Long QT Syndrome, location matters

I just saw a family who had Long QT with a KCNQ1 mutation ripping through them. Which is why I loved this email I received from one of my long time readers the day after I saw them.

Closer Look at Genetic Testing in Long-QT syndrome

One of my favorite lines from this paper was

"Nothing tests the tools of clinical risk prediction quite like sudden death."

Ummmm......Uh Huh.

They go on to say

"The difficulties encountered in the clinical application of genetic data, even in inherited conditions such as the long-QT syndrome (LQTS), in which the transmitted risk of sudden death is several hundred-fold greater than that in the general population, highlight some of the hurdles that must be overcome if DNA diagnosis is ever to transform cardiovascular medicine. "

The reader then went on to send me a release from ScienceDaily

But I should probably give you some background.

Long QT syndrome is a condition where the electrical activity in your heart is faulty. In fact, the conduction system has dangerous delays that can lead to dangerous heart rhythms which cause sudden death.

It is so serious that in every single patient I see, I ask "Has anyone in your family died suddenly or in their sleep? Has anyone had any crib death? Any sudden unexplainable car accidents?"

This is my lay screen for Sudden Cardiac Death (SCD).

Long QT is one of the causes of SCD. The rate is about 1 in 2000 or so. In 10% of people roughly, the first symptom is sudden death. This can be due to exertion, stress, auditory triggers.

A multicenter study was performed to evaluate genetic "noise" in 1400 controls and approximately 400 subjects (Far more than the Norovirus resistance gene for 22andSerge)

What did they find? They found some noise......of course.

This noise was present in about 4% of controls. This is surprisingly low in my estimate......

What else did they find? They found a genotype/phenotype correlation. Which in Autosomal Dominant disease is also no big surprise. Which likely will be augmented with modifier genes.

What is the "noise rate" for other genes? That, my friend is a good question.

What is noise? It could be anything we haven't classified as for certain pathogenic or benign. For BRCA we call these changes "Variants of Uncertain Significance" or affectionately known as VUSes

The VUS rate for BRCA is anywhere between 10 and 15 percent. Which is why I was so surprised about the LQTS study. Heck, there are more than 2 genes involved in LQTS

So why is this noise such a big deal? As we reach the precipitously dropping cost of the genome, we will be able to have a whole bunch of noise......

In fact, I think it will take us at least 20 years to sort out that noise. Add on layers of epigenetics and we may have another 20 years.......

Why so glum? We do have pretty valid clinical testing for Sudden Cardiac Death. It works, MOST of the time. Whole Genome Scanning?

Well, that may be a different story. I have harped on the Incidentalome several times on the blog, but this bears repeating.........

" If practitioners pursue these unexpected genomic findings without thought, there may be disastrous consequences. First, physicians will be overwhelmed by the complexity of pursuing unexpected genomic measurements. Second, patients will be subjected to unnecessary follow-up tests, causing additional morbidity. Third, the cost of genomic medicine will increase substantially with little benefit to patients or physicians (but with great financial benefits to the genomic testing industry), "

-Zak Kohane

"Mathematicians modeled sequencing the whole genome. As they get up to sequencing 10.000 people they find that the fraction of the population with a false positive result skyrockets up to 60%. What does this mean? Well, we have to carefully select who we test. Or better yet we need an immense database of "Normal Variants". At a minimum we will need 1000s of "sequence specialists" or "computer sequence analysis programs" to evaluate and decide if the "work up" is indicated or not. Personal Genomics is very complex, even more than personalized medicine."

-Steven Murphy in 2007

The Sherpa Says: In Genomics, there is going to be a whole lotta maybes........which in case you are curious, computers handle very poorly....

TruValue is coming. Valuation of GMG......

Valuation, it is a fickle beast. I love this post from AskTheVC.com

Valuation – especially for early stage companies – falls in the category of “more art than science.” While buyout investors who are acquiring companies with meaningful cash flow streams love their multi-sheet Excel models with 37 pivot tables, most early stage VCs can do valuations on a napkin (or – if they are good at simple math (e.g. addition and subtraction) – in their head.) In the early stages three things drive valuation: (a) ownership dynamics, (b) market terms, and (c) competitive deal dynamics.

Remember Again - this is art - there is no scientific way to really value three guys and a powerpoint slide or a web service with 10,000 subscribers of which 250 are active (although no one can prove that only 250 are active.)

