Unregulated DTCG saved my life.

Ok, so if Ellen Matloff hasn't flipped her bobbed haircut, 99245 without 60 min of MD care-insurance billing head yet, then this story will make her and the rest of the counselors who get mad when untrained MDs do BRCA testing flip out.

A woman's husband on DNADay takes advantage of 23andMe's rock bottom 99 USD fee. Clearly intended to double their database.....which it did

Only to have her HUSBAND open her results and

WHAMMO! You are a BRCA1 carrier! Mazel Tov! Not exactly the "fun" he had been looking for when he saw that flyer.....

Why does Myriad market to doctors? Their stance "We are missing a ton of BRCA mutations out there"

I agree.

So you would think I am happy that an unregulated DTCG testing company that the FDA pilloried finds a medically valid BRCA1 mutation that wasn't suggested by doctors.

Well, here's the shocker.

I am glad they found it.

Yes, thank god someone did before she had ovarian or breast cancer! If she would have, penetrance here is NOT 100% guys......

I am also glad that the woman who had the test was mentally stable enough and smart enough to seek professional help. I wonder what her husband and her do for a living?

I wonder if they are college educated. I wonder if there demographic is anything like the majority of the United States.....probably not....Oh wait. Princeton Grad, Prior Google Grad, CEO....yeah sounds just like my cousin Billy in Dushore PA (FYI I don't have a cousin Billy) But Dushore is in BFE.....

I am not glad that everyone is NOT like Mrs. Steinberg or her husband. In the right hands and with easy access to health professionals this works, sometimes........That is why the FDA has stepped in. Not everyone lives like the Steinberg's

Without professionals and without a level head, this could be a problem.

But the news story re-emphasizes what is crystal clear. This is an unregulated company that delivered a medical diagnostic. This result then drove clinical decision making.

Seriously. The DTCG BRCA test is a medical test. I think the FDA gets that part. Despite what DTCG says.

The Sherpa Says: I am happy for this woman. We need more testing, I agree with Myriad. I also think CGCs should be out teaching doctors rather than letting pharma reps do it. In fact excellent CGCs like Ms. Matloff should never see patients and should instead teach doctors how to do cancer counseling everyday. That is what is needed here, more education given to those who need it. Because clearly the doctors who told Mrs Steinberg (I assume she is AJ) that she wouldn't "need" genetic testing despite the family history of cancer are likely in need of some schooling.

Barbara Evans is Right! Sliding scale of regulation.

As the FDA debates what they should do, Barbara Evans at the University of Houston Law School and Amy L. McGuire of the Center for Medical Ethics and Health Policy at Baylor College of Medicine in Houston, also includes, Canadian legal expert Timothy Caulfield and Wylie Burke, M.D., of the University of Washington School of Medicine post some guidelines for regulation of DTCG/LDT genetic testing.

I love this sort of handicapping.

You have absolutely brilliant people posing ideas for regulations. I have read a ton. There are those from industry insiders, Ones from industry "Advisors", Ones from politicians who receive funding from industry, Ones from academic centers that do LDT testing. Ones from bioethicists...

But I have paid attention to the mixed group that includes pragmatist Wylie Burke and Barb Evans

In an article I just read from Science published October 8th. They propose rules for DTCG, but I am certain they also would work for LDT.

What they propose is a "sliding scale of potential harm"

Which is sort of what I had been saying for years, which perhaps is why it rings true.

If this is for earwax type, let it go to market, if it is for medically related decision making, probably needs some regulation.

The proponents for a wild west DTCG (WWDTCG), which BTW includes a "registry" say
"Well, there is no proof of harm or risk"

I say, well, this is not about psychologic risk.

Instead, it is about medically actionable risk.

I say this because recently, Kif6 testing has fallen into question, despite a company promoting these tests to physicians.

The test is marketed as a "Statin response" genetic test.

Can you imagine how many people were started on statins? Well, 250,000 tests had been ordered. Even if 10% were started it would be nearly as many people as DCTG 23andMe have tested.

