Compensatory and Serial Processing Models for Relating Electrophysiology, Speech Understanding, and Cognition.

OBJECTIVES: The objective of this study was to develop a framework for investigating the roles of neural coding and cognition in speech perception. DESIGN: N1 and P3 auditory evoked potentials, QuickSIN speech understanding scores, and the Digit Symbol Coding cognitive test results were used to test the accuracy of either a compensatory processing model or serial processing model. RESULTS: The current dataset demonstrated that neither the compensatory nor the serial processing model were well supported. An additive processing model may best represent the relationships in these data. CONCLUSIONS: With the outcome measures used in this study, it is apparent that an additive processing model, where exogenous neural coding and higher order cognition contribute independently, best describes the effects of neural coding and cognition on speech perception. Further testing with additional outcome measures and a larger number of subjects is needed to confirm and further clarify the relationships between these processing domains.

Using tablet-based technology to deliver time-efficient ototoxicity monitoring.

OBJECTIVE: The goal of this article is to highlight mobile technology that is not yet standard of care but could be considered for use in an ototoxicity monitoring programme (OMP) as an adjunct to traditional audiometric testing. Current guidelines for ototoxicity monitoring include extensive test protocols performed by an audiologist in an audiometric booth. This approach is comprehensive, but it may be taxing for patients suffering from life-threatening illnesses and cost prohibitive if it requires serial clinical appointments. With the use of mobile technology, testing outside of the confines of the audiometric booth may be possible, which could create more efficient and less burdensome OMPs. DESIGN: A non-systematic review of new OMP technology was performed. Experts were canvassed regarding the impact of new technology on OMPs. STUDY SAMPLE: OMP devices and technologies that are commercially available and discussed in the literature. RESULTS: The benefits and limitations of portable, tablet-based technology that can be deployed for efficient ototoxicity monitoring are discussed. CONCLUSIONS: New mobile technology has the potential to influence the development and implementation of OMPs and lower barriers to patient access by providing time efficient, portable and self-administered testing options for use in the clinic and in the patient's home.

Applying U.S. national guidelines for ototoxicity monitoring in adult patients: perspectives on patient populations, service gaps, barriers and solutions.

OBJECTIVES: To promote establishment of effective ototoxicity monitoring programs (OMPs), this report reviews the U.S. national audiology guidelines in relation to "real world" OMP application. Background is provided on the mechanisms, risks and clinical presentation of hearing loss associated with major classes of ototoxic medications. DESIGN: This is a non-systematic review using PubMed, national and international agency websites, personal communications between ototoxicity experts, and results of unpublished research. Examples are provided of OMPs in various healthcare settings within the U.S. civilian sector, Department of Defense (DoD), and Department of Veterans Affairs (VA). STUDY SAMPLE: The five OMPs compared in this report represent a convenience sample of the programs with which the authors are affiliated. Their opinions were elicited via two semi-structured teleconferences on barriers and facilitators of OMP, followed by a self-administered questionnaire on OMP characteristics and practices, with responses synthesized herein. Preliminary results are provided from an ongoing VA clinical trial at one of these OMP sites. Participants were 40 VA patients who received cisplatin chemotherapy in 2014-2017. The study arms contrast access to care for OMP delivered on the treatment unit versus usual care as provided in the audiology clinic. RESULTS: Protocols of the OMPs examined varied, reflecting their diverse settings. Service delivery concerns included baseline tests missed or completed after the initial treatment, and monitoring tests done infrequently or only after cessation of treatment. Perceived barriers involved logistics related to accessing and testing patients, such as a lack of processes to help patients enter programs, patients' time and scheduling constraints, and inconvenient audiology clinic locations. Use of abbreviated or screening methods facilitated monitoring. CONCLUSIONS: The most effective OMPs integrated audiological management into care pathways of the clinical specialties that prescribe ototoxic medications. More OMP guidance is needed to inform evaluation schedules, outcome reporting, and determination of actionable ototoxic changes. Guidance is also lacking on the use of hearing conservation approaches suitable for the mass testing needed to support large-scale OMP efforts. Guideline adherence might improve with formal endorsement from organizations governing the medical specialty stakeholders in OMP such as oncologists, pulmonologists, infectious disease specialists, ototolaryngologists and pharmacists.

