Like I said........

If you have been following me at this blog for any amount of time, you know that I have been a careful watcher of these GWAS studies, and the testing companies who sprung up after them.


I have been skeptical of most of these studies unless they have had replication and fairly large Odds Ratios or Relative Risks........why? We are looking for clinical relevance and asking what can we do with this to better our patients lives........

Personalized medicine relies on several things but these 3 are absolutely needed: Prediction, Prevention and Privacy. It is rich in fields like Cancer Genetics, PGx, Preconception Genetics.

You see Personalized medicine is not just Prediction, which these DTC companies are touting, it is therapies and action......which, these tests unfortunately are lacking in.....


Unlike Pharmacogenomics....

To put it bluntly.....based on our current knowledge of what these SNPs are and what they do,

Consumer Genomic Testing is of:

Extremely Limited Clinical Value


We saw this with 9p21.3 one of the most significant findings in this arena.


Yesterday an article was released in PLOS which I just linked to which states that case pretty effectively.

I often say, that once a discovery is made of a gene or SNP or etc.....it will require at minimum 5 years to come to clinical utility.....So how could any company sell something prior to this under the auspices of medicine???


The conclusion from the PLOS paper:


Our analyses and examples show that strong association, although very valuable for establishing etiological hypotheses, does not guarantee effective discrimination between cases and controls. The scientific community should be cautious to avoid overstating the value of association findings in terms of personalized medicine before their time.


Association is NOT causation, nor is it actionable.......


Most of this small time SNP data comes through in guess what????


Family History!!!!! (five exclamation points for Daniel)


The Sherpa Says: Family History is FREE!!!! And Soon SNP testing will be too.

The New BRCA....this time its the Colon!!!

This is a fantastic review. I have been very careful trying to avoid hyping tests. I do this because we need validation and some evidence for use would be nice. The problem is that sometimes a test is so powerful that it should not be sat on.

This was the case with the BRCA genes. Even in 1996 Francis Collins was warning about testing without really thinking out the consequences. From his 1996 article in the New England Journal of Medicine.

The benefits of presymptomatic testing to determine susceptibility to common cancers such as those of the breast, ovary, colon, and prostate are potentially substantial. Nonetheless, it is critical that we create safeguards to ensure that the benefits of testing exceed the risks. The technical ability to perform tests for mutations should not be confused with a mandate to offer them. In the long run, the identification of BRCA1 and other cancer-susceptibility genes should permit the development of new and more effective therapies, so that physicians can not only predict future risks, but also reduce those risks reliably and safely before disease occurs.

I say this because we now have evidence of what I would term a genetic risk factor akin to BRCA1.

Recently published and talked about on Think Gene.....

Germline Allele-specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer.

Why do I say this is the next BRCA and may be even bigger?

New cases of colorectal cancer in the US in 2007: 148, 810
Deaths: 49, 960

How does this line up with Breast Cancer? New cases 182,000. Deaths 41,000

Pretty similar. What percentage of Breast Cancer is "hereditary" approximately 7-10 percent.

BRCA, we think accounts for a significant amount of this.

Colon Cancer? Way more....maybe up to 40% are familial.....but due to a specific gene? Far less 5%...until now.

You see, having a family member with colorectal cancer puts your risk up 400% from the general population. Even having polyps in the family increases your risk.

With that in mind, this study:

Germline Allele-specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer.

Was just published in Science. What is bad about print journals???? This was submitted in April....they (the researchers) have been sitting on this.....and likely creating a clinical test.

What did they find?

Conservative estimates suggest that ASE confers a substantially increased risk of CRC (odds ratio 8.7; 95% confidence interval: 2.6 to 29.1), but these estimates require confirmation and likely will show ethnic differences.

This was a surprise for some, but we had seen hints of this in JAMA. It turns out they estimate 20% maybe up to 30% of familial colorectal cancers have issues with reduced expression of the TGFB receptor subtype 1. This is due to a specific mutations which can be tested for in research and may soon be clinically available at Helix Health of Connecticut and other genetic providers. 30% of 30% of 148,000 per year!!!!! That is 15,000 people who will potentially positive.......that's just the afflicted members not even their family members in the US! This is a much larger number than breast cancer.

I was speaking with a Venture Capital firm this week when a really smart VC partner asked me......how can you project testing to reach this level in 3 years when the current data show a much smaller number? I answered him with this. We are finding new genetic risks that affect a much larger population. This is disruptive technology that could reach not only the small amount of rare diseases that exist today. We are talking testing that would benefit the over 300 million persons in the US. Now that is rapid growth! Tests like this are those harbingers..

