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Wednesday, February 11, 2009

Epidemiology and next-generation(s) sequencing.

I had a very interesting conversation this morning with a co-worker, which ended up as a full fledged conversation about how next generation sequencing will end up spilling out of the research labs to the physician's office. My co-worker originally stated that it will take 20 years or so for it to happen, which seems kind of off to me. While most inventions take a lot longer to get going, I think that next-gen sequencing will cascade over more quickly to general use a lot more quickly than people appreciate. Let me explain why.

The first thing we have to acknowledge is that pharmaceutical companies have a HUGE interest in making next gen sequencing work for them. In the past, pharma companies might spend millions of dollars getting a drug candidate to phase 2 trials, and it's in their best interest to get every drug as far as they can. Thus, any drug that can be "rescued" from failing at this stage will decrease the cost of getting drugs to market, and increases revenues significantly for the company. With the price of genome sequencing falling to $5000/person, it wouldn't be unreasonable for a company to do 5-10,000 genomes for the phase 3 trial candidates, as insurance. If the drug seems to work well for a population associated with a particular set of traits, and not well for another group, it is a huge bonus for the company in getting the drug approved. If the drug causes adverse reactions in a small population of people which associate with a second set of traits, then it's even better - they'll be able to screen out adverse responders.

When it comes to getting FDA approval, any company that can clearly specify who the drug will work for - who it won't work for - and who shouldn't take it, will be miles ahead of the game, and able to fast track their application though the approval process. That's another major savings for the company.

(If you're paying attention, you'll also notice at least one new business model here: retesting old drugs that failed trials to see if you can find responsive sub-populations. Someone is going to make a fortune on this.)

Where does this meet epidemiology? Give it 5-7 years, and you'll start to see drugs appear on the shelf with warnings like "This drug is counter-indicated for patients with CYP450 variant XXXX." Once that starts to happen, physicians will really have very little choice but to start sending their patients for routine genetic testing. We already have PCR screens in the labs for some diseases and tests, but it won't be long before a whole series of drugs appear with labels like this, and insurance companies will start insisting that patients have their genomes sequenced for $5000, rather than have 40-50 individual test kits that each cost $100.

Really, though, what choice will physicians have? When drugs begin to show up that will help 99% of the patients for which they should be prescribed, but are counter indicated for genomic variations, no physician will be willing to accept the risk of prescribing without the accompanying test. (Malpractice insurance is good... but only gets you so far!) And as the tests get more complex, and our understanding of underlying cause and effect of various SNPs starts to increase, this is going to quickly go beyond the treatment of single conditions.

I can only see one conclusion: every physician will have to start working closely with a genetic councilor of some sort, who can advise on relative risk and reward of various drugs and treatment regimes. To do otherwise would be utterly reckless.

So, how long will it be until we see the effects of this transformation on our medical system? Well, give it 5 years to see the first genetic counter-indications, but it won't take long after that for our medical systems (on both sides of the border in North America) to feel the full effects of the revolution. Just wait till we start sequencing the genomes of the flu bugs we've caught to best figure out which anti-viral to use.

Gone are the days when the physician will be able to eye up his or her patient and prescribe whatever drug he or she comes up with off the top of their head. Of course, the hospitals aren't yet aware of this tsunami of information and change that's coming at them. Somehow, we need to get the message to them that they'll have to start re-thinking the way they treat people, instead of populations of people.

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Blogger Will said...

Great post! It's fun to look up from the fray of current research and imagine where we are going to be 20 or even 50 years down the road.

I absolutely agree that high throughput sequencing has the potential to change everything, and change it sooner rather than later. With sequencing following a sort of Moore's law on steroids, I think things are on course for personalized medicine to become relevant within the next decade, especially in cancer chemotherapy and other treatments in which the therapeutic ratio is very narrow.

However, I think your suggestion that every physician will need a genetic councilor consult is off the mark. With electronic medical records advancing rapidly, the most likely progression is for the consult to be in the computer. I've used several EMR systems, and there is an enormous amount of potential to use quantitative, up to date analysis of individual patient information to flag possible concerns or make suggestions to the physician. As scary as it is to think that we might be diagnosed and treated more by a computer than a doctor, I think that as this plays out it will become clear that computationally augmented care will massively outperform the physician alone, particularly as the wealth of genetic considerations become overwhelming.

February 12, 2009 7:42:00 AM PST  
Blogger Anthony said...

Hi Will,

Thanks for the comment! For the most part, I tend to agree with you about the course that personalized medicine is on, and I think we also see it moving forward on the pace. It is a lot of fun to predict the future, although I'm definitely no Nostradamus!

Where we differ in our opinion, however, is that I see two major flaws with the prediction of having computers decide the course of treatment: Computers are notoriously bad at making decisions without resorting to heuristics, and much of personalized medicine will really become a discussion around penetrance and "nature vs nurture." I can't see a computer algorithm deciding how to weigh risk factors in a way that a trained genetic councilor would be able to.

(If we run ChIP-Seq on everyone for all genomic signals, and then tie those to maternal and paternal chromosomes, we might be able to have a fully automated system with sufficient material to make absolute decisions, but short of that, the physician or computer will be operating on less than complete information.)

Unfortunately, until computer science evolves beyond the use of expert systems, I don't think we'll have a good replacement for genetic councilors. And, while I'm touching that point - I don't think physicians will be working on a 1:1 ratio with councilors - but I wouldn't be surprised if, in the future, each clinic or hospital will find a reason to keep one employed.

What do you think?

February 12, 2009 9:49:00 AM PST  

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