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.

Follow up to Yesterday's WTF? Harvard, Navi? and Pfizer???

So I was thinking about all of this hullabaloo and how Beth Israel Deaconess flipped the script by using non-clinically validated, non medical tests to teach residents about medical genetics.....

Yes, that is pretty freaking preposterous in and of itself, but I have a deeper concern.....

"Beth Israel has launched the Personalized Genomics and Next Generation Sequencing Training Program, which includes a series of lectures, discussions, and presentations, aimed at promoting a better understanding of the personalized genomics field and next-generation sequencing technologies."

Ok, so my question is. Who will be giving the lectures?

Let me put this another way.....

"NewsFlash" (This is not true, however it is just as preposterous and written to illustrate a point)

Harvard Medical School has agreed to partner with Pfizer to educate young resident physicians about pharmacology.

Residents will receive a series of lectures crafted by Pfizer to help physicians understand the complexities of pharmacology. To help the young physicians a pharmaceutical specialist employed by Pfizer will take the residents out to dinner and give lectures crafted by Pfizer.

To further enhance the training, all physicians will be given free samples of viagra/modafinil to help them understand how the medication works

"We believe that pharmacology and pharmacogenetics will be critical to the future of health care," Mark Boguski, of BIDMC's Department of Pathology and the Center for Biomedical Informatics at Harvard Medical School, said in a statement.

"Training our residents on the leading pharmaceutical services and technologies will be essential to this future."

(End Fake Story)

Do you get what I am saying yet, or are you such a blind supporter of DTC genomics to see the absolutely clear freaking conflict of interests here?

And for such a school which focuses so much on Conflicts of Interest, I am blown away that this program has not yet been shut down.....

You can email Mark Boguski at mark_boguski@hms.harvard.edu if you think this is as crazy as I do. Or maybe a phone call? 617-432-7375

The Sherpa Says: Do you see what I am getting at Mark? This is sketchy at best....

Excuse Me? Harvard and Navigenics? WTF?

Ok,
So I was blown away when I read this juicy little tid bit from Genome Web.

NEW YORK (GenomeWeb News) – Navigenics and Beth Israel Deaconess Medical Center in Boston announced today that they will collaborate on training physicians in personal genomic testing.

Amazing! I had spoken with Mike Murray up there a while ago and have neen involved in his training curriculum with CMEs for providers. I have always interpreted his opinion on the DTC companies to be suspect of what the hell the companies are doing.

In fact when we, Mike and I presented together at the Association of Program Directors in Internal Medicine meeting in 2008 in New Orleans I assumed that their department as well as he didn't much support DTC genomic testing.

Which is why the BID move had me puzzled, so I emailed him. But I also read further.....

As part of the program, residents will be given the opportunity to have their own genomes analyzed through Navigenics' consumer genomics services.

"We believe that genetics and genomics will be critical to the future of health care," Mark Boguski, of BIDMC's Department of Pathology and the Center for Biomedical Informatics at Harvard Medical School, said in a statement. "Training our residents on the leading genetic services and technologies will be essential to this future."

Ahh, I see. It is not the Genetics department who is involved with this. It is the pathologists, you know, the physicians who look at microscopic slides and run the clinical laboratories who are behind this.........

This Makes all the sense in the world now, non clinical geneticists teaching doctors about clinical genetics and how to use a self-avowed NONCLINICAL, NONMEDICAL test to learn medical genomics.....

What the hell is Harvard thinking? I wonder if they received a nice endowment gift from the VCs who fund Navi????

So let me get this straight, Harvard Medical School sponsored Medical Residency at Beth Israel Deaconess is using a NONCLINICALLY validated test, from a company who states that the test should NOT BE USED FOR MEDICINE, to teach MEDICAL residents. To quote the plan

"Among the specific goals of the program are fostering an understanding of issues related to the evaluation of direct-to-consumer genotyping services and familiarizing physicians with the interpretation of genomic information and its correlation with personal medical and health information."

Have they lost their minds???? Shouldn't this be something that the clinical genetics department should be teaching? I wonder if Vance received a faculty position for this horse$h!t?

