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Emerging Therapeutic Approaches for Cystic Fibrosis

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01490

Variable responses to CFTR correctors in vitro: Estimating the design effect in precision medicine

 Elizabeth Matthes1, 2, Julie Goepp1, 2, Carolina Martini1, 2,  Jiajie Shan1, 2,  Jie Liao1, 2,  David Y. Thomas2, 3 and  John W. Hanrahan2, 4, 5*
  • 1Department of Psychology, McGill University, Canada
  • 2Cystic Fibrosis Translational Research Centre (CFTRc), Canada
  • 3Department of Biochemistry, McGill University, Canada
  • 4Physiology, McGill University, Canada
  • 5Research Institute of the McGill University Health Center, Canada

Interest in precision medicine has grown in recent years due to the variable clinical benefit provided by some medications, their cost, and by new opportunities to tailor therapies to individual patients. In cystic fibrosis (CF) it may soon be possible to test several corrector drugs that improve the folding and functional expression of mutant CFTR prospectively using cells from a patient to find the one that is best for that individual. Patient-to-patient variation in cell culture responses to correctors and the reproducibility of those responses has not been studied quantitatively. We measured the functional correction provided by lumacaftor (VX-809) using bronchial epithelial cells from 20 patients homozygous for the F508del-CFTR mutation. Significant differences were observed between individuals, supporting the utility of prospective testing. However, when correction of F508del-CFTR was measured repeatedly using cell aliquots from the same individuals, a design effect was observed that would impact statistical tests of significance. The results suggest that the sample size obtained from power calculations should be increased to compensate for the group sampling effect when CFTR corrector drugs are compared in vitro for precision medicine.

Keywords: precision medicine, Cystic Fibrosis, correctors, Orkambi®, Group sampling, Design effect, power calculations, personalized medicine

Received: 03 Oct 2018; Accepted: 05 Dec 2018.

Edited by:

Nicoletta Pedemonte, Istituto Giannina Gaslini (IRCCS), Italy

Reviewed by:

Oscar Moran, Istituto di biofisica (IBF), Italy
David N. Sheppard, University of Bristol, United Kingdom
Deborah M. Cholon, University of North Carolina at Chapel Hill, United States  

Copyright: © 2018 Matthes, Goepp, Martini, Shan, Liao, Thomas and Hanrahan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. John W. Hanrahan, McGill University, Physiology, Montreal, H3G 1Y6, Quebec, Canada,