Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases.

Population-scale biobanks that combine genetic data and high-dimensional phenotyping for a large number of participants provide an exciting opportunity to perform genome-wide association studies (GWAS) to identify genetic variants associated with diverse quantitative traits and diseases. A major challenge for GWAS in population biobanks is ascertaining disease cases from heterogeneous data sources such as hospital records, digital questionnaire responses, or interviews. In this study, we use genetic parameters, including genetic correlation, to evaluate whether GWAS performed using cases in the UK Biobank ascertained from hospital records, questionnaire responses, and family history of disease implicate similar disease genetics across a range of effect sizes. We find that hospital record and questionnaire GWAS largely identify similar genetic effects for many complex phenotypes and that combining together both phenotyping methods improves power to detect genetic associations. We also show that family history GWAS using cases ascertained on family history of disease agrees with combined hospital record and questionnaire GWAS and that family history GWAS has better power to detect genetic associations for some phenotypes. Overall, this work demonstrates that digital phenotyping and unstructured phenotype data can be combined with structured data such as hospital records to identify cases for GWAS in biobanks and improve the ability of such studies to identify genetic associations.

Repurposing biomedical informaticians for COVID-19.

The COVID-19 pandemic is an unprecedented challenge to the biomedical research community at the intersection of great uncertainty due to the novelty of the virus and extremely high stakes due to the large global death count. The global quarantine shut-downs complicated scientific matters because many laboratories were closed down unless they were actively doing COVID-19 related research, making repurposing of activities difficult for many biomedical researchers. Biomedical informaticians, who have been primarily able to continue their research through remote work and video conferencing, have been able to maintain normal activities. In addition to continuing ongoing studies, there has been great grass roots interest in helping in the fight against COVID-19. In this commentary, we describe several projects that arose from this desire to help, and the lessons that the authors learned along the way. We then offer some insights into how these lessons might be applied to make scientific progress be more efficient in future crisis scenarios.

Quantifying the Severity of Adverse Drug Reactions Using Social Media: Network Analysis.

BACKGROUND: Adverse drug reactions (ADRs) affect the health of hundreds of thousands of individuals annually in the United States, with associated costs of hundreds of billions of dollars. The monitoring and analysis of the severity of ADRs is limited by the current qualitative and categorical systems of severity classification. Previous efforts have generated quantitative estimates for a subset of ADRs but were limited in scope because of the time and costs associated with the efforts. OBJECTIVE: The aim of this study is to increase the number of ADRs for which there are quantitative severity estimates while improving the quality of these severity estimates. METHODS: We present a semisupervised approach that estimates ADR severity by using social media word embeddings to construct a lexical network of ADRs and perform label propagation. We used this method to estimate the severity of 28,113 ADRs, representing 12,198 unique ADR concepts from the Medical Dictionary for Regulatory Activities. RESULTS: Our Severity of Adverse Events Derived from Reddit (SAEDR) scores have good correlations with real-world outcomes. The SAEDR scores had Spearman correlations of 0.595, 0.633, and -0.748 for death, serious outcome, and no outcome, respectively, with ADR case outcomes in the Food and Drug Administration Adverse Event Reporting System. We investigated different methods for defining initial seed term sets and evaluated their impact on the severity estimates. We analyzed severity distributions for ADRs based on their appearance in boxed warning drug label sections, as well as for ADRs with sex-specific associations. We found that ADRs discovered in the postmarketing period had significantly greater severity than those discovered during the clinical trial (P<.001). We created quantitative drug-risk profile (DRIP) scores for 968 drugs that had a Spearman correlation of 0.377 with drugs ranked by the Food and Drug Administration Adverse Event Reporting System cases resulting in death, where the given drug was the primary suspect. CONCLUSIONS: Our SAEDR and DRIP scores are well correlated with the real-world outcomes of the entities they represent and have demonstrated utility in pharmacovigilance research. We make the SAEDR scores for 12,198 ADRs and the DRIP scores for 968 drugs publicly available to enable more quantitative analysis of pharmacovigilance data.

Pharmacogenomics and big genomic data: from lab to clinic and back again.

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.

Global Biobank Engine: enabling genotype-phenotype browsing for biobank summary statistics.

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.

RedMed: Extending drug lexicons for social media applications.

Social media has been identified as a promising potential source of information for pharmacovigilance. The adoption of social media data has been hindered by the massive and noisy nature of the data. Initial attempts to use social media data have relied on exact text matches to drugs of interest, and therefore suffer from the gap between formal drug lexicons and the informal nature of social media. The Reddit comment archive represents an ideal corpus for bridging this gap. We trained a word embedding model, RedMed, to facilitate the identification and retrieval of health entities from Reddit data. We compare the performance of our model trained on a consumer-generated corpus against publicly available models trained on expert-generated corpora. Our automated classification pipeline achieves an accuracy of 0.88 and a specificity of >0.9 across four different term classes. Of all drug mentions, an average of 79% (±0.5%) were exact matches to a generic or trademark drug name, 14% (±0.5%) were misspellings, 6.4% (±0.3%) were synonyms, and 0.13% (±0.05%) were pill marks. We find that our system captures an additional 20% of mentions; these would have been missed by approaches that rely solely on exact string matches. We provide a lexicon of misspellings and synonyms for 2978 drugs and a word embedding model trained on a health-oriented subset of Reddit.

A New Era in Pharmacovigilance: Toward Real-World Data and Digital Monitoring.

