Answer to GenomicsLawyer's Question. What the FDA will do with DTCG.

Dan Vorhaus JD on his blog says "The path of least resistance may be to simply agree with the FDA....The viability will depend on how the FDA intends to categorize the specific product...."

I agree, these companies have big choices to make. If it is any indication, Counsyl (full of smart people) and now, Pathway Genomics (full of smart people) have both decided to go the route of Medical test.

Perhaps it is because they think the burden will cost less to investors than fighting the "Man"

Well, in guessing what the FDA will do, it is always best to see what they have done to a "similar" product. In this case, they have a great product that is very similar. That would be the FDA's approval of AmpliChip.

A friend of mine in Canada argues about the holes in this platform, but unfortunately it is the only FDA approved platform.

You can read the letter for the FDA approval here

This was cleared in 2005! I wonder if the DTCG companies ever looked at AmpliChip as a model before?

In the letter it is clear, microarray technology used for drug metabolism prediction is considered a Class II medical device. The letter indicated that this applied not only to AmpliChip, but also to similar devices.

It also does not waive premarket submission.

Both of these are very important points in how the DTCG groups evaluate their future business models and potential market.

The Sherpa Says: Why Conjecture? Just look at what the FDA decided for AmpliChip. It will be a similar template.

Hackers, HITECH and HIPAA in DTC Genomics, Oh My!

At our practice we run a pretty tight ship when it comes to security of patient records. Why do we do this? Well there are 2 big reasons.

1. It's the right thing to do.

2. The law will put you in the hurt locker if you don't

I want to talk about reason 2 a little bit.

Why?

With all of this protection of health information and DTC genomics companies going bankrupt, I begin to really wonder who a covered entity is.

Daniel Vorhaus over at Genomics Law Review has a pretty good break down of it, but I think there may be some nuances not covered. As well as a notable lack of coverage of HITECH policies in the ARRA.

Wha?

Yes the recovery act has stuff on Health care privacy in it. In HIPAA DTC Genomics may not be covered, but I think in HITECH they are.

Why have I been reading this stuff? Because it's my job.

According to HITECH

H.R.1 150 Title XIII (HITECH)

SEC. 13404

For the purposes of compliance with privacy and security regulations, a "covered entity" and its "business associate" are equally liable as if each were itself was a covered entity.

Which means if I send a DTC genomic test off with a doctor's order, AKA Illumina, a breach in that data due to the lab or interpretive business associate THEY are just as liable as the physician.

This means that DTC Genomic tests ordered by physicians fall into a completely more risky category than those ordered by Joe Blow.

This one risk may be why DTC is dying not to make these tests gatekeeper specific. Once these tests become gatekeeper specific, DTC will

A. No longer be DTC

B. No longer be free of HITECH and HIPAA

Which means a big 'ol nightmare for these companies as they want to emphasize the social networking part. You see, social networks have always balanced growth versus security and the same is true for any Internet Technology.

But let's say this is just one rogue hacker who has decided to hack a genome record ordered by a physician.......Via say a hacked email or website........

What is the penalty?

CITE 42USC1320-6

This is the scary part.

Sec. 1320d-6. Wrongful disclosure of individually identifiable          health information           (a) Offense      A person who knowingly and in violation of this part--         (1) uses or causes to be used a unique health identifier;         (2) obtains individually identifiable health information      relating to an individual; or         (3) discloses individually identifiable health information to      another person,  shall be punished as provided in subsection (b) of this section.  (b) Penalties      A person described in subsection (a) of this section shall--         (1) be fined not more than $50,000, imprisoned not more than 1      year, or both;          (2) if the offense is committed under false pretenses, be fined      not more than $100,000, imprisoned not more than 5 years, or both;      and         (3) if the offense is committed with intent to sell, transfer,      or use individually identifiable health information for commercial      advantage, personal gain, or malicious harm, be fined not more than      $250,000, imprisoned not more than 10 years, or both. 

So let's say someone hacked a record to get the one up on you, maybe you are a political candidate or maybe a business competitor, or maybe they want to sue you.......

If this rogue hacker performs an act of this on genomic information ordered by a doctor or that can be defined as PHI, these are the penalties. If it is not considered PHI, it is a far lesser offense.......

