Personal Genomes in Clinical Care. Quake paper Falls Short!

With all due respect to the scientists involved in analyzing Stephen Quake's genome in clinical context.

You did a major league $h!tty job.

No offense.

I can only assume this based on what you reported in the lancet paper.

Start by asking yourself.

"Is Stephen healthier because of what that genome and clinical assessment added to his care?"

I am speaking precisely on this topic at the Consumer Genomics Conference on June 3rd at 830 AM. So I will hold off on all my arguments....But,

The Paper even says

"We noted that most of the sequence information is difficult to interpret, and discussed error rates"

Ummm, ok. Nice counseling session.

"patients with whole genome sequence data need information about more diseases with a wide clinical range"

Perhaps that person could actually be a physician, maybe a generalist?

"For this we offered extended access to clinical geneticists, genetic counsellors and clinical lab directors"

Nice! Joubert's is not Gilbert's is not Plavix. Thanks for stopping by.

I did appreciate that your paper calculated pretest probabilities. Unfortunately these were based on a pedigree which had no ethnicity and incomplete clinical data.

1. No Glycohemoglobin to evaluate for diabetes risk or maybe even diagnose it
2. No Iron Studies to evaluate for Hemochromatosis, yet you state genes may set him up for it.
3. No documentation of a physical exam including DRE for prostate hypertrophy/cancer or PSA
4. No dietary history? No Smoking history? No social history?

Shall I go on?

You show increased risk for Diabetes post test as well as prostate cancer, obesity, CAD, MI, Asthma, NHL, RA (no ESR/CRP/CCP?)

You projected an increased risk for 7 and decreased for 8. Yet no Assessment of MCI etc in Alzhemiers disease? My god, you did a stress test in an asymptomatic patient who exercises daily.

"Although the methods we used are nascent, the results provide proof of principle that clinically meaningful information can be derived about disease and response to drugs in patients with whole genome sequence data"

Translated: We made up a system and used novel DNA results to hypothesize about disease risk using research fellows, computer programs an excellent cardiologist (Not a GP) and an Echo machine.......But we skimped on the physical exam, use of primary care doctors, complete blood counts and other clinically useful testing and procedures.

I admire your efforts, but

A. You have missed the boat in using not all the tools at hand
B. By being Genome-centric, we miss the clinical picture.

"Although no methods exist for statistical integration of such conditionally dependent risks, interpretation in the context of the causal circuit diagram allows assessment of the combined effect of environmental and genetic risk for EVERY individual"

Translation: Nothing exists statistically to evaluate disease interaction and how it may increase risks of interlinked disease.

Ask yourself, "What have we done to make Stephen Quake healthier from this test?". Other than hype the use of a genome clinically?

This paper was all genome and NO CLINICAL ASSESSMENT!

The Sherpa Says: The only thing of note that is important here is the CYP2C19 data.......
I have seen abnormal CGH data in a child with severe developmental delay come directly from a high functioning mother who was a power litigator. The genome scan as it stands now is noise. It also requires a full team a month to intepret. Clearly not ready for medical prevention or prognostication, sorry.

Of Slelling and Men

Way back in 2004 I was bouncing off the ideas of Helix Health of Connecticut. My ex-partner and I even spoke of how great it would be to have datasets with genomes, biomarkers, physical exam and medical history data. We posited how great it would be to sell these datasets to pharma.....We even thought about creating a CRO to carry out the genetic integration of pharma testing creating PGx specialized research.

I only mention this because I got a little blasted for tying 23andME with Tuskegee. Well, not really blasting, just a blog post from a really great new blog called Genetic Future.

First, we said "Is this a viable business model?" The answer, a resounding yes
Second we said "Will patients be ok with us giving their data to Pharma companies?" The answer, maybe...but only if they received something back.
Thirdly we said "Is it ethical to sell your patients' data?" We had seen it done. So we went to some notable ethicists....

What occurred during that time? CRO scandals, researcher kickbacks, fradulent studies, all things poised to make physicians look less than hippocratic.

That's when we abandoned the idea of physicians selling this data without EXPLICIT permission of patients. We did not want to revolutionize medicine AND look like profiteers. If we were not to tell our patients EXPLICITLY, we would just be pulling a scam. I couldn't exactly find the words but then...

The term Slel then came across my radar. It was brought up again by Jason Bobe

Slel: To take DNA from someone against his will, to create avatars of him, or perhaps children.

Well Avatars may not being created and it may not be unwillingly, but a profit could be made. I say could, only because it is not being made yet. Data acquisition is going to be required first.

Why do I react so vehemently against this? Because I sit on the Yale New Haven Health/Greenwich Hospital IRB. The US is a little different than those boys across the pond!

What do ethicists feel? Here is a great take.

