Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Evaluating Reporting Completeness of Patient-Reported Outcomes in Esophageal Motility Disorders: A Cross-Sectional Analysis of Randomized Controlled Trials.

Esophageal motility disorders (EMD) can have significant effects on quality of life. Patient-reported outcomes (PROs) provide valuable insight into the patient's perspective on their treatment and are becoming increasingly used in randomized controlled trials (RCTs). Thus, our investigation aims to evaluate the completeness of reporting of PROs in RCTs pertaining to EMDs. We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for published RCTs focused on EMDs. Included RCTs were published between 2006 and 2020, reported a primary outcome related to an EMDs, and listed at least one PRO measure as a primary or secondary outcome. Investigators screened and extracted data in a masked, duplicate fashion. Data extraction was carried out using both the CONSORT-PRO adaptation and Cochrane Collaboration Risk of Bias 2.0 tool. We assessed overall mean percent completion of the CONSORT-PRO adaptation and a bivariate regression analysis was used to assess relationships between trial characteristics and completeness of reporting. The overall mean percent completion of the CONSORT-PRO checklist adaptation was 43.86% (SD = 17.03). RCTs with a primary PRO had a mean completeness of 47.73% (SD = 17.32) and RCTs with a secondary PRO was 35.36% (SD = 13.52). RCTs with a conflict of interest statement were 18.15% (SE = 6.5) more complete (t = 2.79, P = .009) than trials lacking a statement. No additional significant associations between trial characteristics and completeness of reporting were found. PRO reporting completeness in RCTs focused on EMDs was inadequate. We urge EMD researchers to prioritize complete PRO reporting to foster patient-centered research for future RCTs on EMDs.

Discovery and characterization of two new stem rust resistance genes in Aegilops sharonensis.

KEY MESSAGE: We identified two novel wheat stem rust resistance genes, Sr-1644-1Sh and Sr-1644-5Sh in Aegilops sharonensis that are effective against widely virulent African races of the wheat stem rust pathogen. Stem rust is one of the most important diseases of wheat in the world. When single stem rust resistance (Sr) genes are deployed in wheat, they are often rapidly overcome by the pathogen. To this end, we initiated a search for novel sources of resistance in diverse wheat relatives and identified the wild goatgrass species Aegilops sharonesis (Sharon goatgrass) as a rich reservoir of resistance to wheat stem rust. The objectives of this study were to discover and map novel Sr genes in Ae. sharonensis and to explore the possibility of identifying new Sr genes by genome-wide association study (GWAS). We developed two biparental populations between resistant and susceptible accessions of Ae. sharonensis and performed QTL and linkage analysis. In an F6 recombinant inbred line and an F2 population, two genes were identified that mapped to the short arm of chromosome 1Ssh, designated as Sr-1644-1Sh, and the long arm of chromosome 5Ssh, designated as Sr-1644-5Sh. The gene Sr-1644-1Sh confers a high level of resistance to race TTKSK (a member of the Ug99 race group), while the gene Sr-1644-5Sh conditions strong resistance to TRTTF, another widely virulent race found in Yemen. Additionally, GWAS was conducted on 125 diverse Ae. sharonensis accessions for stem rust resistance. The gene Sr-1644-1Sh was detected by GWAS, while Sr-1644-5Sh was not detected, indicating that the effectiveness of GWAS might be affected by marker density, population structure, low allele frequency and other factors.

Phasing millions of samples achieves near perfect accuracy, enabling parent-of-origin classification of variants.

Haplotype phasing, the process of determining which genetic variants are physically located on the same chromosome, is crucial for various genetic analyses. In this study, we first benchmark SHAPEIT and Beagle, two state-of-the-art phasing methods, on two large datasets: > 8 million diverse, research-consented 23andMe, Inc. customers and the UK Biobank (UKB). We find that both perform exceptionally well. Beagle's median switch error rate (SER) (after excluding single SNP switches) in white British trios from UKB is 0.026% compared to 0.00% for European ancestry 23andMe research participants; 55.6% of European ancestry 23andMe research participants have zero non-single SNP switches, compared to 42.4% of white British trios. South Asian ancestry 23andMe research participants have the highest median SER amongst the 23andMe populations, but it is still remarkably low at 0.46%. We also investigate the relationship between identity-by-descent (IBD) and SER, finding that switch errors tend to occur in regions of little or no IBD segment coverage. SHAPEIT and Beagle excel at 'intra-chromosomal' phasing, but lack the ability to phase across chromosomes, motivating us to develop an inter-chromosomal phasing method, called HAPTIC ( HAP lotype TI ling and C lustering), that assigns paternal and maternal variants discretely genome-wide. Our approach uses identity-by-descent (IBD) segments to phase blocks of variants on different chromosomes. HAPTIC represents the segments a focal individual shares with their relatives as nodes in a signed graph and performs bipartite clustering on the signed graph using spectral clustering. We test HAPTIC on 1022 UKB trios, yielding a median phase error of 0.08% in regions covered by IBD segments (33.5% of sites). We also ran HAPTIC in the 23andMe database and found a median phase error rate (the rate of mismatching alleles between the inferred and true phase) of 0.92% in Europeans (93.8% of sites) and 0.09% in admixed Africans (92.7% of sites). HAPTIC's precision depends heavily on data from relatives, so will increase as datasets grow larger and more diverse. HAPTIC enables analyses that require the parent-of-origin of variants, such as association studies and ancestry inference of untyped parents.

Reporting of patient-reported outcomes in trials on alcohol use disorder: a meta-epidemiological study.

OBJECTIVES: Currently, limited research exists to assess the extent of patient-reported outcome (PRO) reporting among randomised controlled trials (RCTs) evaluating alcohol use disorder (AUD). We sought to investigate the completeness of reporting of PROs using the Consolidated Standards of Reporting Trials-PRO (CONSORT-PRO) extension in AUD RCTs. DESIGN SETTING: Meta-epidemiological study. METHODS: We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) on 29 June 2021 for published RCTs focused on AUD. Following these searches, title and abstract screening, and full-text screening were performed by two investigators. To be included, a study must have employed a randomised trial design, published in English, focused on treatment of AUD and included at least one PRO. Trials meeting inclusion criteria were evaluated for completeness of reporting using the CONSORT-PRO extension adaptation. These trials were also evaluated for risk of bias (RoB) using the Cochrane RoB V.2.0 tool. Additionally, an exploratory analysis of each RCT's therapeutic area was extracted using the Mapi Research Trust's ePROVIDE platform. Screening and data collection were all performed in masked, duplicate fashion. MAIN OUTCOME MEASURES: PRO completeness of reporting, identification of factors associated with completeness of reporting and PRO measures used in RCTs to evaluate patients with AUD. RESULTS: Nineteen RCTs were evaluated in our analysis. Our primary outcome, the mean completion score for CONSORT-PRO, was 40.8%. Our secondary outcome-the identification of factors associated with completeness of reporting-found that trials published after 2014 (ie, 1 year after the publication of the CONSORT-PRO extension) were 15.0% more complete than trials published before 2014. We found no additional associations with better reporting. CONCLUSIONS: We found that the completeness of PRO reporting in RCTs involving AUD was deficient. Complete reporting of PROs is instrumental in understanding the effects of interventions, encourages patient participation in their treatment and may increase clinician confidence in the value of PROs. High quality treatment strategies for AUD require properly reported PROs.

Hunter-gatherer genomes reveal diverse demographic trajectories during the rise of farming in Eastern Africa.

The fate of hunting and gathering populations following the rise of agriculture and pastoralism remains a topic of debate in the study of human prehistory. Studies of ancient and modern genomes have found that autochthonous groups were largely replaced by expanding farmer populations with varying levels of gene flow, a characterization that is influenced by the almost universal focus on the European Neolithic.1-5 We sought to understand the demographic impact of an ongoing cultural transition to farming in Southwest Ethiopia, one of the last regions in Africa to experience such shifts.6 Importantly, Southwest Ethiopia is home to several of the world's remaining hunter-gatherer groups, including the Chabu people, who are currently transitioning away from their traditional mode of subsistence.7 We generated genome-wide data from the Chabu and four neighboring populations, the Majang, Shekkacho, Bench, and Sheko, to characterize their genetic ancestry and estimate their effective population sizes over the last 60 generations. We show that the Chabu are a distinct population closely related to ancient people who occupied Southwest Ethiopia >4,500 years ago. Furthermore, the Chabu are undergoing a severe population bottleneck, which began approximately 1,400 years ago. By analyzing eleven Eastern African populations, we find evidence for divergent demographic trajectories among hunter-gatherer-descendant groups. Our results illustrate that although foragers respond to encroaching agriculture and pastoralism with multiple strategies, including cultural adoption of agropastoralism, gene flow, and economic specialization, they often face population decline.