Multiple-testing corrections in case-control studies using identity-by-descent segments We developed an automated, reproducible, and scalable workflow to perform scans for disproportionate identity-by-descent sharing between cases and controls, determining well-controlled significance le...

🧬New from @sdtemple.bsky.social et al!
📄Multiple-testing corrections in case-control studies using identity-by-descent segments

FLARE2: local ancestry inference with poorly-matched reference panels www.biorxiv.org/content/10.1101/2025.10....

Multiple-testing corrections in case-control studies using identity-by-descent segments - PubMed Identity-by-descent (IBD) mapping provides complementary signals to genome-wide association studies (GWAS) when multiple causal haplotypes or variants are present, but not directly tested. However, fa...

Overall, the method is a scalable and interpretable way to look for haplotype homozygosity in biobanks. I have spent a lot of time implementing it to make it user friendly. Running this can be important to check for confounding: see our other preprint.
pubmed.ncbi.nlm.nih.gov/40672175/

While we have improved (made a more conservative threshold for the African American analysis), there are still unmodeled complexities and likely fine-scale structure that violates our assumption. Buyer beware if signal is weak (barely GW significant)!

We filter to have small admixture proportions in our African American analysis. We think that admixture is more likely to deflate our "selection signal", not inflate it. This is a robustness check.

We think that low-mappability, problematic regions are more likely to deflate our "selection" signal, not inflate it. See Appendix B. This is a robustness check.

The Architecture of Long-Range Haplotypes Shared within and across Populations Abstract. Homologous long segments along the genomes of close or remote relatives that are identical by descent (IBD) from a common ancestor provide clues

There is a large signal of unusual haplotype structure at a chr16 locus in all groups. I also see this when analyzing other consortia data. We describe it in more detail as a complicated region enriched with deletions. Gusev et al have also reported on it.
academic.oup.com/mbe/article/...

Multiple-testing corrections in selection scans using identity-by-descent segments Failing to correct for multiple testing in selection scans can lead to false discoveries of recent genetic adaptations. The scanning statistics in sel…

The final thesis chapter is published OA at
@ajhgnews.bsky.social!
In short, we determine a valid significance level for a "selection" scan and apply it to 3 ancestry groups in 2 biobanks. 🧵 for updates from the helpful peer review.
www.sciencedirect.com/science/arti...

This is a new conceptual figure which explains how to make our proofs. I hope this idea is helpful to other population geneticists.

Our paper on the limiting distribution of IBD rates (Gaussian) is now published in TPB. Really an amazing experience to work with and learn from Prof Elizabeth Thompson!
doi.org/10.1016/j.tp...

This project completes my development of our suite of methods called isweep, which can detect recent selection and case-control associations, can narrow in on the selection signal, and has fast local simulations to perform statistical inference.

You can also run a fast scan with randomized phenotypes to double check if selection is confounding.

Sadly, the test is prone to confounding due to very strong positive and recent selection (see LCT in European ancestry cohorts). You can automatically check for this as a part of the automated workflow.

Two of the six genome-wide significant signals are about current therapeutic targets, e.g., at the NBAS gene.

We ran the scalable scan for three ancestry cohorts (European, African, and Amish) in the Alzheimer's Disease Sequencing Project.

The null model is again motivated by the Temple and Thompson (2025) central limit theorems, which is now published in Theoretical Population Biology.

The test is a two-sample modification of the one-sample selection scan from my prior work (Temple and Browning, 2025): high IBD rates differences in cases versus controls could indicate a genetic association.

Presenting our new scan that uses IBD segments to detect genetic associations with cohorts stratified by a categorical variable (i.e., case-control studies).
www.biorxiv.org/content/10.1...

The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure Abstract. RNA viruses like SARS-CoV-2 have high mutation rates, which contribute to their rapid evolution. Mutation rates depend on mutation type and can v

The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure
academic.oup.com/nar/article/...

Strong positive selection biases identity-by-descent-based inferences of recent demography and population structure in Plasmodium falciparum - Nature Communications Identity-by-descent (IBD) is used to infer malaria parasite population demography, but positive selection imposed by drug pressure can bias IBD estimates. This study shows that strong selection distor...

And the tskibd paper itself on positive selection in Pf. is very interesting.
www.nature.com/articles/s41...

GitHub - bguo068/tskibd: Calculate IBD segments from tree sequence using tskit C API Calculate IBD segments from tree sequence using tskit C API - bguo068/tskibd

We discuss the use cases of local versus genome-wide IBD simulation. I'll say I have had a great time using msprime + tskibd for genome-wide simulations. We find it is accurate w.r.t. to our work. I highly recommend it.
github.com/bguo068/tskibd

One fantastic suggestion from both peer reviewers was to validate the accuracy of IBD segment length distributions w.r.t. existing tools. These studies are now included as Figures S7-10.

Fast simulation of identity-by-descent segments - Bulletin of Mathematical Biology The worst-case runtime complexity to simulate haplotype segments identical by descent (IBD) is quadratic in sample size. We propose two main techniques to reduce the compute time, both of which are mo...

I'm excited to share our open-access publication of my simulation paper with Sharon Browning and Elizabeth Thompson @springernature.com . We show approximately linear runtime to simulate local IBD, which was essential for my other thesis work.
link.springer.com/article/10.1...

I'm excited to present my work on rigorous and scalable multiple-testing corrections for complex haplotype scans in WGS at ASA STATGEN 2025!
t.co/rv205OBCs1

Correction: 3) should be approx. has the first-order Markov property. This is what I get for tweeting fast.

A pair of manuscripts from Sharon Browning on applications of IBD segments for mapping disease-associated loci and detecting natural selection.

www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...

There are long tables of the genes/loci identified. I put all tables and figures at end of papers, so easy to print and staple those. Pay attention to the shared signals. That's a wrap. 🎁

Beyond the Temple and Thompson asymptotics, empirically the IBD rates look ~= normally distributed, outside of many the selected loci

The assumption of IBD rates having exponentially decaying correlations has good empirical evidence across ancestry groups and simulations. We're thinking about if an IBD segment covers both positions, and the segment lengths are often modeled as exponential/Gamma.

The main reason we wrote this is to have a GW significance level for an African ancestry analysis, whereas everyone already knows about LCT selection in Europeans. We replicated a few signals across TOPMed and UKBB samples. I find the chr16 hit compelling.