Robust identification of deletions in exome and genome sequence data based on clustering of Mendelian errors

Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs). Using our Mendelian Error Method (MEM), we identified 127 deletions (inherited and de novo) in 2,601 WES trios from the Pediatric Cardiac Genomics Consortium, with a validation rate of 88% by digital droplet PCR. MEM identified additional de novo deletions compared with XHMM, and a significant enrichment of 15q11.2 deletions compared with controls. In addition, MEM identified eight cases of uniparental disomy, sample switches, and DNA contamination. We applied MEM to WGS data from the Genome In A Bottle Ashkenazi trio and identified deletions with 97% specificity. MEM provides a robust, computationally inexpensive method for identifying deletions, and an orthogonal approach for verifying deletions called by other tools

Systemic and Renal Hemodynamics in Oliguric Hepatic Failure: Effect of Volume Expansion

Systemic and renal hemodynamics were studied by indicator dilution techniques before and after infusion of 500 ml of dextran 40 in 21 patients with renal failure developing in the course of decompensated cirrhosis. Cardiac index was directly correlated with total blood volumes. Renal blood flow was low and renal vascular resistance elevated in 13 of 15 patients. Renal vascular resistance was directly related to total systemic nonrenal vascular resistance. Two patients with the highest cardiac outputs in the group were oliguric with high renal blood flow. Plasma volume expansion increased cardiac output in 19 of 21 patients and increased renal blood flow in 12 of 14. The patients were divided into two groups on the basis of control cardiac index. Those with lower cardiac index had lower blood volumes and responded to dextran with a 73% increase in cardiac output, a 148% increase in renal blood flow, and a rise in renal fraction. Those with high control cardiac index had significantly higher blood volumes and responded to dextran with only a small average rise in cardiac output and renal blood flow. Systolic arterial pressure was less than 100 mm Hg in 12 patients. When compared to the normotensive subjects, this hypotension was characterized by a lower vascular resistance, a tendency for a lesser rise in renal blood flow after volume expansion, and a more rapid demise. The prompt circulatory improvement after volume expansion in many of these patients indicates that functional plasma volume depletion may be an important factor in the renal vasoconstriction of oliguric hepatic failure. In an attempt to sustain volume expansion, reinfusion of ascitic fluid was accomplished in four patients. Normal renal blood flow was maintained during reinfusion and a diuresis always occurred, but the response usually was not maintained after the infusion was terminated