2009, Kansas is going Bye Bye!

Ok, So last year I closed with a joke from Francis Collins, who by the way, I predict to be the next head of the NIH....

The Joke?

"There is this woman who is married to a research geneticist......... He keeps telling her how great their sex life WILL be."

That certainly was the hype from 2008. As we finally begin to wash ourselves off from the greatest hype and over-selling ever committed in Genomics, we may be a little skeptical...Even the FDA has now jumped on the regulation bandwagon. That's ok. But please don't dismiss Personalized Medicine as dead. Trust me, We've only just begun....

To prove this works.....

First, I am proud to announce that Helix Health of Connecticut is the newest member of the Personalized Medicine Coalition. In addition, I will be serving on their Clinical Science Committee. I am excited for the meeting on Feb. 12th!

Second, I look forward to developments from Coriell. I am told that their "disruptive move" by offering patients a Genome SNP scan at no cost, shook up 23andMe, encouraged Navigenics to partner with Scripps on a "similar" study and Caused Kari to Scream with fits of four letter expletives at a recent NIH/CDC conference.....

Why at no cost as opposed to the study funded by Navigenics and Scripps, which charges participants? They feel (and rightly so) that no one should ever have to pay for research which is being implemented through them. Yes, true they are non-profit. But have you ever seen BMS, Pfizer or Novartis charge patients for drug research????? It just doesn't make sense.

Coriell is at its heart a Medical Research Institute. My hope is that Helix Health of Connecticut will learn to be the same. A patient-centered genomic healthcare instutute.

We are also looking forward to several other announcements likely to come out in the month of January.

As for the rest of the field, things are progressing nicely. Some of the barriers we have discovered are finally being ascended. See, Cue4, Generation Health and another company I had done some work with.....

But, without further ado.......

Finally, what you all have been eagerly anticipating.

The Sherpa's Predictions for 2009.

Mind you they come in 3 groups. Highly likely, Possible and Ridiculous

Highly Likely:

1. Francis Collins will become the director of the NIH and collaborate with Kari from Iceland to create a national database of genomes. This is the only way to jumpstart personalized medicine. My feeling is that Kari knows how to do this, is a friend of Francis, and Obama is likely to give him the greenlight on this, despite public sentiment....

2. We will see our first lawsuit for a pharmacogenomic cause. My colleague over at ASU, Gary Marchant says it will only take one and the flood gates will open. The lawsuit will be based on something called "Loss of Chance" doctrine. The theory goes, "did you cause the patient to lose a chance at a better health outcome?" If the answer is yes, well then you can be sued. This recently has been the case for delayed diagnoses in several states (24 to be precise). All it takes is one smart, enterprising, hungry attorney to go after this....I can see it now.

Plantiff's attorney(PA) "Doctor, who is the FDA?"

Doctor(MD): "The US Food and Drug Administration"

PA "and what do they do?"

MD: "FDA provides safety information on drugs and other FDA-regulated products, and allows for adverse event reporting."

PA: "Would you use a drug that was not approved by the FDA?"

MD: "No"

PA: "Doctor, would you mind reading this label?"

MD: "…genetic variations in the CYP2C9 and VKORC1 enzymes may influence the response of the patient to warfarin.” In the “Dosage and Administration” section, it states that lower initial doses should be considered for patients with genetic variations in CYP2C9 and VKORC1."

PA: "Doctor, what is the genotype of the defendant Mr. X?"

MD: Silence....

PA: "Doctor?"

MD: "I do not know"

PA: "Doctor, why do you not know everything you need to know about a patient PRIOR to giving this deadly rat poison"

MD: Silence

PA: "Doctor, is there evidence showing that patients with poor metabolism would need a lower dose than the one you prescribed Mr. X?"

MD: "Yes, but......"

PA: "But what doctor? Why would the FDA put something on the label if there wasn't solid evidence behind it?"

PA: "furthermore, if you knew your patient had a liver problem with metabolizing the medication, would you give the dose you gave to Mr. X?"

MD: "Well, hepatic dysfunction is (cut off by attorney)

PA: "CYP2C9 genetic mutations ARE hepatic dysfunction doctor"

I think you get where I am headed. In economic lean times, people will try anything....and this sure is like the Statue of Liberty play. It WILL score a touchdown, that's why people still run it.

3. We will see George Church's Exome project results and they will certainly confuse all of us as to what it really means. We may even see a broken ladder?

Possible:

1. We will have an X-Prize winner. If PacBio and the black box known as Complete Genomics work out, this will be ready by November 2009. Seriously.....now, to sort out what the hell it means......We need a database, someone to actually take liability (Unlike the chickeSh!^ companies today), and someone to counsel on this.....do you really think 2700 people is enough???? That is only a cool 111,533 people per provider......at 2 hours per evaluation that is only 223,066 hours of work, only 9294 days of straight work, or 25 years straight!.....give me a freakin break NSGC/ABMG/ABGC/ACMG!

2. Mr. Stoicescu sues KNOME for a 345,000 USD refund. It could happen, the oligarchs lost a ton of money last year. I am sure he could use the money back in exchange for Complete Genomics Genome evaluation.

3. Oprah will have a third hoax on her hands as she discovers her genome scan was bogus. 3 strikes and your out Oprah!

Ridiculous:

1: Mark Cuban will buy the rights to 23andMe's database. If I have at least one thing, it is tenacity.....this one will happen

2: A new technology called next-next-next-next gen sequencing will debut and have your genome done in 15 minutes. They will say the technology will be ready for prime time in 2 years.

3. The United States will fracture into 6 territories controlled by Russia, Mexico, China, Canada....I think I played this game in the 1980s.

The Sherpa Says: Happy New Year! May the new year be as good for you as it already has been for me. Here's to personalized medicine in 2009!!!!!

