Narrow-Band Imaging in Transoral Laser Surgery for Early Glottic Cancer:A Randomized Controlled Trial

Objective: Assessing whether the additional use of narrow-band imaging (NBI) in transoral laser surgery (TOLS) for early laryngeal cancer improves clinical outcomes. Study Design: Randomized controlled trial, performed between September 2015 and November 2022. Setting: A tertiary referral hospital in The Netherlands. Methods: TOLS was carried out in 113 patients. The procedure was performed with white light imaging (WLI, n = 56) alone, or combined with NBI (n = 57). Patients received frequent follow-up laryngoscopy. Resection margin status, recurrence rate, and recurrence-free survival at 12 months, 18 months, and after study termination (maximum 86 months) were analyzed. Results: Thirty-one cases in the WLI group had a positive resection margin, versus 16 in the NBI group (p =.002). After 12 months, the recurrence-free survival was 92%: 87% for WLI versus 96% for NBI, p =.07. The recurrence rate was 7/56 (13%) for WLI, versus 2/57 (4%) for NBI, p =.09. After 18 months, the recurrence-free survival was 84% for WLI versus 96% for NBI, p =.02. The recurrence rate was 9/56 (16%) for WLI, versus 2/57 (4%) for NBI, p =.02. After study termination, the recurrence-free survival was 71% for WLI versus 83% for the NBI group (p =.08). The recurrence rate was 16/56 for WLI, versus 10/57 for NBI (p =.16). Conclusion: The additional use of NBI during TOLS significantly decreased the number of positive resection margins. Although not statistically significant at all time points, patients treated with NBI-supported TOLS showed a lower recurrence rate and better recurrence-free survival. Further studies in larger patient groups are needed to confirm these results.</p

Differences in the diagnostic value between fiberoptic and high definition laryngoscopy for the characterisation of pharyngeal and laryngeal lesions:A multi-observer paired analysis of videos

Objectives High definition laryngoscopy (HDL) could lead to better interpretation of the pharyngeal and laryngeal mucosa than regularly used fiberoptic laryngoscopy (FOL). The primary aim of this study is to quantify the diagnostic advantage of HDL over FOL in detecting mucosal anomalies in general, in differentiating malignant from benign lesions and in predicting specific histological entities. The secondary aim is to analyse image quality of both laryngoscopes. Design Retrospective paired analysis with multiple observers evaluating endoscopic videos simulating daily clinical practice. Setting A tertiary referral hospital. Participants In 36 patients, both FOL and HDL videos were obtained. Six observers were provided with additional clinical information, and 36 FOL and HDL videos were evaluated in a randomised order. Main outcome measures Sensitivity, specificity, positive and negative predictive value and diagnostic accuracy of observers using both flexible laryngoscopes were calculated for detection of mucosal lesions in general and uncovering malignant lesions. Sensitivities were calculated for prediction of specific histological entities. Image quality (scale 1-10) was assessed for both flexible laryngoscopes. Results HDL reached higher sensitivity compared to FOL for detection of mucosal abnormalities in general (96.0% vs 90.4%; P = .03), differentiating malignant from benign lesions (91.7% vs 79.8%; P = .03) and prediction of specific histological entities (59.7% vs 47.2%; P <.01). Image quality was judged better with HDL in comparison with FOL (mean: 8.4 vs 5.4, P <.01). Conclusions HDL is superior to FOL in detecting mucosal anomalies in general, malignancies and specific histological entities. Image quality is considered as superior using HDL compared to FOL

High-definition videolaryngoscopy is superior to fiberoptic laryngoscopy:a 111 multi-observer study

PURPOSE: This study aims to analyse differences in fiberoptic laryngoscopy (FOL) versus high definition laryngoscopy (HDL) by examining videolaryngoscopy images by a large group of observers with different levels of clinical expertise in ear, nose and throat (ENT) medicine. METHODS: This study is a 111 observer paired analysis of laryngoscopy videos during an interactive presentation. During a National Meeting of the Dutch Society of ENT/Head and Neck Surgery, observers assessed both FOL and HDL videos of nine cases with additional clinical information. Observers included 41 ENT consultants (36.9%), 34 ENT residents (30.6%), 22 researchers with Head and Neck interest (19.8%) and 14 with unspecified clinical expertise (12.6%). For both laryngoscopic techniques, sensitivity, specificity, positive and negative predictive value and diagnostic accuracy were determined for identifying a normal glottis, hyperkeratosis, radiotherapy adverse effects and squamous cell carcinoma. The sensitivities for FOL and HDL were analysed with regard to the different levels of clinical expertise. RESULTS: The overall sensitivity for correctly identifying the specific histological entity was higher in HDL (FOL 61% vs HDL 66.3%, p < 0.05). HDL was superior to FOL in identifying a normal glottis (FOL 68.1% vs HDL 91.6%, p < 0.01) and squamous cell carcinoma (FOL 70.86% vs HDL 79.41%, p = 0.02). Residents and researchers with Head and Neck interest diagnosed laryngeal lesions more correctly with HDL (p < 0.05). CONCLUSIONS: In a large population of observers with different levels of clinical expertise, HDL is superior to FOL in identifying laryngeal lesions

Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands'

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with ‘true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05–0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r2, increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r2 improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r2 increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits

Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies

Background: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels. Methods: We applied summary-data–based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data–based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels. Results: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before. Conclusions: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies