Integrating enriched case data from national laboratory testing with population-based case-control analyses: a novel statistical likelihood-ratio methodology for PS4 applied to 325,345 breast cancer cases and 671,006 controls
Year: 2026
Type: preprint
Abstract: Background: For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods: Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Results: ). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). Conclusion: This flexible, variant-level methodology combines nationally-collected 'enriched' datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.
Source: medRxiv
Authors: Sophie Allen, Charlie F. Rowlands, Alice Garrett, Fergus Couch, Marcy E. Richardson, Tina Pesaran, Joanna Pethick, Katrina Lavelle, Fiona McRonald, Sally Vernon, Beth Torr, Lucy Loong, Riyaad Aungraheeta, Miranda Durkie, George J. Burghel, Alison Callaway, Rachel Robinson, Joanne Field, Bethan Frugtniet, Sheila Palmer-Smith, Jonathan Grant, Judith Pagan, Trudi McDevitt, Katie Snape, Helen Hanson, Terri McVeigh, Chey Loveday, Michael Jones, Steven Hardy, Clare Turnbull, CanVIG-UK
Institutions: Institute of Cancer Research, NHS England, St George’s University Hospitals NHS Foundation Trust, Mayo Clinic, Ambry Genetics (United States), North Bristol NHS Trust, Sheffield Children's NHS Foundation Trust, University of Manchester, Manchester University NHS Foundation Trust, University Hospital Southampton NHS Foundation Trust, Leeds Teaching Hospitals NHS Trust, Nottingham University Hospitals NHS Trust, Cardiff and Vale University Health Board, NHS Greater Glasgow and Clyde, Queen Elizabeth University Hospital, Western General Hospital, Children's Health Ireland at Crumlin, University of Exeter, Royal Devon University Healthcare NHS Foundation Trust, Royal Marsden NHS Foundation Trust, Royal Marsden Hospital
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7161503106