Aided Cortical Auditory Evoked Potentials in Infants with Frequency Specific Synthetic Speech Stimuli: Sensitivity, Repeatability, and Feasibility

Objectives: the cortical auditory evoked potential (CAEP) test is a candidate for supplementing clinical practice for infant hearing aid users and others who are not developmentally ready for behavioral testing. Sensitivity of the test for given sensation levels (SLs) has been reported to some degree, but further data are needed from large numbers of infants within the target age range, including repeat data where CAEPs were not detected initially. This study aims to assess sensitivity, repeatability, acceptability, and feasibility of CAEPs as a clinical measure of aided audibility in infants.Design: one hundred and three infant hearing aid users were recruited from 53 pediatric audiology centers across the UK. Infants underwent aided CAEP testing at age 3 to 7 months to a mid-frequency (MF) and (mid-)high-frequency (HF) synthetic speech stimulus. CAEP testing was repeated within 7 days. When developmentally ready (aged 7-21 months), the infants underwent aided behavioral hearing testing using the same stimuli, to estimate the decibel (dB) SL (i.e., level above threshold) of those stimuli when presented at the CAEP test sessions. Percentage of CAEP detections for different dB SLs are reported using an objective detection method (Hotellings T2). Acceptability was assessed using caregiver interviews and a questionnaire, and feasibility by recording test duration and completion rate.Results: the overall sensitivity for a single CAEP test when the stimuli were ≥0 dB SL (i.e., audible) was 70% for the MF stimulus and 54% for the HF stimulus. After repeat testing, this increased to 84% and 72%, respectively. For SL >10 dB, the respective MF and HF test sensitivities were 80% and 60% for a single test, increasing to 94% and 79% for the two tests combined. Clinical feasibility was demonstrated by an excellent >99% completion rate, and acceptable median test duration of 24 minutes, including preparation time. Caregivers reported overall positive experiences of the test.Conclusions: by addressing the clinical need to provide data in the target age group at different SLs, we have demonstrated that aided CAEP testing can supplement existing clinical practice when infants with hearing loss are not developmentally ready for traditional behavioral assessment. Repeat testing is valuable to increase test sensitivity. For clinical application, it is important to be aware of CAEP response variability in this age group

Aided cortical auditory evoked potentials in infants with frequency-specific synthetic speech stimuli: sensitivity, repeatability, and feasibility

Objectives: the cortical auditory evoked potential (CAEP) test is a candidate for supplementing clinical practice for infant hearing aid users and others who are not developmentally ready for behavioral testing. Sensitivity of the test for given sensation levels (SLs) has been reported to some degree, but further data are needed from large numbers of infants within the target age range, including repeat data where CAEPs were not detected initially. This study aims to assess sensitivity, repeatability, acceptability, and feasibility of CAEPs as a clinical measure of aided audibility in infants.Design: one hundred and three infant hearing aid users were recruited from 53 pediatric audiology centers across the UK. Infants underwent aided CAEP testing at age 3 to 7 months to a mid-frequency (MF) and (mid-)high-frequency (HF) synthetic speech stimulus. CAEP testing was repeated within 7 days. When developmentally ready (aged 7-21 months), the infants underwent aided behavioral hearing testing using the same stimuli, to estimate the decibel (dB) SL (i.e., level above threshold) of those stimuli when presented at the CAEP test sessions. Percentage of CAEP detections for different dB SLs are reported using an objective detection method (Hotellings T2). Acceptability was assessed using caregiver interviews and a questionnaire, and feasibility by recording test duration and completion rate.Results: the overall sensitivity for a single CAEP test when the stimuli were ≥0 dB SL (i.e., audible) was 70% for the MF stimulus and 54% for the HF stimulus. After repeat testing, this increased to 84% and 72%, respectively. For SL >10 dB, the respective MF and HF test sensitivities were 80% and 60% for a single test, increasing to 94% and 79% for the two tests combined. Clinical feasibility was demonstrated by an excellent >99% completion rate, and acceptable median test duration of 24 minutes, including preparation time. Caregivers reported overall positive experiences of the test.Conclusions: by addressing the clinical need to provide data in the target age group at different SLs, we have demonstrated that aided CAEP testing can supplement existing clinical practice when infants with hearing loss are not developmentally ready for traditional behavioral assessment. Repeat testing is valuable to increase test sensitivity. For clinical application, it is important to be aware of CAEP response variability in this age group

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR