We study the genetics of drug efficacy using longitudinal biomarker and medication prescription data from #EHRs. 🧬💊 Have a look at the 🧵 on i) modelling drug response and biomarker progression, ii) using #PRS to predict efficacy and iii) the challenges with #EHRs. www.nature.com/articles/s41... - ThreadSky

smarie-smarie.bsky.social • 60 days ago

We study the genetics of drug efficacy using longitudinal biomarker and medication prescription data from #EHRs. 🧬💊

Have a look at the 🧵 on i) modelling drug response and biomarker progression, ii) using #PRS to predict efficacy and iii) the challenges with #EHRs.

https://www.nature.com/articles/s41467-025-58152-3

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smarie-smarie.bsky.social•60 days ago

1/10 We identified drug regimens from medication prescriptions and extracted biomarker levels before and after drug initiation for ten cardiometabolic drug-biomarker pairs. For example, following statin treatment, LDL-C levels levels drop by ~40% which is below the levels of statin-free controls.

smarie-smarie.bsky.social•60 days ago

2/10 We then conducted #pharmacogenetic GWAS and rare variant burden tests. Discovery GWAS were conducted in the @ukbiobank.bsky.social and replication analyses in the #AllOfUSResearch. We don’t discover any new pharmacogenetic signals, but also don’t miss any major signal reported previously.

smarie-smarie.bsky.social•60 days ago

3/10 A major challenge with EHR data is that medication start, baseline and post-treatment measures are not reported as such. We tested multiple strategies and found prescription regularity to be important as well as the time between prescription start and the first post-treatment measure.

smarie-smarie.bsky.social•60 days ago

4/10 In a systematic comparison with the literature, we find that GWAS derived from EHRs have comparable statistical power to GWAS conducted on PGx consortia and clinical trial data.

smarie-smarie.bsky.social•60 days ago

5/10 The contribution of rare variants to drug efficacy was found to be modest compared to common variants. We identified GIMAP5, a gene associated with autoimmune diseases, to impact absolute HbA1c response to metformin, however, the association did not replicate in the All of Us data.

smarie-smarie.bsky.social•60 days ago

6/10 To avoid spurious associations with genetic variants that are also associated with baseline biomarker genetics, we propose a theoretical framework to model drug response and longitudinal phenotypes in an unbiased manner which implies not adjusting biomarker differences for baseline levels.

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