Kif 6, Genetic Findings = Useful Medicine 1 in 1000 times

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Way back in 2008 I mentioned an article, which I hoped would pan out. Or at least I hoped it would point the way to a model of PGx research which would be followed by pharma and alike to find associations to help us target the right medication for the right patient.

While the similar model followed through with Plavix, the initial study did not.

Which is why when the Berkeley Heart Lab guy came last week, I told him I would not be testing for Kif6. It had not been replicated in further GWAS.

A VAP cholesterol panel, a HsCRP, a family history and a blood pressure can help me predict risk much better.

The problem and backlash facing DTCG and DTMD genetic test purveyors is

the 'Ol "Your million dollar major study now rushed to market has just been refuted"

Yes this happens in biomedical science and in medicine ALL THE TIME.
Bed rest for MI anyone?
Low Dose Dopamine?
I could go on and on, but I won't

Put simply, the majority of the genome is NOT ready for clinical medicine or clinical decision making.

It won't be for 20 years.

That doesn't mean there aren't some things we can use.

1. BRCA1/2
2. MMR genes
3. CYP2C19
4. CYP2D6, sometimes.....
5. SCD genes
6. Counsyl universal carrier screening

If a gene test comes to market that purports disease risk it had better be studied for at least 5 years before it comes to market.

Post market surveillance did not protect all those patients on Statins, "just because" of Kif6 risk.

Get it? These tests can lead to incorrect medical decisions....
Which can lead to risk.
Yes, even the DTCG tests can fool doctors and patients.

The Sherpa Says: If 2008 was the year of the GWAS, will 2011 be the year of the overturned GWAS?

A Whole Month Off, for Good Reason!

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I have a lot of friends and readers who have emailed me over the month.

The recurring comments: "Has the DTCG field run you off of your blog?"

The answer: "Uh No"

Why I have I stopped blogging so much? For multiple reasons.

1. DTCG has been put on the Radar of the FDA and Government. I have nothing more to say about that.
2. Journalists and Genomics aficionados have been correctly pointing out the hype behind some tests. Most notably lately with the ADHD stuff, which BTW should not have been put out there in the press....Maybe, I need to blog more.....
3. My practice and patients have really taken up my time. I am working to apply personalized medicine daily. Because that is what is needed. We need to show the public and the press how it is done on a daily basis.

I will be back soon, to dissect shotty science and poor clinical studies. But for now, our boots are on the ground and we are climbing the mountain....

See you soon!

Plavix and 2C19 BrewHahHah

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Yes,
I am a little slow

Yes,
It has been a long time.

But,

I am back. With a serious hankering to smash some studies. I already pooh pooh'd the Migraine SNP study on Twitter, but the Plavix stuff.....That deserves a blogpost.

To quote a famous caridologist and friend

"If Plavix really didn't work for 30% of patients, why don't we see more in-stent thrombosis?"
Translation: Your science is nice, but how does it fly in the real world?

I have to tell you, at first I couldn't answer. It was a great question. Do a full third of people have that severe failure?

The obvious answer is NO. If 1/3 rethrombosed, we wouldn't be using Drug Eluting Stents.

So what is the answer:

Apparently a BMS (I.E. Plavix maker) funded study investigated this

We hypothesized that the benefits of clopidogrel as compared with placebo would be decreased in persons who carry a loss-of-function CYP2C19 allele and increased in carriers of the gain-of-function *17 allele.

What did this team study?

we examined the efficacy and safety of clopidogrel as compared with placebo according to genotype status among patients in two randomized trials: the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, in which patients with acute coronary syndromes were enrolled, and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) A, in which patients with atrial fibrillation were enrolled.

Ok, so they took 2 different populations and bundled them into the same article....

The 2 studies?

CURE-randomized, double-blind, placebo-controlled trial comparing clopidogrel (at a dose of 75 mg per day) with placebo — both in combination with aspirin — among 12,562 patients with acute coronary syndromes without ST-segment elevation.

ACTIVE A- was a randomized, double-blind trial comparing clopidogrel, at a dose of 75 mg per day, with placebo — both in combination with aspirin — for reducing the risk of stroke among patients with atrial fibrillation and at least one additional risk factor for stroke who were not eligible for warfarin therapy.

What did they find? No difference between Poor Metabolizer and Wild Type in secondary and primary outcomes.

So are we wrong with our studies showing 2C19 genotype matters in outcomes?

Probably not.

1st the authors note why.

1. One possible explanation for the divergence between our findings and those of previous studies involving patients with acute coronary syndromes is the difference in the rates of PCI with stenting. Only 18.0% of patients in the CURE population included in our study underwent PCI, and only 14.5% underwent PCI with placement of a stent, as compared with more than 70% in previous studies

2. We cannot definitely exclude the possibility of an interaction in the subgroup of patients who receive stents, particularly those who receive drug-eluting stents, which were not in use at the time of the CURE trial.

3. the ACTIVE A genetic data set contained fewer participants and outcome events than did the CURE data set and therefore had less statistical power.