Prediction from a Reader.

Ok, another sleepy day up in New Haven.......

But not with me. I received some comments from my last post which were interesting and I want to share one with all of you....

This year we will see some new genetic tests being developed and improved. We will also see 23andMe start to follow the business plan of DNA Direct.

This is a pretty insightful comment. Will we see 23andMe go for the DNADirect business? If the data behind genome scans is currently weak, how can 23andMe monetize their model? Yes, we all know about the database thing....Isn't that what landed Celera in a heap of pain?

Seriously, will 23andMe begin offering single gene tests? I am always confused by this one. DNADirect states that they do not mark up their tests, but how do they make money? I am curious about this one too. But if you look, their BRCA testing it costs 3465 USD which includes pre and post test counseling. The Cost of the Test through Myriad is 3120 USD, which is a difference of 345 USD. But the test through DNA Direct includes pre- and post- test counseling.

So 345 for counseling? I think that is an incredibly cheap amount. In fact it pushes the limits of the true value, which I think is around 1000 USD.

How do they do it? Through, telegenetics. And, if you look closely, if all you want is counselling, they only charge you 150 USD...likely per consultation, thus making 45 USD, which doubtfully can cover overhead. So I ask again, would 23andME like this model? I say yes, because if you use a genetic counselor rather than a physician you can pay them about 50-70,000 USD.

So, if we do the math 1200 consults need to be provided per year to cover the CGC salary. What if that is a physician at 150,000 USD? I think you get the picture.

So what do you get from a physician that you don't from a CGC? I think I have been over that one a few times now. Thus the higher salary. But for a business, do they care about that difference? More importantly, would 23andMe care?

Doubtful......

So I tend to agree with my reader. If 23andMe can sell medically relevant tests to consumers skipping the doctor and using the counselor instead, then this is an attractive business to them. But if you throw in physicians, then you may have a problem. So heads up Ryan, looks like you may have a healthy competition....

Now, here's the big question. Who is ordering the test? In CA like many other states a physician has to be responsible for ordering these tests, just like the Viagra Scheme.....

So, will we see more of this "creative" entrepreneurism which will likely disintegrate the trust between providers and patients? A most resounding yes. At the same time, should patients trust providers who often miss these diagnoses or fail to test?

How do we solve this? My gut tells me the responsible way to do this is out there. It doesn't include cutting corners for patient empowerment. What it does include is education for physicians and healthcare practitioners on a scale so massive that it only can be done over the television, radio and internet. It will take millions and millions of dollars.......Didn't Navigenics get 25 million? That should cover the first few years of what I propose we do.......

The Sherpa Says: I am still waiting for a press release to be drafted before I announce my news. Don't switch that dial......genomicTV will be right back!

Sherpa's Batting Average for 2008.

I make some pretty outlandish predictions on this blog, including Francis Collins will become director of the NIH.....I am not afraid to be wrong. If I see a trend or a problem, I call it. What has gotten people's attention is that I tend to be right more often than I am wrong....at least for now.....

I start out every year with some of these predictions, so I figure, why not look at the one's I made last year in 2008

As I looked into my magic 8-ball/Complete Genomics Scanner. Which came true? Here are the predictions:

1. Jim Watson will die.
Well, only a few base pairs off on this one. The legend Victor McKusick did pass, God rest his soul.....Damn that 10x coverage.

2. Mark Cuban would buy the rights to 23andMe's genome database.....I knew he would do something dastardly.....only it was not genome stealing.....it was insider trading..

3. The X-Prize would be won by a little known start up........At that time I thought Pac Bio would be ready to launch.....Guess I was wrong....

4. Oprah will have her genome sequenced.....Pretty pleased to say I was spot on.

5. Obama too........maybe not until 2009 when he comes to visit Helix Health of Connecticut....

6. Academia will start to market personalized medicine..........Duke, Harvard, Mayo, Scripps, Mount Sinai, UCSF, Stamford, Wisconsin, Ohio State all joined the ranks. I wonder why Yale is not there????

7. GINA will be passed........Thank god this one's in the books!

8. One of the DTC companies will be sued.....Well, you can always count on California to regulate something....NY too..

Welcome to the Big Leagues of Healthcare my VC brethern!

9. Navigenics would launch and use telemedicine. Man was I wrong....instead they tried to pass themselves off as medicine despite stating in their terms of service you cannot use this for healthcare decisions.......Yet MDVIP is....so how does that work??? Oh, you pay 2500 USD....got it.

So, where did I stand.....

Absolutely Correct:
4 of 9, if you count legal proceedings from a state as getting sued......

Close to correct:

1 of 8, McKusick dying is pretty damn close to Watson.....Damn that magic 8 ball....

Dead wrong:

4 of 9, Well........you can't guess them all. But I was right when it mattered most, which is more than I can say for A-Rod!

A near .500 Average will get you paid pretty well in the MLB. And most definintely will get you paid well in the world of Venture Capital.....or Wall Street.

The Sherpa Says: When you spend as much time climbing as I do, you see a lot of climbers come and go.......One thing is for sure, that Mountain never goes anywhere.

We have a lot of climbing left to do in 2009, we haven't even finsihed the approach!

Plavix Failure and Patient Non-Compliance? I don't think so Jeptha.

A colleague of mine Jeptha up here at Yale told me....people fail plavix because they don't take it. He said this in response to a patient we had taken care of who had just received a stent for his heart attack. This situation is actually very common in clinical practice. I told him about 2 years ago now "No, people don't metabolize it into active compounds and may have platelet polymorphisms that lead to its ineffectiveness"

I said this based on preliminary data in 2006 and my clinical identification of several patients with in-stent thrombosis who are not exactly the non-compliant types......

Turns out....I may be right.

