCNQ1 mutation ripping through them. Which is why I loved this email I received from one of my long time readers the day after I saw them.

Closer Look at Genetic Testing in Long-QT syndrome

One of my favorite lines from this paper was

"Nothing tests the tools of clinical risk prediction quite like sudden death."

Ummmm......Uh Huh.

They go on to say

"The difficulties encountered in the clinical application of genetic data, even in inherited conditions such as the long-QT syndrome (LQTS), in which the transmitted risk of sudden death is several hundred-fold greater than that in the general population, highlight some of the hurdles that must be overcome if DNA diagnosis is ever to transform cardiovascular medicine. "

The reader then went on to send me a release from ScienceDaily

But I should probably give you some background.

Long QT syndrome is a condition where the electrical activity in your heart is faulty. In fact, the conduction system has dangerous delays that can lead to dangerous heart rhythms which cause sudden death.

It is so serious that in every single patient I see, I ask "Has anyone in your family died suddenly or in their sleep? Has anyone had any crib death? Any sudden unexplainable car accidents?"

This is my lay screen for Sudden Cardiac Death (SCD).

Long QT is one of the causes of SCD. The rate is about 1 in 2000 or so. In 10% of people roughly, the first symptom is sudden death. This can be due to exertion, stress, auditory triggers.

A multicenter study was performed to evaluate genetic "noise" in 1400 controls and approximately 400 subjects (Far more than the Norovirus resistance gene for 22andSerge)

What did they find? They found some noise......of course.

This noise was present in about 4% of controls. This is surprisingly low in my estimate......

What else did they find? They found a genotype/phenotype correlation. Which in Autosomal Dominant disease is also no big surprise. Which likely will be augmented with modifier genes.

What is the "noise rate" for other genes? That, my friend is a good question.

What is noise? It could be anything we haven't classified as for certain pathogenic or benign. For BRCA we call these changes "Variants of Uncertain Significance" or affectionately known as VUSes

The VUS rate for BRCA is anywhere between 10 and 15 percent. Which is why I was so surprised about the LQTS study. Heck, there are more than 2 genes involved in LQTS

So why is this noise such a big deal? As we reach the precipitously dropping cost of the genome, we will be able to have a whole bunch of noise......

In fact, I think it will take us at least 20 years to sort out that noise. Add on layers of epigenetics and we may have another 20 years.......

Why so glum? We do have pretty valid clinical testing for Sudden Cardiac Death. It works, MOST of the time. Whole Genome Scanning?

Well, that may be a different story. I have harped on the Incidentalome several times on the blog, but this bears repeating.........

" If practitioners pursue these unexpected genomic findings without thought, there may be disastrous consequences. First, physicians will be overwhelmed by the complexity of pursuing unexpected genomic measurements. Second, patients will be subjected to unnecessary follow-up tests, causing additional morbidity. Third, the cost of genomic medicine will increase substantially with little benefit to patients or physicians (but with great financial benefits to the genomic testing industry), "

-Zak Kohane

"Mathematicians modeled sequencing the whole genome. As they get up to sequencing 10.000 people they find that the fraction of the population with a false positive result skyrockets up to 60%. What does this mean? Well, we have to carefully select who we test. Or better yet we need an immense database of "Normal Variants". At a minimum we will need 1000s of "sequence specialists" or "computer sequence analysis programs" to evaluate and decide if the "work up" is indicated or not. Personal Genomics is very complex, even more than personalized medicine."

-Steven Murphy in 2007

The Sherpa Says: In Genomics, there is going to be a whole lotta maybes........which in case you are curious, computers handle very poorly....

Good Enough Science? Apparently so at 23andme

"A total of 61 individuals involved in five norovirus outbreaks in Denmark were genotyped at nucleotides 428 and 571 of the FUT2 gene, determining secretor status, i.e., the presence of ABH antigens in secretions and on mucosa. A strong correlation (P 0.003) was found between the secretor phenotype and symptomatic disease, extending previous knowledge and confirming that nonsense mutations in the FUT2 gene provide protection against symptomatic norovirus (GGII.4) infections."

This from a report at 23andSerge's "Norovirus Resistance" report.

I don't know what I would do with a Norovirus resistance report........Go on more cruises? Work in a daycare? Have more kids?

I bring this up because I begin to wonder what level of science is good science.

Is highlighting every article as useful as highlighting important and valid articles?