My take

The ACTIVE A trial to assess the hypothesis was powered at 45% to detect a difference, thus it is a worthless study and should not be included in this analysis.

While I agree that a placebo group may be useful. It is not needed to assess a difference between people using Plavix with normal Plavix metabolism and Poor metabolism. In fact it may even confuse the situation as it introduces further confounding factors not genotyped or phenotyped out.

The authors disagree
First, the inclusion of a randomized placebo group in our analyses reduces various sources of confounding, such as potential pleiotropic genetic effects or population stratification.

Well, did they test or assess for pleiotropic genetic effects? No.

Further, by introducing a study COMPLETELY underpowered to observe and eval the hypothesis into this article, it ONLY creates a false image of scientific validity.

The authors disagree
Third, we observed consistent benefits of clopidogrel, irrespective of CYP2C19 genotype, in two different patient populations, which validates our findings and suggests that they could be generalizable to other populations.

Again to quote the article

Among patients with atrial fibrillation in ACTIVE A, our study had much lower power (45%) to detect a similar interaction.

So why did they include the POORLY POWERED study?

" in two different patient populations, which validates our findings and suggests that they could be generalizable to other populations."

While I laud the effort to have Randomized and Observational versus retrospective efforts. I think we have to be very careful in our study design to make sure

1. We are properly powered to observe differences.
2. That we assess pleoitropic effects, rather than claim to control for them mysteriously.

The Sherpa Says: Why include the second study? It is improperly powered, further the CURE study did not include Drug Eluting Stents! Why? Plavix goes generic in 2011. They did this to save the market......Expect more screwy studies published in NEJM etc. As PGx gains traction, contrarians and Pharm will always fight it.....

NASA Calls Last Minute Press Event For Bill Signing (Update)

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WASHINGTON -- Media representatives are invited to participate in a teleconference at 11 a.m. EDT, Oct. 11, for reaction to Monday's anticipated signing of the National Aeronautics and Space Administration Authorization Act of 2010 by President Barack Obama.

The President is expected to sign the bill later this afternoon after it was passed overwhelmingly by Congress last week. It provides bipartisan support for NASA's new direction in space exploration.

Participants in the media teleconference include:

* NASA Administrator Charles Bolden
* NASA Deputy Administrator Lori Garver
* U.S. Sen. Bill Nelson, Florida
* U.S. Rep. Suzanne Kosmas, Florida's 24th District
* Former Augustine Committee member, physicist, and former astronaut Sally Ride

Media representatives who want to participate in the teleconference should contact Katherine Trinidad either by telephone at 202-281-8171 or email at katherine.trinidad@nasa.gov. The teleconference also will be made available on the Internet at: http://www.nasa.gov/newsaudio For more information about NASA and agency programs, visit: http://www.nasa.gov

Keith's note: The news media got 90 minute advance warning about this. Today is a Federal holiday. Why not wait until tomorrow when everyone is around - and so that people can actually participate?

Keith's update: I was unable to participate in this telecon due to its last minute scheduling. However I have spoken/exchanged email with multiple media participants who did. Mr. Bolden made a brief statement and then left. He was therefore not available to answer questions from the media. How anyone can characterize this as "participation" in a media teleconference baffles me.

Mr. Bolden seems to be uninterested in playing a personal role in the agency's engagement with the media, the public, or his workforce. First he schedules foreign travel of dubious value to the agency at a time when thousands of his employees are being laid off and critical congressional battles are being fought. Then he goes out of his way not to make himself available to the media after the President signs this critical legislation into law. How much longer is this going to continue? Phoning in and doing flyby appearances is not what the agency needs right now.

Oh yes, this bill passed the House and Senate with bipartisan support - often times with Republicans being more supportive of the legislation than members of the President's own party. Yet were there any Republicans participating in this media telecon? No.

Home Sweet Home-Away-From-Home

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Long a staple in  SciFi, terraforming is the hypothetical process by which the properties of another celestial body are changed, allowing it to support terrestrial plants and animals.  While terraforming isn’t within our current capabilities, it’s not as far off as you might think.

There are several good reasons for developing this technology; exploration, adventure, advancement, over-crowding on Earth, and survival.  Yes, survival.  Eventually the Earth will no longer be able to support life.  That’s a given.  Further down the line of the Sun’s lifespan, it will expand.  It might not completely engulf the Earth (the Earth will be pushed away some as the Sun expands), but it will certainly get too close for life.

More than likely, the Moon will be our first destination for colonization, but not for terraforming.  Not only is its mass too low to easily retain an atmosphere, it’s too close if we’re trying to buy some time to get away from the expanding Sun.  Still, we’ll need that moon colony to be able to launch manned missions to Mars that will also be transporting equipment.

