Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants

Q1Q1Artículo original445-453Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness

Cervical vestibular evoked myogenic potentials (cVEMPs) in patients with superior canal dehiscence syndrome (SCDS)

OBJECTIVE: To determine the usefulness of both amplitude and threshold data from tone-burst cervical vestibular evoked myogenic potential (cVEMP) testing for the evaluation of superior canal dehiscence syndrome (SCDS). STUDY DESIGN: Case series with chart review. SUBJECTS AND METHODS: Sixty-seven patients underwent cVEMP testing. We correlated mean tone burst cVEMP amplitude and threshold data with temporal bone CT findings. Patients were excluded for Meniere\u27s disease, middle ear disease, or otologic surgery. RESULTS: Superior canal dehiscence patients had higher mean cVEMP amplitudes (SCDS 173.8 microV vs non-SCDS 69.7 microV, P=0.031) and lower mean thresholds (SCDS 72.8 dB nHL vs non-SCDS 80.9 dB nHL) at 500 Hz. CONCLUSION: Patients with SCDS have larger amplitudes and lower thresholds on cVEMP testing at 500 Hz. This study supports the utility of tone burst cVEMPs for the evaluation of SCDS and is one of few large single-center studies to establish normative data

Surgeon volume impacts hospital mortality for pancreatic resection

OBJECTIVE: Improved outcomes after pancreatic resection (PR) by high volume (HV) surgeons have been reported in single center studies, which may be confounded with potential selection and referral bias. We attempted to determine if improved outcomes by HV surgeons are reproducible when patient demographic factors are controlled at the population level. METHODS: Using the Nationwide Inpatient Sample, discharge records with surgeon identifiers for all nontrauma PR (n = 3581) were examined from 1998 to 2005. Surgeons were divided into 2 groups: (HV; \u3e or = 5 operations/year) or low volume (LV; \u3c5 operations\u3e/year). We created a logistic regression model to examine the relationship between surgeon type and operative mortality while accounting for patient and hospital factors. To further eliminate differences in cohorts and determine the true effect of surgeon volume on mortality, case-control groups based on patient demographics were created using propensity scores. RESULTS: One hundred thirty-four HV and 1450 LV surgeons performed 3581 PR in 742 hospitals across 12 states that reported surgeon identifier information over the 8-year period. Patients who underwent PR by HV surgeons were more likely to be male, white raced, and a resident of a high-income zip code (P \u3c 0.05). Significant independent factors for in-hospital mortality after PR included increasing age, male gender, Medicaid insurance, and surgery by HV surgeon. HV surgeons had a lower adjusted mortality compared with LV surgeons (2.4% vs. 6.4%; P \u3c 0.0001). CONCLUSIONS: After controlling for patient demographics and factors, pancreatic resection by a HV surgeon in this case-controlled cohort was independently associated with a 51% reduction in in-hospital mortality

High volume and outcome after liver resection: surgeon or center

INTRODUCTION: In a case controlled analysis, we attempted to determine if the volume-survival benefit persists in liver resection (LR) after eliminating differences in background characteristics. METHODS: Using the Nationwide Inpatient Sample (NIS), we identified all LR (n = 2,949) with available surgeon/hospital identifiers performed from 1998-2005. Propensity scoring adjusted for background characteristics. Volume cut-points were selected to create equal groups. A logistic regression for mortality was then performed with these matched groups. RESULTS: At high volume (HV) hospitals, patients (n = 1423) were more often older, white, private insurance holders, elective admissions, carriers of a malignant diagnosis, and high income residents (p \u3c 0.05). Propensity matching eliminated differences in background characteristics. Adjusted in-hospital mortality was significantly lower in the HV group (2.6% vs. 4.8%, p = 0.02). Logistic regression found that private insurance and elective admission type decreased mortality; preoperative comorbidity increased mortality. Only LR performed by HV surgeons at HV centers was independently associated with improved in-hospital mortality (HR, 0.43; 95% CI, 0.22-0.83). CONCLUSIONS: A socioeconomic bias may exist at HV centers. When these factors are accounted for and adjusted, center volume does not appear to influence in-hospital mortality unless LR is performed by HV surgeons at HV centers

Using the phenome and genome to improve genetic diagnosis for deafness

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