The natural history, clinical outcomes, and genotype-phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review.

Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

Extended High-Frequency Audiometry using the Wireless Automated Hearing Test System Compared to Manual Audiometry in Children and Adolescents.

Objectives: Reliable wireless automated audiometry that includes extended high frequencies (EHF) outside a sound booth would increase access to monitoring programs for individuals at risk for hearing loss, particularly those at risk for ototoxicity. The purpose of the study was to compare thresholds obtained with 1) standard manual audiometry to automated thresholds measured with the Wireless Automated Hearing Test System (WAHTS) inside a sound booth, and 2) automated audiometry in the sound booth to automated audiometry outside the sound booth in an office environment. Design: Cross-sectional, repeated measures study. Twenty-eight typically developing children and adolescents (mean = 14.6 yrs; range = 10 to 18 yrs). Audiometric thresholds were measured from 0.25 to 16 kHz with manual audiometry in the sound booth, automated audiometry in the sound booth, and automated audiometry in a typical office environment in counterbalanced order. Ambient noise levels were measured inside the sound booth and the office environment were compared to thresholds at each test frequency. Results: Automated thresholds were overall about 5 dB better compared to manual thresholds, with greater differences in the extended high frequency range (EHF;10-16 kHz). The majority of automated thresholds measured in a quiet office were within ± 10 dB of automated thresholds measured in a sound booth (84%), while only 56% of automated thresholds in the sound booth were within ± 10 dB of manual thresholds. No relationship was found between automated thresholds measured in the office environment and the average or maximum ambient noise level. Conclusions: These results indicate that self-administered, automated audiometry results in slightly better thresholds overall than manually administered audiometry in children, consistent with previous studies in adults. Ambient noise levels in a typical office environment did not have an adverse effect on audiometric thresholds measured using noise attenuation headphones. Thresholds measured using an automated tablet with noise attenuating headphones could improve access to hearing assessment for children with a variety of risk factors. Additional studies of extended high frequency automated audiometry in a wider age range are needed to establish normative thresholds.

Reference equivalent threshold sound pressure levels for the Wireless Automated Hearing Test System.

This paper presents reference equivalent threshold sound pressure levels (RETSPLs) for the Wireless Automated Hearing Test System (WAHTS), a recently commercialized device developed for use as a boothless audiometer. Two initial studies were conducted following the ISO 389-9 standard [ISO 389-9 (2009). "Acoustics-Reference zero for the calibration of audiometric equipment. Part 9: Preferred test conditions for the determinations of reference hearing threshold levels" (International Organization for Standardization, Geneva)]. Although the standard recruitment criteria are intended to yield otologically normal test subjects, the recruited populations appeared to have slightly elevated thresholds [5-10 dB hearing level (HL)]. Comparison of WAHTS thresholds to other clinical audiometric equipment revealed bias errors that were consistent with the elevated thresholds of the RETSPL populations. As the objective of RETSPLs is to ensure consistent thresholds regardless of the equipment, this paper presents the RETSPLs initially obtained following ISO 389-9:2009 and suggested correction to account for the elevated HLs of the originally recruited populations. Two additional independent studies demonstrate the validity of these corrected thresholds.

Clinical Effectiveness of an At-Home Auditory Training Program: A Randomized Controlled Trial.