Diabetes-Associated Changes in Cortical Auditory-Evoked Potentials in Relation to Normal Aging.

OBJECTIVES: (1) To characterize the influence of type 2 diabetes mellitus (DM) on cortical auditory-evoked potentials (CAEPs) separate from the effects of normal aging, and (2) to determine whether the disease-related effects are modified by insulin dependence. DESIGN: A cross-sectional study was conducted in a large cohort of Veterans to investigate the relationships among type 2 DM, age, and CAEPs in randomly selected participants with (N = 108) and without (N = 114) the disease and who had no more than a moderate hearing loss. Participants with DM were classified as insulin-dependent (IDDM, N = 47) or noninsulin-dependent (NIDDM, N = 61). Other DM measures included concurrent serum glucose, HbA1c, and duration of disease. CAEPs were evoked using a passive homogeneous paradigm (single repeating stimulus) by suprathreshold tones presented to the right ear, left ear, or both ears. Outcome measures were adjusted for the pure-tone threshold average for frequencies of 0.5, 1, and 2 kHz and analyzed for differences in age effects between participant groups using multiple regression. RESULTS: There is little variation across test ear conditions (left, right, binaural) on any CAEP peak in any of the groups. Among no-DM controls, P2 latency increases about 9 msec per decade of life. DM is associated with an additional delay in the P2 latency of 7 and 9 msec for the IDDM and NIDDM groups, respectively. Moreover, the slope of the function relating P2 latency with age is similar across participant groups and thus the DM effect appears constant across age. Effects on N1 latency are considerably weaker, with age effects of less than 4 msec per decade across all groups, and DM effects of only 2 (IDDM) or 3 msec (NIDDM). In the NIDDM group, the slope relating N1 latency to age is steeper relative to that observed for the no-DM group, providing some evidence of accelerated "aging" for this CAEP peak. DM does not substantially reduce N1-P2 amplitude and age relationships with N1-P2 amplitude are effectively absent. There is no association between pure-tone average at 0.5, 1, and 2 kHz and any aspect of CAEPs in this cohort. CONCLUSIONS: In a large cohort of Veterans, we found that type 2 DM is associated with prolonged N1 and P2 latencies regardless of whether insulin is required to manage the disease and independent of peripheral hearing thresholds. The DM-related effects on CAEP latencies are threefold greater for P2 compared with N1, and there is little support that at the cortical level, IDDM participants had poorer responses compared with NIDDM participants, although their responses were more variable. Overall, these results indicate that DM is associated with slowed preattentive neural conduction. Moreover, the observed 7 to 9 msec P2 latency delay due to DM is substantial compared with normal age changes in P2, which are 9 msec per decade of life in this cohort. Results also suggest that whereas N1 latency changes with age are more pronounced among individuals with DM versus without DM, there was no evidence for more rapid aging of P2 among patients with DM. Thus, the damage responsible for the major DM-related differences may occur early in the DM disease process. These cross-sectional results should be verified using a longitudinal study design.

A Store-and-Forward Tele-Audiology Solution to Promote Efficient Screenings for Ototoxicity during Cisplatin Cancer Treatment.

BACKGROUND: Tele-audiology improves access, controls cost, and improves efficiency of many aspects within health care. We have developed and validated a device, the ototoxicity identification device (OtoID), which enables remote hearing monitoring by a patient during chemotherapy treatment. Aspects of the design such as patient self-testing and texting of results to the audiology clinic are important features of this device. PURPOSE: The purpose of this article is to present the efficacy and effectiveness of the OtoID hearing screener. RESEARCH DESIGN: A repeated measures design was used in this study. STUDY SAMPLE: Twenty-one veterans undergoing cisplatin chemotherapy were recruited in this study. DATA COLLECTION AND ANALYSIS: Participants were tested using the OtoID at each cisplatin treatment by an audiologist using the manual mode of test and the participant using the automated mode of test. Test sensitivity and specificity were developed from the detection (yes/no) of an American Speech-Language-Hearing Association (ASHA) change in hearing. RESULTS: The OtoID had a test sensitivity of 80.6% and specificity of 85.3%. A logistic regression model analysis of the probability of an ASHA shift identified by the automated OtoID was conducted. Separate models were fit to establish effects of age, average baseline thresholds in the sensitive range for ototoxicity (SRO), and dose of cisplatin on the probability of a positive hearing change result. Interactions were also included to evaluate these effects on the sensitivity and false-positive rates of the automated test. Results indicated no statistically significant effects of age, of baseline hearing in the SRO frequencies, or of cisplatin dose. CONCLUSIONS: The OtoID automated test can be recommended for use. The automated test provides significant personnel efficiencies. The modem with simple text messaging function recently added to the device improves on these efficiencies.

