Paper
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Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, Thompson WK, Besser L, Kukull WA, Holland D, Chen CH, Brewer JB, Karow DS, Kauppi K, Witoelar A, Karch CM, Bonham LW, Yokoyama JS, Rosen HJ, Miller BL, Dillon WP, Wilson DM, Hess CP, Pericak-Vance M, Haines JL, Farrer LA, Mayeux R, Hardy J, Goate AM, Hyman BT, Schellenberg GD, McEvoy LK, Andreassen OA, Dale AM. Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS Med. 2017 Mar;14(3):e1002258. Epub 2017 Mar 21 PubMed.
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Comments
Over the past few days, I have received personal emails from individuals asking about getting our polygenic hazard score (PHS) for themselves and physicians asking about clinical availability of this test for their patients. On the other hand, in several news stories, I have seen comments from researchers and clinicians stating that our PHS "is nowhere near ready for clinical use" and needs "additional validation in large independent cohorts."
As a practicing clinician, my main concern would be improper use and interpretation of our new PHS. However, I think it is important to better understand whether, and in what context, our PHS can be currently used, what next steps are needed for broad clinical use, and to dispel any false claims about usability/non-usability of our test.
First, our research study likely represents one of the largest genetic studies ever conducted in the United States, and we used all available genetic data from U.S.-based individuals of European descent. Importantly, we developed our PHS in one sample and independently replicated our score in three independent samples (replication n > 20,000 individuals). Although our findings need replication in non-U.S., non-Caucasian populations (see below), a blanket statement that "these findings still need to be replicated in larger independent samples" is incorrect and misleading.
Second, perhaps the most important issue for clinical use is prospective validation. That is, can you use our genetic score prospectively in non-demented older individuals to predict cognitive and clinical decline? We have just completed our follow-up study suggesting that beyond APOE, we can indeed use our PHS to prospectively identify non-demented older folks (from U.S.-based memory clinics) who decline cognitively and clinically over time.
Third, another important point is the need for evaluating our score in community-based samples. As we mention in our paper, our PHS was developed and validated on individuals from specialized memory clinics from the U.S. Given that folks from specialized clinics have faster rates of progression to AD than older folks from the general community, our score needs to be validated on a prospective sample from the general community. We are in the process of working on this.
Finally, we need to replicate our findings on non-U.S., non-Caucasian cohorts. For non-U.S. cohorts, we actually have preliminary evidence suggesting that our PHS works well at predicting Alzheimer's age of onset in older individuals from the general population from Iceland and Norway. For non-Caucasian populations, this is much harder to do as we currently do not have access to large U.S. or non-U.S. studies that have genotype, Alzheimer's age of onset, and clinical decline data.
In conclusion, our PHS right now is primarily intended for research and clinical trial use. However, given the results within our PLOS Medicine paper and our recent findings in using PHS to identify non-demented older individuals at greatest risk for clinical decline, subtitles and statements such as "Warning: False health news?'" and "we're so far away from a test that can be used clinically" (Mar 26 CBC news) are misleading and incorrect.
Bottom line, if you are an individual who is similar in make-up to the older, U.S.-based, Caucasian participants of European descent we evaluated in our study, we are working on options for offering PHS scores for Alzheimer's disease in clinical routine, and through executive health clinics.
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