So with that being said, some caveats:

1. This is only in caucasians....replication is needed for other ethnicities
2. Clinical testing is not YET available

3. No screening protocols have been clinically defined yet. BRCA took 10 years to have most of the kinks worked out. I am certain the public won't tolerate that long for this test. But it may need a few years of study....

The Sherpa Says:

An odds ratio of 8.7 for developing colorectal cancer in carriers of these alleles is a huge risk akin to the BRCAs. Even more impressive is that this could affect WAY more patients than the BRCAs. So I say, let's start studying this clinically and launch the test as soon as we have a good screening strategy!!!

OK for Journals but Cut From the LA Times

It is important for all of us to contribute to the literature and assure the success of new and upcoming journals. I want to point you in the direction of 2 of these journals published by Future Medicine in London.

I mention this because I just finished my manuscript for The Journal entitled Personalized Medicine. This is an excellent journal with a tremendous potential. I recently published here and intend to send a significant amount of my work its way. But what is most important about these journals, Pharmacogenomics and Personalized Medicine, is that they are giving an opportunity for younger scientists, physicians and stake holders a voice.

This is important especially because as we interview with reporters, there is no guarantees that it will end up in their article. BTW Anna, I loved the article. Anna Gosline wrote an LA Times article which she spoke with me about. Well, I guess Muin is a bigger name than me ;)

Everyone should read this article....It is excellent. And Anna, if you need some medical advice feel free to call us and you can be one of our cadre of Navigenics patients.

I have recently begun to realize the potential of pairing patient centered care with genomic medicine. By putting these two ideas together....we may have a winner. I think that these two parallel ideals may actually be synergistic. Put plainly, moving the care in a patient centered way that DOES NOT REMOVE the healthcare practitioner, but places them as the coach, enables patients to make better choices by understanding their genomic risk. First by taking a family history and secondly by using appropriate genetic testing. Just like Muin said.

Ok, now the gossip fix. Did anyone read the Sunday Times? Well Navigenics was in it. Slapping 23andMe in the face. From the article

The company has been authorized to sell the service to residents of every state except New York (Told you so), Ms. DuRoss said. New York residents must join a waiting list until state health officials license the company’s designated lab to provide services to New Yorkers.

Even if that regulatory hurdle had been cleared, Ms. DuRoss said she doubted that the company would have invited customers to provide saliva samples on the spot. “It’s a little awkward to ask people to spit in public,” Ms. DuRoss said. “It’s a very private thing.”

Woah!!! We (Navigenics) are classy and tactful, You (23andME) are classless. That's what it sounds like to me ;)

The Sherpa Says:
When my next article is published I will let you know. I hope it serves as a good compass. Speaking of compass, take a looksie at Daniel's post at Genetic Future....he seems to think these big corporate genomic companies will be fighting each other for quite some time....He may be right. Maybe they could read my article? Then they would realize what they needed to do. Differentiating themselves is definitely a start.

A New Hope

I just got out of a meeting with a Very Nice Angel Investor. He had some really interesting ideas that I am dying to tell you about....but I just can't.....for now.

But what I can do is now tell you about how sad I am that I missed "Navigenics 2008 Opening Day" I don't know who was pitching...but from what I heard it was a success. Speaking of success, I just had another patient come to me with the magic 84 page printout. It will be interesting to see how the Mayo study comes out regarding all of these lab reports and patient comprehension. A few days ago a patient was seen by us for Pharmacogenomic analysis and he was puzzled by the laboratory reports and data. He actually thought that the boiler plate information on the bottom of the report was actually personalized. He asked "If I only have 2 copies of this, then why does it have 9 different types on my report?" I kindly reported that it was the boilerplate explaining all of the poor metabolizing alleles. Of which this patient had 2. Yes reading lab reports can even be tricky for physicians. Think it has changed since the 90s? Dream on!

It is no surprise that genetic counselors are on staff at Navigenics. It is the right thing to do....but how many genetic counselors know what CYP 450 is? Oh I mean what CYP 450 are. How in the world can we reconcile this? Even better question....how may physicians know what CYP 450 are? But there is a new hope. An institution being set up by myself and others. We are currently looking for donors and we endeavor to set up educational events and group sessions. We will work with Corporate Genomics, Academic Genetics, Corporate Labs, Academic Medicine to develop training workshops. Interested???? Email me.