Recently I was talking with my wife (who is also an Internist) and I said "What came in the mail?"

She said "Oh, nothing. Just the NEJM, but there wasn't anything good in it"

Just today I was able to read it online. Holy crap!!! Nothing Good. My wife actually said this...But then I realized that the articles were online first!

Well, In the NEJM they studied CYP 2C19 polymorphisms and risk for cardiovascular events. In addition, they brilliantly assessed plasma levels of active metabolite. The study breakdown and then the results

We tested the association between functional genetic variants in CYP genes, plasma
concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel
in 162 healthy subjects. We then examined the association between these genetic
variants and cardiovascular outcomes in a separate cohort of 1477 subjects with
acute coronary syndromes who were treated with clopidogrel in the Trial to Assess
Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–
Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38

Translation: Does having an inability to activate Plavix lead to ineffect and thus increased risk of event?

the Answer? In short, Yes

In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19
reduced-function allele (approximately 30% of the study population) had a relative
reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as
compared with noncarriers (P<0.001). p =" 0.01)">and an increase by
a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P = 0.02).

Well it turns out the Lancet also had an article on this (HT GTO) as well.

The Take Away there?

The same......

So why all the fuss??? Well, getting another event because your plavix isn't working is a huge deal.

Even bigger deal? Do you know that every patient who has a heart attack and stented is put on plavix, most people who have angioplasty ALSO are put on Plavix....and with recent literature showing Plavix better than other medications for secondary stroke prevention....This study answers a huge clinical question. "Who will fail Plavix therapy?"

I think we found the answer. Now the second question....

"What the hell do we do about it?"

Three, Maybe 4 solutions

1. The poor metabolism was related to lower drug levels, so BOOST the dose. The problem: Will we have more bleeding events...Plavix is a "blood thinner"

2. We use another medication. With Prasugrel being approved, will this have as big or any effect there? It too requires biotransformation from ProDrug to active metabolite....and had more bleeding

3. We double the dosing schedule, we increase the amount of time Plavix pills are taken, twice a day instead of once a day, hoping to get more converted....

4. We stop PPIs, we do know that PPIs can interfere with 2C19 metabolism, so maybe we should do better med-med-gene reconciliation

The Sherpa Says: We have a clinically actionable test, with action which may not yet be precisely studied. If we know someone is a poor liver or kidney metabolizer what do we do? We avoid that drug. Is that well studied? No.....So what the hell is stopping us from watching these patients more closely and practicing personalized medicine???? One Answer....Physician Ignorance....

Merry Christmas!!! Happy New Year!! Looking forward to my traditional New Years Day post!

We have no clue what it really means....Merry Christmas

The scene, a roundtable of geneticists reviewing a case.

Geneticist 1: Well, some one (Non geneticist) astutely ordered genetic testing for condition X before we saw them. When we saw them we ordered a Chromosomal Micro Array (CMA) and a karyotype....

Geneticist 2: Well, did you ate least think of condition X?

Geneticist 1: Not really, it was pretty atypical for condition X so we thought we might find something with a CMA.

Geneticist 3: You'll certainly find things with a CMA. Now what the hell you will do with those rare deletions and duplication is another topic.

Geneticist 4 and Training Geneticist 5: "Chuckle, Chuckle"

Geneticist 1: Well, while we were waiting for the CMA, we were notified by the patient's family, they have condition X....

Geneticist 2: Wow, I would have thought it was Condition Y based on your presentation which would have been picked up on CMA.....

Geneticist 1: Well, we did pick up something on CMA...

Geneticist 5: Let me guess, a rare unknown duplication

Geneticist 1: Correct, how did you know???

Training Geneticist 5: 50-50 shot.

Geneticist 2: So now what will you do.

Geneticist 1: Same thing we always do. Test mother and father, if they're "normal" we will say it is a benign event......

Training Geneticist: Too bad we can't say "We have no clue what it really means....Merry Christmas"

Close scene....

Today this is happening at an alarming rate in clinical genetics services in academic centers everywhere.....

Here's the catch.....It will only get worse before it gets better, and it will take a very long time or 10 million people to make it better.

We really have no idea what is in store when we start looking at all these genomes....My guess is that even the smartest geneticist will be rendered a bumbling idiot at least 10 times in the next decade.....

The Sherpa Says: A smart entrepreneur finds solutions to this and many other problems that wil stem from this crazy genomic data......and when Francis becomes NIH director, the US will turn into DeCode/Iceland, it is the only way to figure this stuff out.....too bad the public isn't ready for it.....Franics is no Kari and the US is no Iceland....Merry Christmas!

Copy Number Variation, Epigenetics. Bio 400? No, NatGeo!

I was watching National Geograpghic HD last night. Yes, I do have a few minutes to watch TV. I always love to watch their in the womb specials. This time it was Twins.

What I love is the way they tell the story and teach the science (very lightly). I have to say, I have tried to teach doctors these subjects for a while now and most of what I get are these blank stares.

NatGeo has these wonderful graphic animations and weave a story around the animations with real clinical examples that bring the science to life.

Maybe we need to start having physicians watch NatGeo. We could scrub NCHPEG and anything EMedicine or UpToDate has to offer (which are average tools and topics).

Why? In one brief 60 minutes episode of NatGeo, they covered

1. Twins have epigenetic differences, explained epigenetics including methylation and presented Russell Silver syndrome in an Identical Twin

2. Identical Twins have different Copy Number Variation, yes they even explain what CNV is! BTW I mentioned this in the Autism studies being done up at Yale

3. They presented a MZ twin set where one boy was gay the other straight, v. interesting stuff on testosterone sensitivity.

They then took the fact that these people were identical and showed how based on these other subtle genetic differences they were at different risks for diseases.

This is probably one of the best ways to teach physicians, via case based learning and science. The big problem? Those episodes cost perhaps a million dollars to make. I don't see anyone handing over that kind of money in this economic environment. But what if they did? What if there was a channel just for physician education that produced such films? Sure the public could subscribe too.....what a great freakin' channel!

Yes, if we could have TV teach the physician we may be better off. Just an hour a night. 3 nights a week. Imagine how quick we could jumpstart the Personalized Medicine revolution. Turn off Grays Anatomy and tune into something worthwhile. But alas, most doctors are looking to escape medicine when they turn on the TV, not learn. But if you offered CMEs???? Might be something there....

The Sherpa Says: Why does it take a million dollar budget and a set of production professionals to create a palatable lecture on epigenetics? Alas, because the scientists and physicians have the Curse of Knowledge.

Ouch!! CNV with lackluster results....

All it takes is 2 seconds to step on some of my readership's toes and I feel it. Yesterday I posted on a 5% error rate for Whole Genome sequencing, I argued that even at 30x coverage it would not be ready for clinical diagnosis. I had CEOs of sequencing companies emailing me and VPs calling me. I even had pound for pound one of the best bloggers in the space say he was embarrassed for me.....Ouch!

Why do I get pushback from people, when all I am doing is throwing some cold water on the party???

Get ready, because I am about to throw some more.....Remember yesterday when I said SNPs were one of 7 or 8 factors that will differentiate each of us??? Well, CNVs are another of those 7 or 8, 2 more include histone modification and methylation, telomerase activity and size would be another factor, the rest I am saving for my own....for now. I first heard about CNV is 2006 when Mike Murray at Harvard keyed me into these guys, since then I have been following the literature and hoping we could get some results....well, we have but......

Here's the cold water, CNVs are not everything either, despite what some very learned people say.....just like genetic and genomic testing is only PART of the armamentarium for a personalized medicine specialist, CNVs are only part of the story.

True, we may find some very high Odds Ratios and some very specific diagnostics in the CNV space.....unfortunately, the American Journal of Human Genetics lays an egg with a chinese study of osteoporosis CNVs that lead to an Odds Ratio of 1.7 for osteoporotic hip fracture. I was hoping some of these CNV stories would be much more exciting than SNPs....My guess is that alot of the SNPs that we found previously with GWAS may actually just be markers for CNVs....and if that is the case, can we expect that much more from CNV than SNP?

I know some who would say yes, and I look forward to their comments. I think we may see this as the key in some areas, where amount of transcript plays a huge role, like metabolism of compounds or perhaps in cell signalling and migration events, but what about diseases that don't need that so much, structural protein diseases, ciliopathies, etc......

Most importantly, what about the diseases that sneak up on us over time like diabetes or atherosclerosis? I don't think that these will be the answer here. I have a very strong feeling that my equation Genome + Environment = Phenome + Metabolome will still hold true....

The one thing I am certain of is how to make things clinically applicable and right now, CNVs, SNPs, or Whole Genome Scans....there are only a very few limited cases where we can use this stuff......Until the sequencing companies are willing to take the liability for how their product are used, there are going to be problems trying to sell it as medicine without medical professionals......

So sorry to GC, PM, CV, JR, DM and who ever else decided to email me or call me expressing their problems with my cold shower: shake it off, look for solutions and get back to climbing the mountain.

The Sherpa Says: I just want to keep the marketers from overhyping.....Because if we don't, they will "create" our science.....Through slick words and number play published in the New York Times or Wall Street Journal.

What's 5 % between friends?

You gotta love the breakneck speed at which whole genome sequencing is proceeding. Hell, by the end of 2010 we will have a complete genome for 1000. But the big rub is......how accurate will it be?

I was just telling a partner at Burrill and Company about how the whole field of genetic esoteric testing goes out the window when you can have a genome for 1000 USD. But what I didn't say was, "That's assuming the data is valid"

You see, we can be pretty accurate when sequencing a gene or 2. But when it comes to whole genome sequencing the best these companies can get is 95% correct. So I say, what's 5% between friends..........For clarity, this is per read according to some companies. But I maintain that even with 30x coverage, you will still have too much error to trust this, at least when it comes to making healthcare decisions....

I say this in response to the "pinheads" selling SNP scans DTC and "claiming that they hold the keys to all disease.....That 0.1% difference is not all that matters, in fact I would guess it is merely one of approximately 7 or 8 factors that play heavily into common human disease.....That's why the SNP Chip companies dropped prices and may have destroyed the commercial market for this test....Slide pic brought to you by Andrew....Thanks Drew!

In fact, that is precisely why Coriell will be tremendously successful at recruiting volunteers for their study. People realize 2500 USD is not the cost of a 1 million SNP can, in fact by the end of the year it may very well be the cost of a complete genome....

But here's the question...how is the accuracy of that "Discount DNA" to quote the author David Ewing Duncan......

We know that Helicos actually kept their error rate quiet for some time. But then

"Initial commercial specifications for the Helicos™ Genetic Analysis Platform were set at 50 Mb per hour; 10 Gb per run in 8 days. Early adopters can expect 8 million reads at length-of-read from 25 to 50 bases in each of the 50 flow cell channels utilized, totaling 400 million reads per run. Aftermarket costs are approximately $1.80 per megabase sequenced or $45 per million reads. Additionally, performance is independent of template sizes anywhere from 25 b to 8 Kb. The total error rate is less than or equal to 5%, with a competitive 0.5% substitution error rate. Further, the error rate is independent of the read length. The HeliScope Sequencer is capable of accurately sequencing samples with 20% to 80% GC content. "

The dirty truth..........Yes, now those SNP scans are looking a heck of a lot more accurate than the wonderful complete genomes we may have....Hmmmmm...can some one do the math for me.....what's 5% of 3 billion? What about 6 billion? Even if not that high, what is 0.1%....isn't that what the SNP companies tell you can cause "all disease???"