Meta-Analysis of Distortion Product Otoacoustic Emission Retest Variability for Serial Monitoring of Cochlear Function in Adults.

OBJECTIVE: Distortion product otoacoustic emissions (DPOAEs) have long been heralded as a means to objectively monitor cochlear function and increasingly are becoming a key component in hearing surveillance programs for individuals at risk for ototoxic- and occupational noise-related hearing loss. Yet clinicians are unsure how to define clinically meaningful shifts in DPOAE level. In this study, a meta-analysis approach is used to synthesize the DPOAE level test-retest literature to construct a set of DPOAE level shift reference limits that can be used clinically to define a statistically significant emission change. DESIGN: The authors reviewed all published articles identified through a Medline search using the terms "Otoacoustic Emission Variability," "Otoacoustic Emission Reliability," "Otoacoustic Emission Repeatability," and "Otoacoustic Emission Test Retest" restricted to DPOAEs, adults, and English language. Articles with DPOAE level data elicited by moderate stimulus levels for f2 frequencies of 1000, 2000, 4000, or 6000 Hz were selected because these stimulus parameters were relatively well represented in the literature. The authors only included articles that reported the standard error of the measurement (SEM) or from which the SEM could be calculated. Meta-analysis was used to estimate the population mean SEM over the included studies. Models were fit separately for each f2 primary and included days since baseline and study-specific random effects. RESULTS: Ten DPOAE test-retest studies met inclusion criteria for this meta-analysis. The SEM values varied widely across published studies (0.57 to 3.9 dB) and were provided for relatively short time intervals (less than 15 days on average). Time, or days since baseline, was statistically significant at higher f2 frequencies (4000 and 6000 Hz). From the model results, 90% reference limits specific to the f2 and elapsed time between baseline and follow-up measurements were established. Reference limits provided correspond to negative (emission decrement) and positive (emission enhancement) shifts indicative of the amount of measurement variability that, using this approach, must be tolerated as "normal" fluctuations over time. Changes larger than the reference limits are considered significant and warrant follow-up testing. CONCLUSIONS: The meta-analysis presented provides reference limits that are appropriate for a set of specific f2 frequencies and time intervals. The meta-analysis concerns the SEM statistic directly, so that any preferred reference limit can be computed from the results and should be predicated upon the screening application. The presumed advantage of this meta-analytic approach is increased precision relative to limits suggested by any of the individual studies included in the analysis.

Hearing Impairment in Relation to Severity of Diabetes in a Veteran Cohort.