This type of education is the future. We need to walk patients and physicians through reports, through taking family histories, through medications....together. Preferably face to face or television to television. It is my belief that we cannot do this through a scalable 84 page report....or a Flash'd/XML'd out site. No amount of money will replace the human element. So we need to train more Sherpas....and I am looking for funding to do it.

The Sherpa Says:

I am headed to SoHo tonight. Maybe they will have a million or two lying around???? After all, this is a new industry ;)

T minus 21 hours

Till Navigenics Launch.......
Stay Tuned!
-Steve
p.s. Congrats to Amy over at....oh wait...she hasn't started a blog yet ;) But in all seriousness, congratulations. Thanks to Jonathan at Tree of Life for leaking this......

500 Hospitals want to know....

Lots of stuff happening online today. I just left a conference call where I was the invited guest panelist along with Robert Resta CGC. The Advisory Board Company and The Innovations Center presented an Issue Brief entitled-The Genetic Testing Frontier: Impact on Clinical Care, Market Opportunities. Hundreds of hospitals were online wondering how they too can get a piece of the action.....

Also....did anyone read the Washington Post today? Genetic Testing Gets Personal again another article on this "revolution" non subscription link here

"We call it consumer-enabled research," said Linda Avey, co-founder of 23andMe, based in Mountain View, Calif. "It's about changing the paradigm of how research is done."

Well Said.......You could also call it uninformed cohort analysis...."Free Kits?" Come-On....nothing is free. Davos, you sold your DNA for some fancy flash animation and trinkets....I am guessing the Belmont Report is not required reading in MBA schools...Hey guys don't worry, here are the Cliff Notes

The Belmont Report explains the unifying ethical principles that form the basis for the National Commission’s topic-specific reports and the regulations that incorporate its recommendations.

The three fundamental ethical principles for using any human subjects for research are:

(1) respect for persons: protecting the autonomy of all people and treating them with courtesy and respect and allowing for informed consent;

(2) beneficence: maximizing benefits for the research project while minimizing risks to the research subjects; and

(3) justice: ensuring reasonable, non-exploitative, and well-considered procedures are administered fairly (the fair distribution of costs and benefits.)

These principles remain the basis for the HHS human subject protection regulations.

Paradigm of how research is done???? Isn't that why we developed IRBs? To protect from those who want to change the paradigm and injure the patients? IMHO these companies need to immediately develop research protocols and IRBs. End of story....nothing less. The consumer should be allowed to at least ask questions to another person.

It can be entertaining, Venter said, to learn one has a gene for soggy earwax. "But if you're on the receiving end of one of these tests and are told your probability of having a serious problem is 62 percent, what the hell does that mean?"

And that is assuming the results are correct. As it turns out, many gene tests today search for DNA patterns that have been linked to a disease or trait in only one or two studies. Such findings are often overturned by later research.

Enter the trained professional.....This is precisely why we need more Sherpas!!!

Dr Venter is completely correct....the brick and mortar where professionals exist is the transition point. Even 500 hospitals online today acknowledged that. Now where do we get these individuals?

Exacerbating the problem is that virtually no one is watching over the industry. The Food and Drug Administration does not regulate most gene-based tests, and there is no federal proficiency-testing system for companies offering them.

Enter the SACGHS and EGAPP...2 organizations devoted to helping best practices....In addition, the ICOB at the Delaware Valley Personalize Medicine Project will also help shape this future.

"It creates an air of charlatanism that doesn't help the field," Venter said.
All told, concluded a study in this month's issue of the American Journal of Human Genetics, "There is insufficient scientific evidence to conclude that genomic profiles are useful in measuring genetic risk for common diseases or in developing personalized diet and lifestyle recommendations for disease prevention."

That is my number one concern. Here's why...geneticists and genetic counselors require referrals from physicians who don't speak genetics, but watch the national news and read the New York Times...If they link Medical Geneticists with Scientific Match.....There Ain't no way in hell any self-respecting, butt-covering, good physician will refer patients to such "Qwacks" simply due because of the confusion. All press is good press? Don't think so...especially when the NEJM posts such a confusing article failing to clarify the difference.

"I very much worry that all this emphasis on a 'gene for this' and 'gene for that' raises the risk that people will conclude that that's the whole story," Collins said. Instead of empowering people to make healthful changes in their lives, that could simply make them "more fatalistic," he said, "in which case, what's the point?"

