Hierarchical data-driven analysis of clinical symptoms among patients with Parkinson's disease

Tal Kozlovski, Alexis Mitelpunkt, Avner Thaler, Tanya Gurevich, Avi Orr-Urtreger, Mali Gana-Weisz, Netta Shachar, Tal Galili, Mira Marcus-Kalish, Susan Bressman, Karen Marder, Nir Giladi, Yoav Benjamini, Anat Mirelman

Research output: Contribution to journalArticlepeer-review


Mutations in the LRRK2 and GBA genes are the most common inherited causes of Parkinson's disease (PD). Studies exploring phenotypic differences based on genetic status used hypothesis-driven data-gathering and statistical-analyses focusing on specific symptoms, which may influence the validity of the results. We aimed to explore phenotypic expression in idiopathic PD (iPD) patients, G2019S-LRRK2-PD, and GBA-PD using a data-driven approach, allowing screening of large numbers of features while controlling selection bias. Data was collected from 1525 Ashkenazi Jews diagnosed with PD from the Tel-Aviv Medical center; 161 G2019S-LRRK2-PD, 222 GBA-PD, and 1142 iPD (no G2019S-LRRK2 or any of the 7 AJ GBA mutations tested). Data included 771 measures: demographics, cognitive, physical and neurological functions, performance-based measures, and non-motor symptoms. The association of the genotypes with each of the measures was tested while accounting for age at motor symptoms onset, gender, and disease duration; p-values were reported and corrected in a hierarchical approach for an average over the selected measures false discovery rate control, resulting in 32 measures. GBA-PD presented with more severe symptoms expression while LRRK2-PD had more benign symptoms compared to iPD. GBA-PD presented greater cognitive and autonomic involvement, more frequent hyposmia and REM sleep behavior symptoms while these were less frequent among LRRK2-PD compared to iPD. Using a data-driven analytical approach strengthens earlier studies and extends them to portray a possible unique disease phenotype based on genotype among AJ PD. Such findings could help direct a more personalized therapeutic approach.

Original languageEnglish
Article number531
JournalFrontiers in Neurology
Issue numberMAY
StatePublished - 1 Jan 2019


  • G2019S-LRRK2
  • GBA
  • Hierarchical testing
  • Parkinson's disease
  • Selective inference

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology


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