An Attorney General, A Genetic Counselor and Gap Phase

Today my phone blew up. I had five different Venture Capital firms call me to pick my brain about "The New deal with Illumina" as well as "Viability of Microarrays in Pharmaceuticals"

I must say thank you to those who called. I look forward to speaking with each of your esteemed groups.

That being said......I must say that there is a general consensus of the physician side that the time for whole genome analysis for your health is not now. I agree. An excellent scientist Dr Bettinger over at the Genetic Genealogist posed a great question.

"What is your opinion on Gap Phase?....."

"that inevitably long period of time between (1) the availability of inexpensive whole-genome sequencing, and (2) the point when the medical field produces enough specialists in genetics to handle the work load."

Well....I don't think that is what gap phase is. Currently there are less than 1300 geneticists for the WHOLE country. In addition. If we expect personalized medicine to affect things like Coumadin, a drug which is dosed by adult doctors primarily, then shouldn't we have some adult geneticists? There are less than 100 of these doctors in the US. LESS THAN 100!!!!!!! Even scarier, there were less physicians sitting for the genetics boards this year than 5 years ago.

I don't think Gap phase has anything to do with these people. I think GAP phase has to do with literature and evidence based medicine. In medicine, doctors try not to do anything without good data that shows long term outcomes. When they veer from this path you get train wrecks like drug eluting stent mishaps and Vioxx!!!! Soon to be Avandia!!

So what do we do with the gap? We mind it!! We don't jump blindly without looking out for the fall that it may cause. Overselling genomics could destroy personalized medicine's promise! I will not let some overzealous "Let's do it because the technology is there, and so cool" people ruin our future. Even for a quick set of chromosomes!

As for trained professional shortage....When we have fighting between lab companies and the people who traditionally order tests, then we have a problem. Which is the case with Myriad.

There is a great NPR spot coming up. A colleague and teacher of mine Ellen Matloff. She will be on there with Attorney General Richard Blumenthal discussing the controversial Myriad advertisement campaign that is now running in CT, MA and NY. You can listen in online Sunday Evenings at 6:00 PM http://www.wnpr.org/

Ellen is the bane of Myriad's existence and because of this the genetic counselor is notably absent from the Myriad commercials.....hmmmmmm

She has started an online petition to start asking state's attorney generals to investigate misrepresentation in genetic testing. My genetic counselor has a wonderful take on this whole thing. BRCA testing is NOT in Gap Phase, unlike whole genome sequencing for healthcare. It has significant amounts of data and studies. It is clinically useful and can be of benefit when used properly. The problem.....The Fox is watching the Hen house. Lab reps are probably not the best people to be teaching physicians about using these tests, trained counselors and Geneticists are.

I am scared for physicians and this should serve as a warning call.

MYRIAD/23andME/Navigenics/futureunnamedbiotech are saying, "if you aren't with us, then you're against us, AND WE WILL REPLACE YOU WITH COMPUTERS!!"

The Sherpa Says: When my phone blew up today, the question was not, how can we invest in a safe product and service that will benefit people's medical care. It was..."How can we make this scalable?"......The answer does not lie in training genetics professionals....that takes at least 9 years after college. The Answer......All roads lead to Google.......Too bad the data is not there and computer guys haven't been burned as bad as those Vioxx doctors......

NYT and WSJ cover Myriad's campaign

I have been silent on this for too long. Why? I was awaiting the review by my attorneys. The last thing I need is another threat of litigation. Why litigate? Because, critics like myself and the esteemed Ellen Matloff from Yale :) have been telling physicians that testing for BRCA ain't like checking a sodium.....or even better a pregnancy test.

Why can you get a pregnancy test over the counter? Because its results are crystal clear. The FDA has requirements for OTC testing. This whole issue was raised with at home HIV testing. The issues were portrayed here.

The interesting questions poses include these.

What test characteristics favor possible approval of an OTC home-use HIV test?

• The test is simple to use compared to other types of HIV tests and earlier versions of rapid HIV tests, suggesting that untrained persons will be able to perform the test properly.
• The test does not require special storage conditions.

The most interesting one was......

• Informational materials supplied with the test are sufficient to provide adequate information to potential users on performing the test and to substitute for live counseling.

Now my question is....has it even been proven that written materials substitute for adequate face to face counseling? Never for BRCA testing. So why does it take evidenced based medicine to prove a drugs efficacy? Well, partially because the FDA's evaluation is not about efficacy. It is about danger to the patient. Is there danger in not getting cancer screening if your BRCA test is negative? (Which BTW is not an appropriate counseling answer to the patient)

Yes, I do agree with Hsien. Direct to consumer advertising is a great way to introduce new products. Like the iPOD.

"Advertising serves to bring new products to our attention and to stimulate interest as well as the desire for more information. In the case of genetics and genetic testing, I would venture to say that all of us need to learn more, not less."

But the best way to learn about breast cancer risk is by being able to ask question to a knowledgeable, trained, health professional. How do we learn more about genetics? Take a freaking class, don't try to do self counseling for G-d Sake. Has anyone seen the Edward Jones commercial where the surgeon is telling a guy sitting at his kitchen table how to do surgery? Over the phone the surgeon asks "Did you sterilize the field?.....Good now with your kitchen knife make a 3 inch incision.........."