Me too Francis...Me Too....

The Sherpa Says:

To climb the mountain we need unreasonable people that won't quit....Corporate and Academic can exist together...provided they do the right thing. Do it yourself surgery is probably just as "Revolutionary" so why isn't anyone on that money train? BTW the pic is of do it yourself LASIK.....I bet that is a best seller.

A thought....

What if we had a 1000 USD genome by next year? Where would we be? What would we have? What problems would that create? Who would benefit? Who would lose?

I have been thinking alot about this lately. Mainly because I had known for a while that the Applied Biosystems' Product was coming in under 60k. Trust me....under 60k USD. My friend and ex-President of TV Guide had sent me something this week and I wondered how quick this would move up the charts and into the press.

So I ask my readers..."Where would we be in 1 year from this date if we had the capability to sequence a whole genome for 1000 USD? No not the SNP scans being paraded on the Today show...A whole genome, CNVs and all. What problems would that create? Who would lose? Who would benefit?

I have some ideas and will post them in the coming weeks....Starting with "Where would we be?"

The Sherpa Says:

Let me know what you think....

I am so getting sued by ABC!!! Or NBC take your pick!

60 is the trigger for Alzheimers

Finally, a weekday post! I know, I have gotten in this vicious cycle of posting on the weekends and keeping them up for the first few days of the week, just so those readers who don't check the rss or even switch on a CPU on the weekends don't miss a beat. Listen, I read Tim Ferriss' book too...but I now have to step it up.....

Today I want to bring an interesting topic to light. Why are people scared of genetic testing? Is it the discrimination (which doesn't exist) or is it something more deeply rooted like "Genetic Determinism"? In counseling for things like breast cancer risk, some often say..."You may have outlived your risk for early onset breast cancer" This is a sticking point for me.....Who ever outlives genetic risk? Completely, I mean. There are so many variables out there that can give you cancer...who is to say that just because you are 65 your BRCA mutation won't give you that cancer? I couldn't be hard pressed to say that so vociferously. I say this because even with the strongest genetic influences there is always an exception. This is exactly the case with Alzheimers and ApoE4.

Well now a study recently released called the Arizona ApoE4 Cohort Longitudinal Study of Cognitively Normal Individuals (Say that 3 times fast) indicates that 60 may be the age of kickoff for cognitive decline in ApoE4 carriers.

According to the article in Internal Medicine News......
There is a particular pattern of decline in ApoE4 homozygotes (2 copies) that tend to precede any diagnosis of mild cognitive impairment (a stage prior to full blown alzheimers or other dementia). Or prior to anything that can be seen on radiologic brain imaging....

So what does this mean for the clinician? It is huge....Instead of outliving your risk...we now may identify those with ApoE4 who will likely get Alzheimers......CAUTION, these results are currently being replicated and I wouldn't want to promise anyone that we have a perfect ApoE4 phenotype detector quite yet. But it is important to have this....Why? Because up to 10-40% of homozygotes will NEVER develop Alzheimers. So when can we say you have "Outlived your risk"? The answer is never...but we can say "You will be less likely to have ApoE4 related Alzheimers than someone who is your same age with this cognitive deficit." That is what should be said.

Now the real quandary..."How can we stop it from getting worse doc?" That is for another post.

The Sherpa Says:
Too many in the genetics field are quick to give medical advice. I warn that perhaps we should check our training and liability insurance before we start doing this. I recommend that all of us in this field work together to provide the best care possible. I never say never and never say always....in genetics as in life, there are NEVER any definitive answers...except "sometimes" and "it depends" That being said..........We should always be performing routine screening exams on carriers of any genetic changes. Confused yet? Don't be. Just follow my lead.

Navigenics? Who was that?

So after the New England Journal of Medicine has given Personal Genome Sequencing the thumbs down, I ask you...."What will happen to these personal genome companies?"

I have several ideas....

1. They all morph into non-health related information tools. Every bell and whistle that can be marketed that will not face the scrutiny of physicians will come out of the wood works.

2. They will begin to say "The medical field has no sense of what the promise of genomic medicine is" They will attack physicians' lack of genomic knowledge. This is the tactic which nutraceutical companies use. The 'Ol "We have a secret....most physicians don't know or won't share......because they want you to have disease"

3. They will disappear, like the dinosaurs. A neat phenomenon that gave us something to write about for 4 months. Somehow I don't think Google will let that happen. But hey, ya never know.

4. They all will say "Not to be Used to Diagnose or Treat Disease" EVEN NAVIGENICS!!!

5. A new tool that uses evidence based SNP testing to identify risk will come out of the woodwork and crush them all.

6. They will create dating services around their genome scans. "Find out your perfect mate" "Discover the person who you will have super children with"

7. They will contract the Sherpa, buy Helix Health of Connecticut and it's model. Enabling the spread of directed genetic testing and personalized medicine.

8. DNA Direct and direct to consumer targeted testing will begin to partner with traditional models of genetic and genomic healthcare. They will create a more useful alternative to Genome Scanning, leaving Kleiner & Perkins smoldering for not consulting us first.

9. They will keep on, keeping on. Hoping that the limited scans which they now offer will appeal to those persons who bought a space flight, those who bought the cereal box sized mobile phone, or even those who bought Betamax

The Sherpa Says:

We must remember that Genomic and Genetic Health has nothing to do with these companies and everything to do with Personalized Medicine. My concern is that physicians will now be given a free ticket to blow of genetics and genomic healthcare. It is easy for the ignorant to not know what they are missing.

As the NEJM article says "For the patient who appears with a genome map and printouts of risk estimates in hand, a general statement about the poor sensitivity and positive predictive value of such results is appropriate, but a detailed consumer report may be beyond most physicians' skill sets." Detailed patient reports are in the skill sets of my physicians.

deCODEme results, Thanks Med-Source!

The Sherpa Says: Thanks to Megan for publishing this to the web. I am certainly interested in the medical aspects of these companies. Being pragmatic is different than being skeptical. I am both. Thanks to my other pragmatic skeptic Dr. Colby for pointing this video out for me.

Genomics Into the New Year

What will the New Years bring genomics. Well, I have had my ear to the ground and have some ideas.

First the obvious
1. GINA will be passed by hitching a ride on another bill. How sad is that?
2. Navigenics will enter the fray and telemedicine will have a whole new face. What that face will look like is yet to be completely determined.
3. One of these companies will get sued

Next the less obvious
1. Academia will start to market personalized medicine
2. Helix Health of Connecticut will not be the only face to face private (non-Academic center) personalized medicine service...and they will be welcome friends. There are so many out there who need this.
3. Oprah will have her Genome sequenced ( I swear it will happen)...Obama too

Finally the inconceivable
1. Jim Watson will pass from this earth
2. A little unnamed startup will win the X-Prize
3. Mark Cuban will buy the rights to all of 23 and Me's genome database

The Sherpa Says:
To know the future we must look at the past. And if we fail to learn the mistakes from our past, we can always blame our genes. Or at least have the journalists tell us we can.

Education Initiatives

I have been sick with a nasty virus this week. Vomiting has been the order of the day....yuck :(

Because of this, I will keep this post extremely short but useful. The SACGHS meeting was held last month and I think it was huge. There are a lot of good webcasts that are a must watch.

The rate limiting step of personalized medicine is physician uptake, and the rate limiting step in uptake is education. The SACGHS meeting on the 20th of November was huge reviewing efforts and ideas for education

Overview of Session
Barbara Burns McGrath, R.N., Ph.D. Research Associate Professor at the University of Washington School of Nursing. She reviews nicely the outline for the day and gives us a guideline.

Please check out the lecture given by the National Coalition for Health Professional Education in Genetics Executive Director. He describes a database similar to the one we are working on.

In addition, we need to utilize physician extenders. The advantage of having nurses in genetics is the fact that they have had some education in medication dosages and medical conditions. The same applies for physician assistants in genetics. But they will never replace the counseling abilities of professionals who have trained for 2 years in the field of genetic counseling.

Elizabeth Pestka, M.S. Assistant Professor of Nursing at the Mayo Clinic College of Medicine describes the 80 or so nursing organizations. It turns out 40 of those, 50% agreed to help include genetics into the nursing competencies. In 2006 there was a meeting to implement these competencies into practice.....This is where I sat back in awe. It is 2006 and they are just getting around to integrating these competencies? We are screwed for the next 4-5 years! But it turns out according to Nurse Pestka that these proceedings often take up to 17 years to become integrated!!!

I have worked with a nurse geneticist at Yale and I have to tell you how wonderful it is to share call with a nurse practitioner who is trained in genetics as well. I think we can really leverage our efforts with these talented individuals....I hope it doesn't take 17 years!

The Sherpa Says:
Now if we can only train genetics counselors in medicine!!!