The real problem here: Pharmacogenomics tests are not something you hide, you ask your doctor to use these results. Unless you are a doctor, you can't use these results to dose medications.......

That is a real risk. Despite what WWDTCG proponents say.

Another risk, BRCA testing. I cringe at the thought that a doctor would use 23andMe results and only those results to infer carrier status of BRCA 1/2
The same goes for CF carrier status.

These DTCG medical tests aren't recreational. These companies added these tests because NO ONE wanted to pay hundreds, hell thousands of dollars to find out these risks.....

In a business decision, they fell short of looking at the medical risks.

So yes, a sliding scale of regulation is likely coming. But not because of Wylie, because of the FDA.

It is obvious. Again, medical testing will be regulated as medical. Ear Wax as ear wax. Will LDT be forced to go through pre-market review? Probably not if they can only be ordered by licensed professionals.....

It's not a form a rent seeking, it is a form of guidance and protection for consumers. That's why physicians are licensed and malpractice covered.

Yes, yes. Someday everyone will have these genomes done and everyone will be educated enough to know what they mean. And all humans will have medical education and we can replace the oligarchy of physicians and the tyrannical healthcare system once and for all........

But until that day, we will have to rely on trained professionals who don't have their retirements tied to their company's new genetic test......

The Sherpa Says: Handicapping of the FDA by the Sherpa. If it has any medical utility it will be regulated as either Class II or III. If only ordered via physician it will more likely be Class II. If not, will need Class III.

Kif 6, Genetic Findings = Useful Medicine 1 in 1000 times

Way back in 2008 I mentioned an article, which I hoped would pan out. Or at least I hoped it would point the way to a model of PGx research which would be followed by pharma and alike to find associations to help us target the right medication for the right patient.

While the similar model followed through with Plavix, the initial study did not.

Which is why when the Berkeley Heart Lab guy came last week, I told him I would not be testing for Kif6. It had not been replicated in further GWAS.

Heck, I don't even use the 9p21.3 test......Why?

A VAP cholesterol panel, a HsCRP, a family history and a blood pressure can help me predict risk much better.

The problem and backlash facing DTCG and DTMD genetic test purveyors is

the 'Ol "Your million dollar major study now rushed to market has just been refuted"

Yes this happens in biomedical science and in medicine ALL THE TIME.

Bed rest for MI anyone?

Low Dose Dopamine?

I could go on and on, but I won't

Put simply, the majority of the genome is NOT ready for clinical medicine or clinical decision making.

It won't be for 20 years.

That doesn't mean there aren't some things we can use.

1. BRCA1/2

2. MMR genes

3. CYP2C19

4. CYP2D6, sometimes.....

5. SCD genes

6. Counsyl universal carrier screening

That is why the FDA is all hepped up about DTCG and even DTMD.

If a gene test comes to market that purports disease risk it had better be studied for at least 5 years before it comes to market.

Post market surveillance did not protect all those patients on Statins, "just because" of Kif6 risk.

Get it? These tests can lead to incorrect medical decisions....

Which can lead to risk.

Yes, even the DTCG tests can fool doctors and patients.

The Sherpa Says: If 2008 was the year of the GWAS, will 2011 be the year of the overturned GWAS?

A Whole Month Off, for Good Reason!

I have a lot of friends and readers who have emailed me over the month.

The recurring comments: "Has the DTCG field run you off of your blog?"

The answer: "Uh No"

Why I have I stopped blogging so much? For multiple reasons.

1. DTCG has been put on the Radar of the FDA and Government. I have nothing more to say about that.
2. Journalists and Genomics aficionados have been correctly pointing out the hype behind some tests. Most notably lately with the ADHD stuff, which BTW should not have been put out there in the press....Maybe, I need to blog more.....
3. My practice and patients have really taken up my time. I am working to apply personalized medicine daily. Because that is what is needed. We need to show the public and the press how it is done on a daily basis.