Terraforming Mars - artistic impression - image by Doein Ballard

The mass of Mars, in the absence of plate tectonics, may also be too low to effectively hold a viable atmosphere (viable for us, that is).  It does look feasible to build up enough of an atmosphere that we could survive with a little help, like protected enclosures, breathing apparatuses, and protective clothing.  That’s not much, when you compare it to living inside sealed, pressurized domes, wearing pressurized suits, and having clothing that must withstand sub-Arctic temperatures.  This is “living on the summit of Mt. Everest”, compared to “living at the bottom of the ocean”.

Our first challenges with Mars will be (A) to build up the atmosphere, (B) keep the atmosphere from escaping into space, and (C) keeping the planet – or at least parts of it – warm.  We already know a low-mass planet with no plate tectonics can hold heat through greenhouse gas effects (Venus), but it’s extremely arid.  Some scientists think we could get around that problem by manipulating the orbit of a celestial body with an abundance of water to “join” Mars (i.e. crash Ceres into Mars).  I’m not kidding.

(Hmmmm. Maybe not.)

It just got so quiet out there I can hear crickets chirping.

Okay, not as flashy but much safer is the idea of artificially raising the temperature of the Martian South Pole a few degrees, which would cause the CO2 stored there as “dry ice” to sublimate, releasing CO2 into the atmosphere.  CO2 is a greenhouse gas.  This should raise the temperature enough to have areas of liquid water released from the permafrost below the surface.  Next, you introduce basic plant life like plankton, and critters which produce oxygen as a waste product of metabolism.  The beauty of this plan is it doesn’t take much for sublimation to occur; we see it all the time on Earth.  Think about when a pile of snow gets smaller and smaller, but isn’t melting.  Or when ice cubes in the freezer shrink over time.  That’s sublimation.  Matter goes from a solid to a gas without passing through a liquid form.

Once the process gets a toe-hold, there is much we can do to speed things along.  We could make Mars less “shiny” (reduce the albedo) by seeding it with lichens, algae, and a whole zoo full of cyanobacteria.  This would make it so the surface would retain more heat, and add a bit more oxygen to the mix.

..

..
While we’re on the path to having the ability to terraform Mars, there’s still the question of whether or not we have the right.  There are people who feel that we have no business spreading our microbes to any other environment, even ones we consider to currently be devoid of life.  That’s the school of thought that says humanity is an infectious disease to the rest of the solar system… and that’s a discussion I’ll save for another day.

Google’s Self-Driving Cars Are Cruising the California Highways | 80beats

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google-carGoogle announced this weekend that it has been driving automated cars around California’s roads, and that the vehicles have already logged about 140,000 miles. A fully automated car just finished a big trip–all the way from Google’s campus in Mountain View, California to Hollywood.

Larry and Sergey founded Google because they wanted to help solve really big problems using technology. And one of the big problems we’re working on today is car safety and efficiency. Our goal is to help prevent traffic accidents, free up people’s time and reduce carbon emissions by fundamentally changing car use. [Official Google Blog]

A Google car drives with the help of a variety of sensors–including cameras on the roof and in front, radars, and laser range finders–which build a detailed map of the car’s surroundings. This information is transmitted to the Google servers and processed to detect and react to any obstacles that get in the car’s way, mimicking the decisions a human driver would make.

In the official Google blog post about the announcement, Google said it believes automated cars could cut the number of deaths by traffic accidents by up to a half. The vehicles could also reduce car usage if more people pile into self-piloted shared cars, or what Google calls the “highway trains of tomorrow.”

Right now, the company doesn’t have a detailed plan for how to use the technology, it seems more focused on proving that it works. And while the cars’ technology is quite advanced, it will still be several years–possibly more than eight–before the cars could be commercially available. The big question looming over this computer-controlled software is safety.

And in the event of an accident, who would be liable — the person behind the wheel or the maker of the software? “The technology is ahead of the law in many areas,” said Bernard Lu, senior staff counsel for the California Department of Motor Vehicles. “If you look at the vehicle code, there are dozens of laws pertaining to the driver of a vehicle, and they all presume to have a human being operating the vehicle.” [The New York Times]

Google’s CEO Eric Schmidt hinted at the project in a speech at TechCrunch Disrupt, discussing the next wave of computing: teaching computers to do the things we can’t do well.

Schmidt noted that it’s ridiculous that humans and not computers drive cars. “Your car should drive itself. It just makes sense,” Schmidt said. “It’s a bug that cars were invented before computers,” Schmidt remarked. [TechCrunch]

The cars weren’t able to log all of those driving miles (1,000 of which were completely human-intervention free) without being spotted. The self-driven Priuses have been caught driving along California’s roads for over a year, but most people seemed to think they were upgraded versions of Google’s mapping cars.

Related content:
80beats: Location-Software Maker Sues Google, Saying It’s Being Evil (& Microsoft-like)
80beats: Scientists Use Google Earth to Spot a Meteor Crater in Egypt
Science Not Fiction: The Car of the Future Is Looking More Gadgetmobile Than KITT
Science Not Fiction: Knight Rider: The self-driving car
Discoblog: How to Build a Car for Blind Drivers: With Vibro-Gloves and Air Puffs

Image: Flickr/karlnorling