The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification

Charlie F Rowlands; Alice Garrett; Sophie Allen; Miranda Durkie; George J Burghel; Rachel Robinson; Alison Callaway; Joanne Field; Bethan Frugtniet; Sheila Palmer-Smith; Jonathan Grant; Judith Pagan; Trudi McDevitt; Terri P McVeigh; Helen Hanson; Nicola Whiffin; Michael Jones; Clare Turnbull; CanVIG-UK

doi:10.1136/jmg-2024-110034

The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification

J Med Genet. 2024 Sep 24;61(10):983-991. doi: 10.1136/jmg-2024-110034.

Authors

Charlie F Rowlands^#¹, Alice Garrett^#^{1

2}, Sophie Allen¹, Miranda Durkie³, George J Burghel⁴, Rachel Robinson⁵, Alison Callaway⁶, Joanne Field⁷, Bethan Frugtniet², Sheila Palmer-Smith⁸, Jonathan Grant⁹, Judith Pagan¹⁰, Trudi McDevitt¹¹, Terri P McVeigh¹², Helen Hanson^{13

14}, Nicola Whiffin^{15

16}, Michael Jones¹, Clare Turnbull^{17

12}; CanVIG-UK

Collaborators

CanVIG-UK:
C Turnbull, A Garrett, L Loong, S Choi, B Torr, S Allen, M Durkie, A Callaway, J Drummond, G J Burghel, R Robinson, I R Berry, A J Wallace, D M Eccles, M Tischkowitz, S Ellard, H Hanson, E Baple, D G Evans, E Woodward, F Lalloo, S Samant, A Lucassen, A Znaczko, A Shaw, A Ansari, A Kumar, A Donaldson, A Murray, A Ross, A Taylor-Beadling, A Taylor, A Innes, A F Brady, A Kulkarni, A C Hogg, A Ramsay Bowden, A Hadonou, B Coad, B McIldowie, B Speight, B DeSouza, B Mullaney, C McKenna, C Brewer, C Olimpio, C Clabby, C Crosby, C Jenkins, C Armstrong, C Bowles, C Brooks, C Byrne, C Maurer, D Baralle, D Chubb, D Stobo, D Moore, D O Sullivan, D Donnelly, D Randhawa, D Halliday, E Atkinson, E Rauter, E Johnston, E Maher, E Sofianopoulou, E Petrides, F McRonald, F Pelz, I Frayling, G Corbett, G Rea, H Clouston, H Powell, H Williamson, H Carley, Hjw Thomas, I Tomlinson, J Cook, J Hoyle, J Tellez, J Whitworth, J Williams, J Murray, J Campbell, J Tolmie, J Field, J Mason, J Burn, J Bruty, J Callaway, J Grant, J Del Rey Jimenez, J Pagan, J VanCampen, J Barwell, K Monahan, K Tatton-Brown, K R Ong, K Murphy, K Andrews, K Mokretar, K Cadoo, K Smith, K Baker, K Brown, K Reay, K McKay Bounford, K Bradshaw, K Russell, K Stone, K Snape, L Crookes, L Reed, L Taggart, L Yarram-Smith, L Cobbold, L Walker, L Walker, L Hawkes, L Busby, L Izatt, L Kiely, L Hughes, L Side, L Sarkies, K-L Greenhalgh, M Shanmugasundaram, M Duff, M Bartlett, M Watson, M Owens, M Bradford, M Huxley, M Slean, M Ryten, M Smith, M Ahmed, N Roberts, C O'Brien, O Middleton, P Tarpey, P Logan, P Dean, P May, P Brace, R Tredwell, R Harrison, R Hart, R Kirk, R Martin, R Nyanhete, R Wright, R Martin, R Davidson, R Cleaver, S Talukdar, S Butler, J Sampson, S Ribeiro, S Dell, S Mackenzie, S Hegarty, S Albaba, S McKee, S Palmer-Smith, S Heggarty, S MacParland, S Greville-Heygate, S Daniels, S Prapa, S Abbs, S Tennant, S Hardy, S MacMahon, T McVeigh, T Foo, T Bedenham, T Cranston, T McDevitt, V Clowes, V Tripathi, V McConnell, N Woodwaer, Y Wallis, Z Kemp, G Mullan, L Pierson, L Rainey, C Joyce, A Timbs, A-M Reuther, B Frugtniet, B DeSouza, C Husher, C Lawn, C Corbett, D Nocera-Jijon, D Reay, E Cross, F Ryan, H Lindsay, J Oliver, J Dring, J Spiers, J Harper, K Ciucias, L Connolly, M Tsang, R Brown, S Shepherd, S Begum, S Daniels, T Tadiso, T Linton-Willoughby, H Heppell, K Sahan, L Worrillow, Z Allen, C Watt, M Hegarty, R Mitchell, R Coles, G Nickless, E Cojocaru, I Doal, F Sava, C McCarthy, R Jeeneea, D Goudie, M McConachie, S Botosneanu, G Kavanaugh, K Russell, C Sherlaw, O Tsoulaki, C Forde, E Petley, A-B Jones, K Oprych, S Pryde, Z Hyder, N Elkhateeb, R Braham, L Hanington, C Huntley, R Irving, A Sadan, M Ramos, C Elliot, D Wren, D Lobo, J McLean, D May, L Kearney, T Campbell, K Asakura, L Alwadi, R O'Shea, J Gabriel, L Chiecchio, P Bowman, L A Sutton, C Walsh, V Cloke, D Ucanok, J Davies, B Pleasance, E Maguire, A Whaite, S Best, S Westbury, A Logan, D Navarajasegaran, A Bench, P Wightman, A Cartwright, E Higgs, J Bott, H Whitehouse, J Stevens, D Martin, J Dunlop, S Thomas, C Sau, S Farndon, N Coleman, P Angelini, M Duff, H Massey, C Rowlands, C Garcia-Petit, K Gillespie, A Alder, E Middleton, C Cassidy, N Orfali, A Webb, A Luharia, N Walker, J Charlton, A Andreou, J Peddie, M Khan, L Wilkinson, H Bezuidenhout, M Edis, A Callard, P Ostrowski, P Moverley, K Bean, A Dunne, A Moleirinho, S Waller, K Cox, L Greensmith, A Brittle, N Gossan, L Freestone, C Shak, T Langford, Y Clinch, H Livesey, S Borland, A Joshi, K Wall, A Whitworth, A Wilsdon, K Edgerley, S Pugh, N Chrysochoidi, S Mutch, C McMullan, Y Johnston, M Muraru, A May, R Begum, C Smith, R Patel, I Bhatnagar, A Taylor, D Brown, J Willan, S Taylor, K Jones, K Cox, C Ramsden, O Taiwo, J Jaudzemaite, R Sharmin, L Young, C O'Dubhshlaine, L McSorley, I Abreu Rodriguez, S Lillis, P Alexopoulos, E Mortensson, L Kingham, R Moore, M Kosicka-Slawinska, S Aslam, R Wells, A Carter, H Warren, E Rolf, H Reed, L Pearce, D Lock, F Ali

