Doctor E tips his hat to a reader who sent a pointer to a new Web resource for all manner of medical subjects that include calculations that can be expressed as algorithms. The site is The Medical Algorithms Project . It requires registration but registration is free.

Log-in comes with the caution that:

The material at this website is intended only for the educational and personal use of health care students and professionals. It is not intended for persons who have not received appropriate medical training, and should not be used for making clinical decisions pertaining to patient diagnosis, care, or management. Algorithms predicting outcomes use data based on the original articles. Outcomes may vary between institutions and are impacted by newer developments in diagnostics and therapeutics. These should be validated prior to use

Any computations obtained from these algorithms should be compared with, and tempered by, personal clinical knowledge and judgment.

Most of us are aware of some very basic algorithms that are a part of daily medical practice. A fasting lipid panel, for example, will correct the total cholesterol number by a fixed proportion (20 percent) of the triglyceride result.

Creatinine clearance is another important number. Probably during residency you knew the formula off the top of your head, but today you’re more likely to send the timed urine sample off to the lab and wait to see the calculations.

Apropos of this blog, which focuses on topics in genetics, is the Algorithm Project’s section on medical genetics, which includes all manner of calculations.

Many of the algorithms for calculating the probability of paternity were new to me. They conjure up the possibility of real life sticky social situations and can surely provide the raw material for at least a couple episodes of “House.” Consider the avuncular index, which takes its name from the avunculus, the Latin for “uncle”. This algorithm calculates the probability that a child’s uncle is actually his biological father. Then there’s the RMNE algorithm—for Random Male Not Excluded—defined as “the probability that a random, unrelated male from the same racial background would not be excluded as the potential father of the child.

I find this stuff fascinating. Check it out.

Technorati Tags: medical genetics, paternity testing, medical algorithms, “House”

Medicare Part D has been a headache for doctors and patients alike. Not a few of us have suggested that the D should stand for “disaster.” But, as long as we’re stuck with it, there are things to be aware of.

The most important thing to know is that the new enrollment period for Part D starts on Wednesday, November 15 and continues until December 31, 2006. It’s crucial to sign up during this period, because late sign-ups are subject to a premium penalty. Jane Brody’s recent article “Time to take another look at Medicare drug plans” in the November 7 NewYork Times is an excellent summary of the issues. I recommend it for everyone.

Technorati Tags: Medicare Part D, health care costs

This will be familiar to all of you who maintain a clinical practice.

It was ten years ago. I get a phone call from a friend who asks me if I will see a friend of his who is visiting from Indiana and has developed a bad cough. So I agree. The cough turns out to be pneumonia. The pneumonia is not bad enough to require a hospitalization, but it’s definitely something that needs an antibiotic.

So I prescribe a well-known antibiotic—a super drug that requires only a five-day course and once-a-day dosing.

A few hours later the friend-of-a-friend calls me from the pharmacy. “I can’t get the medicine you prescribed,” he says, “because they want $140.00. A hundred and forty dollars for six pills!” To be honest, I had no idea. For nearly twenty years I have been practicing in a prepaid health plan in which most patients pay somewhere between a dollar and $15 for any prescription. I was leading a sheltered life!

For the friend of a friend, I wrote a new prescription: a ten-day course of generic doxycycline that cost him less than $20.00. It worked. A few weeks later I got thank-you email.

It turns out I’m not the only doc who has been shielded from the cost of prescription drugs. A recent study published in the Journal of Managed Care revealed that only about a third of the time did physicians discuss cost issues with their patients. Conversely, patients initiated discussion of cost issues only two-percent of the time.

I hasten to add that since my experience with the expensive antibiotic, I always ask about cost issues when I prescribe a new medication. Some of these costs are statospheric. The newer disease modifying agents for rheumatoid arthritis, for example, can run more than $1000 per month.

And speaking of drug costs, my next posting concerns the upcoming Medicare Part D enrollment period. Check it out.

Technorati Tags: prescription drugs, health care costs, generic drugs

I guess it’s inevitable that when you tell people that you’ve been writing about pharmacogenetics, they’ll want to know if you can tell them anything about the medications that they’re taking or that they’re thinking about taking.  Recently a friend asked me about a particular immune suppressive drug that had been recommended as a treatment for her multiple sclerosis.  My quick search of the literature didn’t find any immediately available tests, but it did find that lots of people were thinking about them.

The first Web site I found was that of a personal injury law firm that was recruiting clients who might have been harmed by an MS drug (not the one my friend was thinking of taking).  In the law firm’s statement was a comment that pharmaceutical companies were ignoring developments in pharmacogenetics.

Other sites discussed current research aimed at looking for pharmacogenetic, pharmacogenomic, and proteonomic aspects of MS.  Here are two studies discussed in the September 2005 issue of the Journal of Neurology:

“Two forthcoming studies will investigate the long-term effects of early treatment with interferon beta-1b (IFNβ) on the course of MS. The BENEFIT (BEtaseron®/Betaferon® in Newly Emerging MS for Initial Treatment) study will incorporate pharmacogenetic and pharmacogenomic analyses to determine the genetic elements controlling treatment response. BEST-PGx (Betaferon®/Betaseron® in Early relapsing-remitting MS Surveillance Trial—Pharmacogenomics) is an exploratory 2-year study that will investigate the value of RNA expression profiling and pharmacogenetics in predicting treatment response to IFNβ in patients with early relapsing MS. The main goal of BEST-PGx is the identification of differences in gene expression profiles of patients showing differential treatment responses. In addition, this study may reveal new information relevant to the mechanism of action of interferon treatment in MS and also to differences in the underlying pathology of the immune system.”

As an aside, I wonder where the practice of assigning cute acronyms to clinical trials actually started.  BENEFIT indeed.  I await their findings.

Technorati Tags: pharmacogenetics, multiple sclerosis, interferon

My recovery continues . On Sunday I walked two-and-a-half miles. That’s not a big deal for someone who used to run marathons, but for four weeks out from bypass surgery it’s not bad.

I left the hospital with prescriptions for all sorts of medicines. So many, in fact, that to keep things straight I got one of those plastic boxes with individual slots for each day of the week. Now, one thing to remember about all these medications—medicines for blood pressure, for cholesterol, for heart rhythms, and my favorite, for pain—is that they are really powerful chemicals. The have effects and they have side effects.

Some of the effects are predictable. The blood pressure medicine, atenolol, makes me a bit light-headed when I stand up. Other effects are not predictable. Is it medicine that’s making me have a runny nose? Is it a medicine that’s making me have weird dreams? I’m not sure, but I’ll bet some of the strangeness I’m experiencing is because of the pharmacological stew that’s coursing through my veins.

Today I got to discontinue one of the medicines—amiodarone—that was stared in the hospital when I had a brief run of atrial fibrillation. Now, the experience of having a heart bypass operation is probably sufficient to engender weird dreams, but I’m holding out for the possibility that it might be the amiodarone. One thing my patients have taught me over the years that I’ve been in practice is that not every side effect is listed on the package insert. If a patient tells me that he or she is having a funny reaction to a medicine, I’m inclined to believe it. These are, after all, very powerful substances.

It’s probably not utopian to think that in a few more years our knowledge of pharmacogenetics will have expanded to the point that we will have reasonably priced tests that will screen for hundreds of genetically mediated drug effects and side effects. Already some researchers are talking about a chip that can help determine an entire human genome and do it for $1000 or less.

The shadows are getting long. It’s time to turn on the porch light and get ready for the trick-or-treaters. I’ll let you know how my dreams go.

Technorati Tags: side effects, bypass, pharmacogenetics

The FDA advisory committee that met yesterday has recommended that Tamoxifen prescribing information now include mention of the possibility that the drug may be ineffectual for post-menopausal breast cancer survivors who carry the “poor metabolizer” CYP2D6 genotype. Here’s the story from the Chicago Sun Times.

Technorati Tags: breast cancer, tamoxifen, FDA, CYP2D6, poor metabolizer

This Wednesday, October 18, 2006, an advisory committee of the US FDA will meet to discuss possible changes in the package insert recommendations for tamoxifen. Currently more than 500,000 post-menopausal women with estrogen receptor positive breast cancer take tamoxifen. Recent pharmacogenetic discoveries suggest that a significant proportion of these women may not be getting the full benefit of tamoxifen either because of their genetic constitution, because of drug interactions, or because of both.

Tamoxifen is a prodrug, meaning that it must be metabolized to an active form—endoxifen—before it can exert its full influence as an estrogen receptor blocker. The enzyme mostly responsible for this metabolic transformation is the 2D6 form of cytochrome P450 (CYP2D6). Perhaps as many as ten-percent of women who take tamoxifen have a form of CYP2D6 that cannot metabolize tamoxifen to endoxifen.

Further, some of the popular selective serotonin uptake inhibitor (SSRI) antidepressants, including Paxil and Prozac, can inhibit the metabolism of tamoxifen by blocking the action of the CYP2D6 enzyme. Many women take both tamoxifen and SSRIs.

If the FDA committee concludes these findings have significant implications for the treatment of breast cancer, the language of the tamoxifen package insert will likely be changed. One consequence will be the more widespread use of genetic testing for forms of the CYP2D6 enzyme. Such tests are already available, though not always covered by health insurance.

Technorati Tags: tamoxifen, CYP2D6, breast cancer, FDA

I may never have the chance to travel to outer space, but I recently had the opportunity to experience first hand another marvel of the Twentieth Century.  I just had open heart surgery with a three-vessel bypass.  That’s the reason why I have not been able to tend to this blog for the last three weeks.

In the days to follow, I’ll try to keep you all abreast of developments in pharmacogenetics with maybe in the short term a little extra coverage of the pharmacogentics of cardiovascular medications.

My own heart disease was self-diagnosed.  I’m 62 years old, a non-smoker (I quit many years ago), and a fitness devotee.  Three weeks ago I set out on my customary 4-mile run when, about half a mile into the run, I experienced a very mild burning sensation along the right side of my breast bone.  Whatever this was—I thought—it sure didn’t suggest any sort of heart problem.  The sensation went away and I continued my run.

The next day I did the same run and experienced the same sensation at the same point.  Again this was a sensation and not really anything I’d call pain.  Nevertheless, recalling the lesson of the late James Fixx, a runner and best selling author who died of heart disease while running, I went to see a cardiologist and had a treadmill stress test.

Ten minutes into the stress test, dripping with sweat with a pulse of 140, I saw the nurse’s eyes get a little wider as she looked at my EKG strip.  Positive!  The next day I took the same test with a concurrent echocardiogram.  Again positive.  So I was admitted to the hospital. The next morning I had a cardiac catheterization.  Although heavily sedated,  I do recall the cardiologist who did the cath showing me the images and saying “surgical…bummer.”

So here I am, two weeks post-op.  My only real complaint is that I’m very tired, a common post-operative symptom no matter what the operation.  The doctors tell me that I should be back to most activities in three months.  I didn’t have a heart attack and there’s no permanent damage.  Every morning I look in the mirror and ask myself “can this really be happening to me?”

Enough for now.  I’m tired.   More to follow.

Just playing with Google this morning, I got the following statistics:

Direct to Consumer Medicine: 12,700,000 results
Direct to Consumer Genetics: 3,510,000 results
Pharmacogenomics (PGX): 1,450,000 results
Pharmacogenetics: 1,330,000 results
CYP2D6: 350,000 results

Of course, many of these results have nothing to do with the subject at hand, reflecting instead the way that Google searches by certain key words. Nevertheless, direct-to-consumer (DTC) genetic testing is hardly an obscure subject.

Recent newspaper articles in The New York Times and Boston Globe
have looked at direct to consumer genetic testing. Ryan Phelan, the CEO of DNA Direct (the business that sponsors this blog) is quoted in the Boston Globe article.

It’s important to recognize that “DTC genetic testing” covers an enormous spectrum. Much of this testing is ancestry testing, using mitochondrial or Y-chromosome DNA, or genomic screening to estimate the probability that an individual has descended from a particular set of geographic or ethnic ancestors. Other testing looks for genetic traits that are associated with disease risk or responses to medications (PGX). While there is some controversy about the significance or accuracy of some of these tests, all of them are based on serious science.

Unfortunately there is also some genetic testing that is simply bogus. This is testing that claims to use DNA analysis to specify, for example, dietary plans or skin care regimens. It’s unfortunate that this testing is conflated with the more serious analyses.

Please take a look at the articles cited above. You may need to register to view them on-line, but registration is free. I welcome your comments.

Technorati Tags: PGX, ancestry testing, direct to consumer

National Institutes of Health to Map Genomic Changes of Lung, Brain, and Ovarian Cancers The National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health (NIH), today announced the first three cancers that will be studied in the pilot phase of The Cancer Genome Atlas (TCGA) project. The cancers to be studied in the TCGA Pilot Project are lung, brain (glioblastoma), and ovarian. These cancers, which collectively account for more than 210,000 cancer cases each year in the United States, were selected because of the availability of biospecimen collections that met TCGA’s strict scientific, technical, and ethical requirements… The whole story is at The Cancer Genome Atlas site.

Technorati Tags: human genome, cancer genome atlas, lung cancer, ovarian cancer, brain cancer, glioblastoma