Eric Vallabh Minikel1, Sonia M Vallabh2, Margaret C Orseth2, Jean-Philippe Brandel2, Stéphane Haïk2, Jean-Louis Laplanche2, Inga Zerr2, Piero Parchi2, Sabina Capellari2, Jiri Safar2, Janna Kenny2, Jamie C Fong2, Leonel T Takada2, Claudia Ponto2, Peter Hermann2, Tobias Knipper2, Christiane Stehmann2, Tetsuyuki Kitamoto2, Ryusuke Ae2, Tsuyoshi Hamaguchi2, Nobuo Sanjo2, Tadashi Tsukamoto2, Hidehiro Mizusawa2, Steven J Collins2, Roberto Chiesa2, Ignazio Roiter2, Jesús de Pedro-Cuesta2, Miguel Calero2, Michael D Geschwind2, Masahito Yamada2, Yosikazu Nakamura2, Simon Mead2. 1. From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK. eminikel@broadinstitute.org. 2. From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK.
Abstract
OBJECTIVE: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease. METHODS: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials. RESULTS: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. CONCLUSION: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
OBJECTIVE: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease. METHODS: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials. RESULTS: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. CONCLUSION: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
Authors: Sonia M Vallabh; Chloe K Nobuhara; Franc Llorens; Inga Zerr; Piero Parchi; Sabina Capellari; Eric Kuhn; Jacob Klickstein; Jiri G Safar; Flavia C Nery; Kathryn J Swoboda; Michael D Geschwind; Henrik Zetterberg; Steven E Arnold; Eric Vallabh Minikel; Stuart L Schreiber Journal: Proc Natl Acad Sci U S A Date: 2019-04-01 Impact factor: 11.205
Authors: Michael D Geschwind; Amy L Kuo; Katherine S Wong; Aissa Haman; Gillian Devereux; Benjamin J Raudabaugh; David Y Johnson; Charles C Torres-Chae; Ron Finley; Paul Garcia; Julie N Thai; Hugo Q Cheng; John M Neuhaus; Sven A Forner; Jacque L Duncan; Katherine L Possin; Stephen J Dearmond; Stanley B Prusiner; Bruce L Miller Journal: Neurology Date: 2013-10-11 Impact factor: 9.910
Authors: C Lerman; S Narod; K Schulman; C Hughes; A Gomez-Caminero; G Bonney; K Gold; B Trock; D Main; J Lynch; C Fulmore; C Snyder; S J Lemon; T Conway; P Tonin; G Lenoir; H Lynch Journal: JAMA Date: 1996-06-26 Impact factor: 56.272
Authors: Jens Wagner; Sergey Ryazanov; Andrei Leonov; Johannes Levin; Song Shi; Felix Schmidt; Catharina Prix; Francisco Pan-Montojo; Uwe Bertsch; Gerda Mitteregger-Kretzschmar; Markus Geissen; Martin Eiden; Fabienne Leidel; Thomas Hirschberger; Andreas A Deeg; Julian J Krauth; Wolfgang Zinth; Paul Tavan; Jens Pilger; Markus Zweckstetter; Tobias Frank; Mathias Bähr; Jochen H Weishaupt; Manfred Uhr; Henning Urlaub; Ulrike Teichmann; Matthias Samwer; Kai Bötzel; Martin Groschup; Hans Kretzschmar; Christian Griesinger; Armin Giese Journal: Acta Neuropathol Date: 2013-04-19 Impact factor: 17.088
Authors: Simon Mead; James Uphill; John Beck; Mark Poulter; Tracy Campbell; Jessica Lowe; Gary Adamson; Holger Hummerich; Norman Klopp; Ina-Maria Rückert; H-Erich Wichmann; Dhoyazan Azazi; Vincent Plagnol; Wandagi H Pako; Jerome Whitfield; Michael P Alpers; John Whittaker; David J Balding; Inga Zerr; Hans Kretzschmar; John Collinge Journal: Hum Mol Genet Date: 2011-12-30 Impact factor: 6.150