Which brings me to my next point. How do you value a service which has an undisclosed amount of users, immense governmental regulation, and a company who is moving to offer the service for free?

The Art would say, unless you are going to sell the data to someone AND have that contract in hand......it is pretty much B.S.

I am surprised Pathway launched simply because of this reason.

Which makes me wonder, do these companies have contracts to sell YOUR genetic data? Did they disclose to you who they have contracts with?

Which also makes me wonder about this whole research revolution. What's so revolutionary about it? Maybe how they don't use independent reviewers to approve the research and monitor the safety of the participants? Aside from Nazi Germany and Tuskegee, that is pretty much a revolutionary concept....

One thing is for certain, the company which says takes us seriously as we charge you 2500 USD for Gornish has seen the light.

Take their recent Twitter posts

"Navigenics Health Compass: $499 until August 31st. Take control of your health. Use promotion code COMPASS-LTO-26225 http://bit.ly/11FvS2

and

New price on genetic testing http://bit.ly/oRsLF

So one has to be asking yourself, when market segmentation doesn't work and Big Blimps don't work and Celebrity endorsement doesn't work and super cool bubble conferences don't work what is the value of this and how does the public view it? The value or perceived value must be on the users themselves OR their data..........

I personally wouldn't pay any amount of money to give a single drop of spit to these companies UNLESS I could profit from their companies and the data they sell. Maybe after the companies offer free testing, they will next try to give you dividends for the investment of DNA?

It could happen. Why? 1 year ago asked attorneys about doing this grand Genome Phenome Metabolome study and if we could give people who participate shares in the company....... The lawyers freaked out. Which is precisely why it sounds just like the thing 23andSergey would do.....and in the end Navi would follow in their footsteps........ Just like they are doing now.

I have been asked why I dislike these companies and distrust them.

1. They give geneticists and genomics a bad name by hyping inaccuracy
2. They are screwing with the public perception of genetics and personalized medicine
3. The infer clinical value and don't offer it
4. They purposely avoid regulations put in place to protect people
5. They have given absolutely NOTHING back to the field of genetics or medicine
6. They are doing "research" on human subjects without protecting them

I could go on and on here, but I will save it for now.....

I like to close with a great quote, edited for Genomics purposes.

"The Silicon Valley is a system, Neo. That system is our enemy. But when you're inside, you look around, what do you see? Businessmen, Marketers, Hyped Scientists, Programmers. The very minds of the people we are trying to save. But until we do, these people are still a part of that system and that makes them our enemy. You have to understand, most of these people are not ready to be unplugged. And many of them are so inured, so hopelessly dependent on the system, that they will fight to protect it."

Have an idea, hype it, put it on Oprah, and hope the hell the sheep buy it........ I have a bad feeling about this. The public is awakening from the slumber here and it is likely that the usual VC stunts are not working......... Uh....Oh........Genomics for free, at a price.

The Sherpa Says: All the tricks the matrix pulls, all of the bamboozling, Ahh Gornish Helfn.

No Gene is an Island

This is a saying I have been using for about 4 years now.
When someone asked about testing for HFE and why we don't do it as the first screening step anymore.....

They often looked at me confused.....I then bring up the case of sickle cell disease.

Most doctors have seen a sickle cell patient in the hospital.......They may have even seen a family in the hospital, brother and sister, Son and Mother......but what most don't know is that the majority of sicklers never go into the hospital.....

That's when I ask, what is the mutation that the son and mother have? The answer Sickle-cell anemia is caused by a point mutation in the β-globin chain of hemoglobin, causing the amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position.


Now what about the patients who never come into the hospital?

Sickle-cell anemia is caused by a point mutation in the β-globin chain of hemoglobin, causing the amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position.

Why is that? I answer my question as they have lots of guesses....

"No Gene is an Island"

You see, there are several things linked to the development of the adverse outcomes with sickle cell disease. Environment, Modifier Genes, Epigenetics (which ultimately is environment) I could go on from there........but suffice to say, genes can only provide us a small answer into the majority of diseases......

Drug metabolism, is a very different story at times.....

I then go on to say that there are very, very few diseases for which severity of disease or even disease itself is attributable to JUST one gene........ Or frankly to JUST ONE MUTATION..........

The body is a set of systems and by being super reductionist and looking at one gene or one mutation versus another, we ultimately end up missing the boat and making a big deal out of something which is not so big a deal......

