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Re: frogdreaming post# 53343

Sunday, 12/24/2006 12:54:29 PM

Sunday, December 24, 2006 12:54:29 PM

Post# of 82595
The marker referred to in the PR IS the marker identified in the patent. Specifically, it is:

[0141] More specifically, these studies showed an association between myalgia and one particular CYP2D6 poor metabolizer allele, the CYP2D6*4, rather than a more generalized "poor metabolizer" status. For example, no associations were found between myalgia response and CYP2D6 poor metabolizer alleles other than the CYP2D6*4 allele.

The results were confirmed using a second (though relatively small set) of blind validation samples. The specific conclusions were as follows:

[0146] Overall, and in summary, these results clearly show:

1. The claimed CYP2D6 marker 179-172 alleles are linked completely with and therefore part of the well-known CYP2D6*4 haplotype.

2. That the claimed CYP2D6 marker 179-172 alleles equivalent to the well-known CYP2D6*4 haplotype were highly associated with atorvastatin-induced myalgia in a first set of 75 samples.

3. That the claimed CYP2D6 marker 179-172 alleles equivalent to the well-known CYP2D6*4 haplotype were also highly associated with atorvastatin induced myalgia in a second set of 64 validation samples.

4. Therefore, the claimed CYP2D6 marker 179-172 alleles equivalent to the well-known CYP2D6*4 haplotype constitute a validated risk factor for atorvastatin induced myalgia.


This is not "old" news as you continuously assert. While it's original US filing date is December of 2004, this patent application was just published Internationally in May of 2006. To my knowledge, the company has NEVER announced the existence of these associations publicly, save the abstract presented last March in Baltimore.

The significance of this PR at this time is that the science described in that patent application has been validated in a 750 patient study, and the results have survived the "peer review" process. Surely you know the importance of peer review.

As to your continued mistatement and apparent misunderstanding of the statistics and accuracy of the classifier, it would take far too long to address in detail. But generally, you are attempting to apply the statistical evidence of association (as described in the PR) to the level of accuracy acheivable in the completed classifier. The only thing you seem to understand correctly is that they are NOT the same thing.

As I have stated in past posts, the classifier WILL NOT rely on that marker alone. That marker constitutes a penetrant response related marker. There is at least one other (highly relevant) penetrant marker identified in the patent that is protective. In other words, it's existence is highly indicative of normal (non-myalgia) response. In addition, there are a number of latent response related markers whose presence or absence improves the classifer accuracy.

Here is the summary from the patent that describes some of these additional markers and their relevance:

D. CLASSIFICATION ACCURACY WITHIN DISCOVERY SET

[0154] The results described above demonstrate that alleles of two separate Cytochrome P450 genes are associated with atorvastatin-induced myalgia response. The following conclusion can be drawn from the data presented above:

1) The CYP2D6 gene, where the CYP2D6*4 allele marked by the CYP2D6 179-172 TT-TC or TC-TC genotype pair, or directly with a CYP2D6*4 genotyping assay, is indicative of likelihood to express atorvastatin induced myalgia

2) The CYP2D6*10 allele marked by the 179-172 CC-TC genotype pair, or directly with a CYP2D6*10 genotyping assay, is indicative of likelihood to express normal (non-myalgia) response to atorvastatin.

3) Certain CYP2C8 haplotypes as discussed above, are indicative for myalgia or normal response to atorvastatin.

4) Native American and East Asian admixture as discussed above are indicative for myalgia or normal response to atorvastatin.

[0155] A simple classification can be used to combine the CYP2D6 and CYP2C8 risk alleles into a scheme, where possession of a "risk allele" or "factor" can be used to infer the classification as a myalgia responder, and possession of a "protective allele" or "factor" can be used to infer the classification as a normal responder, and lack of a "risk" or "protective" allele or factor bestows upon the individual an inconclusive classification...(Table 19 is not shown in the document)

[0156] As shown in Table 19, approximately 2/3rds of the patients carried a risk or protective allele and could therefore be classified; of these, 97% were correctly classified using the above classification scheme.


Understand that Paragraph [0156] provides an example of a "simple" classification scheme. Table 3, referred to in my original post on this subject and questioned in your post, shows the results of a "complex" classifer. I don't know, and obviously, you don't know what the final marketed version will be able to achieve.

But the ONE thing that appears evident is that DNAPrint IS moving forward with their original research...which if I'm not mistaken would make these statements...

Haven't you wondered why DNAG has given up on its SNP based agenda?...

We can certainly watch the latest programs unfold, but you can rest assured that SNP based 'personalized medicine' is a thing of the past...

Not to mention the six years wasted on DNAG, who will apparently have no part to play in the eventual triumphs of personalized medicine...

The old paradigm that assumed that all of the diversity in the genome was haplotype based and thus amenable to SNP based diagnostics is, in fact dead. My earlier posts that 'conveyed' (Your word) that DNAG's SNP maps were no longer viable were intended to say exactly that. DNAG's exclusively SNP based maps and classifiers are useless...

The 'reason' that DNAG's SNP maps are useless, while SNPs themselves maintain their value, is the underlying assumptions that have changed...

This new understanding not only explains the difficulties experienced by DNAG with their 'nomes', it renders the entire approach obsolete...


Wrong...

The opinions expressed in this post are my own. The information and data is excerpted from publicly available information. Please make your own investment decisions based on your own due diligence.

Merry Christmas,
W2P