Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson's disease. Issue 5 (29th November 2019)

• Record Type: Journal Article
• Authors: Leonard, Hampton; Blauwendraat, Cornelis; Krohn, Lynne; Faghri, Faraz; Iwaki, Hirotaka; Ferguson, Glen; Day-Williams, Aaron G; Stone, David J; Singleton, Andrew B; Nalls, Mike A; Gan-Or, Ziv
• Other Names: author non-byline.; Adarmes-Gómez Astrid D author non-byline.; Aguilar Miquel author non-byline.; Aitkulova Akbota author non-byline.; Akhmetzhanov Vadim author non-byline.; Alcalay Roy N author non-byline.; Alvarez Ignacio author non-byline.; Alvarez Victoria author non-byline.; Bandres-Ciga Sara author non-byline.; Barrero Francisco Javier author non-byline.; Bergareche Yarza Jesús Alberto author non-byline.; Bernal-Bernal Inmaculada author non-byline.; Billingsley Kimberley author non-byline.; Blauwendraat Cornelis author non-byline.; Blazquez Marta author non-byline.; Bonilla-Toribio Marta author non-byline.; Botía Juan A author non-byline.; Boungiorno María Teresa author non-byline.; Bras Jose author non-byline.; Brice Alexis author non-byline.; Brockmann Kathrin author non-byline.; Bubb Vivien author non-byline.; Buiza-Rueda Dolores author non-byline.; Cámara Ana author non-byline.; Carrión-Claro Fátima Carrillo Mario author non-byline.; Viorica Chelban Debora Cerdan author non-byline.; Clarimón Jordi author non-byline.; Clarke Carl author non-byline.; Compta Yaroslau author non-byline.; Cookson Mark R author non-byline.; Corvol Jean-Christophe author non-byline.; Craig David W author non-byline.; Danjou Fabrice author non-byline.; Diez-Fairen Monica author non-byline.; Dols-Icardo Oriol author non-byline.; Duarte Jacinto author non-byline.; Duran Raquel author non-byline.; Escamilla-Sevilla Francisco author non-byline.; Escott-Price Valentina author non-byline.; Ezquerra Mario author non-byline.; Faghri Faraz author non-byline.; Feliz Cici author non-byline.; Fernández Manel author non-byline.; Fernández-Santiago Rubén author non-byline.; Finkbeiner Steven author non-byline.; Foltynie Thomas author non-byline.; Gan-Or Ziv author non-byline.; Garcia Ciara author non-byline.; García-Ruiz Pedro author non-byline.; Gasser Thomas author non-byline.; Gibbs J Raphael author non-byline.; Gomez Heredia Maria Jose author non-byline.; Gómez-Garre Pilar author non-byline.; González Manuel Menéndez author non-byline.; Gonzalez-Aramburu Isabel author non-byline.; Guelfi Sebastian author non-byline.; Guerreiro Rita author non-byline.; Hardy John author non-byline.; Hassin-Baer Sharon author non-byline.; Hernandez Dena G author non-byline.; Heutink Peter author non-byline.; Hoenicka Janet author non-byline.; Holmans Peter author non-byline.; Houlden Henry author non-byline.; Infante Jon author non-byline.; Iwaki Hirotaka author non-byline.; Jesús Silvia author non-byline.; Jimenez-Escrig Adriano author non-byline.; Kaishybayeva Gulnaz author non-byline.; Kaiyrzhanov Rauan author non-byline.; Karimova Altynay author non-byline.; Kia Demis A author non-byline.; Kinghorn Kerri J author non-byline.; Koks Sulev author non-byline.; Krohn Lynne author non-byline.; Kulisevsky Jaime author non-byline.; ALabrador-Espinosa Miguel author non-byline.; Leonard Hampton L author non-byline.; Lesage Suzanne author non-byline.; Lewis Patrick author non-byline.; Lopez-Sendon Jose Luis author non-byline.; Lovering Ruth author non-byline.; Lubbe Steven author non-byline.; Lungu Codrin author non-byline.; Macias Daniel author non-byline.; Majamaa Kari author non-byline.; Manzoni Claudia author non-byline.; Marín Juan author non-byline.; Marinus Johan author non-byline.; Marti Maria Jose author non-byline.; Martinez Maria author non-byline.; Torres Irene Martínez author non-byline.; Martínez-Castrillo Juan Carlos author non-byline.; Mata Marina author non-byline.; Mencacci Niccolo E author non-byline.; Méndez-del-Barrio Carlota author non-byline.; Middlehurst Ben author non-byline.; Mínguez Adolfo author non-byline.; Mir Pablo author non-byline.; Mok Kin Y author non-byline.; Morris Huw R author non-byline.; Muñoz Esteban author non-byline.; Nalls Mike A author non-byline.; Narendra Derek author non-byline.; Noyce Alastair J author non-byline.; Ojo Oluwadamilola O author non-byline.; Okubadejo Njideka U author non-byline.; Pagola Ana Gorostidi author non-byline.; Pastor Pau author non-byline.; Errazquin Francisco Perez author non-byline.; Periñán-Tocino Teresa author non-byline.; Pihlstrom Lasse author non-byline.; Plun-Favreau Helene author non-byline.; Quinn John author non-byline.; R'Bibo Lea author non-byline.; Reed Xylena author non-byline.; Rezola Elisabet Mondragon author non-byline.; Rizzu Patrizia author non-byline.; Robak Laurie author non-byline.; Rodriguez Antonio Sanchez author non-byline.; Ruiz-Martínez Javier author non-byline.; Ruz Clara author non-byline.; Ryten Mina author non-byline.; Sadykova Dinara author non-byline.; Scholz Sonja W author non-byline.; Schreglmann Sebastian author non-byline.; Schulte Claudia author non-byline.; Sharma Manu author non-byline.; Shashkin Chingiz author non-byline.; Shulman Joshua M