I will be back soon, to dissect shotty science and poor clinical studies. But for now, our boots are on the ground and we are climbing the mountain....

See you soon!

Plavix and 2C19 BrewHahHah

Yes,

I am a little slow

Yes,

It has been a long time.

But,

I am back. With a serious hankering to smash some studies. I already pooh pooh'd the Migraine SNP study on Twitter, but the Plavix stuff.....That deserves a blogpost.

To quote a famous caridologist and friend

"If Plavix really didn't work for 30% of patients, why don't we see more in-stent thrombosis?"

Translation: Your science is nice, but how does it fly in the real world?

I have to tell you, at first I couldn't answer. It was a great question. Do a full third of people have that severe failure?

The obvious answer is NO. If 1/3 rethrombosed, we wouldn't be using Drug Eluting Stents.

So what is the answer:

Apparently a BMS (I.E. Plavix maker) funded study investigated this

We hypothesized that the benefits of clopidogrel as compared with placebo would be decreased in persons who carry a loss-of-function CYP2C19 allele and increased in carriers of the gain-of-function *17 allele.

What did this team study?

we examined the efficacy and safety of clopidogrel as compared with placebo according to genotype status among patients in two randomized trials: the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, in which patients with acute coronary syndromes were enrolled, and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) A, in which patients with atrial fibrillation were enrolled.

Ok, so they took 2 different populations and bundled them into the same article....

The 2 studies?

CURE-randomized, double-blind, placebo-controlled trial comparing clopidogrel (at a dose of 75 mg per day) with placebo — both in combination with aspirin — among 12,562 patients with acute coronary syndromes without ST-segment elevation.

ACTIVE A- was a randomized, double-blind trial comparing clopidogrel, at a dose of 75 mg per day, with placebo — both in combination with aspirin — for reducing the risk of stroke among patients with atrial fibrillation and at least one additional risk factor for stroke who were not eligible for warfarin therapy.

What did they find? No difference between Poor Metabolizer and Wild Type in secondary and primary outcomes.

So are we wrong with our studies showing 2C19 genotype matters in outcomes?

Probably not.

1st the authors note why.

1. One possible explanation for the divergence between our findings and those of previous studies involving patients with acute coronary syndromes is the difference in the rates of PCI with stenting. Only 18.0% of patients in the CURE population included in our study underwent PCI, and only 14.5% underwent PCI with placement of a stent, as compared with more than 70% in previous studies

2. We cannot definitely exclude the possibility of an interaction in the subgroup of patients who receive stents, particularly those who receive drug-eluting stents, which were not in use at the time of the CURE trial.

3. the ACTIVE A genetic data set contained fewer participants and outcome events than did the CURE data set and therefore had less statistical power.

My take

The ACTIVE A trial to assess the hypothesis was powered at 45% to detect a difference, thus it is a worthless study and should not be included in this analysis.

While I agree that a placebo group may be useful. It is not needed to assess a difference between people using Plavix with normal Plavix metabolism and Poor metabolism. In fact it may even confuse the situation as it introduces further confounding factors not genotyped or phenotyped out.

The authors disagree
First, the inclusion of a randomized placebo group in our analyses reduces various sources of confounding, such as potential pleiotropic genetic effects or population stratification.

Well, did they test or assess for pleiotropic genetic effects? No.

Further, by introducing a study COMPLETELY underpowered to observe and eval the hypothesis into this article, it ONLY creates a false image of scientific validity.

The authors disagree
Third, we observed consistent benefits of clopidogrel, irrespective of CYP2C19 genotype, in two different patient populations, which validates our findings and suggests that they could be generalizable to other populations.

Again to quote the article

Among patients with atrial fibrillation in ACTIVE A, our study had much lower power (45%) to detect a similar interaction.

So why did they include the POORLY POWERED study?

" in two different patient populations, which validates our findings and suggests that they could be generalizable to other populations."