It seems to me that the best thing these companies can do is focus on good things and play a role in dispelling the not so good studies.

Heck, this is something I wanted to do on the Sherpa, but lack the resources....i.e the 13 million to burn on curators. So I select only the most relevant studies for PM and review.

I wonder if they (DTC Genomics) are just pulling up every study possible or if they are actively curating the data.

Because if they are curating, I wonder who is at the helm.

These are the studies they chose for the Norovirus report

Le Pendu et al. (2006) . “Mendelian resistance to human norovirus infections.” Semin Immunol 18(6):375-86.

Lindesmith et al. (2003) . “Human susceptibility and resistance to Norwalk virus infection.” Nat Med 9(5):548-53.

Hutson et al. (2005) . “Norwalk virus infection associates with secretor status genotyped from sera.” J Med Virol 77(1):116-20.

Kindberg et al. (2007) . “Host genetic resistance to symptomatic norovirus (GGII.4) infections in Denmark.” J Clin Microbiol 45(8):2720-2.

Thorven et al. (2005) . “A homozygous nonsense mutation (428G-->A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (GGII) infections.” J Virol 79(24):15351-5.

Just from reading the abstracts not a single study had any number greater than 63 symptomatic patients.

Not a single study in my mind had statistical significance required for an association or a linkage study.

What in the hell is going on with the science?

If an apomediary is to be given free reign (Which I argue they should not in medicine), they better prove they are

1. An expert
2. Knowledgeable about the statistics required for the information presented
3. Not given false information, in science, non statistically valid information
4. Not a harm to the people they provide information to.

I think this is an example of a Big Fail here.

Yet they put it out from the rooftops, yelling on twitter, facebook, their blog, ALL OVER.

What in the hell is this information to be used for?

Even if for fun, it doesn't help if scientifically it is suspect. Isn't this what we bashed DNA Dynasty for? If this company wants to do right by people, they shouldn't boost the unimportant to the level of importance......

The biggest problem about this and other examples is the fact that the studies are not being vetted properly and the rushing to make a big deal out of suspect studies. This is analogous to the press publishing some crap study on the news. Which BTW, I have managed to tune out, because most of what they report is wrong. If they were a news organization, I would not be as pissed here, but they are not clearly just a reporting service, despite what SB 482 said.

23andSerge tests human biologic samples and gives diagnoses. As well as promotes unimpressive studies in an attempt to sell more tests......GREAT BIG FAIL!

The Sherpa Says: If this is the example of expert information that patients/customers can use to empower themselves, I would say they (Both 23andSerge and Customers) could do better reading the National Enquirer for health tips...

Change IS Needed. I agree with William, sometimes.

Over the past day or so I have been engaged with one of my fiercest critics. No a critic of me per se, but a critic of my opinions in the space of Personalized Medicine.

We may have a "truce", maybe......

William Gunn PhD is a pretty amazing guy and if you read his CV you can see he is very involved in the space and an excellent scientist.

Yesterday he and I exchanged emails and he posted a letter to the medical community. I think it is a great letter. He expresses some of the EXACT SAME frustration I have.

"I believe, as does pretty much everyone, that medicine is on the cusp of great changes and that personalized medicine holds great promise. I believe that an informed patient is an empowered patient, and ultimately a healthier one. Every good doctor should want this, and every below-average doctor should pray this day never comes."

I love his opening lines, but there are some problems that I see.

First let me state I agree with most of what he says, but:

1. There are a whole bunch of people who think personalized medicine is a pipe dream created while chilling with the caterpillar and Alice. Namely, doctors, scientists and politicians

2. I think most doctors try to help people, even the less than average ones. An empowered patent would be a benefit to them, but it depends on what the definition of empowered means.....

That is the major league difference between doctors and "super early adopters" in the DTC genomics space.

What is the difference?

The definition of empowered patient.

I have heard it described broadly such as

"Patient empowerment in the health care context means to promote autonomous self-regulation so that the individual’s potential for health and wellness is maximised."

This could be just about anything, including diagnosis and treatment. Which is interesting because in all states of the US you need a medical license to do that.

I also have heard it stated specifically in the Patients Bill of Rights as

"The providing of information regarding therapeutic options so that a Patient can actively participate in the decision on whether to undergo a diagnostic or therapeutic procedure, or pursue alternatives." See Patient Bill of Rights

This is obviously more specific and falls in the realm of, you have a disease, now you can be empowered to actively participate in the discussion. I have always thought that if you don't have the terminology of medicine, this part puts you as a one legged man at an ass kicking contest.