This is the type of thing that DTC testing is trying to get you to do. Patient empowerment aside, I don't let my patients prescribe their own meds. I even guide them on vitamins that they take. Did anyone see the expose on the Vitamin Shoppe's vitamins containing abnormally high amounts of lead. It was on Good Morning America a couple month's ago.

Well as the post was entitled the NYT and the WSJ had article on this yesterday. The ad campaign is telling you to go see you internist, OB/Gyn, or family practitioner. Guess what none of them have had training regarding this topic. There are less than 100 internist/geneticists in the country and even fewer OB's and FP's. According to the WSJ

Myriad says it is developing a program to school primary-care doctors about the test. Dr. Critchfield said the company is focusing on primary-care doctors, oncology specialists and tertiary-care centers, along with genetic counselors, "to get the message out."

What struck me was the benevolence of Dr Critchfield, who in the NYT article

Dr. Critchfield said Myriad waited nearly five years to start the new campaign to give more time for health care providers to learn to handle genetic testing. “We are in a far different place today than we were then,” he said.

The Sherpa Says: Well Dr Critchfield, you are incorrect. Clearly he has no clue or doesn't want to sour the internists' palate. OB's regularly fail to recognize at risk and not at risk groups, so do internists. As for the newest batch? I just tested primary care residents at a major academic center and only 30% recognized that a BRCA test was NOT indicated. Maybe that's what Myriad is looking for? If you want the literature I have quoted, send me an email and I will be more than happy to forward it on. As for the 8 month wait, Helix Health of Connecticut is open for business and seeing patients in less than a month!!!

Gene Genie and George's Blog

First....Gene Genie is up at Cancer Genetics. Thanks to Ramunas who put up an excellent edition!!

Second and even more importantly......My excellent Chief of Genetic Counseling brought George Church's blog to my attention. My gosh....

His evaluation is right on point. His question is a wonderful one...... Great now we have genomes....so what. How do we get to systems biology? Once we have systems biology on point, we will then have truly personalized medicine. We will be able to manipulate the systems....and physicians will become engineers, systems analysts....

So when will we get there? How will we get there? My gut says there are 25 different signalling systems and perhaps four different common pathways....these will corroborate with the 4 humours........ Welcome back Galen and great to see you again Hippocrates.

The Sherpa Says: Stick around for 2010 it's gonna be huge! I am a firm believer in systems biology. I feel that be understanding cellular signalling pathways, we will see the link between previously unrelated disease. For an example if this take a look at this NYT article.

Genomics as a Lifestyle

As I watch things such as the wonderful Personalized Genome Project, The Personal Genome Education Project, 23andMe and all sorts of venture capital lining up to hit the "cash cow" known as the genetic lifestyle. Hsien over at Eye On DNA has been posting on this for quite some time. This one takes the cake.

This is much more than Personalized Medicine. It is the economic equivalent of the "Organic" movement on bovine growth hormones :)

Why? I would like to name 3 reasons

1. Organic healthcare sells to a group who go outside the "mainstream".....But genetics IS soon to become mainstream, unlike Organic/alternative healthcare, which took almost 50 years to gain acceptance

2. Organic Foods can now be shifted into Molecular foods. This allows them to position as Nutrigenomic Foods. Not to mention the fact that the manufacturing infrastructure required to make nutraceuticals is already in place.....clearly bioactive compounds will allow your genetic predisposition to be tweaked.

3. Personalized nutrition, workouts, etc..., just for you, Google already knows and is starting to cash in on the next wave.....Personalized everything.

My only concern about this living style is that we start discriminating because of predisposition....

But clearly we are headed to an age of genetics as lifestyle.....even before the literature will bear it out.

The Sherpa Says: I can only hope that this can enhance our lives and not just lighten our wallets. P.S. Dr Mishkin has sent me Salugen's data......stay tuned

LRP8 and Familial MI....Ho Hum

This month in the American Journal of Human Genetics we have some interesting publications. Including an association study identifying a gene known as LRP8. So what is LRP8? It is a receptor for bad cholesterol. When bad cholesterol binds this receptor, platelets (the bricks in your blood that build a clot) become sticky making it easier to thrombose (form a clot).





I am interested in this study for several reasons. First, it has been shown that platelets get stick even after ingesting a Big Mac. That's correct. Just one fast food hamburger can theoretically precipitate a heart attack. So naturally we would love to know who. Think Personalized Diet/Nutrigenomics. I wonder if Salugen can hear me now? I still haven't received their "Scientific Data" yet. I will publicize it if they do.





Back to the study. So what was studied is a group called the GeneQuest families of familial MI, the control group was some white men who were given cardiac catheterization and found to have no atherosclerosis burden (OOPS). Well, that control does not mean they did not have atherosclerotic burden, because catheterization cannot identify 30% occluded vessel plaques.





In addition their findings were replicated on an Italian cohort of familial heart attack as well. So why do I say Ho Hum?





