1.
Gottlieb, Assaf, et al.
(author)
Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans
2017
In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 9:1
Journal article (peer-reviewed) abstract
Background: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects. Methods: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. Results: We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Conclusions: Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort.
2.
Hamberg, Anna-Karin, 1964-, et al.
(author)
Warfarin dose prediction in children using pharmacometric bridging : comparison with published pharmacogenetic dosing algorithms
2013
In: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 69:6, s. 1275-1283
Journal article (peer-reviewed) abstract
PurposeNumerous studies have investigated causes of warfarin dose variability in adults whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children.MethodAn adult population PK/PD-model for warfarin, with CYP2C9 and VKORC1 genotype, age and target INR as dose predictors, was bridged to children using allometric scaling methods. Its predictive properties were evaluated in an external dataset of children 0-18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children.ResultsOverall, the bridged model predicted INR response well in 64 warfarin treated Swedish children (median age 4.3 years), but with a tendency to over predict INR in children ≤ 2 years old. The bridged model predicted 20 of 49 children (41%) within ± 20% of actual maintenance dose (median age 7.2 years). In comparison the published dosing algorithms predicted 33-41% of the children within ± 20% of actual dose. Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within ± 20% of actual dose to 70%.ConclusionA mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.
3.
Wadelius, Mia, et al.
(author)
Phenotype Standardization of Angioedema in the Head and Neck Region Caused by Agents Acting on the Angiotensin System
2014
In: Clinical Pharmacology and Therapeutics. - : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 96:4, s. 477-481
Research review (peer-reviewed) abstract
Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.
