Sunday, June 27, 2010

Paper on Microarray Analysis of "Watchful Waiting" Prostate Cancer Cohort

Last week, I noticed an interesting paper that was published in BMC Medical Genomics this March.

The authors of this paper wanted to use microarrays to develop an effective prostate cancer diagnostic defined by gene expression patterns.  More specifically, the authors were studying tissue samples taken from the Swedish "Watchful Waiting" cohort.  This large collection of patients developed prostate cancer between 1977 and 1999.  The length of follow-up time for clinical data recorded in this study is significantly longer than has been used in any other attempt to develop a microarray-based prostate cancer diagnostic.  In some cases, clinical information about individuals in this cohort was recorded over 2 decades before the microarray was even invented.

There were two aspects of this study I found particularly interesting.  First, it is pretty rare to find a cohort studied as carefully as the Watchful Waiting cohort.  Second, the authors concluded that "none of the predictive models using molecular profiles significantly improved over models using clinical variables only."

The findings of this study seem to agree with an earlier post where I mentioned two earlier studies to show that GWAS data did not significantly improve risk models for heart disease and type II diabetes.  Although those studies utilized a fundamentally different tools for analysis (the earlier studies looked at genomic sequence whereas this newer study examined gene expression patterns), it was interesting to see examples of cases where genomic technology has not been able to improve upon existing clinical diagnostics.

Of course, these studies leave the reader asking several important questions.  For example, why do these large studies result in negative results?  How long will it take for genomic research to make substantial impacts on clinical diagnostics and therapeutics?  What are the practical limits for developing applications based upon medical genomic research?

I'm not going to even pretend like I know the answers to all of these questions.  Although I'm certain that genomic research will ultimately result in disappointing results for some major studies, this paper did provide some hope that genomic research can still pave the way for future breakthroughs.

For example, the authors discuss how there is significant heterogeneity within and between prostate cancer samples - expression patterns in one region of a given tumor can be significantly different than other regions of that same tumor, and this makes it especially difficult to compare gene expression patterns between different tumors.  It is also important to determine the optimal time to take tissue samples for analysis; diagnostics taken too far in the advance will not yield clinically useful information, and feasible treatments may not even exist for results of a diagnostic applied during a late stage of cancer development.  The authors also point out that several other diagnostic microarray studies resulted in similar lists of prostate cancer biomarkers.  In other words, microarray analysis can probably yield reasonably accurate results - the problem is that the biomarkers aren't a significant improvement over current diagnostics.

I find it encouraging that the authors have a plausible explanation for their negative results and that independent microarray studies have come to similar conclusions, and I continue to be hopeful that genomics research can help achieve important medical breakthroughs in the future.


FYI, Nakagawa et al. 2008 is also an excellent prostate cancer study utilizing microarray data.

Monday, June 21, 2010

Seth Berkley's TED Talk on HIV/Flu Vaccine Development

Seth Berkley's recent TED talk focuses on HIV and influenza vaccine research.  In general, I think the talk does a good job of reviewing why it is so hard to develop an AIDS vaccine or a universal flu vaccine.  However, there are some times when I thought that Dr. Berkley was overselling the research results.

For example, Dr. Berkley says "let's take a look at a video that we're debuting at TED, for the first time, on how an effective HIV vaccine might work."  Now, I think the video does do a very good job illustrating the general principle of how vaccines work, but it does not provide any specific details regarding how an effective HIV vaccine can be developed.

At another point in the video, Dr. Berkley suggests that a universal flu vaccine can be created by designing vaccines that target conserved regions on the surface of the influenza vaccine.  These proteins would be located in roughly the equivalent of the blue region of the following 3D rendition of a flu virus (from

As you might imagine, these proteins have not been used because the scientists believed that the immune system would not respond well to them because the H and N spikes (the green and yellow things in the picture above) would block most antibodies produced during the immune response.  Judging from a quick search of the internet, it seems like most images agree with the picture shown above (and in the TED talk).

To be fair, I found one example of a flu virus with less densely packed surface proteins, and the candidate proteins (M2e proteins) may be large enough to clear enough room to interact with the host antibodies.  However, I fear this new vaccine design may be based on data which shows encouraging results during pre-clinical research but is not very effective during clinical trails.  That said, I would obviously be pleasantly surprised if this design does lead to a successful universal flu vaccine, and I honestly do think Dr. Berkley does a good job of broadly describing of how new technology can aid in rational vaccine design.

I also thought that Dr. Berkley did an excellent job describing how changes in vaccine production could significantly increase the effectiveness of flu vaccines.  Namely, Dr. Berkley points out that flu vaccines have been produced from chicken eggs ever since the 1940s.  Different flu strains vary in their ability to grow in chicken eggs, and production of flu vaccines using chicken eggs takes "more than half a year."  Dr. Berkley proposes a method that would allow companies to produce flu vaccines in E. coli.  I think this is an excellent strategy that could significant improve the process of vaccine development.

I think it is also worth mentioning that Dr. Berkley does acknowledge how hard it is to predict the future of vaccine development.  When asked to give a time line to expect an effective HIV vaccine, Dr. Berkley responds "everybody says it's 10 years, but it's been 10 years every 10 years."  In general, it is always important for people to always interpret preliminary research findings with a grain of salt.

Overall, I think Dr. Berkley does a good job providing an interesting talk about a very important subject.
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My Biomedical Informatics Blog by Charles Warden is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 United States License.