The ideal place for patient empowerment is not sick in the hospital, by that time it is too late. You are sick and not likely to be able to learn as well as if you were healthy.

Which is why the empowerment piece should come in at the doctor's office or even at home in your underwear on your MacBook. I agree. I love when patients come in having read stuff. Just recently a patient came in knowing just about everything about a familial disease....the consult was super awesome and we had a great discussion. But again, this was a motivated subject.

But I ask, is that what the DTC Genomics coummunity thinks empowerment is? Is empowerment education? That is what the health community thinks.

But, William et.al. think it is more than that. They think it is access to biometric data AND interpretation of that. In some aspects, this could be considered education......

I agree, it is education of a sort. When it is from your doctor it is called good medical care.

But often it is through an Apomediary.

What's an apomediary? Well, 23andME considers themselves such.
even I consider myself an apomediary in things for which I am not licensed for (golf, start ups, etc). I.E. a self defined expert providing guidance to information about their "expert subject"

But for medicine, I am a licensed, board certified physician who has worked long and hard to stand by my expertise (8 years of work after my undergraduate work). Unlike DTC genomics companies, who are neither regulated, nor accredited to give expert medical opinion.

Thus, they are apomediaries. Is patient empowerment, unregulated access to apomediaries? Well, maybe. But I argue that DTC genomics are more than just Apomediaries.

They test human biologic samples and provide a diagnostic result, despite stating they are not providing diagnosis. Think BRCA carrier status here. Which BTW is a medical diagnosis. With a medical test.

So, is patient empowerment the ability to obtain diagnoses from a non licensed diagnostician?

I would argue that this is precisely what I am opposed to. This can lead to all sorts of danger. Last time I checked, laudanum was not FDA approved, nor were the apothecaries.......

The Sherpa Says: We have come a long way since then and going back there would put us squarely into the stone ages for quality of care. Which is why I am so vehemently against a company that tests your human biologic sample and provides a diagnosis without being licensed to do so. Change is Needed William, I agree.

Away and now back, What did I miss???? 23andme layoffs? Selling Genomes for cheap up next!

23andSerge has layoffs, big surprise.

When Linda left, she had a tribe that left too. I am working on hiring one or 2 and will see what exactly was going on over there......Likely a huge cash bleed

GAPPNet has their first meeting, which I missed.

I will email Dr. Khoury and find out how it went.

Daniel MacArthur pointing out that 23andSerge could have bashed bad science, yet instead promoted it......No surprise there either.

It looks like 23andSerge fired the engineers and scientists.....and kept the PR and marketing wonks.......

Well, in the end it is crystal clear

It turns out the lawyers questioned this as well as Misha.....Turns out, if you took the genome, then you probably can sell it.......better yet, if you "acquired it via firesale" you also can probably sell it and break all kinds of "terms of service"

What's important? Not having your genome sold off? What's important? Being able to be certain the person who has your information won't sell it to the highest bidder......Now do you see why it is important to have a doctor involved in this? We CAN'T sell it off. Even if we wanted to. It would be against the law......10 years in Folsom or 250,000 USD......OR BOTH!

The main problem is that a lot of people are confusing things.

What is important IS "What is important" not cocktail parties, blimps or CEO's from insurance companies

(hmmm, I wonder what Navigenics is thinking about doing with it's company?) Maybe Humana wants Navi, to profile their patients?

The Sherpa Says: Companies are most dangerous to their customers and the public when the chips are down. They often do unthinkable and crazy things........for cheap. Anything to survive, that is the motto of the startup. Do or should they have any loyalty to you, AFTER they already have your money? No, unless legally bound.....This is yet another reason why a doctor should be involved here.

Gluco...Wha? Parkinson's Disease and Glucocerebrosidase mutations.

In 2007 I diagnosed a 74 year old woman with CF.

She had a positive sweat test and positive mutation with an intronic mutation as well.

I investigated this after she had bronchiectasis and no history of smoking. And a grandson with CF......... Why did I do the sweat test?
I needed to know if her bronchiectasis was due to CFTR mutations. Maybe she didn't need COPD treatment after all.