author non-byline.; Sierra María author non-byline.; Siitonen Ari author non-byline.; Simón-Sánchez Javier author non-byline.; Singleton Andrew B author non-byline.; Suarez-Sanmartin Esther author non-byline.; Taba Pille author non-byline.; Tabernero Cesar author non-byline.; Tan Manuela X author non-byline.; Tartari Juan Pablo author non-byline.; Tejera-Parrado Cristina author non-byline.; Toft Mathias author non-byline.; Tolosa Eduard author non-byline.; Trabzuni Daniah author non-byline.; Valldeoriola Francesc author non-byline.; van Hilten Jacobus J author non-byline.; Keuren-Jensen Kendall Van author non-byline.; Vargas-González Laura author non-byline.; Vela Lydia author non-byline.; Vives Francisco author non-byline.; Williams Nigel author non-byline.; Wood Nicholas W author non-byline.; Zharkinbekova Nazira author non-byline.; Zharmukhanov Zharkyn author non-byline.; Zholdybayeva Elena author non-byline.; Zimprich Alexander author non-byline.; Ylikotila Pauli author non-byline.; Shulman Lisa M. author non-byline.; Coelln Rainervon author non-byline.; Reich Stephen author non-byline.; Savitt Joseph author non-byline.; Agee Michelle author non-byline.; Alipanahi Babak author non-byline.; Auton Adam author non-byline.; Bell Robert K. author non-byline.; Bryc Katarzyna author non-byline.; Elson Sarah L. author non-byline.; Fontanillas Pierre author non-byline.; Furlotte Nicholas A. author non-byline.; Huber Karen E. author non-byline.; Hicks Barry author non-byline.; Jewett Ethan M. author non-byline.; Jiang Yunxuan author non-byline.; Keng-Han Lin Aaron Kleinman author non-byline.; Litterman Nadia K. author non-byline.; McCreight Jennifer C. author non-byline.; McIntyre Matthew H. author non-byline.; McManus Kimberly F. author non-byline.; Mountain Joanna L. author non-byline.; Noblin Elizabeth S. author non-byline.; Northover Carrie A.M. author non-byline.; Pitts Steven J. author non-byline.; Poznik G. David author non-byline.; Sathirapongsasuti J. Fah author non-byline.; Shelton Janie F. author non-byline.; Shringarpure Suyash author non-byline.; Tian Chao author non-byline.; Vacic Vladimir author non-byline.; Wang Xin author non-byline.; Wilson Catherine H. author non-byline.; Anderson Tim author non-byline.; Bentley Steven author non-byline.; Dalrymple-Alford John author non-byline.; Fowdar Javed author non-byline.; Gratten Jacob author non-byline.; Halliday Glenda author non-byline.; Henders Anjali K. author non-byline.; Hickie Ian author non-byline.; Kassam Irfahan author non-byline.; Kennedy Martin author non-byline.; Kwok John author non-byline.; Lewis Simon author non-byline.; Mellick George author non-byline.; Montgomery Grant author non-byline.; Pearson John author non-byline.; Pitcher Toni author non-byline.; Sidorenko Julia author non-byline.; Silburn Peter A. author non-byline.; Vallerga Costanza L. author non-byline.; Visscher Peter M. author non-byline.; Wallace Leanne author non-byline.; Wray Naomi R. author non-byline.; Xue Angli author non-byline.; Yang Jian author non-byline.; Zhang Futao author non-byline.;
• Is Part Of: Journal of medical genetics. Volume 57:Issue 5(2020)
• Page Start: 331
• Page End: 338
• Publication Date: 2019-11-29
• Subjects: genetics -- parkinson-s disease -- clinical genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2019-106283
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Classical randomisation of clinical trial patients creates a source of genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was to quantify genetic difference between randomised trial arms and determine how imbalance can affect trial outcomes. Methods: 5851 patients with Parkinson's disease of European ancestry data and two simulated virtual cohorts based on public data were used. Data were resampled at different sizes for 1000 iterations and randomly assigned to the two arms of a simulated trial. False-negative and false-positive rates were estimated using simulated clinical trials, and per cent difference in genetic risk score (GRS) and allele frequency was calculated to quantify variance between arms. Results: 5851 patients with Parkinson's disease (mean (SD) age, 61.02 (12.61) years; 2095 women (35.81%)) as well as simulated patients from virtually created cohorts were used in the study. Approximately 90% of the iterations had at least one statistically significant difference in individual risk SNPs between each trial arm. Approximately 5%–6% of iterations had a statistically significant difference between trial arms in mean GRS. For significant iterations, the average per cent difference for mean GRS between trial arms was 130.87%, 95% CI 120.89 to 140.85 (n=200). Glucocerebrocidase (GBA) gene-only simulations see an average 18.86%, 95% CI 18.01 to 19.71 difference in GRS scores between trial arms (n=50). When adding a drug effect of −0.5 points in MDS-UPDRS per year at n=50, 33.9% of trials resulted in false negatives. Conclusions: Our data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects as expected. Clinical trials should undergo pretrial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials.