Pilot study...Buy Stock in Kimball Genetics now!

On Friday I was picking on what I term haters of Personalized Medicine. You know those people who just shoot down the idea because of several reasons

1. Negative articles get print (contrarians always get published)


2. The doubters often have no genetic training (or combined with internal medicine) and are afraid of what they may have to do if Personalized Medicine succeeds (Which it will)


3. Their idea of Personalized Medicine is the snazzy websites of certain whole genome analysis, DTC testing or nutrigenomic fly by the night companies. Which are BTW putting a horrible stain on the name of Personalized Medicine. Francis Collins recently said "over promising can often kill a movement" so stop it. Or at least don't over promise. Please, I beg you.

Recently an article was published in the Journal of Family Practice. I won't link to it because, frankly it is a review which is skeptical, pragmatic, and clearly was written by someone who doesn't travel in the personalized medicine circles.

Why? The authors said that there is no clinical utility literature regarding the newest FDA recommendations for coumadin metabolism genotyping. Well......they were wrong. Perhaps they haven't heard of Harvard's CROWN study or this recently published article in the journal Blood.

I would like to analyze the article and first state that validation is the corner stone of any algorithm study. Well.......that too is coming soon. So before we have wise guy commenters on this study, please know that there is always a validation study in the hopper by the time an algorithm gets published.

So this study was performed on orthopaedic patients having knee replacements or revision surgery (I can hear the Cardiologists already.....well, that's not atrial fibrillation) Hold your horses, that study is coming.

The mean age for a patient was 58 years, with a range of 21 to 83 years and median of 59 years. Pretty close to the average warfarin user.

So what are the limitations let's let the authors speak.....

"this study has other limitations. First, our study population consisted entirely of patients initiating warfarin for deep vein thrombosis prophylaxis following total hip or knee arthroplasty. The ability to generalize our model for other indications is unknown and should be studied in a broad population. In particular, the appropriate starting doses and the ability to safely initiate warfarin without genetic information need to be examined in other patient groups—including nonsurgical populations"

The Sherpa Says: Well, this will be the first of many studies analyzing algorithms. Do I think it will be worthwhile? Absolutely. The end point was the therapeutic warfarin dose. They defined therapeutic dose as a dose that gave an INR (blood test indicating thinness of blood) in the target therapeutic range after 7 consecutive days. They managed to establish an algorithm which matched needed dose to approximately 80%. Which is more than I can say for the average Internist who may not even know the average dose based on ethnicity. So I await the validation but refuse to say there is no clinical utility literature. So to both extremes I say "Stop hating on personalized medicine and please stop over promising. If you both can tone it down, then we can get somewhere....safely" Oh and BTW for you VCs/Investors/Hedge Funders out there, Kimball Genetics has an FDA approved genotype test for warfarin metabolism........

Chemotherapy Toxicity Genes

Imagine if you could predict who would get the nasty side effects of chemotherapy before giving it. We could then taper the chemotherapy giving less of a dose and achieve the same response. Well, the first part of that dream is here today. At St Jude Children's Research Hospital they have been actively investigating pharmacogenomics and chemotherapy. In a study to be released in the May 15th edition of Blood we have just that.

The major findings include

• During the induction phase Vitamin D Receptor polymorphisms were linked with gastrointesinal symptoms (diarrhea, nausea, vomiting) 6.85 times more likely.
• Polymorphisms in Cytochrome p450-Family 3-subfamily A-number 5, were almost 5 times more likely to have infections and Neurotoxicity
• During consolidation phase the Reduce Folate Carrier polymorphism led to the GI side effects with a 10.4 odds ratio.
• UGT1a1 polymorphisms led to jaundice as well as reduced clearance of an agent called methotrexate (a chemo drug) perhaps leading to increased toxicity as well

This is a major study, that has had some replication in one gene or another. But the compiling of these polymorphisms has not been done. Likely we will need one more round of evaluation. But after that...we could have a pharmacogenomic test for side effects.

The Gene Sherpa says: This is great, but how do we adjust the chemo to avoid these reactions. We will likely need an adjustment scale based on polymorphisms. AKA Personalized Medicine! I am certain St Jude's has this in the works. Let's keep our eyes peeled :)

Family History and Stroke Risk

This week at the American Academy of Neurology's annual meeting results from a study were announced. Persons who had a brother or sister who suffered a stroke were almost 2 times as likely to have a stroke. All strokes in the study were due to an occlusion of a blood vessel which either resolved in less than 24 hours (TIA) or not. Of note the risk to Mexican Americans was even higher. Not surprising to me especially because they have a higher rate of metabolic syndrome in their population. Interestingly this risk was almost 3 fold in Mexican American men! My questions are many fold and will be found out over time. What role do hormones play? What about epigenetic changes in sperm? The list goes on forever.

So once again family history rules the day. I hate to tell all of these testing companies, but family history is the cheapest and best genetic test you have. Now if we can only convince physicians that family history is never noncontributory unless you believe in spontaneous generation!

True there are those like myself with only half a tree and that is where targeted testing guided by a physician will play a role.