Russ Altman, Doctoral Dissertation Advisor (AC)
Pharmacogenomics Clinical Annotation Tool (PharmCAT).
Clinical pharmacology and therapeutics
Pharmacogenomics (PGx) decision support and return of results is an active area of precision medicine. One challenge of implementing PGx is extracting genomic variants and assigning haplotypes in order to apply prescribing recommendations and information from CPIC, FDA, PharmGKB, etc. PharmCAT (1) extracts variants specified in guidelines from a genetic dataset derived from sequencing or genotyping technologies; (2) infers haplotypes and diplotypes; and (3) generates a report containing genotype/diplotype-based annotations and guideline recommendations. We describe PharmCAT and a pilot validation project comparing results for 1000 Genomes sequences of Coriell samples with corresponding Genetic Testing Reference Materials Coordination Program (GeT-RM) sample characterization. PharmCAT was highly concordant with the GeT-RM data. PharmCAT is available in GitHub to evaluate, test and report results back to the community. As precision medicine becomes more prevalent, our ability to consistently, accurately, and clearly define and report PGx annotations and prescribing recommendations is critical. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/cpt.1568
View details for PubMedID 31306493
Global Biobank Engine: enabling genotype-phenotype browsing for biobank summary statistics.
Bioinformatics (Oxford, England)
Summary: Large biobanks linking phenotype to genotype have led to an explosion of genetic association studies across a wide range of phenotypes. Sharing the knowledge generated by these resources with the scientific community remains a challenge due to patient privacy and the vast amount of data. Here we present Global Biobank Engine (GBE), a web-based tool that enables exploration of the relationship between genotype and phenotype in biobank cohorts, such as the UK Biobank. GBE supports browsing for results from genome-wide association studies, phenome-wide association studies, gene-based tests, and genetic correlation between phenotypes. We envision GBE as a platform that facilitates the dissemination of summary statistics from biobanks to the scientific and clinical communities.Availability and implementation: GBE currently hosts data from the UK Biobank and can be found freely available at biobankengine.stanford.edu.
View details for PubMedID 30520965
Pharmacogenomics and big genomic data: from lab to clinic and back again.
Human molecular genetics
2018; 27 (R1): R72–R78
The field of pharmacogenomics is an area of great potential for near-term human health impacts from the big genomic data revolution. Pharmacogenomics research momentum is building with numerous hypotheses currently being investigated through the integration of molecular profiles of different cell lines and large genomic data sets containing information on cellular and human responses to therapies. Additionally, the results of previous pharmacogenetic research efforts have been formulated into clinical guidelines that are beginning to impact how healthcare is conducted on the level of the individual patient. This trend will only continue with the recent release of new datasets containing linked genotype and electronic medical record data. This review discusses key resources available for pharmacogenomics and pharmacogenetics research and highlights recent work within the field.
View details for PubMedID 29635477
Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study
2018; 9: 1612
Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as "human knockouts," across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.
View details for PubMedID 29691392
Frameshift indels introduced by genome editing can lead to in-frame exon skipping.
2017; 12 (6)
The introduction of frameshift indels by genome editing has emerged as a powerful technique to study the functions of uncharacterized genes in cell lines and model organisms. Such mutations should lead to mRNA degradation owing to nonsense-mediated mRNA decay or the production of severely truncated proteins. Here, we show that frameshift indels engineered by genome editing can also lead to skipping of "multiple of three nucleotides" exons. Such splicing events result in in-frame mRNA that may encode fully or partially functional proteins. We also characterize a segregating nonsense variant (rs2273865) located in a "multiple of three nucleotides" exon of LGALS8 that increases exon skipping in human erythroblast samples. Our results highlight the potentially frequent contribution of exonic splicing regulatory elements and are important for the interpretation of negative results in genome editing experiments. Moreover, they may contribute to a better annotation of loss-of-function mutations in the human genome.
View details for DOI 10.1371/journal.pone.0178700
View details for PubMedID 28570605