The Sherpa Says: I knew that this wouldn't come from the clinical genetics side. I hope they don't have any fingerprints on this one.....But my guess is Raju is involved in this one some how.....Now Harvard is confusing what is Important.

Stated Another Way.......

Last week I was criticized harshly about the shock and awe I used with the picture of a parasite being passed from an animal and comparing it to what needs to be done with DTC Genome Scans.

I was asked to be critical and analyze the work. And frankly, I am a little embarrassed. That doesn't mean I will take down the post. It means I will begin to state the rationale for my argument.

The premise is this, DTC Genomics has cast a shadow on the field of genetics and genomics. In not only the clinical utility but also the scientific utility, this boondoggle has screwed the field. The community had been seduced by receiving offers of "Advisorship" for "The Next Google" or whatever the pitch was.

A few smart people bit, including George Church, who I think was hurt the most. His PGP received less attention and less gravitas as it was lumped in with 23andSerge and Navigenics cocktail parties in SoHo......

I said this back in 2007 when I had coffee with Amy Harmon, prior to her Pulitzer . She asked me why I was against this DTC movement. Well, unlike then I have thought about this for a while now.

The singular reason is: "The marketing and promotion of these services has caused a tremendous amount of confusion as to what exactly is important"

????

"You don't mean your rant about how this is medicine and should be regulated as such?"

Well, that is an issue of importance. They have been playing important, just like a TV doctor would.

"You don't mean the issue where they steal your genome?" Well, again, they may be confusing what is important in the genome and making you think their 500k SNP analysis IS important.....

"You don't mean the rant about how doctors confuse Personalized Medicine with DTC Genomics?"

Again, this is an issue about what is important and what is not.

Detracting attention from that which is important is probably the biggest crime that is being committed here. What we are now going to see is a phase of skepticism drawn to the whole field of genomics. Don't believe me? Read here

"As scientists including Venter aim to usher in an era of personalized medicine based on individuals’ biological differences, companies such as 23andMe and Navigenics already offer tests that plumb people’s genetic makeup. The article’s authors said “the nascent industry” could improve predictions by developing a consensus on how to do the analyses."

So I ask, "Is the nascent industry personalized medicine? Or is it 23andME and Navigenics?"

By lumping Personalized Medicine with these companies, you begin to take on their traits......

"Google-Backed DNA testers Don't always agree"

Ok, so now personalized medicine is Google Backed and the results are sketchy at best.......

Do you see what I mean?

Don't believe me? Read This
The Journal? Personalized Medicine. the Article? DTC Genomics......

I hope you see what I am getting at. Still having a hard time?

Take David Agus' MD Quote

"Make preventative genomic medicine part of your practice"

Meaning: Use Navigenics DTC Genomics test and you will be practicing "preventative genomic medicine" The new Marketing Word for "Personalized Medicine"

So, there ya go. They want to be personalized medicine, yet disclaim any use of the test for personalized medicine.

This huge circus is one of the biggest distractions to ever befall Personalized Medicine, especially as the story of the epigenome begins to unfold.

We have to ask ourselves
1. "What was gained by supporting these companies?"
2. "What did these companies do to advance personalized medicine?"
3. "What researcher gained greater attention or funding because of the DTC Genomic Buzz?"
4. "What percentage of physicians gained greater appreciation of genomic medicine?"

IMHO, these companies have mad a mockery of personalized medicine and the research that is going on in the space

The Sherpa Says: Hopefully that will explain why I feel that these companies are parasites playing off of our name.....

A few months late to the party....

This month's Internal Medicine News has Dr. Patricia Ganz on the cover.

I couldn't help but say, "Why does she look familiar???" But then I read and remembered

"Few physicians feel prepared to interpret findings from direct-to-consumer genetic tests and incorporate the results into clinical practice, according to speakers at a National Academy of Sciences workshop on DTC genetic testing."

Ahh, yes, she was at the National Academy meeting which served as the official hammer to DTC genomics....

These first intro words from the one of many articles in the Internal Medicine News about Genomics hits home

"Few physicians feel prepared to interpret findings from direct-to-consumer genetic tests" I have a serious question.

