Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. EADI. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the

Objective The COVID-19 pandemic changed clinician electronic health record (EHR) work in a multitude of ways. To evaluate how, we measure ambulatory clinician EHR use in the United States throughout the COVID-19 pandemic. Materials and Methods We use EHR meta-data from ambulatory care clinicians in 366 health systems using the Epic EHR system in the United States from December 2019 to December 2020. We used descriptive statistics for clinician EHR use including active-use time across clinical activities, time after-hours, and messages received. Multivariable regression to evaluate total and after-hours EHR work adjusting for daily volume and organizational characteristics, and to evaluate the association between messages and EHR time. Results Clinician time spent in the EHR per day dropped at the onset of the pandemic but had recovered to higher than prepandemic levels by July 2020. Time spent actively working in the EHR after-hours showed similar trends. These differences persisted in multivariable models. In-Basket messages received increased compared with prepandemic levels, with the largest increase coming from messages from patients, which increased to 157% of the prepandemic average. Each additional patient message was associated with a 2.32-min increase in EHR time per day (P < .001). Discussion Clinicians spent more total and after-hours time in the EHR in the latter half of 2020 compared with the prepandemic period. This was partially driven by increased time in Clinical Review and In-Basket messaging. Conclusions Reimbursement models and workflows for the post-COVID era should account for these demands on clinician time that occur outside the traditional visit.

The majority of variants identified by genome-wide association studies (GWAS) reside in the noncoding genome, affecting regulatory elements including transcriptional enhancers. However, characterizing their effects requires the integration of GWAS results with context-specific regulatory activity and linkage disequilibrium annotations to identify causal variants underlying noncoding association signals and the regulatory elements, tissue contexts, and target genes they affect. We propose INFERNO, a novel method which integrates hundreds of functional genomics datasets spanning enhancer activity, transcription factor binding sites, and expression quantitative trait loci with GWAS summary statistics. INFERNO includes novel statistical methods to quantify empirical enrichments of tissue-specific enhancer overlap and to identify co-regulatory networks of dysregulated long noncoding RNAs (lncRNAs). We applied INFERNO to two large GWAS studies. For schizophrenia (36,989 cases, 113,075 controls), INFERNO identified putatively causal variants affecting brain enhancers for known schizophrenia-related genes. For inflammatory bowel disease (IBD) (12,882 cases, 21,770 controls), INFERNO found enrichments of immune and digestive enhancers and lncRNAs involved in regulation of the adaptive immune response. In summary, INFERNO comprehensively infers the molecular mechanisms of causal noncoding variants, providing a sensitive hypothesis generation method for post-GWAS analysis. The software is available as an open source pipeline and a web server.

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The majority of variants identified by genome--wide association studies (GWAS) reside in the noncoding genome, where they affect regulatory elements including transcriptional enhancers.We propose INFERNO (INFERring the molecular mechanisms of NOncoding genetic variants), a novel method which integrates hundreds of diverse functional genomics data sources with GWAS summary statistics to identify putatively causal noncoding variants underlying association signals. INFERNO comprehensively infers the relevant tissue contexts, target genes, and downstream biological processes affected by causal variants. We apply INFERNO to schizophrenia GWAS data, recapitulating known schizophrenia--associated genes including CACNA1C and discovering novel signals related to transmembrane cellular processes.