As if I wasn’t skeptical enough about personalized predictions based on genomic signatures, Jeff Leek recently had a surprising post about a “A surprisingly tricky issue when using genomic signatures for personalized medicine“. Leek (on his blog Simply Statistics) writes:
My student Prasad Patil has a really nice paper that just came out in Bioinformatics (preprint in case paywalled). The paper is about a surprisingly tricky normalization issue with genomic signatures. Genomic signatures are basically statistical/machine learning functions applied to the measurements for a set of genes to predict how long patients will survive, or how they will respond to therapy. The issue is that usually when building and applying these signatures, people normalize across samples in the training and testing set.
….it turns out that this one simple normalization problem can dramatically change the results of the predictions. In particular, we show that the predictions for the same patient, with the exact same data, can change dramatically if you just change the subpopulations of patients within the testing set.
Here’s an extract from the paper,”Test set bias affects reproducibility of gene signatures“:
Test set bias is a failure of reproducibility of a genomic signature. In other words, the same patient, with the same data and classification algorithm, may be assigned to different clinical groups. A similar failing resulted in the cancellation of clinical trials that used an irreproducible genomic signature to make chemotherapy decisions (Letter (2011)).
This is a reference to the Anil Potti case:
Letter, T. C. (2011). Duke Accepts Potti Resignation; Retraction Process Initiated with Nature Medicine.
But far from the Potti case being some particularly problematic example (see here and here), at least with respect to test set bias, this article makes it appear that test set bias is a threat to be expected much more generally. Going back to the abstract of the paper: Continue reading