Heart Disease Diagnosis Patent

Insilicos was issued a patent for diagnosis of cardiovascular disease. The method is for analysis of proteins carried by HDL particles. It's directly related to our ongoing clinical study to predict heart attacks in advance from a blood test. I'm really excited about the potential for this test to be a breakthrough in diagnosing CVD. You never know for sure until you have the data in hand, but I'm optimistic.

Molecular Modeling joint venture

Insilicos has formed a joint venture with the University of Washington to further develop and commercialize the Rosetta molecular modeling software developed in David Baker's lab. The product is Rosetta@cloud, a cloud-based service for protein modeling and similar services.

Task Force Finalizes Prostate Recommendation

In a move that should have surprised no one, the US Preventative Services Task Force issued a final decision on their recommendation against routine PSA testing for prostate cancer. The task force noted, correctly, that PSA testing saves few if any lives, yet causes significant suffering and expense.

Supremes Burn Prometheus

Prometheus Laboratories had two patents on diagnostic methods. The patented methods were to measure certain metabolites in blood, and to adjust drug dosing accordingly.

The Mayo clinic was a Prometheus customer, but eventually developed (but never sold) a diagnostic that infringed the Prometheus patents. Prometheus sued. Long story short, the case got to the Supreme Court. What did the Supremes have to say? “To transform an unpatentable law of nature into a patent­ eligible application of such a law, a patent must do more than simply state the law of nature while adding the words ‘apply it,’ ” wrote Stephen Breyer in the unanimous decision. Ouch.

You can read read about the case in Reuters, and Genomeweb.

There are some commentators who feel like this ruling was somehow bad for personalized medicine. I disagree. This ruling is fantastic for personalized medicine. Had the Supremes upheld this patent, then there would have been a land rush to patent all sorts of facts about how the human body responds to this or that class of drug. The result would have been a logjam of dubious patents, uncertain freedom to practice, and personalized medicine would have been set back five, maybe ten years.

Look at it this way: one of the most successful personalized medicine companies, Genomic Health, has succeeded with no patent protection at all. Another personalized medicine company, Myriad, has kept a test that some observers view as mediocre and inflexible on the market, because Myriad's patents keep competitors at bay. Which scenario leads to better medicine?

It appears that the consensus is that this ruling bodes ill for Myriad's BRCA patents. So much the better.

NCATS: I can has translational science

The NIH has created the National Center for Advancing Translational Sciences (NCATS), the first new institute in some time, arguably since 1990 when NCRR was created. Ironically, a big part of NCATS is comprised of parts scavenged from the corpse of NCRR, which was eliminated to make way for NCATS.

There has been some complaining that NIH moved too quickly in creating NCATS. Well, one should think twice before complaining that anything in government or health science is happening too quickly. The purpose of NCATS is to make more therapies available more quickly, because patients with life-threatening illnesses can't wait. The creation of NCATS sets a precedent for nimbleness. Let's hope NCATS is able to apply that agility to their mission.

(I looked for a funny Lolcats picture involving a doctor to illustrate this post. Unfortunately, none of the Lolcats pictures involving doctors or medical themes was remotely funny, or even particularly cute. Sorry.)

USPSTF on Prostate Screening: "Meh."

The US Preventative Services Task Force (USPSTF) has recommended that men not get the PSA test for prostate cancer. The recommendation applies to men who have not already been diagnosed with prostate cancer, nor have "symptoms that are highly suspicious for prostate cancer." So, USPSTF recommends that the PSA test not be used at all for screening. USPSTF recommends that the test can be used for men who pretty obviously already have prostate cancer, but the test isn't all that important for such men anyway.

Here's what's going to happen: USPSTF is going to start accepting comments on October 11. There will be a firestorm of criticism from patient advocacy groups, individual prostate cancer survivors, and physicians and companies that make a good living treating prostate cancer. Then the USPSTF will stick to its guns and issue a recommendation statement very similar to the draft. Treatment guidelines will change, and most men will never get a PSA test.

In 2009, USPSTF issued a similarly controversial recommendation on mammogram screening for breast cancer, recommending that most women between 40 and 50 no longer receive mammogram screening. At the time, many people had trouble understanding how more diagnosis can be a bad thing. The short answer is, a diagnostic test can lead to treating disease that otherwise would not have become a health problem, and the treatment itself carries significant risks.

Now USPSTF has dropped the other shoe, and made a similar recommendation for PSA, for the same reasons. USPSTF went further with the PSA test, essentially recommending that men never be screened with the PSA test for prostate cancer.

Here's the problem: if you have a prostate, and you live long enough, you'll get prostate cancer. Cancer is almost a normal part of aging for this organ. Few of these cancers will ever become aggressive enough to be life-threatening, and the majority of deaths from prostate cancer are in men over the age of 75, who were not likely to live many decades longer if cured anyway.

So, if you screen men, you can find a lot of prostate cancer. If you treat these men, almost all of them will survive the treatment, because their prostate cancer wasn't going to kill them anyway. A few men with aggressive cancer will be detected earlier, but it doesn't appear that detecting aggressive prostate cancer earlier has much effect on survival rates.

And prostate cancer treatment is very invasive. A positive PSA test leads to a biopsy. If the biopsy confirms cancer, then surgery typically follows. Impotence and incontinence are frequent side-effects of surgery. Some men are treated with hormone therapies that cause erectile dysfunction, hot flashes, and the development of breasts. And, some men die from their treatment.

But that could still be worth it, right? All of that suffering and expense could still save lives, right? Well, it could, but it happens that more men die younger if they are screened than if they are not. And furthermore, the men who are not screened are happier: they have fewer cancer worries, and they do not suffer the serious side effects that result from treatment.

The biggest problem with the PSA test is, it has a high false-positive rate. Make that a very high false positive rate. For every 10 men with a positive PSA test, 2 actually have prostate cancer. But 8 think they have prostate cancer and will get biopsied. Some fraction of the men who are biopsied will have a false-positive biopsy, and continue on down the treatment path for no good reason. (These numbers apply to the "cut point" that is normally used for the PSA test.)

Diagnostics are tough. It is often the case that there is a rock-solid relationship between a testable biomarker and a medical condition, but a useful diagnostic test only comes years or decades later. The science of PSA is sound. The mistake was using PSA to screen for disease. The USPSTF is in the process of correcting that mistake.

Elizabeth Dragon

Elizabeth Dragon died of "natural causes" in February, shortly before she was due to be sentenced for securities fraud. Her death brings to mind the importance of scientific ethics in one's life and the lives of others.

Dragon had an illustrious career as a senior scientist at Roche before leading R&D at Sequenom. Eventually, certain scientific results became part of an internal investigation, leading to an SEC investigation. Dragon pled guilty to securities fraud and had her sentencing delayed, as she agreed to cooperate with the ongoing investigation.

What did she do to destroy her career, nearly wreck a prominent diagnostics company, change the course of her life utterly, and even possibly shorten her life? In describing results of Sequenom's trisomy test, she describe results as blinded, when in fact researchers had been unblinded. That simple yet critical element of scientific dishonesty had dramatic consequences for her and everyone she worked with.

This sad story reminds me that it is easier than we like to think for even brilliant and talented people to become so convinced of the rightness of their ideas that they bend the truth until it breaks away beneath them. As far as we know, Elizabeth Dragon set out not to deceive, but to do good in the world. But at some point, she decided she was above the rules of science, and above the law. She was wrong, at great cost.

The Long Tail of Global Health Equity

Partners in Health is a great and thoughtful organization that has a real impact on human health. In this conference they discussed chronic disease among the poorest billion people. PIH's message: the suffering of chronic disease among the poorest can be understood and addressed.

KIF6: Game Over?

JACC recently reported a gigantic meta-analysis study looking at the relationship between cardiovascular disease and the popular test from Celera. Short answer: the study found no relationship whatsoever between test results and cardiovascular disease. None. A test that has been conducted over 150,000 times in the last two years has, according to the authors, no validity.

The KIF6 test measures one SNP in the KIF6 gene called Trp719Arg. Individuals who have the 719Arg mutation, comprising about half of many human populations, were alleged to be at elevated risk for coronary artery disease (CAD). This study involved meta analysis of 19 other studies involving 19,000 CAD cases and 39,369 controls. The study was large enough for the authors to conclude with high confidence that any possible relationship between 719Arg and CAD is extremely weak. The study concludes with a finding of "uniform lack of elevated risk of clinical CAD among carriers of the KIF6 719Arg allele compared with noncarriers in 19 case-control studies performed around the world."

There are some aspects of the study that are open to question, but not much. This study is damning. Either 69 presigious authors completely messed up a high-profile study or KIF6 has no known diagnostic value.

Celera responds that, since the meta analysis did not control for statin use, the study might be masking the importance of the KIF6 variant.

There are two problems with Celara's line of reasoning. First, The Sample quotes Eric Topol and Samir Damani's conclusion that it's not likely the case that statin status significantly affected the study results.

Second, statins are the current standard of care. If 719Arg carriers are getting on statins at a high enough rate to mask the disease impact of the variant, then that calls into question the clinical utility of the KIF6 test. If everyone who needs statins is getting them, then there's literally no point in testing for what would happen to certain genetic subpopulations, were they not to be on statins.

If the KIF6 test could find people who would otherwise get statins but can't possibly benefit from them, then there might be a case for the test, but there's no reason to suspect that the KIF6 test can do that. Even then, it would be hard to justify the expense of the test on this basis.

KIF6 may not be over, but it's not looking good. Celera was widely expected to apply for FDA approval of KIF6. That's suddenly not such an obviously good idea. As the FDA expands regulation of laboratory "homebrew" tests like KIF6, it's not clear that FDA will continue to permit the test to be offered. And besides, even if FDA doesn't shut down the test, cardiologists aren't likely to order a test if they have no idea how to use results in clinical decisions.

Full disclosure: I work for a company developing a CVD test that would arguably compete with KIF6.

Checklist Manifesto

I reviewed this great new book by Atul Gawande here. For the P4 blog, I'll add a few comments realative to P4 Medicine.

Briefly, Atul Gawande's new book is about how simple checklists can bring a surgical team together, reduce infection rates, and save lives.

What does a book ostensibly about surgery have to say about P4 medicine? Well, surgery is personalized, so it's part-way to P4 anyway. But This book addresses issues that are even broader than medicine. Atul's concept of checklists comes straight out of aerospace, particularly pilots' checklists. So the application isn't limited to surgery or even medicine.

In reading this book, one of my thoughts was that many of the same issues with diligent quality control apply to diagnostic tests as well. It's well known that variability in phlebotomy has a dramatically bad effect on many diagnostic tests. Many reference lab tests are quite complex, and especially if technicians don't do these tests every day, it's often easy to make mistakes that can have drastic consequences for people's well-being.

Personalized medicine is going to be personalized in a sense we don't always think of: it will still be performed by people. Personalized medicine means that, in many cases, both patients and clinicians will confront more complex processes. Tools like well-designed checklists are worth understanding, because we'll need them.