Let's see: No Odds Ratio was greater than 1.43 This 43% increase in heart attack and coronary artery disease is still less than the family history risk itself. The only good thing was that this risk persisted even when controlling for plasma total cholesterol levels, triglyceride levels, hypertension, and diabetes, in addition to age and sex.





What is your odds ratio for heart attack if your father had one prior to 65?


The Answer: 5.8 according to Maren Scheuner's article on familial risk for MI.





Do you now see why I say HO HUM about this gene? When will we see the gene card panel for MI??????

The Sherpa Says: Listen to all of this hulabaloo about Ventner's Genome. Even Men's Health magazine says you should bank your parents DNA if they die. What good is all of this if we don't have a key to the map? The map will make no sense! LRP8, APOE4, I could go on and on. What good is a genome map, without a guide? What good is the guide without the studies? Why did you buy the iPOD early, only to have late adopters get it cheaper? For the rebate? Doubtful. This is why primary care physicians are late adopters. If you want to get your genome (and I do) then you better be prepared to find someone who will help you understand it...becasue cliff notes, or Navigenics just won't do. Nor will scarfing down Big Macs....

1000 Genomes???? Coming Soon.

I have been looking at the genome of Craig Ventner. What Surprises me is that we haven't do this sooner. If you haven't heard the diploid genotype of Craig Ventner is up. And several of my buddy bloggers have posted on it. Blaine posted on it here and has a nice wrap up.

From The Canadian site The Globe and Mail

Most experts predict that routinely reading individual genomes will become a reality within five years as the technology to unravel the six billion chemical units that make up DNA gets faster and cheaper.

Kathy Siminovitch, director of genomic medicine at Toronto's Mount Sinai Hospital and the Samuel Lunenfeld Research Institute, noted that the first Human Genome Project rang in at roughly $1-billion (U.S). But with the new generation of "ultra-fast" DNA sequencing machines that have hit the market within the past two years, she said the bill is expected to drop to less than $100,000 by year's end.

The Sherpa Says: Coming soon 1000 USD genomes. Now who will read and interpret them? Even crazier....where is the evidence base behind treatment guidelines adjusted to your genome??? I can here the uneducated physicians now.But don't be scared my brethren internists. Stick with the Sherpa. We will find our way.

Pilot study...Buy Stock in Kimball Genetics now!

On Friday I was picking on what I term haters of Personalized Medicine. You know those people who just shoot down the idea because of several reasons

1. Negative articles get print (contrarians always get published)


2. The doubters often have no genetic training (or combined with internal medicine) and are afraid of what they may have to do if Personalized Medicine succeeds (Which it will)


3. Their idea of Personalized Medicine is the snazzy websites of certain whole genome analysis, DTC testing or nutrigenomic fly by the night companies. Which are BTW putting a horrible stain on the name of Personalized Medicine. Francis Collins recently said "over promising can often kill a movement" so stop it. Or at least don't over promise. Please, I beg you.

Recently an article was published in the Journal of Family Practice. I won't link to it because, frankly it is a review which is skeptical, pragmatic, and clearly was written by someone who doesn't travel in the personalized medicine circles.

Why? The authors said that there is no clinical utility literature regarding the newest FDA recommendations for coumadin metabolism genotyping. Well......they were wrong. Perhaps they haven't heard of Harvard's CROWN study or this recently published article in the journal Blood.

I would like to analyze the article and first state that validation is the corner stone of any algorithm study. Well.......that too is coming soon. So before we have wise guy commenters on this study, please know that there is always a validation study in the hopper by the time an algorithm gets published.

So this study was performed on orthopaedic patients having knee replacements or revision surgery (I can hear the Cardiologists already.....well, that's not atrial fibrillation) Hold your horses, that study is coming.

The mean age for a patient was 58 years, with a range of 21 to 83 years and median of 59 years. Pretty close to the average warfarin user.

So what are the limitations let's let the authors speak.....

"this study has other limitations. First, our study population consisted entirely of patients initiating warfarin for deep vein thrombosis prophylaxis following total hip or knee arthroplasty. The ability to generalize our model for other indications is unknown and should be studied in a broad population. In particular, the appropriate starting doses and the ability to safely initiate warfarin without genetic information need to be examined in other patient groups—including nonsurgical populations"

The Sherpa Says: Well, this will be the first of many studies analyzing algorithms. Do I think it will be worthwhile? Absolutely. The end point was the therapeutic warfarin dose. They defined therapeutic dose as a dose that gave an INR (blood test indicating thinness of blood) in the target therapeutic range after 7 consecutive days. They managed to establish an algorithm which matched needed dose to approximately 80%. Which is more than I can say for the average Internist who may not even know the average dose based on ethnicity. So I await the validation but refuse to say there is no clinical utility literature. So to both extremes I say "Stop hating on personalized medicine and please stop over promising. If you both can tone it down, then we can get somewhere....safely" Oh and BTW for you VCs/Investors/Hedge Funders out there, Kimball Genetics has an FDA approved genotype test for warfarin metabolism........