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Original research
Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease
  1. Hampton Leonard1,2,
  2. Cornelis Blauwendraat1,
  3. Lynne Krohn3,
  4. Faraz Faghri1,4,
  5. Hirotaka Iwaki1,5,
  6. Glen Ferguson6,
  7. Aaron G Day-Williams7,
  8. David J Stone7,
  9. Andrew B Singleton1,
  10. Mike A Nalls1,2,
  11. Ziv Gan-Or3,8
  12. On behalf of the International Parkinson's Disease Genomic Consortium (IPDGC)
    1. 1 National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
    2. 2 Data Tecnica International, Glen Echo, Maryland, USA
    3. 3 Department of Human Genetics, McGill University, Montreal, Québec, Canada
    4. 4 University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
    5. 5 Michael J Fox Foundation for Parkinson's Research, New York, New York, USA
    6. 6 Caserta Concepts LLC, New York City, New York, USA
    7. 7 Merck and Co, Boston, Massachusetts, USA
    8. 8 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada
    1. Correspondence to Dr Ziv Gan-Or, McGill University, Montreal, QC H3A 1A1, Canada; ziv.gan-or{at}; Dr Mike A Nalls, Data Tecnica International, Glen Echo, MD, USA; mike{at}


    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.

    • genetics
    • parkinson-s disease
    • clinical genetics

    Statistics from


    • MAN and ZG-O contributed equally.

    • Contributors MAN and ZG-O conceived the study. MAN, ZG-O and HL contributed to study design. MAN and HL contributed to data analysis. MAN, ZG-O and HL contributed to data interpretation. MAN and CB contributed to data management and storage. HL drafted the manuscript and MAN, ZG-O, CB, LK, FF, HI, GF, AGD-W, DJS, IPDGC and ABS performed critical review and additional writing. All authors gave approval for publication.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests ZG-O reports personal fees from Sanofi/Genzyme, Lysosomal Therapeutics, Idorsia, Denali, Prevail Therapeutics, Ventus, Deerfield and Allergan. ZG-O is also supported by the Fonds de recherche du Québec-Santé (FRQS) Chercheurs-boursiers award given in collaboration with Parkinson Quebec, and is a Parkinson Canada New Investigator awardee. AGD-W reports personal fees from Merck and Co and other from Biogen. DJS reports funding from Merck and Co.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available in a public, open access repository.

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