While I laud the effort to have Randomized and Observational versus retrospective efforts. I think we have to be very careful in our study design to make sure

1. We are properly powered to observe differences.
2. That we assess pleoitropic effects, rather than claim to control for them mysteriously.

The Sherpa Says: Why include the second study? It is improperly powered, further the CURE study did not include Drug Eluting Stents! Why? Plavix goes generic in 2011. They did this to save the market......Expect more screwy studies published in NEJM etc. As PGx gains traction, contrarians and Pharm will always fight it.....

What is medical testing? Why it matters for DTCG survival.

I just was threatened by Daniel MacArthur over at GenomesUnzipped that he was about to delete my comments.

He called it trivial. I think he is missing the tremendously simple point.

Why is the FDA mad as hell? Medical Claims.

Hell, they even told Mary Carmichael in the interview.

Alberto Gutierrez = AG

"AG: The concern is with everything."

"AG: The law requires us to clear devices or approve devices BEFORE they go into the marketplace when they make medical claims"

This to me is crystal clear. Make a medical claim. Get regulated.

Which is interesting. Because I would say some of what DTCG did was, infer medical claims without making outright claims- silly games . I happen to think that is a shitty way to sell something. But heck it is a way to create a discussion rather than instant regs.....

"AG: The question with 23andMe has been whether their claims were medical or not. The original claims they were making were very much on the edge."

"AG: We actually told them that WE(FDA) thought they were medical claims, but it was at least possible you could argue that they were not"

Do you get it? The judge thought they were medical claims, but let the company proceed. Giving it just enough rope to hang itself.......

The question here is clear. What is a medical claim?

Which boils down to: What is medical?

I can tell you what I do as a doctor.


I diagnose, treat, cure, palliate, prevent human suffering and advance human health.

If you are making claims to do any of those things, I would call it medicine.


This is very important to understand and I hope you VC are listening........

Diagnose, Treat, Cure, Palliate or Prevent human suffering.......and advance human health.

Words matter. Did you notice I didn't say disease. Because what's today's disease may not be tomorrow's.

And Vice Versa....

Is a priest a doctor? Well, they used to be.

Is a counselor practicing medicine, well, I would say yes, they are in the healthcare arena

Yes, it is now sinking in. That huge pit in your gut. The millions invested trying to game the system that is millenia old........


It will not work. DTCG has just proven that. And, do you think the vitamin industry has a chance over the next decade?

No.

I will begin the deep dive into the FDA comments shortly. But rest assured, I just gave you some insight into what medical really means......

The Sherpa Says: There Daniel, there you have it. I have told you what medicine is. Now if you wish to argue against that go ahead bub.......

Reporter Mary Carmichael, will she do it? Newsweek and DTC Genomics!

" I don't even know if that was a hammer that got dropped on their heads. More like a piano."
-Anon Quote re: DTCG and Congressional hearings....

When Ms. Carmichael approached me to answer a burning question for her. She got an answer alright, more like a diatribe and then and answer.

In case you didn't know, Mary is a writer for Newsweek and is thinking about doing a DTC genetic test kit. In fact, she bought the kit and it is staring her in the face. FYI, she's not in New York, where such activity is illegal, she is in Boston, where it is encouraged......

She is taking opinions from just about everyone in the biz. And, yes, she has a comments section for all those Yahoos who feel left out.......

My recap here is what Newsweek wouldn't put in their print, but as you know.....I am more than happy to put here for my readers enjoyment......

Hi Mary,

You think you are set and ready to get, DTCG'd. Just hold on a second. I think you need to really think about what you can and can't learn from this sort of testing. Some say nothing, others say these little babies hold the secrets that the government is trying to keep from you, other say Google's overlords are plotting to steal your children's DNA.

I want to know, have you thought about it? What can you and what can't you learn? Since I have seen probably more patients with these types of tests than just about any clinician out there, I can tell you what the patients ask and what I tell them.