OBJECTIVE: Type 2 diabetes is epidemic among veterans, approaching three times the prevalence of the general population. Diabetes leads to devastating complications of vascular and neurologic malfunction and appears to impair auditory function. Hearing loss prevention is a major health-related initiative in the Veterans Health Administration. Thus, this research sought to identify, and quantify with effect sizes, differences in hearing, speech recognition, and hearing-related quality of life (QOL) measures associated with diabetes and to determine whether well-controlled diabetes diminishes the differences. DESIGN: The authors examined selected cross-sectional data from the baseline (initial) visit of a longitudinal study of Veterans with and without type 2 diabetes designed to assess the possible differences in age-related trajectories of peripheral and central auditory function between the two groups. In addition, the diabetes group was divided into subgroups on the basis of medical diagnosis of diabetes and current glycated hemoglobin (HbA1c) as a metric of disease severity and control. Outcome measures were pure-tone thresholds, word recognition using sentences presented in noise or time-compressed, and an inventory assessing the self-perceived impact of hearing loss on QOL. Data were analyzed from 130 Veterans ages 24 to 73 (mean 48) years with well-controlled (controlled) diabetes, poorly controlled (uncontrolled) diabetes, prediabetes, and no diabetes. Regression was used to identify any group differences in age, noise exposure history, and other sociodemographic factors, and multiple regression was used to model each outcome variable, adjusting for potential confounders. Results were evaluated in relation to diabetes duration, use of insulin (yes, no), and presence of selected diabetes complications (neuropathy and retinopathy). RESULTS: Compared with nondiabetics, Veterans with uncontrolled diabetes had significant differences in hearing at speech frequencies, including poorer hearing by 3 to 3.5 dB for thresholds at 250 Hz and in a clinical pure-tone average, respectively. Compared with nondiabetic controls, individuals with uncontrolled diabetes also significantly more frequently reported that their hearing adversely impacted QOL on one of the three subscales (ability to adapt). Despite this, although they also had slightly poorer mean scores on both word recognition tasks performed, these differences did not reach statistical significance and all subjects performed well on these tasks. Compared with Veterans with controlled diabetes, those with uncontrolled disease tended to have had diabetes longer, be insulin-dependent, and have a greater prevalence of diabetic retinopathy. Results are generally comparable with the literature with regard to the magnitude of threshold differences and the prevalence of hearing impairment but extend prior work by providing threshold difference and hearing loss prevalence effect sizes by category of diabetes control and by including additional functional measures. CONCLUSIONS: In a cohort of Veterans with type 2 diabetes and relatively good hearing, significant effects of disease severity were found for hearing thresholds at a subset of frequencies and for one of the three QOL subscales. Significant differences were concentrated among those with poorly controlled diabetes based on current HbA1c. Results provide evidence that the observed hearing dysfunction in type 2 diabetes might be prevented or delayed through tight metabolic control. Findings need to be corroborated using longitudinal assessments.

OtoID: new extended frequency, portable audiometer for ototoxicity monitoring.

Portability of equipment is an increasingly important component in the practice of audiology. We report on a new device, the OtoID, that supports evidence-based ototoxicity testing protocols, provides capability for hearing testing on the hospital treatment unit, and can automate patient self-testing. The purpose of this article is to report on the validation and verification of the OtoID portable audiometer in 40 subjects both young and old, with and without hearing impairment. Subjects were evaluated by an audiologist using the manual hearing test program and then self-tested via an automated testing program. Testing was done in a sound booth and on a hospital treatment unit. Therefore, data were collected in four conditions (booth vs hospital unit and automated vs manual testing) and analyzed for testing bias, repeatability, and American Speech-Language-Hearing Association-significant ototoxicity false-positive rate. Repeatable hearing threshold results were obtained on all subjects who performed the test, regardless of hearing status or testing location.

ABR obtained from time-efficient train stimuli for cisplatin ototoxicity monitoring.

BACKGROUND: Nonbehavioral methods for identifying cisplatin ototoxicity are important for testing patients with cancer who become too tired or sick to provide a reliable response. The auditory brainstem response (ABR) is a nonbehavioral test that is sensitive to ototoxicity but can be time consuming to implement over a range of frequencies and/or levels. To address this issue, trains of stimuli were developed that offer reliable ABR testing over a range of tone-burst frequencies and levels at a time savings of 77% relative to tone-burst stimuli presented individually. The clinical accuracy of this new method has yet to be determined on a clinical population. PURPOSE: This project was designed to determine the test performance of a time-effective ABR methodology aimed at identifying hearing shifts from cisplatin among veterans. A secondary goal was to determine whether improved test performance could be achieved by including our previously developed ototoxicity risk assessment model in the ABR prediction algorithm. RESEARCH DESIGN: A set of discriminant functions were derived using logistic regression to model the risk for cisplatin-induced hearing change. Independent variables were one of several ABR metrics alone and combined with an ototoxicity risk assessment model that includes pre-exposure hearing and cisplatin dose. Receiver operating characteristic curve analysis was used to evaluate the test performance of these discriminant functions. STUDY SAMPLE: Twenty-two male veterans treated with cisplatin for various cancers provided data from a total of 71 monitoring appointments. DATA COLLECTION AND ANALYSIS: Data were collected prospectively from one ear of each participant as designated below. Hearing shift was determined for frequencies within an octave of each patient's high-frequency hearing limit, tested in 1/6th-octave steps. ABRs were monitored using a set of two intensity trains from the highest two multiple frequency tone-burst center frequencies (up to 11.3 kHz) that yielded a robust response at baseline. Each intensity train was presented at 65-105 dB peSPL in 10 dB steps. Scorable ABRs were generally limited to the highest two intensities; therefore, analyses concern those levels. RESULTS: The ABR measurement failure was high, up to 52% for some frequencies and levels. Furthermore, the ABR was not frequently obtained at levels below 85 dB peSPL, consistent with previous studies that suggest a stimulus level of greater than 80 dB peSPL is required to obtain a reliable response to trained stimuli. Using multivariate metrics that included the dose-ototoxicity model, the most accurate scoring function was change in amplitude at lowest half-octave frequency obtained at 105 dB (change in wave V amplitude at frequency 2/105). However, absence of wave V at a monitor patient visit of the ABR response at levels 105 or 95 dB peSPL was deemed the preferred scoring function, because it had lower measurement failure and was within one standard error of the most accurate function. CONCLUSIONS: Because of the large number of responses that could not be measured at baseline, this technique as implemented holds limited value as an ototoxicity-monitoring method.