Or we apply something which may be clinically valid but have little clinical utility.......

Even worse, we take something which has wonderful analytic validity and to use it clinically, with a huge waste of money and a huge waste of resources........ This is the case with DTC.

Some may argue that we should allow people to waste their money on anything they want. I tend to agree with this.

However, what should not be tolerated is false claims and manipulation of claims without scrutiny.

In addition, something which meets the definitions of medicine, should be held to that standard......plain and simple........ Taking human tissues/samples and using them for research requires an IRB, taking human tissues and using them to predict risk of disease IS MEDICINE..........and should be regulated as such......

There are a whole host of laws which regulate how a doctor can advertise, why are we not applying them to these companies who are performing such analysis?

But more importantly, why are these companies the only people educating the public. And doing a very slanted and manipulative job here......

No Gene is an Island......thus no SNP is the end all or be all of risk.....It is much more complex than that.

Which is why I say "Family History is the cheapest and most clinically useful Whole Genome analysis"

The Sherpa Says: Someone is watching these claims, I hope you come here to debunk their junk.

Personal Health Record, Vital to Personalized Medicine

I am a huge proponent of Personal Health Records. What is a PHR? Let me first tell you what a PHR is not.

A PHR is Not

1. An electronic medical record

2. An always secure way to store your health information

3. Always compatible with other software.

I admitted a woman the other day to the hospital. She wasn't a patient of ours at Helix Health of Connecticut of CT, instead she was a patient of a group who we were covering. In the ED she handed me 7 pages of (typed in Times New Roman as a Word .doc), her Health Records. It didn't have lab values nor did it have all the exact results of the studies which she had. Instead this was HER record of everything that had happened to HER medically. It was written through HER interpretation, misspellings and all.

I wondered how long it took her to compile this information. I imagine it must have been at least a few days work, if not more. It was fairly accurate, but failed to precisely capture the data that I as a doctor was looking for.

This was her own creation.

There exist many of these companies on the internet today. You can order your PHR through a company or through Google. Although, with the security problems that Google has been having lately, I imagine perhaps a record stored on your USB may be superior......Maybe.....I am not certian about that.

I began to wonder, has anyone done any academic study on which way is the best to have your records? Just then, the weekly copy of the New England Journal of Medicine pops up in my mailbox.

In it was an editorial entitled-

"Your Doctor's Office or the Internet? Two Paths to Personal Health Records"

In the article, they talk about several topics which are salient and ask very important questions, which I hope someone will answer. They talk about a patient named Mary, a patient who is on multiple medications for her 4 chronic conditions.

1. As the baby boomers age and develop chronic diseases, the gap between patients' desire for information and physicians' ability to provide it is likely to increase. How will this gap be filled?

2. What if Mary could view her test results within hours after her blood was drawn? What would she do with the results*?(*is my question)

3. Unlike the stand-alone models, integrated PHRs are essentially portals into the EHRs of patients' health care providers. Is that important*? (*is my question)

4. Microsoft says it will seek patients' consent before sharing data with third parties, but none of these application suppliers are covered by HIPAA. Is that important*? (*is my question) what about CCHIT??

Here is my take. Well, before that let me clarify my stance on tech and health. Many feel that I am a detractor towards patient empowerment in this space simply because of my railing against DTC genomic companies.

This is simply untrue. I am a big supporter of PHRs and EMRs and patient controlled data. In fact I have advised several PHR companies on this and have even worked with an EMR company to find a way to amend its PHR applications.

This space IS the key to personalized medicine. Why? Well, for one, you are giving patients clinically meaningful data AND a plan to act on it. You are sharing responsibility for data gathering of information which has been PROVEN to be clinically useful.

You are not confusing your patients with stuff that likely won't matter in the end. Nor will it have close to the meaning of a good family history. Which is why Ancestry companies would be really smart to start working in this space.

The Sherpa Says: In the end, everyone will have a PHR. And in the end everyone will have a genome scan. Which will come first may well be a result of needing the other. Which will make more of an impact on health and wellness? Well, that's easy. The PHR.

Yale's Healthcare 2009 Conference and the Sherpa

I am preparing to speak at Yale School of Management's Healthcare 2009 conference. It looks to be quite a conference. The theme this year will be

"Where is the Value? Managing Cost and Quality in a Healthcare System Facing Reform."