Even in the salmon, there are recommendations to use Sanger still!

Uh-Oh.....we may have a complete genome for 2500 USD, but whose genome is it? 0.1% makes us different, right? This problem will hamper the entire field for quite some time. Imagine all the false positive data that may be generated here. If you think GWAS needed replication, wait until you see W-GWAS studies. We are going to have so much false positive data out there until we can perfect the technology...I can't wait to see the next level of commercial ventures to arise prematurely from Complete Genomics....Have they said their error rate? I have a big problem with any company who says "Don't do the sequencing....we'll do the sequencing and give you the data.

In fact, there is a guy on house arrest in Manhattan for doing a similar thing. His name is Madoff. He said "I have a secret formula, trust me, I can give you fantastic returns.....Until my kids turn me in"

I wonder if Complete Genomics is the Genome's Ponzi scheme. I wouldn't assume so, since George Church is on their board and if anyone is a purist it's him. But hey, how will anyone know that without "double checking" the books???? Even if they have a dramatically lower error rate than Helicos.......

Unless the error rate gets to about 0.001% then we may have to wait a while before we can do most meaningful things with the "Whole Genome and nothing but the Genome"

The Sherpa Says: My take, we need to study how SNP scans AND whole genome scans may affect healthcare outcomes. If we aren't answering questions for clinicians and the public what are we doing? Providing neat websites based on false or lackluster data? We have to be serious here and figure what it all means before we start using this. That's precisely why 23andMe says that there scan shouldn't be used for healthcare....because they too know it is not ready for prime time.....I wonder how Complete Genomics feels about that? Because, I for one am a little concerned about the whole "black box" technology movement and applying it to my patients' care. But it is pretty obvious MDVIP doesn't care.

Raiding the medical commons!!!! A pirate's life for me.

I just got back from Disney World the other day.....What a great trip.....my take is that if you keep believing and work hard enough your dream will come true....or at least Disney wants you to think that's true.....But I have a little problem......how can anyone believe without some evidence?....You can, but then it is not belief, it then becomes faith. Faith is belief with the absence of proof.....

Unfortunately, that is how alot of blind individuals see personalized medicine....Too bad they are dead wrong. There is proof. For Pharmacogenomics all one has to do is scan the pharmacology literature.....but that's tough for scientists to do, even tougher for doctors, and toughest for genetic counselors...but it exists.....just take a look at the nearly 4000 papers published on CYP 2D6....

Unfortunately, Time did not name Pharmacogenomic testing, invention of the year. Instead they chose Personal Genome Scans.......While a unique technology (sort of) this type of testing requires further study. Several colleauges will be speaking at a conference of heavy hitters in the space. The conference sponsored by the CDC and NIH will examine the role of these scans....They need to especially as Muin Khoury noted that only 3% of all genomic studies addressed questions related to clinical integration or outcomes....Scary Statistic for sure, but how can we expect lab physicians and scientists to understand clinical intergration?

From the site

This 2-day workshop, cosponsored by CDC and NIH, will explore the type of scientific foundation that is crucially needed to make the promise of personal genomics a reality. The workshop participants will explore how the integration of genomics into personalized health can follow an evidence-based process. The process for using genomic applications in personalized healthcare (e.g. pharmacogenomics, early detection markers, testing in clinical trials) is being discussed.

It starts on December 17th and ends on the 18th.

I have sent some speakers case presentations that we have experienced evaluating these scans. All confidential mind you, but some are pretty interesting.....

Most of the people at this meeting agree that the role of genome scans and primary healthcare remains in the realm of the primary care physician. But we all know the limitations they have.

1. Education on genetics and genomics

2. Limited Time Schedules

3. Ability to order and get these tests and their care paid for.

4. Lack of clear studies demonstrating clinical utility

Dr Wylie Burke writes in JAMA last week about this topic "An Unwelcome Side Effect of Direct-to-Consumer Personal Genome Testing: Raiding the Medical Commons" In it she posits that the incidentalome that is unleashed will waste healthcare dollars in investigations that are unwarranted, based on meager risk estimates...She may be right. She may also be wrong....But there is only one way to know this.....we have to study how genetic information such as genome scans is used in the clinic.....

Helix Health of Connecticut is in prime position to do just that. Starting at the end of this month we will....I can't tell you how now....but it will change the way genetic research is done. It is time to move out of academia and into the field....That's where we are headed. Armed with a physician a counselor and the internet! Together, not exclusive of each other.....

The Sherpa Says: I am back with a vengeance! I am about to blow the doors off of this Genome Scan land.....With the help of some other Sherpas! Oh did I forget to mention that we are all connected now???? For me, I do believe it will come true.

Sherpa on Vacation

Keep Climbing. I'll be out for seven days....and when I return, I am going to change the game for DTC testing, Research on Personalized Medicine, and finally show everyone where they can set up camp!

So Keep Climbing!

-Steve

Gate Keepers for Genetic Information

A recent set of comments came to me from a Genetic Counselor. They were well thought out, but I think she may have misinterpreted me...

I pray that your attitude changes before you have a practice of your own and I pray for the genetic counselors at Yale who have to work with now, knowing that you think they are unnecessary and undeserving of respect.

This was said in response to my asking that if someone is billed a code 99245 that a person should be seen by a physician or at least someone who could perform a physical exam. Billing without the physical exam is more disrespectful and illegal than I was in the prior post... Unfortunately, that post was taken as if I think genetic counselors don't matter. In fact the reader further went on to feel as if I wanted to replace the whole field.

"What you are proposing will actually hurt patients, the medical system and the personalized medicine effort altogether."