So the question is, do you want these protections if you are a customer/patient? I would say Hell Yeah.

But do you want them as a covered entity? Uhhhhh.....Ahem.......Well........

As a doctor we have to follow these. Why shouldn't anyone else who has been given the responsibility of handling human samples?

The Sherpa Says: As a consumer HITECH is great. But as a start up company it can prove to be a nightmare. But those who have to risk the most are the huge companies making millions of dollars....can you say class action lawsuit for millions? I know a few lawyers who would be interested in that! I wonder if the DTC Genomics investors thought of that

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....

Love my readers!

The other day I was flooded with emails from my readers about my post about the whole genome scan dirty little secret. Some agreed with me others vociferously defended the need for "further study" But the best was an email from someone who worked for one of the big scan companies, can't say which one, can't say who.

I Quote

"The speculative questions that you ask about interpreting whole genome sequencing indirectly relates to exactly what the cyclical problem is with an industry of genomic researchers who don’t practice science. Instead, they practice following the recommendations and protocols developed by instrumentation vendors, as if Mike Hunkapillar, Sue Siegel, and Jay Flatley had once parted the Red Sea"

I tend to agree that this comes down to a question of thought leaders in the field. This reminds me to the initial flack received by David Goldstein and even the Ire by Kari Stefansson expressed towards David. But then others soon stepped up and voiced their concerns here. The same thing happened when I expressed concern and reminded everyone about the laws that exist for DTC testing...

Why as a field, does genetic have this lack of willingness to challenge? I think it is for a fear that the spotlight which now shines so brightly will be dimmed because of controversy.

I disagree. Controversy is what will make this field the most robust, the best press worthy and most exciting field of "everything" for the next century.

Let's face it, there is no way that the lights will dim on Genomics. The real question is what will be the representative face of the field. Right now, it is all hype and iPhones and California Silicon Valley.........

I await to see its next face.

Maybe it will be Moses?

The Sherpa Says: It all comes down to the fact that there are so many more data points to look at than just the genome.......

The Genome Scan Dirty Little Secret

You know what I love, you take a company who is inferring that science IS clinical utility and then you hire them to perform interpretation on something that in it's current for is often uninterpretable......and then you sell that for something on the lines of 90-48, 000 USD.

My business is healthcare, my business is also risk prediction, but what my business is most is disease prevention......

My profession is physician, my oath is to do no harm and if I must harm, do so healing or palliating suffering....A noble profession to be sure.

But no one, I repeat no physician is leading the charge to do whole genome scans for risk prognostication.

Maybe for certain disease detection, but not for true risk prediction.

But, guess what? The business people are...... The business side of Genomics is all about getting "these little babies" into the hands of everyone......

Billions of people at 99 dollars a piece is a lot of money.....but the one thing that may hobble this model is what I like to call the dirty little secret of whole genome scanning.

You can read about it at my other posts
1. We have no clue what it really means.....Merry Christmas
2. Nature is So Wrong
3. Ok Guys, Seriously.
4. Rading the Medical Commons, A Pirate's Life for Me

Or you can let me recap. Currently DTC genomic companies are testing 1 million single nucleotide polymorphisms. We have in our body combined, 6 billion of these little nucleotides....

Sure the SNPs were safe, heck a SMALL minority had some science behind them.....but most were razzle dazzle and hyped by researchers to the press.....

Oversold and Overhyped.......If you thought that was something, wait to see the hype from the "Whole Genome" crowd.....

You see, even the most skilled, erudite, knowledgeable geneticist can be hobbled by the explanation of certain genomic changes......

A. If they changes often aren't in genes, then the biology needs to be elucidated, that takes years.
B. If the changes are in genes but that no one has seen before, how do you know what to predict will happen?
C. If we see a change which has been seen but has a wide variety of phenotypes, how do we explain the risk?
D. Most importantly, how do we modify disease risk based on genomic information for most of these things?????

My point is, you have disparate DTC companies calculating risks in different ways and even worse, recommending or "inferring" recommendations for lifestyle changes. Unfortunately, the quit smoking and lose weight isn't exactly "Science" or medicine, which is why they can get away with it.....

