Monday, November 13, 2006

Small results, big press release


The medical world is full of horrible diseases which need tackling, but you can't track them all. For me, it is natural to focus a touch more on those to which I have a personal connection.

Lupus is one such disease, as I have a friend with it. Lupus is an autoimmune disease in which the body produces antibodies targeting various normal cellular proteins. The result can be brutal biological chaos.

The pharmaceutical armamentarium for lupus isn't very good. Anti-lupus therapies fall into two general categories: anti-inflammatory agents and low doses of cancer chemotherapeutics (primarily anti-metabolite therapies such as methotrexate). Few of these have been adequately tested in lupus, and certainly not well tested in combination. The docs are flying by the seat of their pants. The side effects of the drugs are quite severe, so much so that lupus therapy can be an endless back-and-forth between minimizing disease damage & therapy side effects.

One reason lupus hasn't received a lot of attention from the pharmaceutical industry is that we really don't understand the disease. It is almost certainly a 'complex disease', meaning there are multiple genetic pathways that lead to or influence the disease. Different patients manifest the disease in different ways. For many patients, the most dangerous aspect is an autoimmune assault on the kidneys. but for my friend the most vicious flare-ups are pericarditis, an inflammation of the sac around the heart. These differences could reflect very different disease mechanisms; we really don't know.

We need to understand the mechanisms of lupus, so it is with interest I read items such as this one: New biomarkers for lupus found. The item starts promisingly

A Wake Forest University School of Medicine team believes it has found biomarkers for lupus that also may play a role in causing the disease.

The biomarkers are micro-ribonucleic acids (micro-RNAs), said Nilamadhab Mishra, M.D. He and colleagues reported at the American College of Rheumatology meeting in Washington that they had found profound differences in the expression of micro-RNAs...


So far, so good -- except now things go south
...between five lupus patients and six healthy control patients who did not have lupus.


Five patients? Six controls? These are exquisitely tiny samples, particularly when looking at microRNAs, of which there are >100 known for human. With so few samples, the risk of a chance association is high. And are these good comparisons? Were the samples well matched for age, concurrent & previous therapies, gender, etc?

Farther down is even more worrisome verbiage
In the new study, the researchers found 40 microRNAs in which the difference in expression between the lupus patients and the controls was more than 1.5 times, and focused on five micro-RNAs where the lupus patients had more than three times the amount of the microRNAs as healthy controls, and one, called miR 95 where the lupus patients had just one third of the gene expression of the microRNA of the controls.


Fold-change cutoffs are popular in expression studies, because they are intuitive, but are generally meaningless. Depending on how tight the assays are, fold changes of 3X can be meaningless (in an assay with high technical variance) and ones smaller than 1.5X can be quite significant (in an assay with very tight technical variance). Well-designed microarray studies are far more likely to use proper statistical tests, such as T-tests.

And one last statement to complain about
The team reported the lesser amount of miR 95 "results in aberrant gene expression in lupus patients."

Is this simply correlation between miR 95 and other gene expression -- which suffers both from the fact that correlation is not causation and that with such small samples gene expression differences will be found from pure chance. Are these genes which have previously been shown to be targets of miR 95? Has it been shown that actually interfering with miR 95 expression in the patient samples reverts the gene expression changes?

Of course, it is patently unfair for me to beat up on a scientific poster of preliminary results for which I have only seen a press release - one hopes that before this data gets to press a much more detailed workup is performed (please, please let me review this paper!). But, it is also patently unfair to yank the chains of patients with understudied diseases with press releases that take a nub of a preliminary result and headline it into a major advance.

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