Transport of persistent organic pollutants across the human placenta

Environment International 65, 107-115 (2014

A database and digital signal processing framework for the perceptual analysis of voice quality

Bermúdez de Alvear RM, Corral J, Tardón LJ, Barbancho AM, Fernández Contreras E, Rando Márquez S, Martínez-Arquero AG, Barbancho I. A database and digital signal processing framework for the perceptual analysis of voice quality. Pan European Voice Conferenc: PEVOC 11 Abstract Book. Aug. 31-Sept.2, 2015.Introduction. Clinical assessment of dysphonia relies on perceptual as much as instrumental methods of analysis [1]. The perceptual auditory analysis is potentially subject to several internal and external sources of bias [2]. Furthermore acoustic analyses which have been used to objectively characterize pathological voices are likely to be affected by confusion variables such as the signal processing or the hardware and software specifications [3]. For these reasons the poor correlation between perceptual ratings and acoustic measures remains to be a controversial matter [4]. The availability of annotated databases of voice samples is therefore of main importance for clinical and research purposes. Databases to perform digital processing of the vocal signal are usually built from English speaking subjects’ sustained vowels [5]. However phonemes vary from one language to another and to the best of our knowledge there are no annotated databases with Spanish sustained vowels from healthy or dysphonic voices. This work shows our first steps to fill in this gap. For the aim of aiding clinicians and researchers in the perceptual assessment of voice quality a two-fold objective was attained. On the one hand a database of healthy and disordered Spanish voices was developed; on the other an automatic analysis scheme was accomplished on the basis of signal processing algorithms and supervised learning machine techniques. Material and methods. A preliminary annotated database was created with 119 recordings of the sustained Spanish /a/; they were perceptually labeled by three experienced experts in vocal quality analysis. It is freely available under Links in the ATIC website (www.atic.uma.es). Voice signals were recorded using a headset condenser cardioid microphone (AKG C-544 L) positioned at 5 cm from the speaker’s mouth commissure. Speakers were instructed to sustain the Spanish vowel /a/ for 4 seconds. The microphone was connected to a digital recorder Edirol R-09HR. Voice signals were digitized at 16 bits with 44100 Hz sampling rate. Afterwards the initial and last 0.5 second segments were cut and the 3 sec. mid portion was selected for acoustic analysis. Sennheiser HD219 headphones were used by judges to perceptually evaluate voice samples. To label these recordings raters used the Grade-Roughness-Breathiness (GRB) perceptual scale which is a modified version of the original Hirano’s GRBAS scale, posteriorly modified by Dejonckere et al., [6]. In order to improve intra- and inter-raters’ agreement two types of modifications were introduced in the rating procedure, i.e. the 0-3 points scale resolution was increased by adding subintervals to the standard 0-3 intervals, and judges were provided with a written protocol with explicit definitions about the subintervals boundaries. By this way judges could compensate for the potential instability that might occur in their internal representations due to the perceptual context influence [7]. Raters’ perceptual evaluations were simultaneously performed by means of connecting the Sennheiser HD219 headphones to a multi-channel headphone preamp Behringer HA4700 Powerplay Pro-XL. The Yin algorithm [8] was selected as initial front-end to identify voiced frames and extract their fundamental frequency. For the digital processing of voice signals some conventional acoustic parameters [6] were selected. To complete the analysis the Mel-Frequency Cepstral Coefficients (MFCC) were further calculated because they are based on the auditory model and they are thus closer to the auditory system response than conventional features. Results. In the perceptual evaluation excellent intra-raters agreement and very good inter-raters agreement were achieved. During the supervised machine learning stage some conventional features were found to attain unexpected low performance in the classification scheme selected. Mel Frequency Cepstral Coefficients were promising for assorting samples with normal or quasi-normal voice quality. Discussion and conclusions. Despite it is still small and unbalanced the present annotated data base of voice samples can provide a basis for the development of other databases and automatic classification tools. Other authors [9, 10, 11] also found that modeling the auditory non-linear response during signal processing can help develop objective measures that better correspond with perceptual data. However highly disordered voices classification remains to be a challenge for this set of features since they cannot be correctly assorted by either conventional variables or the auditory model based measures. Current results warrant further research in order to find out the usability of other types of voice samples and features for the automatic classification schemes. Different digital processing steps could be used to improve the classifiers performance. Additionally other types of classifiers could be taken into account in future studies. Acknowledgment. This work was funded by the Spanish Ministerio de Economía y Competitividad, Project No. TIN2013-47276-C6-2-R has been done in the Campus de Excelencia Internacional Andalucía Tech, Universidad de Málaga. References [1] Carding PN, Wilson JA, MacKenzie K, Deary IJ. Measuring voice outcomes: state of the science review. The Journal of Laryngology and Otology 2009;123,8:823-829. [2] Oates J. Auditory-perceptual evaluation of disordered voice quality: pros, cons and future directions. Folia Phoniatrica et Logopaedica 2009;61,1:49-56. [3] Maryn et al. Meta-analysis on acoustic voice quality measures. J Acoust Soc Am 2009; 126, 5: 2619-2634. [4] Vaz Freitas et al. Correlation Between Acoustic and Audio-Perceptual Measures. J Voice 2015;29,3:390.e1 [5] “Multi-Dimensional Voice Program (MDVP) Model 5105. Software Instruction Manual”, Kay PENTAX, A Division of PENTAX Medical Company, 2 Bridgewater Lane, Lincoln Park, NJ 07035-1488 USA, November 2007. [6] Dejonckere PH, Bradley P, Clemente P, Cornut G, Crevier-Buchman L, Friedrich G, Van De Heyning P, Remacle M, Woisard V. A basic protocol for functional assessment of voice pathology, especially for investigating the efficacy of (phonosurgical) treatments and evaluating new assessment techniques. Guideline elaborated by the Comm. on Phoniatrics of the European Laryngological Society (ELS). Eur Arch Otorhinolaryngol 2001;258:77–82. [7] Kreiman et al. Voice Quality Perception. J Speech Hear Res 1993;36:21-4 [8] De Cheveigné A, Kawahara H. YIN, a fundamental frequency estimator for speech and music. J. Acoust. Soc. Amer. 202; 111,4:1917. [9] Shrivastav et al. Measuring breathiness. J Acoust Soc Am 2003;114,4:2217-2224. [10] Saenz-Lechon et al. Automatic Assessment of voice quality according to the GRBAS scale. Eng Med Biol Soc Ann 2006;1:2478-2481. [11] Fredouille et al. Back-and-forth methodology for objective voice quality assessment: from/to expert knowledge to/from automatic classification of dysphonia. EURASIP J Appl Si Pr 2009.Campus de Excelencia Internacional Andalucía Tech, Universidad de Málaga. Ministerio de Economía y Competitividad, Projecto No. TIN2013-47276-C6-2-R

LINE-1 methylation in leukocyte DNA, interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk

BACKGROUND: Aberrant global DNA methylation is shown to increase cancer risk. LINE-1 has been proven a measure of global DNA methylation. The objectives of this study were to assess the association between LINE-1 methylation level and bladder cancer risk and to evaluate effect modification by environmental and genetic factors. METHODS: Bisulphite-treated leukocyte DNA from 952 cases and 892 hospital controls was used to measure LINE-1 methylation level at four CpG sites by pyrosequencing. Logistic regression model was fitted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Interactions between LINE-1 methylation levels and environmental and genetic factors were assessed. RESULTS: The risk of bladder cancer followed a nonlinear association with LINE-1 methylation. Compared with subjects in the middle tertile, the adjusted OR for subjects in the lower and the higher tertiles were 1.26 (95% CI 0.99–1.60, P=0.06) and 1.33 (95% CI 1.05–1.69, P=0.02), respectively. This association significantly increased among individuals homozygous for the major allele of five single-nucleotide polymorphisms located in the phosphatidylethanolamine N-methyltransferase gene (corrected P-interaction<0.05). CONCLUSIONS: The findings from this large-scale study suggest that both low and high levels of global DNA methylation are associated with the risk of bladder cancer

SARS-CoV-2 Breakthrough Infections: Incidence and Risk Factors in a Large European Multicentric Cohort of Health Workers.

Background: The research aimed to investigate the incidence of SARS-CoV-2 breakthrough infections and their determinants in a large European cohort of more than 60,000 health workers. Methods: A multicentric retrospective cohort study, involving 12 European centers, was carried out within the ORCHESTRA project, collecting data up to 18 November 2021 on fully vaccinated health workers. The cumulative incidence of SARS-CoV-2 breakthrough infections was investigated with its association with occupational and social-demographic characteristics (age, sex, job title, previous SARS-CoV-2 infection, antibody titer levels, and time from the vaccination course completion). Results: Among 64,172 health workers from 12 European health centers, 797 breakthrough infections were observed (cumulative incidence of 1.2%). The primary analysis using individual data on 8 out of 12 centers showed that age and previous infection significantly modified breakthrough infection rates. In the meta-analysis of aggregated data from all centers, previous SARS-CoV-2 infection and the standardized antibody titer were inversely related to the risk of breakthrough infection (p = 0.008 and p = 0.007, respectively). Conclusion: The inverse correlation of antibody titer with the risk of breakthrough infection supports the evidence that vaccination plays a primary role in infection prevention, especially in health workers. Cellular immunity, previous clinical conditions, and vaccination timing should be further investigated

Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium.

Background The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. Methods We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. Findings Significant dose–response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5–9 years to 89%quit_for_≥ 20 years declined SCLC risk vs. subjects who had quit smoking < 5 years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects. Interpretation This is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study. Abbreviations COPD, chronic obstructive pulmonary disease; CPG, cigarettes per day; ILCCO, International Lung Cancer Consortium; MeSH, medical subject headings; NSCLC, non-small cell lung cancer; OR, odds ratio; SCLC, small cell lung cancer

Genome‐wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk

Genome‐wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large‐scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large‐scale meta‐analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome‐wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, P = 9.10 × 10−8; 4q28.2: rs58404727, Deletion, OR = 1.19, P = 5.25 × 10−7; 12p13.31: rs71450133, Deletion, OR = 1.09, P = 8.83 × 10−7; and 14q22.3: rs34057993, Deletion, OR = 0.90, P = 7.64 × 10−8). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis

Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk