title: Towards causally cohesive genotype-phenotype modelling for characterization of the soft-tissue mechanics of the heart in normal and pathological geometries.
abstract: A scientific understanding of individual variation is key to personalized medicine, integrating genotypic and phenotypic information via computational physiology. Genetic effects are often context-dependent, differing between genetic backgrounds or physiological states such as disease. Here, we analyse in silico genotype-phenotype maps (GP map) for a soft-tissue mechanics model of the passive inflation phase of the heartbeat, contrasting the effects of microstructural and other low-level parameters assumed to be genetically influenced, under normal, concentrically hypertrophic and eccentrically hypertrophic geometries. For a large number of parameter scenarios, representing mock genetic variation in low-level parameters, we computed phenotypes describing the deformation of the heart during inflation. The GP map was characterized by variance decompositions for each phenotype with respect to each parameter. As hypothesized, the concentric geometry allowed more low-level parameters to contribute to variation in shape phenotypes. In addition, the relative importance of overall stiffness and fibre stiffness differed between geometries. Otherwise, the GP map was largely similar for the different heart geometries, with little genetic interaction between the parameters included in this study. We argue that personalized medicine can benefit from a combination of causally cohesive genotype-phenotype modelling, and strategic phenotyping that captures effect modifiers not explicitly included in the mechanistic model.
authors.affiliation: Department of Mathematical Sciences and Technology, Norwegian University of Life Sciences, PO Box 5003, 1432 Ås, Norway.
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Nordbø
authors.affiliation: Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, PO Box 5003, 1432 Ås, Norway.
authors.forename: Arne B
authors.initials: AB
authors.lastname: Gjuvsland
authors.affiliation: International Research Institute of Stavanger, PO Box 8046, 4068 Stavanger, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Nermoen
authors.affiliation: Biomedical Engineering Department, King's College London, London SE1 7EH, UK.
authors.forename: Sander
authors.initials: S
authors.lastname: Land
authors.affiliation: Biomedical Engineering Department, King's College London, London SE1 7EH, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Niederer
authors.affiliation: Biomedical Engineering Department, King's College London, London SE1 7EH, UK.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lamata
authors.affiliation: Biomedical Engineering Department, King's College London, London SE1 7EH, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Lee
authors.affiliation: Biomedical Engineering Department, King's College London, London SE1 7EH, UK.
authors.forename: Nicolas P
authors.initials: NP
authors.lastname: Smith
authors.affiliation: Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, NTNU Norwegian University of Science and Technology, PO Box 8905, 7491 Trondheim, Norway.
authors.forename: Stig W
authors.initials: SW
authors.lastname: Omholt
authors.affiliation: Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, PO Box 5003, 1432 Ås, Norway jonovik@gmail.com.
authors.forename: Jon Olav
authors.identifier: http://orcid.org/0000-0002-7778-4515
authors.initials: JO
authors.lastname: Vik
mesh_terms: D000818:Animals; D005075:Biological Evolution; D003198:Computer Simulation; D055119:Elastic Modulus; D005838:Genotype; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008955:Models, Cardiovascular; D008957:Models, Genetic; D010641:Phenotype; D013314:Stress, Mechanical; D018487:Ventricular Dysfunction, Left / Q000473:pathology* / Q000503:physiopathology*
keywords: finite elasticity; genotype–phenotype map; ventricular mechanics
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