Adverse drug reactions (ADRs) are a major concern for patients, clinicians, and regulatory agencies. The discovery of serious ADRs leading to substantial morbidity and mortality has resulted in mandatory phase IV clinical trials, black box warnings, and withdrawal of drugs from the market. Real-world data, data collected during routine clinical care, is being adopted by innovators, regulators, payors, and providers to inform decision making throughout the product life cycle. We outline several different approaches to modern pharmacovigilance, including spontaneous reporting databases, electronic health record monitoring and research frameworks, social media surveillance, and the use of digital devices. Some of these platforms are well-established while others are still emerging or experimental. We highlight both the potential opportunity, as well as the existing challenges within these pharmacovigilance systems that have already begun to impact the drug development process, as well as the landscape of postmarket drug safety monitoring. Further research and investment into different and complementary pharmacovigilance systems is needed to ensure the continued safety of pharmacotherapy.

Pharmacogenetics at Scale: An Analysis of the UK Biobank.

Pharmacogenetics (PGx) studies the influence of genetic variation on drug response. Clinically actionable associations inform guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), but the broad impact of genetic variation on entire populations is not well understood. We analyzed PGx allele and phenotype frequencies for 487,409 participants in the UK Biobank, the largest PGx study to date. For 14 CPIC pharmacogenes known to influence human drug response, we find that 99.5% of individuals may have an atypical response to at least 1 drug; on average they may have an atypical response to 10.3 drugs. Nearly 24% of participants have been prescribed a drug for which they are predicted to have an atypical response. Non-European populations carry a greater frequency of variants that are predicted to be functionally deleterious; many of these are not captured by current PGx allele definitions. Strategies for detecting and interpreting rare variation will be critical for enabling broad application of pharmacogenetics.

#Science: The Potential and the Challenges of Utilizing Social Media and Other Electronic Communication Platforms in Health Care.

Electronic communication is becoming increasingly popular worldwide, as evidenced by its widespread and rapidly growing use. In medicine, however, it remains a novel approach to reach out to patients. Yet, they have the potential for further improving current health care. Electronic platforms could support therapy adherence and communication between physicians and patients. The power of social media as well as other electronic devices can improve adherence as evidenced by the development of the app bant. Additionally, systemic analysis of social media content by Screenome can identify health events not always captured by regular health care. By better identifying these healthcare events we can improve our current healthcare system as we will be able to better tailor to the patients' needs. All these techniques are a valuable component of modern health care and will help us into the future of increasingly digital health care.

Pharmacogenomics Clinical Annotation Tool (PharmCAT).

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 the Clinical Pharmacogenetics Implementation Consortium (CPIC), the US Food and Drug Administration (FDA), the Pharmacogenomics Knowledgebase (PharmGKB), etc. Pharmacogenomics Clinical Annotation Tool (PharmCAT) (i) extracts variants specified in guidelines from a genetic data set derived from sequencing or genotyping technologies, (ii) infers haplotypes and diplotypes, and (iii) generates a report containing genotype/diplotype-based annotations and guideline recommendations. We describe PharmCAT and a pilot validation project comparing results for 1000 Genomes Project 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.

Genome-Wide Analysis of Cell Cycle-Regulating Genes in the Symbiotic Dinoflagellate Breviolum minutum.

A delicate relationship exists between reef-building corals and their photosynthetic endosymbionts. Unfortunately, this relationship can be disrupted, with corals expelling these algae when temperatures rise even marginally above the average summer maximum. Interestingly, several studies indicate that failure of corals to regulate symbiont cell divisions at high temperatures may underlie this disruption; increased proliferation of symbionts may stress host cells by over-production of reactive oxygen species or by disrupting the flow of nutrients. This needs to be further investigated, so to begin deciphering the molecular mechanisms controlling the cell cycle in these organisms, we used a computational approach to identify putative cell cycle-regulating genes in the genome of the dinoflagellate Breviolum minutum This species is important as an endosymbiont of Aiptasia pallida-an anemone that is used as a model for studying coral biology. We then correlated expression of these putative cell cycle genes with cell cycle phase in diurnally growing B. minutum in culture. This approach allowed us to identify a cyclin/cyclin-dependent kinase pair that may function in the G1/S transition-a likely point for coral cells to exert control over algal cell divisions.

Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting and insertion of tail-anchored proteins.

The small molecule Retro-2 prevents ricin toxicity through a poorly-defined mechanism of action (MOA), which involves halting retrograde vesicle transport to the endoplasmic reticulum (ER). CRISPRi genetic interaction analysis revealed Retro-2 activity resembles disruption of the transmembrane domain recognition complex (TRC) pathway, which mediates post-translational ER-targeting and insertion of tail-anchored (TA) proteins, including SNAREs required for retrograde transport. Cell-based and in vitro assays show that Retro-2 blocks delivery of newly-synthesized TA-proteins to the ER-targeting factor ASNA1 (TRC40). An ASNA1 point mutant identified using CRISPR-mediated mutagenesis abolishes both the cytoprotective effect of Retro-2 against ricin and its inhibitory effect on ASNA1-mediated ER-targeting. Together, our work explains how Retro-2 prevents retrograde trafficking of toxins by inhibiting TA-protein targeting, describes a general CRISPR strategy for predicting the MOA of small molecules, and paves the way for drugging the TRC pathway to treat broad classes of viruses known to be inhibited by Retro-2.

Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.

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.

Frameshift indels introduced by genome editing can lead to in-frame exon skipping.

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.