I actually am not proposing to replace genetic counselors. The 2000 or so are an absolutely needed resource for counseling. The problem is that most counselors are specialized in the classical fields of genetics: Prenatal, Cancer predisposition, Metabolic and Clinical Genetics (Syndromes and Autism)......there are several hurdles for personalized medicine to be implemented, including manpower, and the already busy with long wait list genetic counseling services would be swamped with personalized medicine issues if we were to use them.....The same could be said for the 100 Internal Medicine Geneticists or the 700 or so other MD Geneticists......I see the experts of classical genetics as instrumental...but not as trying to churn through 1000s of patients evaluating drug metabolism. This is especially true in the underserved.

Their expertise really lies in expert systems that busy clinicians.....over 800k doctors in the country.......could consult in real time.....Yes, the classically trained counselors and geneticists will always be needed to see NF, Metabolic Disease, cardiogenetics, Prenatal issues, developmental delay, etc.......but the dual trained Internists Geneticist could be suited seeing pharmacogenomics, adult onset multifactorial disease, etc.......Even if they do, that is 100 or so doctors versus 800,000......

What should be done in the case of counselors and geneticists is in the realm of expert systems and teaching.....rather than take a year or 2 out of your schedule to learn internal medicine, neurology, etc. you could.....

1. Work hand in hand with a provider in a specialty and providing your expertise. This model was shown in Scotland to be very effective, until the CGC left the practice. Then things kinda fell off.

2. Create expert networks that busy clinicians can consult with in real time....thus leveraging your capabilities.....Just like the pioneer Heather Shappell has done.....

3. Go back to school and learn internal medicine, neurology, etc, which you could be doing in option one in real time......

4. Beg that the code for genetic counseling gets paid more, complain when it doesn't, and don't do anything to advance the personalized medicine ball. Which is a silly thing because 2000 genetic counselors will be overwhelmed doing the day to day counseling for Factor V Leiden, Hemochromatosis, and pharmacogenomics for 300 million people....I agree, you should get paid by the hour, just like physicians should, but we have been begging for increased reimbursement and look where that has gotten us...

It is not a viable strategy for long term success....Increased pay is needed for sure, but that is not a solution for the manpower issue. 2 years to be a CGC, 9 years to be an MD geneticist....neither is that attractive right now....You could teach a man how to fish and feed millions in the matter of a few months...Why not do that rather than keep it amongst the "Special Interest Group"?

Like DTC I do see that the small part of the medical field holding this information, even away from other practitioners.....which is dead wrong....

Oh and the last thing from the email I received

"Therefore, please use your time and energy wisely, advocate for genetic counselors. They are the gatekeepers to responsible genetic information."

The Sherpa Says:

Genetic counselors are very much needed. However, so are NPs and PAs and PMDs......We are all part of the solution and trying to maintain gatekeeper status when there is a tsunami of applicable genomic healthcare information is coming down the pike is not smart for such a small group of healtcare providers. The ecosystem needs to change and it can, but Geneticists and Counselors need to get out there and TEACH the NP, PA and MD without fear of not having a job after they do the teaching.......If you don't do the teaching......Slick Marketers with huge budgets will.....and that would be a loss to the entire healthcare system....

4 Days and Crazy $h!t Happens

Did you ever notice how everyone drops out at Thanksgiving, leading to a 4 day weekend? I did, and I dropped out......a little. But I did keep my ear to the ground and found some interesting news I want to share with my wonderful readers!

1. JAMA publishes an article which says, poor glucose control in diabetics puts you at risk for heart disease.....but if you have a 9p21 genetic polymorphism it REALLY puts you at risk....Ok, so what does that mean? Well, they studied patients who had cardiac catheterizations. In those who had 50% or greater blockage of a vessel, you were 4 times more likely to have poor diabetic control AND 9p21 polymorphisms. If you just had poorly controlled diabetes......2 times more likely. What is the clinical take away? Is it ok to have poorly controlled diabetes if you don't have 9p21 polymorphisms? NO......so what difference does it make if you have this risk??? Well, maybe psychologically it will help them control their diabetes. But not if they have the "I like boston creme's from Dunkin Donuts" gene....

2. NEJM was loaded with genetics articles including Gene Signatures in B Cell Lymphomas.....but the best was the report on Speech delay and CNTNAP2....not that exciting for my personalized medicine readers, but tremendously useful for my autism contingent. It turns out this speech delay region is linked to Autism as well. Hopefully, the children geneticists see with autism or speech delay will have a new test to help diagnose these difficult conditions. More importantly, this is a step in the right direction to understand the biological underpinnings of speech delay, a very common condition.

3. We saw just how cruel the world can be. My heart goes out to all in Mumbai whose lives perished at the hands of the Terrorists. I was in NY when those bastards hit NYC.

4. And we saw how silly and self indulgent the world can be with this NYT article on gene testing your kids for sport prowess. I said I wasn't going to comment on this because it is not medically related, so my stance is, buyer beware, rather than outlaw foolish diagnostic tests....But when you are encouraged to start taking DNA samples from your 8 year old....I have to say that this is the most outlandish use of this technology I have ever seen.

It makes 23andMe look like saints. Daniel MacArthur a researcher who published on the topic was pretty convincing.....this test is B.S. Want a good genetic test for sports.....test for hypertrophic cardiomyopathy or Burgada Syndrome and actually save lives! Why? Well, you could pick up risk for sudden cardiac death and prevent it! Rather than predict variation in about 2-5% of strength....you have to be putting me on that this crap shows up in the NYT!

Yes, it certainly was a busy 4 days......

The Sherpa Says:

Ahhh yes, the US leads the world in Vanity and Tom-Foolery.....why would it be any different in the world of genetics???? Danger lurks behind vanity.....Narcissus

The Health Thing to Do This Thanksgiving

In the US, today is Thanksgiving. A day where family and friends come together and appreciate what we have. We consume massive amounts of food, drink, some smoke, and not surprisingly get admitted to the hospital the next day.

