Power and optimal study design in iPSC-based brain disease modelling

Jessie W Brunner; Hanna C A Lammertse; Annemiek A van Berkel; Frank Koopmans; Ka Wan Li; August B Smit; Ruud F Toonen; Matthijs Verhage; Sophie van der Sluis

doi:10.1038/s41380-022-01866-3

Power and optimal study design in iPSC-based brain disease modelling

Jessie W Brunner, Hanna C A Lammertse, Annemiek A van Berkel, Frank Koopmans, Ka Wan Li, August B Smit, Ruud F Toonen, Matthijs Verhage, Sophie van der Sluis

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Studies using induced pluripotent stem cells (iPSCs) are gaining momentum in brain disorder modelling, but optimal study designs are poorly defined. Here, we compare commonly used designs and statistical analysis for different research aims. Furthermore, we generated immunocytochemical, electrophysiological, and proteomic data from iPSC-derived neurons of five healthy subjects, analysed data variation and conducted power simulations. These analyses show that published case-control iPSC studies are generally underpowered. Designs using isogenic iPSC lines typically have higher power than case-control designs, but generalization of conclusions is limited. We show that, for the realistic settings used in this study, a multiple isogenic pair design increases absolute power up to 60% or requires up to 5-fold fewer lines. A free web tool is presented to explore the power of different study designs, using any (pilot) data.

Original language	English
Pages (from-to)	1-12
Number of pages	12
Journal	Molecular Psychiatry
Volume	28
Issue number	4
Early online date	16 Nov 2022
DOIs	https://doi.org/10.1038/s41380-022-01866-3
Publication status	Published - Apr 2023

Bibliographical note

Funding

MV was supported by a European Research Council (ERC) Advanced grant (322966) of the European Union (to MV), COSYN (Comorbidity and Synapse Biology in Clinically Overlapping Psychiatric Disorders; Horizon 2020 Program of the European Union under RIA grant agreement 667301 to MV), ZonMW program Brainmodel (Psider 10250022110003), and PreSSAD consortium (ZonMW/EU JPND/JPco-fuND-2, 733051137). RFT was supported by the Netherlands Scientific Organisation and De Hersenstichting (013-17-002), under the frame of the Neuron Cofund ERA-Net SNAREopathy. ABS, MV and SvdS were supported by the NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetic to Neurobiology (NWO: 024.004.012). The authors thank Vivi Heine for providing iPSC lines, Desiree Schut and Lisa Laan for assistance in the culture of iPSC-derived neurons and preparation of glia feeder plates, Robbert Zalm for cloning and production of lentiviral particles, and Marieke Meijer for help with patch-clamp recording of SH-NGN2 neurons. We thank Vincent Huson for developing scripts used for analysis of the electrophysiological data, Josefin Werme for assistance in the analysis of copy number variants from SNP arrays for quality control purposes, and Iryna Paliukhovich for expert help with the mass spectrometry experiment. We thank Conor Dolan for input regarding the statistical analysis approaches.

Funders	Funder number
Netherlands Scientific Organisation and De Hersenstichting	013-17-002
SNP
European Commission
European Research Council	322966
Royal Irish Academy	667301
ZonMw	10250022110003, 733051137, JPND/JPco-fuND-2
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.004.012

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abstract = "Studies using induced pluripotent stem cells (iPSCs) are gaining momentum in brain disorder modelling, but optimal study designs are poorly defined. Here, we compare commonly used designs and statistical analysis for different research aims. Furthermore, we generated immunocytochemical, electrophysiological, and proteomic data from iPSC-derived neurons of five healthy subjects, analysed data variation and conducted power simulations. These analyses show that published case-control iPSC studies are generally underpowered. Designs using isogenic iPSC lines typically have higher power than case-control designs, but generalization of conclusions is limited. We show that, for the realistic settings used in this study, a multiple isogenic pair design increases absolute power up to 60% or requires up to 5-fold fewer lines. A free web tool is presented to explore the power of different study designs, using any (pilot) data.",

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AU - Li, Ka Wan

AU - Smit, August B

AU - Toonen, Ruud F

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AU - van der Sluis, Sophie

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Power and optimal study design in iPSC-based brain disease modelling

Abstract

Bibliographical note

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