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
² St George's University Hospitals NHS Foundation Trust, London, UK.
³ Sheffield Diagnostic Genetics Service, NEY Genomic Laboratory Hub, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁴ Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University NHS Foundation Trust, Manchester, UK.
⁵ The Leeds Genetics Laboratory, NEY Genomic Laboratory Hub, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁶ Wessex Genetics Laboratory Service, University Hospital Southampton NHS Foundation Trust, Salisbury, UK.
⁷ Genomics and Molecular Medicine Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁸ Institute of Medical Genetics, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, UK.
⁹ West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, Glasgow, G51 4TF, UK.
¹⁰ South East Scotland Clinical Genetics, Western General Hospital, Edinburgh, UK.
¹¹ CHI Crumlin Department of Clinical Genetics, Dublin, Ireland.
¹² The Royal Marsden NHS Foundation Trust, London, UK.
¹³ Peninsula Regional Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
¹⁴ Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.
¹⁵ Big Data Institute, University of Oxford, Oxford, UK.
¹⁶ Program in Medical and Population Genetics, Eli and Edythe L Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
¹⁷ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK turnbull.lab@icr.ac.uk.

^# Contributed equally.

Abstract

Background: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity.

Methods: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1).

Results: PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation.

Conclusion: PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.

Keywords: Genetic Testing; Genetic Variation; Genetics; Genetics, Population.

MeSH terms

Case-Control Studies
Genetic Predisposition to Disease
Genetic Variation*
Humans
Likelihood Functions
Penetrance
Phenotype

Grants and funding

WT_/Wellcome Trust/United Kingdom