As a genetic epidemiologist who has helped develop polygenic risk scores (PRS) for common, multifactoral diseases, I have... thoughts on the launch of a company to provide pre-pregnancy counseling & preimplantation screening based on these PRS. 🧵orchidhealth.com 1) The science doesn’t add up. 2) There are better ways to ensure your (and other) children have healthy and happy lives. 3) The message it sends is… not good.

Our paper developing a multi-‘omic risk model for pancreatic cancer is now out. @CEBP_AACR 1/x cebp.aacrjournals.org/content/early/… Pancreatic cancer is a devastating disease: the average five-year survival is 9%, largely because most cancers are detected are advanced or metastatic, and cannot be removed surgically. 2/x

I want to give more specifics about my main concerns with this pre-print on polygenic scores (PGS) in carriers of rare high-risk variants (e.g. pathogenic mutations in BRCA1). /THREAD

https://twitter.com/EricTopol/status/1207745913466179584

I (and many others) have been enthusiastic about the idea for years, but if we are to move from promise to reality we need to be careful.

Biological and statistical interactions \thread part 2 (for part 1 see quoted tweet)

https://twitter.com/genes_pk/status/1205555022081081349?s=21

If you know something about biology you can hypothesize about the form of the statistical interaction you expect to see—but (a) you need to know a lot already to do this, and (b) not seeing the expected pattern does not automatically mean your hypothesized mechanism is wrong.

Okay #epitwitter and #genepitwitter, let’s talk about how statistical and biological gene-environment interactions relate to each other (or not). \thread (part 1) TL;DR 1: the distribution of a trait conditional on genotype and exposure at the population level (whether there is a statistical interaction or not) is consistent with 1,000s of possible biological models.

The recent Ganna et al. paper on same-sex sexual behavior has prompted questions about rg, the genetic correlation between two traits. What is it? How is it estimated? A technical primer. rg is defined using the SNP-specific per-allele effects on each of two traits: b1i and b2i. (Yes, “effect” is a loaded term—I’ll come back to that. Roll with me for a sec.)

I found the discussion of Quetelet and populations at the beginning of Chapter 3 of Epidemiology and the People’s Health particularly instructive, especially for genetic epidemiology. #epibookclub #epipeopleshealth #gwas #genepitwitter 1/18 The question “who—or what—determines populations or groups that merit comparison” is an important but tetchy one. 2/18

Re-upping my thread on the utility of small-effect GWAS findings in light of discussion at #AACRMolEpi Workshop (ahem @travisgerke). And adding a few comments about polygenic risk scores (PRS). /thread

https://twitter.com/GENES_PK/status/1140950476323639296

While the potential utility of PRS in any particular context is up for debate, a blanket statement that “GWAS findings are not useful for prediction" is unwarranted.

@f2harrell @NPirastu @paulpharoah I worry three very distinct scientific goals for #GWAS and genetic association studies broadly are being conflated on this thread: (1) locus discovery, (2) causal variant discovery, and (3) disease prediction. Each requires different analysis strategies and interpretation. 1/n @f2harrell @NPirastu @paulpharoah As to (1), as @tamar_sofer @paulpharoah and others have noted, the goal is just to find markers that are correlated with a causal variant (or variants). Nobody claims—or nobody should be claiming—that these markers are unique. 2/n

By all means, let’s have a nuanced discussion of pros and cons of bringing genetic risk scores to the clinic. But “deep flaws” is laying it on a little thick, bending the stick too far in the other direction. 1/

https://twitter.com/venkmurthy/status/1029645513795268608

To my mind, the most interesting and important discussion here is given a risk profile similar to that shown in the recent polygenic risk papers—and it need not be a genetic risk factor, could be BMI or circulating plasma rhubarb—what’s the clinical and public health utility? 2/