This year I would like to offer up the one healthy thing you can do. Take your Family History. Started in 2005, the Surgeon General has named today, National Family History Day. So visit the HHS website and find out who has what, who died, how young.....it may end up saving your life. When your done and if you are concerned about it, Come See Us! We even do home visits!

The Sherpa Says: Happy Thanksgiving to all. Today I am thankful for YOU, my readers. Have a great Holiday!

MyGeneticist.com debuts!

I love the web. I have a twitter that is only shared by some good friends....but it never fails that I have people who are interested in what Helix Health of Connecticut is up to "lurking" my twitters......(I always wondered, are the people who use twitter called Twitterers or just Twits?)

This is the case with a company. I was informed today that someone at http://www.mygeneticist.com/ was now following me.. So I went to their site... It was a face page that I have up here....I began to wonder who was following me on twitter, so I dug deeper....

It turns out that MyGeneticist.com was founded by PhD Geneticists, not MD Geneticists and is run by the a company called discoverme technologies.

What is MyGeneticist and who are DiscoverMe Technologies???

From their site

"At the heart of DiscoverMe Technologies is the mission to help people live healthier, more peaceful lives by facilitating informed medical decisions based on our analysis of personal genetic information."

We are committed to high standards of integrity in contributing to the best interests of our clients, health care professionals, our team and our communities, based on our continual pursuit of scientific, clinical and operational excellence."

"Founded and operated by scientists, DiscoverMe serves to complement existing healthcare systems and to make a positive impact on society by facilitating informed health choices."

So I then began to wonder....What is MyGeneticist.com?

myGeneticist is a service that enables individuals to understand the information stored in their DNA, so this knowledge can be used to make healthy life choices.

myGeneticist offers continuously evolving service suites based on scientific advances in pharmacogenomics, where drug prescriptions and dosages are matched to complement an individual's genetic makeup.

Through myGeneticist, clients will gain access to the most comprehensive genetic analysis of their DNA and, with the help of our highly accredited clinical team, be able to understand their most appropriate drug choices and dosages for any given situation, where quality scientific research enables definitive clinical action.

Conversely, our clinical team will work with partnering healthcare providers to facilitate the use of our services to augment existing healthcare clinics and practices.

Lots of words, but still no answers...Who is MyGeneticist.com? i.e. the clinicians and scientists? and most importantly what do they do? A highly accredited clinical team, sounds alot like MD geneticists or maybe clinical pharmacologists or maybe just MDs. I wonder who?

The Sherpa Says: A lurking twitterer reveals a stealth service which looks like it will launch in the PgX space, very, very soon......I look forward to finding out who they are and what they offer....We need more telegenetics services, especially when it comes to PgX.....

Death of the MicroArray/oaCGH

I just got out of a lecture given by Allen Bale M.D. a researcher and clinician here in the Department of Genetics at Yale....

I have come to the conclusion......

MicroArrays are going bye-bye....

Why? Allen detailed several unique strategies to "Trick" High Throughput(HT) Genome scanners into doing the heavy lifting, or what used to be heavy lifting/expensive lifting of microarray analysis.

How will this beat MicroArrays?

1. No more expression Arrays....Instead you can do reverse transcription and then do HT sequencing.....bp length too small? Just link all the sequence together.....

2. No more cytogenetics and Array CGH. Solexa's machine can churn through these sequences pretty quickly....hell, if nanopore comes through we could technically assess methylation at the SAME time!!!

3. It will beat them on price. When you have hungry lab rats trying to use their governmental grants as cost effectively as possible, they will find a way to "Adapt" their research to using these machines.

Bottom line.....places like Yale are already beating the "business" of MicroArray technology. That's why Illumina bought Solexa....they already see it coming..

The Sherpa Says: If I were an investor, I would steer clear of companies that are ONLY in the MicroArray business.......And if you are in the diagnostic space......beware of SMS, it will completely replace standard diagnostic tests...... Why do a BRCA sequence when you can just look at the mutations in a SMS run???? For 6000 Myriad will do all the HNPCC genes.....it costs 12 USD to run them through a sequencer.....you do the math......and the DTC genomics companies are already lining up with NextGen......

Paradigm Shifts.....

I am busily preparing for the Coriell ICOB meeting in Philadelphia coming up shortly. We are set to examine a whole host of new SNPs and their relevance to disease. I also am ramping up our practices in Connecticut and New York City. Traditionally a consult service, Helix Health of Connecticut is going to really put its money where its mouth is...we are taking on a full time role in management of patients.

We certainly are excited about this move. We initially didn't want physicians in our communities to think we would want to "steal" their patients....which has never been our aim....but now after multiple requests by our consulted patients we will begin seeing full time primary care patients in our clinics starting in January of 2009.

Call now to start an intake, we are already filling up quickly.....

We will carry out the usual intakes and genomic consultations, but this time we will also be doing the full time quarterbacking. Sniffles, Chest Pain and Depression all deserve Personalized Medicine, don't you think?

Our team is committed to this and stand ready to serve.

We will be carrying out some amazing projects which I will share with you shortly.

We believe our communities are ready for this care, we hope the government catches on before it's too late......

Real Doctors, Performing Real Personalized Medicine and Genomics.........

To Your Health,

-Steve

Oprah's Community against 23andMe

When Public Relations Backfires

Genes provide Minimal Benefit!!!! Seriously Oprah!

Genotype Score in Addition to Common Risk Factors for Prediction of Type 2 Diabetes......

That's right, the New England Journal of Medicine has 2 publications in the Journal this week. What's the take away?