That same intellectual curiosity is found in a recent study in the NEJM. It turns out they are finding some patients who have Gaucher's also have Parkinson's Disease.

What's even more interesting is that Heterzygotes for Gaucher's are at increased risk of sporadic or familial Parkinson's disease. So one has to wonder, how many Parkinon's cases are due to GBA mutations.....

Well, this study aimed to elucidate that. First off, if the GBA mutations are higher than LRRK2, well, we my have another Ashkenazi Jewish disease.

What did these guys do?

5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel–Haenszel procedure used to estimate odds ratios across centers. Ok, a reasonable method.

Now what did they find?

This finding allows for confidence in reporting the Mantel–Haenszel combined odds ratios for N370S (odds ratio, 3.96; 95% confidence interval [CI], 2.60 to 6.02) and L444P (odds ratio, 6.73; 95% CI, 4.50 to 15.42). After correcting for outliers they can confidently report a Mantel–Haenszel odds ratio of 5.43 for GBA mutations, in patients versus controls Ok, so if you have either of these mutations, you are at a pretty high risk for Parkinson's Disease. Seriously. How many of the Parkinson's cases are due to this type of carrier mutation? Overall, when screening solely for N370S and L444P, one of these two mutations was found in 15% of Ashkenazi Jewish patients as compared with 3% of Ashkenazi Jewish controls and in 3% of non–Ashkenazi Jewish patients as compared with less than 1% of non–Ashkenazi Jewish controls That's a lot of cases.

Way more than the LRRK2 mutation Familial Autosomal Dominant disease that could be counseled by pedigree alone that Serge was so hepped up about.

But if you want a breakdown of LRRK2 versus GBA you can read about it here.

Of note, there are very few papers comparing both, but there is one that disproved my hypothesis that it is likely that the LRRK2's actually are GBA mutation carriers.... But 37 Families still gives me a little hope that Serge was focused on the WRONG gene...

Back to GBA mutation carriers, this like CF now has me asking "Does anyone in your family have a genetic disease like Gaucher's" when I see some PD history.

Which highlights a significant point, if Primary Care Doctors are supposed to perform family histories, then how in the hell are they supposed to know about this?

The answer: This NEJM article? Navigenics? Who? How?

Unfortunately, most Internists will look at the article and say "Meh, another one of those genetics articles I don't understand" Will giving each doctor a FREE Navigenics test break that attitude......doubtful.

The Sherpa Says: Geneticists need to do their job and teach other doctors, not serve on DTC genomics boards.

Did you get your kit? Thanks Dr. Rob from MedCo

I love and hate when GenomeWeb scoops me. I love it because I know someone else is out there assessing the field. But the competitive nature in me hates to be scooped......ah well, you can't win them all.

It turns out that Good 'Ol Dr. Rob and I agree, physician education is the key to get physicians involved in clinically important PGX testing.

Not only is education key, but maybe involving them in research about it may even be better.

A survey conducted by Dr. Rob's Team at MedCo and AMA just published at ASHG says so too.

"The survey, which was conducted in 2008, found that 13 percent of doctors had either ordered or recommended pharmacogenomic tests for their patients in the preceding six months"

That is about spot on as to what I told them about how many would be ordering tests immediately.

"There is a general lack of formalized pharmacogenomics training among physicians, the survey found, with 26 percent of respondents saying that they had received some form of education in the subject either in medical school or after graduation."

I taught pharmacogenomics to Yale and Yale Affiliated residents from 2007-09. I know that the ones who have learned are now actively looking up and interested in this stuff.

"98 percent of these physicians agreed that patient genetic profiles may influence drug therapy"

Obviously, they took pharmacology, the GET pharmacogenomics. It is not a big leap here!

"It's clear that there is wide acceptance that genetic testing has a role in patient care, but the need for formal training and education among physicians is necessary to obtain greater adoption and implementation of these tests in clinical practice. -Robert Epstein MD"

Precisely Dr. Rob, Precisely. No big surprise with the survey. But a big surprise in my mailbox......

Yes, a CYP2C19 study spit kit. MedCo is studying Effient vs Plavix with CYP2C19 testing, head to head.......

BooYah!! I just spoke with the Effient people the other day. They are keen on taking this market.

Now I just happen to be working on something that all of these interested and willing physicians will need.........

The Sherpa Says: Dr. Rob, I hope you are listening........It's time to execute.