1. You will not learn what you will die from.

Yes, this is true. As a physician who has counseled and seen patients who have brought me their 23andMe, et.al., one thing is clear, patients ask about what this means they may die from.

This test won't tell you that, in fact most tests won't tell you that, whether ordered via Amazon or through your doctor. This test may show some scientifically linked risks for disease, but again, they won't tell you what you are going to die from.

As an aside, You will die from something. Everyone dies. Even those transhumanist singularity punks die. No amount of knock off stem cell clinics will help with that one. Even the G-Damn Buddha dies. In fact someone off'd him with rotten food....

2. You will not learn what diet is right for you.

Again, you are getting DTCG'd. But if you were getting some of the Nutrigenomics tests I would tell you the same thing, There is no magic diet currently based on 23andMe data or any other genetic data. We do know some people may benefit from some types of diets to lower cholesterol and lose weight, but the science to accurately predict genes and diet is not ready to bring to market, no matter what Proctor and Gamble tell you....

Second aside, Isn't funny how the GAO bashed these nutrigenomics companies in 2006 and they are still out there slinging there proton pills. Goes to show how much force the FDA or any other organization has to control commerce......I wonder what happens to the first batch who refuse to buy health insurance.....You can buy things that give you cancer or an erection, why not DTC tests? Properly regulated of course......

3. You will not learn if you are of the lost tribes of Israel.

True, your hot little hand will get a hold of a J Haplogroup analysis, but even the ancestry experts will tell you, this is a small window into heritage. Only 50% of the Cohanim have the Cohen Modal Haplotype. Is it a start? Yes, maybe a hint. But no SNP test offered by 23andMe will rule that out or in as J.E. Ekins et al stated. It requires extended STR testing.

Ok, my buddy, who shall remain nameless as he is at Camp in PA for his kids right now had a patient come to him adamant she was of the royal lineage of the Czar (Russia). She paid a bundle to have her mito DNA checked.....Guess what? She wasn't........

P.T. Barnum once said
"You can fool some of the people all of the time; you can fool all of the people some of the time, but you can never fool all of the people all of the time." But what he forgot to say is, some people are fools all of the time......

What will you learn?

Good Question Mary.

1. You may learn you are a carrier of a medically relevant condition.

For all intents and purposes, the lab used by 23andMe is CLIA certified, which means its results for positive carrier tests are just as valid as those ordered by a doctor (in some instances). But remember, this test is better at ruling in than ruling out as it often misses carriers in genes such as CFTR for cystic fibrosis. So if they say you are NOT a carrier, don't trust the results. And if it say you are you can always double check with a doctor.

Mary, this is a medical test. And should be held to the same standards as other medical tests.

2. You may learn you carry a rare mutation putting you at significant increased risk of breast or ovarian cancer.

23andMe tests for 3 mutations in BRCA1 and BRCA2 which could put your risk of breast cancer as high as 85% over your life. Are you ready for what to do with those results if you had them?

Mary, this is a medical tests and I advise you to have some clinician back up when reviewing these results. Even if they are negative, that doesn't rule out a BRCA mutation. This test is confusing and should be regulated as a medical test.

3. You may learn you cannot metabolize medications properly.

23andMe tests for medication metabolism using the same genetic markers as found in other medical tests. Again, they use a CLIA lab, so you may be able to trust their poor metabolizer status. But are you taking Plavix Mary? Tamoxifen? Does it really matter for you now? Or ever?

The whole thing about Pharmacogenomovigilence is that ideally everyone would have a panel of these useful genotypes before dosing medications. But based on the soon to be available rapid turn around time here, we could do these in some labs overnight. The big question here is, is the DTCG test enough of a test to trust clinically?

I am not so certain as they miss certain SNPs and rare mutations that are important.
The Sherpa Says: Ok, Mary. You want it, you got. If you buy a test, you've got a guy just a few Acela Stops away who can help sort out the madness for you.......Clinically of course.....That is, if I haven't convinced you otherwise.....