Authors: T E F Webb; M Poulter; J Beck; J Uphill; G Adamson; T Campbell; J Linehan; C Powell; S Brandner; S Pal; D Siddique; J D Wadsworth; S Joiner; K Alner; C Petersen; S Hampson; C Rhymes; C Treacy; E Storey; M D Geschwind; A H Nemeth; S Wroe; J Collinge; S Mead Journal: Brain Date: 2008-08-30 Impact factor: 13.501
Authors: Kaitlin E Samocha; Elise B Robinson; Stephan J Sanders; Christine Stevens; Aniko Sabo; Lauren M McGrath; Jack A Kosmicki; Karola Rehnström; Swapan Mallick; Andrew Kirby; Dennis P Wall; Daniel G MacArthur; Stacey B Gabriel; Mark DePristo; Shaun M Purcell; Aarno Palotie; Eric Boerwinkle; Joseph D Buxbaum; Edwin H Cook; Richard A Gibbs; Gerard D Schellenberg; James S Sutcliffe; Bernie Devlin; Kathryn Roeder; Benjamin M Neale; Mark J Daly Journal: Nat Genet Date: 2014-08-03 Impact factor: 38.330
Authors: Pierre N Tariot; Francisco Lopera; Jessica B Langbaum; Ronald G Thomas; Suzanne Hendrix; Lon S Schneider; Silvia Rios-Romenets; Margarita Giraldo; Natalia Acosta; Carlos Tobon; Claudia Ramos; Alejandro Espinosa; William Cho; Michael Ward; David Clayton; Michael Friesenhahn; Howard Mackey; Lee Honigberg; Sandra Sanabria Bohorquez; Kewei Chen; Trisha Walsh; Carolyn Langlois; Eric M Reiman Journal: Alzheimers Dement (N Y) Date: 2018-03-08
Authors: Eric Vallabh Minikel; Eric Kuhn; Alexandra R Cocco; Sonia M Vallabh; Christina R Hartigan; Andrew G Reidenbach; Jiri G Safar; Gregory J Raymond; Michael D McCarthy; Rhonda O'Keefe; Franc Llorens; Inga Zerr; Sabina Capellari; Piero Parchi; Stuart L Schreiber; Steven A Carr Journal: Mol Cell Proteomics Date: 2019-09-26 Impact factor: 5.911
Authors: Leandro Oliveira Bortot; Victor Lopes Rangel; Francesca A Pavlovici; Kamel El Omari; Armin Wagner; Jose Brandao-Neto; Romain Talon; Frank von Delft; Andrew G Reidenbach; Sonia M Vallabh; Eric Vallabh Minikel; Stuart Schreiber; Maria Cristina Nonato Journal: Biochimie Date: 2021-09-10 Impact factor: 4.079
Authors: Sonia M Vallabh; Eric Vallabh Minikel; Victoria J Williams; Becky C Carlyle; Alison J McManus; Chase D Wennick; Anna Bolling; Bianca A Trombetta; David Urick; Chloe K Nobuhara; Jessica Gerber; Holly Duddy; Ingolf Lachmann; Christiane Stehmann; Steven J Collins; Kaj Blennow; Henrik Zetterberg; Steven E Arnold Journal: BMC Med Date: 2020-06-18 Impact factor: 8.775
Authors: Mathias Schwartz; Jean-Philippe Brandel; Marie Lise Babonneau; Christilla Boucher; Elodie Schaerer; Stephane Haik; Jean Louis Laplanche; Marcela Gargiulo; Alexandra Durr Journal: Front Genet Date: 2019-09-20 Impact factor: 4.599
Authors: Gregory J Raymond; Hien Tran Zhao; Brent Race; Lynne D Raymond; Katie Williams; Eric E Swayze; Samantha Graffam; Jason Le; Tyler Caron; Jacquelyn Stathopoulos; Rhonda O'Keefe; Lori L Lubke; Andrew G Reidenbach; Allison Kraus; Stuart L Schreiber; Curt Mazur; Deborah E Cabin; Jeffrey B Carroll; Eric Vallabh Minikel; Holly Kordasiewicz; Byron Caughey; Sonia M Vallabh Journal: JCI Insight Date: 2019-07-30
Authors: Emmanuel A Asante; Jacqueline M Linehan; Andrew Tomlinson; Tatiana Jakubcova; Shyma Hamdan; Andrew Grimshaw; Michelle Smidak; Asif Jeelani; Akin Nihat; Simon Mead; Sebastian Brandner; Jonathan D F Wadsworth; John Collinge Journal: PLoS Biol Date: 2020-06-09 Impact factor: 8.029
Authors: Eric Vallabh Minikel; Konrad J Karczewski; Hilary C Martin; Beryl B Cummings; Nicola Whiffin; Daniel Rhodes; Jessica Alföldi; Richard C Trembath; David A van Heel; Mark J Daly; Stuart L Schreiber; Daniel G MacArthur Journal: Nature Date: 2020-05-27 Impact factor: 49.962