If these "tests" are for "fun" and not to be used for medicine, then why should it matter if doctors feel prepared to interpret these tests......

Should they not be interpreting these tests at all?

Since, after all, they are "not to be used for medicine".......

Well, unfortunately, the marketing firms and PR firms have pitched these little babies right next to other OTC medical treatments.......

Which means, the public will "Think" of these tests as medical.

And hell, why not?

Freaking 23andSergey is testing for the Ashkenazi Jewish BRCA founder mutations and placing the results right next to IBD, prostate cancer and heart disease, which BTW is right next to ear wax type.......

The biggest problem here is the confusion of "Medically important" with non medically important.......

When a consumer reviews important sounding stuff with non important sounding stuff, the non important looks more interesting, because it comes with stuff that "Can keep me from dying!!!!" This is the problem here.

And despite what Howard Levy of JHUMC says, I am not down with this problem continuing to exist.......we have allowed it to happen way too many times.....

My prediction is that clinicians will tune out this noise of DTC and use it as another excuse to tune out TRUE CLINICAL GENETICS......How do I know this? Because I know community physicians. They are WAYYYY different from the academic clinicians out there......

Dr Levy is incorrect in assuming that DTC will push the clinician to "Learn Genetics or Consult a geneticist"

Hell, most geneticists couldn't tell you what a heart attack and it's treatment entails these days. Unless of course they have had one. You should have seen the talk about Brugada up in New Haven, what a mess! I leave aside the IM genetics brethren here.....which are less in number than astronauts.......

And now that the team in Mountain View put out a press release about pure swill, it is all too clear to me what the hell is going on.

These guys are desperate. They need to live, or else the empowered genetics patient will die.

Or so they think.

This couldn't be further from the truth.

Genetics and Genomics is doing just fine without these boondoggles...... Do we need NYT spreads to survive and thrive? The answer: No.

Why?
1. Francis Collins is head of NIH
2. Obama proposed bills supporting Personalized Medicine
3. Major corporations are investing in useful genetic technology
4. Clinical research is progressing nicely in the PGx space
5. Clinicians like myself are organizing and practicing personalized medicine

So, I ask you "Why should we support something that distracts from the reality of genomic medicine?"

So we can have them figure out the interpretation algorithms? Well, they have shown what a complete hash of that they made...... For seven diseases, 50% or less of the predictions of two companies agreed across five individuals

So we can get the public supporting Genetics in Medicine? I think we know that the public supports us, with or without them.......In fact they support us more WITHOUT them!!! Because what the public fears can actually legally happen especially if a company goes belly up......

So they can carry out the next level of collaborative research? Have you seen the latest joke research? No thanks, I'll stick with Coriell for now...Maybe Scripps too.......

Suffice to say, from my view point on the mountain, these guys (DTC Genomics) are actually parasites, sucking the energy from the movement. They contribute nothing but hype, which now will turn to backlash......

In conclusion, this backlash will detract more from the movement than the hype added to it.

The Sherpa Says: Why continue to support something that in the long run will damage credibility with community physicians and the public? Why?

Kaiser a protoype for Collins' Aim

Don't know if anyone had heard about the Kaiser Permanente Biobank?

Since Kaiser has millions of lives cared for in a statewide healthcare system, they could easily pound out 500k bio samples overnight.

For the past year or so I have been thinking that the big problem with environmental studies is the need for huge sample size per environment size.

These guys popped up on my radar back in January.
When the AMA News covered there new shiny "biobank"......

" Kaiser Permanente is constructing what is expected to be one of the world's largest and most diverse repositories of genetic, environmental and health data.

The Kaiser repository already has 40,000 DNA samples from members of its giant California-based health plan and expects to have 500,000 samples by 2012."

Well, it turns out that they already have 100k now. Why wouldn't they? They actively care for over 3 million of California's citizens......And with the Government going under, I am certain Kaiser will take care of EVEN MORE.......

In my email inbox an update on this machine.......

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the University of California, San Francisco (UCSF) have been awarded $24.8 million over two years by the National Institutes of Health (NIH) to create a new resource for studying disease, health, and aging.