Paper One: Conclusions A genotype score based on 18 risk alleles predicted new cases of diabetes in the community but provided only a slightly better prediction of risk than knowledge of common risk factors alone. The C-statistic was 0.900 versus 0.901......some on....can we even call that better? The nearer the C statistic to 1, the better the predictive value of the test...so can we really say it is worth it???

Paper Two: Conclusions As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up. In this study they use the area under the ROC, where the change is 0.74 to 0.75....again lackluster results...

You tell me? I just gave a lecture to several residents in Internal Medicine......I asked what the barriers where to taking a family history. One pragmatic resident said "So let's say I get the family history. What will I do clinically different?"

These articles in the New England Journal of Medicine make me pose the same question.......

What do I do with this only slightly, increased ability to pick up disease risk?

The answer? No one knows......Is it worth spending thousands of dollars on a test that doesn't dramatically improve detection of predisease risk?

I am not so sure.....

The bigger question is, are predisposition SNPs what we should be studying instead of rare copy number variants????

The Sherpa Says: With stats like this, DTC companies will be dead and so will the microarray business.....Will we achieve personalized medicine with such disappointing results???? Yes, but not via DTC...or via Oprah.

Not Intended to Diagnose or Treat

Andrew at ThinkGene comments on something that I have not been able to effectively explain.

We trust health assets like “medical advice” to exist. That is, we trust that public medical information describes reality such that it may be applied to measurably improve health. This is a challenge because medical advice, especially preventative medical advice like genomics, is a trust asset: an abstract idea with value applied to the indefinite future.

This is a very precise explanation. We pay for medical advice.......which may include diagnosis or treatment.......We trust trained health professionals to give that advice. We trust that they are capable of giving that advice......Why?

Well, we have a licensing system in this country that helps us assure that quality. In addition to that licensing we have things such as Board Certification or eligibility which also let us know that the practitioner has a certain set of skills, verified by a specialty.

These hurdles are required. Why? They are required to help establish "trust" in the system...

Andrew goes on to say

However, that trust is under attack, and as the immediately profitable but eventually catastrophic erosion of the term “insurance” now jeopardizes the financial industry, the meaning of term “medical advice” is now being eroded by greedy companies.

This system had been under attack for a very long time.....It had appeared that things such as "Alternative Healthcare" or "Nutriceuticals" had carved their own niche and it was Understood by the lay public that this system existed "Outside of the trusted practice of medicine" Thus the DIETARY SUPPLEMENT HEALTH AND EDUCATION ACT OF 1994 opening the field wide open for alternative care.....Prior to this the FDA regulated nutritional supplements.

The public knew that these systems existed in parallel tracks and that the quality of care by alternative systems would likely need to be "backed up" by standard medical care....a very small few, swore off western medicine, but these were the patients who would often present to an Emergency room with some "Morning Report" type case of undiagnosed diabetes, heart disease or cancer. Morning Report cases are often tales of very bad diagnoses (Bad for the patient, incredibly instructive for the resident)

But what is happening now is the replacement and possible erosion of the trust in medical advice. Why? Science or perhaps PseudoScience has evolved. Reporters relying on press release have adopted "Newly Published Results in Nature Science" as the Truth......Despite this not always being the case....even Russ Altman commented on this the other day.

The public is now understanding that Genomics is part of healthcare.....and with good reason, it IS healthcare. But the layperson doesn't have such a nuanced view and can't understand limitations of Non-Medical Medical Advice when it comes to genomics.

I Repeat "But the layperson doesn't have such a nuanced view and can't understand limitations of Non-Medical Medical Advice when it comes to genomics."

A gene is a gene, and to convince them of otherwise takes quite a bit of effort. The string of though goes something like this: "Genes are medicine, thus a genetic test is medicine.....and genetic advice, must be medical advice....

Thus, I implicitly trust the genomic testing advice....which in disclaimer is not for "Diagnosis or Treatment"

Andrew has reported on precisely this confusing thing on a DTC genomic website and press release. It can be easily viewed as confusing when a company tells you "Helps the patient make informed personal health decisions" Despite Andrew highlighting the "state of the art medical advice and services" he should have high lit "Helps the patient make informed personal health decisions"

This is the crux of this argument. When a patient usually wants advice about personal health where do they normally go?

The Doctor....Despite WebMD being the first link for Medical Advice on google, we eventually end up at the doctor's office...BTW the web tools for genetics in medicine are woeful, with over 1/3 having wrong answers or misinformation...

So what is personal health? In my opinion it is the realm of medicine. Health can be viewed in many ways, but protecting health and restoring health has always been viewed as a medical trait. Ever heard of preventative medicine?????

So Andrew is correct, the line is getting awfully blurry. When companies start making claims which blur that line while hiding under the legal nomenclature "This Service is not intended to Diagnose or Treat" it can be very confusing for the public....and with fantastic PR and being named as the invention of the year, we can be certain that the public is starting to lose sight of that line.....

But I say, isn't this what these companies want anyways? They want to replace modern care with "Wiki-Style" care.....I think we have seen that already...

This may or may not be a good thing.....Personally I think it is a horrible thing, but the scientist in me accepts the null hypothesis "There is no relationship"

So when would it be a bad thing? If the replacement of current medical advice takes place without the same licensing and regulatory guidelines that exist in current medical advice, then we may see a true erosion of trust in Medical Advice, which when it happens will lead us right back to where we began, with skilled professionals giving us the trusted advice we sought in the first place....

The Sherpa Says: "Genetic/Medicinal Advice" could be placed back in the dark ages if we start allowing it to be sold without the stringent regulations or to be able to jump the turnstyle through legal jargon and avoid regulations that are placed on it currently. This is one of those dangerous shortcuts that the Sherpa avoids.....you won't jump start the system by cutting the climbers off at the knees simply because you don't have enough crampons to climb the mountain....