From the site:

The Yale Healthcare Conference is a joint effort between the School of Management and the Health Professions Schools at Yale University that aims to bring together professionals, academics, and students to engage in an instructive interdisciplinary conversation concerning current healthcare issues. This will be the 5th consecutive year and we expect the conference to continue growing to over 400 participants.

The planned title and theme for Healthcare 2009 is Where is the Value? Managing Cost and Quality in a Healthcare System Facing Reform. This conference will focus on a theme of value in the healthcare system. The conference aims to address three principle questions:

1) How do we provide better care to more patients while keeping costs under control?
2) What are innovative public and private solutions to this problem?
3) What sort of opportunities and challenges will potential healthcare reform bring?

I think that this is a timely conference. With the administration supporting reform and already a record level of Medicare Audits in the system, it is clear that America will face a drastic change in the way healthcare is provided in this country.

My breakout session is on, guess what......

Personalized Medicine!!

I will be accompanied by Dr Aidan C Power of Pfizer.

Aidan's team is at the forefront of Personalized Medicine and PGx at Pfizer. Aidan has been addressing several issues and study design for personalized medicine. One recent example is the issue of race and ethnicity in PGX.

Aidan has even been briefing the Personalized Medicine Coalition, something we at Helix Health of Connecticut are proud to be a part of.

The Sherpa Says: Healthcare IS Changing. This conference is a great way to learn about some of those changes. I hope to learn alot!

Don't take my Kodachrome Away!!!!

Do you remember when you had to send your film to Rochester NY or Ohio to get developed......you would stop by the store check your last name.........Nope......sorry no pictures yet!! Even the thought of keeping that little tear off tag drove me nutty!

It was exciting, but it also was a huge pain in the a$$......What if the pictures were screwed up, you would have to send your negatives back so that they could get run again.........

That being said, Kodachrome is the gold standard of photo film, but that is so 1980s. In fact, there is only one processor of Kodachrome in the entire US left other than Kodak of course......

These guys had a great economy of scale with the processing centers and in fact it made a very nice business model for a while until Kodak discontinued Kodachrome......

Well in a similar type of move Complete Genomics lifts the veil at the AGBT....

and Bloomberg took notice

"Feb. 5 (Bloomberg) -- Complete Genomics, which offers DNA analysis services to drugmakers and other companies, will begin in June to sequence human genomes for $5,000, a far cry from the $2.3 billion the first sequencing cost in 2003."

"The service will be offered to drugmakers, biotechnology companies, and academic centers, said Clifford Reid, chairman and chief executive officer of the closely held Mountain View, California-based company, in a telephone interview. It won’t be available to individuals. "

From GenomeWeb

It is currently building a production genome center in Mountain View, Calif., that is scheduled to be completed this summer. By the time of its service launch this summer, the company plans to increase the output per sequence run to 200 gigabases, and to 600 gigabases by the end of the year. Its data center will host 5,000 processors and 5 petabytes of disk space initially, which will increase to 60,000 cores and 30 petabytes of storage next year.

This certainly is an interesting model.....I will be very curious as to how long this sort of technology stays this way.......say maybe before we invent The Digital Picture equivalent of Genome Scanning......

But, then what their business model entailed made me chuckle.........

“We think this is what the pharma companies have been waiting for,” he said today in a telephone interview. “We’ll be bringing a new customer to the market that’s potentially the biggest customer for DNA sequencing.”

His point was that Complete Genomics will be targeting Pharma and that this was some new model in the game of sequencing.......

I wonder if he had spoken to any of the old time microarray sales people. You see, Affy and the like actually peddled microarrays to Pharma first, BEFORE they sold that technology to the Academic centers........

That is why we have lag time between what pharma knows and what the rest of the world knows in terms of the microarray and GWAS......

So, peddling to people who have money instead of people who beg the government for money is nothing new, nor is pharma a "New Customer to the Market"

What IS a new customer was hinted at in the GenomeWeb article........

Going forward, Complete Genomics plans to provide human genome sequencing services to large genome centers, research centers, and direct-to-consumer companies.

The Sherpa Says: I wonder if LabCorp, Kimball Genetics, Myriad Genetics et.al. are going to be happy with a company essentially destroying their market by providing a Genome Direct to Consumers at a third of the price of one of their tests????? We'll find out in June!!! See you in the Summer.

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.