12 research outputs found

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

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    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

    Use of complementary and alternative medicine by mid-age women with back pain: a national crosssectional survey

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    Background: The use of complementary and alternative medicine (CAM) has increased significantly in Australia over the past decade. Back pain represents a common context for CAM use, with increasing utilisation of a wide range of therapies provided within and outside conventional medical facilities. We examine the relationship between back pain and use of CAM and conventional medicine in a national cohort of mid-aged Australian women.Methods: Data is taken from a cross-sectional survey (n = 10492) of the mid-aged cohort of the Australian Longitudinal Study on Women's Health, surveyed in 2007. The main outcome measures were: incidence of back pain the previous 12 months, and frequency of use of conventional or CAM treatments in the previous 12 months.Results: Back pain was experienced by 77% (n = 8063) of the cohort in the previous twelve month period. The majority of women with back pain only consulted with a conventional care provider (51.3%), 44.2% of women with back pain consulted with both a conventional care provider and a CAM practitioner. Women with more frequent back pain were more likely to consult a CAM practitioner, as well as seek conventional care. The most commonly utilised CAM practitioners were massage therapy (26.5% of those with back pain) and chiropractic (16.1% of those with back pain). Only 1.7% of women with back pain consulted with a CAM practitioner exclusively.Conclusions: Mid-aged women with back pain utilise a range of conventional and CAM treatments. Consultation with CAM practitioners or self-prescribed CAM was predominantly in addition to, rather than a replacement for, conventional care. It is important that health professionals are aware of potential multiple practitioner usage in the context of back pain and are prepared to discuss such behaviours and practices with their patients

    De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease

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    BackgroundDe novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.MethodsWe studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).ResultsTwo hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.ConclusionsIn patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182
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