7 requirements that systematically elucidate a coherent framework for evaluating the ethics of clinical research studies:

(1) value—enhancements of health or knowledge must be derived from the research;
(2) scientific validity—the research must be methodologically rigorous;
(3) fair subject selection—scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects;
(4) favorable risk-benefit ratio—within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks;
(5) independent review—unaffiliated individuals must review the research and approve, amend, or terminate it;
(6) informed consent—individuals should be informed about the research and provide their voluntary consent;
(7) respect for enrolled subjects—subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored.

So I ask 23andME, deCODE, Knome...Who OWNS the saliva and DNA contained therein?

LRP8 and Familial MI....Ho Hum

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





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





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





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





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





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


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





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

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

Nice Commercial, Bogus Advertisement.

Has anyone seen a company named Navigenics....Unless I have been sleeping and missed my daily rss feeds searching pubmed for pharmacogenomics, personalized medicine, genomics, and GWAS I feel they are lying.......

They have partnered with Affymetrix and plan to NAVigate GENomICS.

The way the Navigenics process works is that you submit a saliva sample and.......

They present your future!!!

Please take a look at the commercial!

What blew me away was this quote......after a misleading commercial where you think that a simple report, delivered in your email, describing your genome will alter your life......

"Now is the time when people should be getting this information(their genome). The Science is there, The Information is there....and Now Navigenics is there"

Even more disturbing is the fact that this was a quote by Greg Simon JD.....Their Chair for the Policy and ETHICS Task Force. Mr Simon is the president of FasterCures an "actiontank" committed to "saving lives by saving times" Mr Simon was the Chief Domestic Policy Advisor to Al Gore from 1993-1997

I don't think saying "The Science is Here" is an ethical statement. In fact it is misleading. He could mean the science to obtain a genome is here.....which is true......He could mean that the science to hold your genome and store it is here....true again.....but the commercial gives you the feel that the SCIENCE IS HERE TO APPLY THE WHOLE GENOME TO YOUR HEALTH. Especially when the tag line is "My genes....My health....My life....My Guide" Perhaps it depends on what your definition of is is......

The Sherpa Says:

Unless I have been asleep at the wheel, the science to send a report via mail and deliver meaningful contribution to you health care ethically and with some validity is not here. Perhaps Mr Simon missed the Bio 200 class where they talked about evidence based medicine???? Oh wait....there wasn't a lecture on that.....

Hemochromatosis stories.

Lisa Lee posted about "House" last night. It made me laugh. I couldn't help but think how the media really portrays health care. It is down right scary. Most, like the media over-hype the non-dramatic and fail to catch the essence of medical culture. It is also scary how they miss the REAL issues. Did you know that in real life if you are "coded" you have less than a 15% chance of leaving the hospital? On TV it is over 75% And the way they portray disease......don't get me started :(

But what's even scarier is having to suffer through disease. I always like to check out the support blogs and this is one I feel strongly about. They express their difficulty with phlebotomy, the traditional treatment for Hemochromatosis.

Which brings me to my last comment. The American Gastroenterological Association recommends Iron Studies to evaluate for Hemochromatosis, not genetic studies. There are some shortcomings to this approach.....What if you are a pre-menopausal woman? Sure your iron will be lower than most with Hemochromatosis. But it will be elevated. The moral of the story, know your ethnicity, know the symptoms, and stay aware.

Lastly thank you to all that have visited The Sherpa's Shoppe. I am not looking to make any money, I just wanted a shirt that said "The Gene Sherpa" and didn't feel like buying 20.

Archon X-Prize Here We Come

This week in the Proceedings of the National Academy of Science an article entitled:
"Single-molecule mass spectrometry in solution using a solitary nanopore" was published.

Why is this mouthful of words important? Well, the future of genetic testing and sequencing is going to change and this is the likely direction. This pore, created by a bacteria (Staph Aureus) is only 1.5 nanometers. For appreciation, the human hair is 10,000 nanometers. What I think is ironic is that the enzyme used to create the pore actually gives staph its ability to really make us humans sick. The technique used is remarkable...I don't know if anyone has seen a tandem mass spec before. But it usually takes up the size of a lab table. This procedure could actually be accomplished on a microchip!!! This study is a proof of concept study done in Ohio and Brazil which demonstrates the fidelity of molecule size prediction. I am sure there will be more to follow.

In addition Harvard has gotten into the game of nanopore sequencing and will likely be the world leader. But this is no surpirse. They have been in this nanopore game since the early 2000s (did I just say that?) The rough estimate for launch in this project has just gone from 7 years to 3.

The biggest problem clinicians have with genetic testing is it often takes too long with some of the quickest results taking longer than 6 hours. Nanopore sequencing could give answers in less than 2 hours. This would allow a physician to dose medicines, change treatments, identify disease in a much more reasonable window of time.

Do I see nanopore sequencing being used in the ED? Not quite yet, but the pharmacogenomic implications for personalized medicine are huge!!!!

Thanks Jason for putting this on the Radar Screen back in March.