With this support, Kaiser Permanente’s RPGEH and UCSF will conduct a genome-wide analysis of DNA samples from 100,000 Kaiser Permanente members from Northern California who have volunteered to join the RPGEH. This new and detailed genetic information – which has never before been generated on such a large and diverse population – will be linked to decades of historical clinical and other health-related information on these participants, taken from health surveys and the Kaiser Permanente electronic health record, the world's largest civilian electronic health record.

This will likely serve as a prototype for which Francis will follow........Why?

Think about it. Lots of national/EPA data on environment, now linked to clinical data and genotypes.

Boy, the government could get a whole crapload of that data if they would just open up the VA EMR for free to all physicians........

Any company looking to get into the EMR business these days is going to fail unless they can give it away for free....

That being said, Kaiser has a huge head start on anyone else looking to do this. Why? 3.3 million medical records paired with DNA......

But, this still could be a boondoggle unless they have much more specific environmental data. "Linking environment to disease ain't like dusting crops boy........"

If you want to learn why, you can start here

In fact, the more I learn about the field, the more madness I discover.....This will be a huge boondoggle unless done very, very carefully. The old adage of collect the right data may actually be something of a moving target as the study continues. Which may make this type of exercise particularly suited for the internet age.....

The Sherpa Says: Yeah, Biobanks are all the rage......but how well does one know how to keep thine own? Ask Coriell, they have been doing it a very, very long time....

Ok, Fine, Back to Plavix

Did anyone else see this?

Scripps and Eric Topol are going to be doing testing for 2C19 polymorphisms in their interventional dept.

"Scripps physicians will initially offer the genetic tests to elective stent patients before they undergo their procedures at Scripps Green Hospital. Eventually, Scripps may extend the offering to its other facilities across San Diego County."

I have been prodding Greenwich Hospital to do this.....I hope they do......They could be the El Camino of the East.

What are these guys, Topol et.al going to be doing? "Scripps patients carrying the gene risk variants will be considered for three treatment choices following their stent procedures, each on an individualized basis. Patients will either:

• Be given a routine 75 milligram dose of Plavix with careful surveillance;
• Be given a 150 milligram dose of Plavix, which has recently been shown to be safe and effective in patients showing lack of response to Plavix; or
• Be given the newly approved medicine Effient (prasugrel), which is not affected by the gene variant Cytochrome (CYP) 2C19."

So there you have it. A cutting edge medical facility doing this. I am only all too certain we will see about 20 hospitals follow in their footsteps in 2010.....

The Sherpa Says: Wha? These guys are like a year behind me......I have been doing this since January........

2D6 Rears its ugly head.....

Ok, I have been to hell and back......but I am back.......

I am working on a video you all may soon love to hate, I am also working on a poster for GAPPNet which you too may also soon love to hate......

Well, for all you Amplichip fans, the data from a recent retrospective analysis of German and US cohorts reveals that null function 2D6 may actually portend a worse prognosis for those taking adjuvant (after surgery) chemotherapy for breast cancer. These are women who had hormone receptor positive breast cancer stages I-III, without metastases and without chermotherapy.

At 9 years of follow up, patients who had null 2D6 CYP 450 enzymes ended up with a 29% recurrence rate instead of those who had active 2D6 enzymes. This compared to 14.9% for extensive metabolizers.

Why does this matter?
1. Tamoxifen is used a lot
2. Aromatase inhibitor therapy (Another Drug) is another option for this type of cancer
3. This test is easy to do
4. This follows the Plavix model......

My guess, Roche is about to make a lot of money on the Amplichip shortly.......

Why is this study important? It is the first sufficiently powered study to assess 2D6 genotypes and outcomes.....

Even more importantly, Tamoxifen is a Pro-Drug.....just like Plavix. This time it requires conversion to Endoxifen which is the active drug derived from Tamoxifen.......

The hazard ration for recurrence with poor metabolizers is 2.12. That is a useful thing, which may prompt refined endocrine therapy for these postmenopausal breast cancers......

The Sherpa Says: I am back!!!