What about when a whole genome comes along at 30x coverage? Well, Illumina plans to do that and "outsource" the interpretation to these companies who are "interpreting" based on some very, very soft science already.

What in the hell do they plan to do with this whole genome interpretation?

In my mind these are the keys to get whole genome scan to utility.
1. Formalize some sort of standard interpretive algorithm AND THEN TEST IT CLINICALLY
2. Research the phenotypes which emerge from each and every genomic change out there.....Some like George Church plan to do this in the wide open....which may not attract the millions of people and dozens of years needed for this one....
3. Study the actions which will be proposed for each of the genomic changes to reduce disease risk or to treat disease.....

IFF you can get 5 common diseases captured with this, then you will have a successful system. But then the problem with this is what Illumina already knows...."you will be diagnosing disease and thus enter the realm of clinical test"

Which they have already prepared for by mandating physician ordering of their whole genome scan....

A long post I know......And a long way to go before this is useful at 99 USD per person.

The Sherpa Says: The incidentalome is just the beginning of the nightmare about to be unleashed with whole genomes.....

OK Guys, Seriously.......

What I loved about the second day of CGS coverage was that Dan now had some partners covering some of the space, heck I even saw twitter messages straight from Illumina.....

I want you all to listen to some very important statements. Francis Collins had his genome sequenced under an alias by 23andMe, deCode Me, and Navigenics - tells them here at Consumer Genetics Show - He says

1. Substantial differences exist in info revealed (carrier, non-medical, ancestry); not clear which markers are tested
2. Interpretations sometimes vary, even with the same data; exhorts DTC companies to collaborate on this.

3. Parents willing to pay nearly $2K for cord blood banking are unlikely to be daunted by cost of genome sequencing as it falls.


So here's the take home. When you get a cholesterol test, don't you want to have a uniform explanation and values? The same is true for genomes. This is why it is so damn hard to run a bread and butter lab.

You have to compete on different things......Insurance preference (Which often involves undercutting your costs), Turn Around Time, Integration into MDs work flow......

By exhorting DTC to have "Uniform" explanations he ultimately spells what will likely be the case for this business.....one big conglomeration of a company doing genome sequencing OR 5 mega companies, all competing on turn around time, Insurance preference, and MD preference........

This is fairly evident by the move made by Illumina.....where
1. ONE Company does Sequencing
2. 5 companies do interpretation
3. 1 company does the medical care

Do you see where I am headed? DTC genomic companies in the current form are doomed, unless it finds a way to adapt.

I told Dietrich Stephan that a way back and his investors rebuffed......Well, I am doing it anyways, without them......

You didn't hear about the Illumina move? Well, in spotlight stealing moment, they showed an iPhone app for your whole genome a whole genome at 30x coverage for 48 Thousand USD. ORDERED BY PHYSICIAN, counseled and then tested, a consumer can then get on their iPhone (maybe) or at least their new Mac and surf their results...

This could be a fantastic thing, if it were not for the Incidentalome that this will unleash!

Incidentalome?

Well, in radiology their is a term for finding something on a radiology scan which you weren't looking for. Most often this "Thing" is a benign cyst that regresses or is just an artifact...... But as physicians we end up doing a full court press work up and costing even more money than we thought possible......

Zak Kohane wrote an article about precisely this in 2006 in JAMA...........

He estimates "false positive" rates could be higher than 60%

So my point is this......50k or 5k or 500 bucks, the genome is going to cost about 500 bucks in less than 5 years.

During that time....WE STILL WILL HAVE NO F*CK*N& CLUE what most of the information in it means......And we will be trying to explains things which may mean nothing......... I remember the blog post I did about the geneticists sitting at a table with Comparative Genomic Hybridization Results.....They all said "I Dunno"

We may not know for a very, very, very long time......Francis Collins tells a joke

"A geneticist's wife was talking with her friends........She says "We've been married 20 years now and He keeps telling me how 'We are GOING to have a great sex life' "

The Sherpa Says: Give me a freaking break, Guys, Seriously. What the hell do you think is so great about this $H!T? Seriously? This will cause more confusion and likely more cost. What revolution does this bring? I can see PGx, but that is really about it. OK, maybe NBS too....