Clinical Yield of Multiple Testing with Respiratory Pathogen Panels

ObjectiveAge-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response.Methods and analysisA retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort.ResultsAssociation with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction.ConclusionIdentifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders.

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Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut ◽

10.1136/gutjnl-2020-323906 ◽

2021 ◽

pp. gutjnl-2020-323906

Author(s):

Jue-Sheng Ong ◽

Jiyuan An ◽

Xikun Han ◽

Matthew H Law ◽

Priyanka Nandakumar ◽

...

Keyword(s):

Risk Factors ◽

Multiple Testing ◽

Association Studies ◽

Barrett’S Oesophagus ◽

Oesophageal Reflux ◽

Oesophageal Adenocarcinoma ◽

Specific Gene ◽

Genome Wide Association Studies ◽

Disease Heterogeneity ◽

Barrett's Oesophagus

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

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Clinical performance of the GenMark Dx ePlex respiratory pathogen panels for upper and lower respiratory tract infections

Journal of Clinical Virology ◽

10.1016/j.jcv.2021.104737 ◽

2021 ◽

Vol 135 ◽

pp. 104737

Author(s):

Junko Jarrett ◽

Katharine Uhteg ◽

Michael S. Forman ◽

Ann Hanlon ◽

Christine Vargas ◽

...

Keyword(s):

Respiratory Tract ◽

Lower Respiratory Tract ◽

Respiratory Tract Infections ◽

Clinical Performance ◽

Respiratory Pathogen ◽

Lower Respiratory Tract Infections ◽

Tract Infections

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Mutation E48K in PB1 Polymerase Subunit Improves Stability of a Candidate Live Attenuated Influenza B Virus Vaccine

Vaccines ◽

10.3390/vaccines9070800 ◽

2021 ◽

Vol 9 (7) ◽

pp. 800

Author(s):

Jongsuk Mo ◽

Stivalis Cardenas-Garcia ◽

Jefferson J. S. Santos ◽

Lucas M. Ferreri ◽

C. Joaquín Cáceres ◽

...

Keyword(s):

Vaccine Candidate ◽

The Elderly ◽

Potential Interaction ◽

Respiratory Pathogen ◽

Influenza B Virus ◽

Influenza B ◽

Epitope Tag ◽

Live Attenuated Vaccine ◽

B Virus ◽

Homologous Challenge

Influenza B virus (IBV) is a major respiratory pathogen of humans, particularly in the elderly and children, and vaccines are the most effective way to control it. In previous work, incorporation of two mutations (E580G, S660A) along with the addition of an HA epitope tag in the PB1 segment of B/Brisbane/60/2008 (B/Bris) resulted in an attenuated strain that was safe and effective as a live attenuated vaccine. A third attempted mutation (K391E) in PB1 was not always stable. Interestingly, viruses that maintained the K391E mutation were associated with the mutation E48K. To explore the contribution of the E48K mutation to stability of the K391E mutation, a vaccine candidate was generated by inserting both mutations, along with attenuating mutations E580G and S660A, in PB1 of B/Bris (B/Bris PB1att 4M). Serial passages of the B/Bris PB1att 4M vaccine candidate in eggs and MDCK indicated high stability. In silico structural analysis revealed a potential interaction between amino acids at positions 48 and 391. In mice, B/Bris PB1att 4M was safe and provided complete protection against homologous challenge. These results confirm the compensatory effect of mutation E48K to stabilize the K391E mutation, resulting in a safer, yet still protective, IBV LAIV vaccine.

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2dFDR: a new approach to confounder adjustment substantially increases detection power in omics association studies

Genome Biology ◽

10.1186/s13059-021-02418-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Sangyoon Yi ◽

Xianyang Zhang ◽

Lu Yang ◽

Jinyan Huang ◽

Yuanhang Liu ◽

...

Keyword(s):

Multiple Testing ◽

Statistical Power ◽

Association Studies ◽

Control Procedure ◽

Multiple Testing Correction ◽

New Approach ◽

False Discovery ◽

Traditional Procedure ◽

Extensive Evaluation ◽

Confounder Adjustment

AbstractOne challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.

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Haemophilus influenzae causes cellular trans-differentiation in human bronchial epithelia

Innate Immunity ◽

10.1177/1753425921994906 ◽

2021 ◽

Vol 27 (3) ◽

pp. 251-259

Author(s):

Michael Glöckner ◽

Sebastian Marwitz ◽

Kristina Rohmann ◽

Henrik Watz ◽

Dörte Nitschkowski ◽

...

Keyword(s):

Epithelial Cells ◽

Haemophilus Influenzae ◽

Bronchial Epithelium ◽

Bronchial Epithelial Cells ◽

Respiratory Pathogen ◽

Chronic Obstructive ◽

Bronchial Epithelial ◽

Extracellular Matrix Components ◽

The Impact ◽

Primary Bronchial Epithelial Cells

Non-typeable Haemophilus influenzae (NTHi) is the most common respiratory pathogen in patients with chronic obstructive disease. Limited data is available investigating the impact of NTHi infections on cellular re-differentiation processes in the bronchial mucosa. The aim of this study was to assess the effects of stimulation with NTHi on the bronchial epithelium regarding cellular re-differentiation processes using primary bronchial epithelial cells harvested from infection-free patients undergoing bronchoscopy. The cells were then cultivated using an air-liquid interface and stimulated with NTHi and TGF-β. Markers of epithelial and mesenchymal cells were analyzed using immunofluorescence, Western blot and qRT-PCR. Stimulation with both NTHi and TGF-ß led to a marked increase in the expression of the mesenchymal marker vimentin, while E-cadherin as an epithelial marker maintained a stable expression throughout the experiments. Furthermore, expression of collagen 4 and the matrix-metallopeptidases 2 and 9 were increased after stimulation, while the expression of tissue inhibitors of metallopeptidases was not affected by pathogen stimulation. In this study we show a direct pathogen-induced trans-differentiation of primary bronchial epithelial cells resulting in a co-localization of epithelial and mesenchymal markers and an up-regulation of extracellular matrix components.

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