OBJECTIVES: To investigate the effectiveness of an at-home frequent-word auditory training procedure for use with older adults with impaired hearing wearing their own hearing aids. DESIGN: Prospective, double-blind placebo-controlled randomized trial with three parallel branches: an intervention group who received the at-home auditory training; an active control group who listened to audiobooks using a similar platform at home (placebo intervention); and a passive control group who wore hearing aids and returned for outcomes, but received no intervention. Outcome measures were obtained after a 5-week period. A mixed research design was used with a between-subjects factor of group and a repeated-measures factor of time (pre- and post-treatment) to evaluate the effects of the at-home auditory training program. The intervention was completed in participants' own homes. Baseline and outcomes measures were assessed at a university research laboratory. The participants were adults, aged 54 to 80 years, with the mild-to-moderate hearing loss. Of the 51 identified eligible participants, 45 enrolled as a volunteer sample and 43 of these completed the study. Frequent-word auditory training regimen completed intervention at home over a period of 5 weeks. The active control group listened to audiobooks (placebo intervention) and the passive control group completed no intervention. The primary outcome measure is a Connected Speech test benefit. The secondary outcome measure is a 66-item self-report profile of hearing aid performance. RESULTS: Participants who received the at-home training intervention demonstrated significant improvements on aided recognition for trained materials, but no generalization of these benefits to nontrained materials was seen. This was despite reasonably good compliance with the at-home training regimen and careful verification of hearing aid function throughout the trial. Based on follow-up post-trial evaluation, the benefits observed for trained materials in the intervention group were sustained for a period of at least 8.5 months. No improvement was seen for supplemental outcome measures of hearing aid satisfaction, hearing handicap, or tolerance of background noise while listening to speech. CONCLUSIONS: The at-home auditory training procedure utilizing frequently occurring words was effective for the trained materials used in the procedure. No generalization was seen to nontrained materials or to perceived benefit from hearing aids.

The Effects of Service-Delivery Model and Purchase Price on Hearing-Aid Outcomes in Older Adults: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

OBJECTIVES: The objectives of this study were to determine efficacy of hearing aids in older adults using audiology best practices, to evaluate the efficacy of an alternative over-the-counter (OTC) intervention, and to examine the influence of purchase price on outcomes for both service-delivery models. DESIGN: The design of this study was a single-site, prospective, double-blind placebo-controlled randomized trial with three parallel branches: (a) audiology best practices (AB), (b) consumer decides OTC model (CD), and (c) placebo devices (P). Outcome measures were obtained after a typical 6-week trial period with follow-up 4-week AB-based trial for those initially assigned to CD and P groups. SETTING: Older adults from the general community were recruited via newspaper and community flyers to participate at a university research clinic. PARTICIPANTS: Participants were adults, ages 55-79 years, with mild-to-moderate hearing loss. There were 188 eligible participants: 163 enrolled as a volunteer sample, and 154 completed the intervention. INTERVENTION(S): All participants received the same high-end digital mini-behind-the-ear hearing aids fitted bilaterally. AB and P groups received best-practice services from audiologists; differing mainly in use of appropriate (AB) or placebo (P) hearing aid settings. CD participants self-selected their own pre-programmed hearing aids via an OTC model. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measure was a 66-item self-report, Profile of Hearing Aid Benefit (Cox & Gilmore, 1990). Secondary outcome measure was the Connected Speech Test (Cox, Alexander, & Gilmore, 1987) benefit. Additional measures of hearing-aid benefit, satisfaction, and usage were also obtained. RESULTS: Per-protocol analyses were performed. AB service-delivery model was found to be efficacious for most of the outcome measures, with moderate or large effect sizes (Cohen's d). CD service-delivery model was efficacious, with similar effect sizes. However, CD group had a significantly (p < .05) lower satisfaction and percentage (CD: 55%; AB: 81%; P: 36%) likely to purchase hearing aids after the trial. CONCLUSIONS: Hearing aids are efficacious in older adults for both AB and CD service-delivery models. CD model of OTC service delivery yielded only slightly poorer outcomes than the AB model. Efficacious OTC models may increase accessibility and affordability of hearing aids for millions of older adults. Purchase price had no effect on outcomes, but a high percentage of those who rejected hearing aids paid the typical price (85%). TRIAL REGISTRATION: Clinicaltrials.gov: NCT01788432; https://clinicaltrials.gov/ct2/show/NCT01788423.

The effects of dosage and duration of auditory training for older adults with hearing impairment.

This study explored a range of training dosages and durations for a word-based auditory-training procedure for older adults with hearing impairment. Three groups received a different "dose": 2x/week; 3x/week; no training. Fifteen training sessions comprised a "cycle" which was repeated three times for each dosage. Groups that completed training performed significantly better than controls for speech-in-noise materials included in the training regimen, with no significant difference observed between the 2x or 3x/week training groups. Based on these results, as well as prior literature on learning theory, training 2x or 3x/week for 5-15 weeks appears to be sufficient to yield training benefits with this training regimen.