Prioritizing disease-linked variants, genes, and pathways with an interactive whole-genome analysis pipeline.

Whole-genome sequencing (WGS) studies are uncovering disease-associated variants in both rare and nonrare diseases. Utilizing the next-generation sequencing for WGS requires a series of computational methods for alignment, variant detection, and annotation, and the accuracy and reproducibility of annotation results are essential for clinical implementation. However, annotating WGS with up to date genomic information is still challenging for biomedical researchers. Here, we present one of the fastest and highly scalable annotation, filtering, and analysis pipeline-gNOME-to prioritize phenotype-associated variants while minimizing false-positive findings. Intuitive graphical user interface of gNOME facilitates the selection of phenotype-associated variants, and the result summaries are provided at variant, gene, and genome levels. Moreover, the enrichment results of specific variants, genes, and gene sets between two groups or compared with population scale WGS datasets that is already integrated in the pipeline can help the interpretation. We found a small number of discordant results between annotation software tools in part due to different reporting strategies for the variants with complex impacts. Using two published whole-exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss-of-function variants in known cancer pathways. gNOME Web server and source codes are freely available to the academic community (http://gnome.tchlab.org).

Effect of Lawyer-Submitted Reports on Signals of Disproportional Reporting in the Food and Drug Administration's Adverse Event Reporting System.

INTRODUCTION: Lawyer-submitted reports may have unintended consequences on safety signal detection in spontaneous adverse event reporting systems. OBJECTIVE: Our objective was to assess the impact of lawyer-submitted reports primarily for one adverse event (AE) on the ability to detect a signal of disproportional reporting for another AE for the same drug in the US FDA Adverse Event Reporting System (FAERS). METHODS: FAERS reports from January 2004 to September 2015 were used to estimate yearly cumulative proportional reporting ratios (PRRs) for three known drug-AE pairs-isotretinoin-birth defects, atorvastatin-rhabdomyolysis, and rosuvastatin-rhabdomyolysis-with and without lawyer-submitted reports. Isotretinoin and atorvastatin have been the subject of high-profile tort litigation regarding other AEs. A lower bound of the 95% confidence interval (CI) of one or more based on three or more reports defined a signal. RESULTS: Cumulative PRRs met signaling criteria in all analyses. For isotretinoin, lawyer-submitted reports increased PRRs for birth defects before 2008, with the largest increase in 2006 (2.9 [95% CI 2.4-3.5] to 3.3 [95% CI 2.8-3.9]); lawyer-submitted reports decreased PRRs for birth defects after 2011, with the largest decrease in 2013 (2.2 [95% CI 2.0-2.5] to 1.9 [95% CI 1.7-2.1]). For atorvastatin, lawyer-submitted reports reduced PRRs for rhabdomyolysis after 2013, with the largest decrease in 2015 (18.0 [95% CI 17.1-19.1] to 15.4 [95% CI 14.5-16.2]). Lawyer-submitted reports had little impact on PRRs for rosuvastatin and rhabdomyolysis. CONCLUSIONS: Inclusion of lawyer-submitted reports in FAERS did not meaningfully distort known safety signals for two drugs subject to high-profile tort litigation for other AEs.

Can survival processing enhance story memory? Testing the generalizability of the adaptive memory framework.

Research from the adaptive memory framework shows that thinking about words in terms of their survival value in an incidental learning task enhances their free recall relative to other semantic encoding strategies and intentional learning (Nairne, Pandeirada, & Thompson, 2008). We found similar results. When participants used incidental survival encoding for a list of words (e.g., "Will this object enhance my survival if I were stranded in the grasslands of a foreign land?"), they produced better free recall on a surprise test than did participants who intentionally tried to remember those words (Experiment 1). We also found this survival processing advantage when the words were presented within the context of a survival or neutral story (Experiment 2). However, this advantage did not extent to memory for a story's factual content, regardless of whether the participants were tested by cued recall (Experiment 3) or free recall (Experiments 4-5). Listening to a story for understanding under intentional or incidental learning conditions was just as good as survival processing for remembering story content. The functionalist approach to thinking about memory as an evolutionary adaptation designed to solve reproductive fitness problems provides a different theoretical framework for research, but it is not yet clear if survival processing has general applicability or is effective only for processing discrete stimuli in terms of fitness-relevant scenarios from our past.