The statistical basis for serial monitoring in audiology.

OBJECTIVES: Audiologists regularly use serial monitoring to evaluate changes in a patient's auditory function over time. Observed changes are compared with reference standards to determine whether further clinical action is necessary. Reference standards are established in a control sample of otherwise healthy subjects to identify the range of auditory shifts that one might reasonably expect to occur in the absence of any pathological insult. Statistical approaches to this seemingly mundane problem typically invoke 1 of 3 approaches: percentiles of the cumulative distribution, the variance of observed shifts, and the "standard error of measurement." In this article, the authors describe the statistical foundation for these approaches, along with a mixed model-based alternative, and identify several necessary, although typically unacknowledged assumptions. Regression to the mean, the phenomenon of an unusual measurement typically followed by a more common one, can seriously bias observed changes in auditory function and clinical expectations. An approach that adjusts for this important effect is also described. DESIGN: Distortion product otoacoustic emissions (DPOAEs) elicited at a single primary frequency, f2 of 3175 Hz, were collected from 32 healthy subjects at baseline and 19 to 29 days later. Ninety percent test-retest reference limits were computed from these data using each statistical approach. DPOAE shifts were also collected from a sample of 18 cisplatin patients tested after 120 to 200 mg of cisplatin. Reference limits established according to each of the statistical approaches in the healthy sample were used to identify clinically alarming DPOAE shifts in the cisplatin patient sample. RESULTS: Reference limits established with any of the parametric methods were similar. The percentile-based approach gave the widest and least precisely estimated intervals. The highest sensitivity for detecting clinically alarming DPOAE shifts was based on a mixed model approach that adjusts for regression to the mean. CONCLUSIONS: Parametric methods give similar serial monitoring criteria as long as certain critical assumptions are met by the data. The most flexible method for estimating test-retest limits is based on the linear mixed model. Clinical sensitivity may be further enhanced by adjusting for regression to the mean.

Development and validation of a cisplatin dose-ototoxicity model.

BACKGROUND: Cisplatin is effective in the treatment of several cancers but is a known ototoxin resulting in shifts to hearing sensitivity in up to 50-60% of patients. Cisplatin-induced hearing shifts tend to occur first within an octave of a patient's high frequency hearing limit, termed the sensitive range for ototoxicity (SRO), and progress to lower frequencies. While it is currently not possible to know which patients will experience ototoxicity without testing their hearing directly, monitoring the SRO provides an early indication of damage. A tool to help forecast susceptibility to ototoxic-induced changes in the SRO in advance of each chemotherapy treatment visit may prove useful for ototoxicity monitoring efforts, patient counseling, and therapeutic planning. PURPOSE: This project was designed to (1) establish pretreatment risk curves that quantify the probability that a new patient will suffer hearing loss within the SRO during treatment with cisplatin and (2) evaluate the accuracy of these predictions in an independent sample of Veterans receiving cisplatin for the treatment of cancer. STUDY SAMPLE: Two study samples were used. The Developmental sample contained 23 subjects while the Validation sample consisted of 12 subjects. DATA COLLECTION AND ANALYSIS: Risk curve predictions for SRO threshold shifts following cisplatin exposure were developed using a Developmental sample comprised of data from a total of 155 treatment visits obtained in 45 ears of 23 Veterans. Pure-tone thresholds were obtained within each subject's SRO at each treatment visit and compared with baseline measures. The risk of incurring an SRO shift was statistically modeled as a function of factors related to chemotherapy treatment (cisplatin dose, radiation treatment, doublet medication) and patient status (age, pre-exposure hearing, cancer location and stage). The model was reduced so that only statistically significant variables were included. Receiver-operating characteristic (ROC) curve analyses were then used to determine the accuracy of the risk curve predictions in an independent Validation sample of observations from over 62 treatment visits obtained in 24 ears of 12 Veterans. RESULTS: Only cumulative cisplatin dose and pre-exposure hearing were found to be significantly related to the risk for hearing shift. The dose-ototoxicity risk curve predictions developed from the Developmental sample yielded area under the ROC curve accuracy estimates of 0.85 when applied to an independent Validation sample. CONCLUSIONS: Cumulative cisplatin dose in combination with pre-exposure hearing provides an indication of whether hearing will shift in the SRO in advance of cisplatin administration. The validated dose-ototoxicity risk curves described herein can be used before and during treatment to anticipate hearing loss. While having such a tool would not replace serial hearing testing, it would be of great benefit to an ototoxicity monitoring program. It would promote relevant pretreatment counseling. Furthermore, for those found to be at risk of SRO shifts within the speech frequencies, the oncology treatment plan could incorporate anticipated dosing adjustments that could stave off the impact that ototoxicity might bring.

Accuracy of distortion-product otoacoustic emissions-based ototoxicity monitoring using various primary frequency step-sizes.

OBJECTIVE: A cisplatin ototoxicity monitoring protocol was recently proposed using distortion-product otoacoustic emissions (DPOAEs) measured in 1/48th octave steps over the highest obtainable quarter octave ( Dille et al, 2010 ). This protocol can take up to 40 minutes to complete in both ears among seriously ill patients in a potentially noisy test environment. The goal of the current study was to contrast the diagnostic accuracy of ototoxicity monitoring protocols based on changes in DPOAE levels at wider, more rapidly tested, primary frequency step sizes. DESIGN: Measure DPOAE levels in 1/48th octave steps over the highest half-octave of obtainable DPOAEs prior to treatment and at each ototoxicity monitoring session during the course of treatment with cisplatin. STUDY SAMPLE: Nineteen cancer patients being treated with cisplatin at the Portland Veterans Affairs Medical Center were observed over 56 monitoring appointments. Hearing thresholds in the sensitive region for ototoxicity (SRO) were measured concurrently with DPOAE levels. RESULTS: DPOAE levels measured in 1/24th octave steps provided comparable accuracy, and half the testing time, to the 1/48th octave step protocol previously described. CONCLUSIONS: DPOAE level shifts measured in 1/24th octave steps may provide a basis for rapid ototoxicity monitoring among adult cancer patients treated with cisplatin.

Multivariate DPOAE metrics for identifying changes in hearing: perspectives from ototoxicity monitoring.

Distortion-product otoacoustic emissions (DPOAEs) provide a window into real-time cochlear mechanical function. Yet, relationships between the changes in DPOAE metrics and auditory sensitivity are still poorly understood. Explicating these relationships might support the use of DPOAEs in hearing conservation programs (HCPs) for detecting early damage leading to noise-induced hearing loss (NIHL) so that mitigating steps might be taken to limit any lasting damage. This report describes the development of DPOAE-based statistical models to assess the risk of hearing loss from cisplatin treatment among cancer patients. Ototoxicity risk assessment (ORA) models were constructed using a machine learning paradigm in which partial least squares and leave-one-out cross-validation were applied, yielding optimal screening algorithms from a set of known risk factors for ototoxicity and DPOAE changes from pre-exposure baseline measures. Single DPOAE metrics alone were poorer indicators of the risk of ototoxic hearing shifts than the best performing multivariate models. This finding suggests that multivariate approaches applied to the use of DPOAEs in a HCP, will improve the ability of DPOAE measures to identify ears with noise-induced mechanical damage and/or hearing loss at each monitoring interval. This prediction must be empirically assessed in noise-exposed subjects.

Age-related changes in the auditory brainstem response.

PURPOSE: This cross-sectional study had two goals: (1) Identify and quantify the effects of aging on the auditory brainstem response (ABR); (2) Describe how click rate and hearing impairment modify effects of aging. RESEARCH DESIGN AND ANALYSIS: ABR measures were obtained from 131 predominately male Veteran participants aged 26 to 71 yr. Metrics analyzed include amplitude and latency for waves I, III, and V, and the I-V interpeak latency interval (IPI) at three repetition rates (11, 51, and 71 clicks/sec) using both polarities. In order to avoid confounding from missing data due to hearing impairment, participants had hearing thresholds <40 dB HL at 2 kHz and 70 dB HL at 4 kHz in at least one ear. Additionally, the median 2, 3, and 4 kHz pure tone threshold average (PTA2,3,4) for the sample, ∼17 dB HL, was used to delineate subgroups of better and worse hearing ears, and only the better hearing sample was modeled statistically. We modeled ABR responses using age, repetition rate, and PTA2,3,4 as covariates. Random effects were used to model correlation between the two ears of a subject and across repetition rates. Inferences regarding effects of aging on ABR measures at each rate were derived from the fitted model. Results were compared to data from subjects with poorer hearing. RESULTS: Aging substantially diminished amplitudes of all of the principal ABR peaks, largely independent of any threshold differences within the group. For waves I and III, age-related amplitude decrements were greatest at a low (11/sec) click rate. At the 11/sec rate, the model-based mean wave III amplitude was significantly smaller in older compared with younger subjects even after adjusting for wave I amplitude. Aging also increased ABR peak latencies, with significant shifts limited to early waves. The I-V IPI did not change with age. For both younger and older subjects, increasing click presentation rate significantly decreased amplitudes of early peaks and prolonged latencies of later peaks, resulting in increased IPIs. Advanced age did not enhance effects of rate. Instead, the rate effect on wave I and III amplitudes was attenuated for the older subjects due to reduced peak amplitudes at lower click rates. Compared with model predictions from the sample of better hearing subjects, mean ABR amplitudes were diminished in the group with poorer hearing, and wave V latencies were prolonged. CONCLUSIONS: In a sample of veterans, aging substantially reduced amplitudes of all principal ABR peaks, with significant latency shifts limited to waves I and III. Aging did not influence the I-V IPI even at high click rates, suggesting that the observed absolute latency changes associated with aging can be attributed to changes in auditory nerve input. In contrast, ABR amplitude changes with age are not adequately explained by changes in wave I. Results suggest that aging reduces the numbers and/or synchrony of contributing auditory nerve units. Results also support the concept that aging reduces the numbers, though perhaps not the synchrony, of central ABR generators.

Ototoxicity risk assessment combining distortion product otoacoustic emissions with a cisplatin dose model.

An objective method for identifying ototoxic hearing loss among patients receiving cisplatin is necessary since the ability of patients to take a behavioral test may change over the course of treatment. Data from 56 monitoring visits by 19 Veterans taking cisplatin were used to identify combinations of distortion-product otoacoustic emission (DPOAE) metrics and ototoxicity risk factors that best identified ototoxic hearing loss. Models were tested that incorporated DPOAE metrics generated statistically using partial least-squares analysis. Models were also tested that incorporated a priori DPOAE change criteria, such as a minimum DPOAE level shift of 6 dB. Receiver Operating Characteristic analysis was used to compare the accuracy of these models. The best performing model incorporated weighted combinations of pre-treatment hearing, cumulative cisplatin dose and DPOAE metrics that were determined using partial least-squares and evaluated over a quarter octave range near each subjects' high frequency DPOAE limit. Using this model and the DPOAE recording methods described herein, the chance of ototoxic hearing change can be determined at any given observed change in DPOAE level. This approach appears to provide an accurate and rapid ototoxicity risk assessment (ORA) that once validated can be used clinically.

Tinnitus onset rates from chemotherapeutic agents and ototoxic antibiotics: results of a large prospective study.

BACKGROUND AND PURPOSE: To report on the incidence and relative risk of tinnitus onset from a variety of drug therapies known to be ototoxic. Two main questions were asked: (1) What is the prevalence and incidence of tinnitus among patients treated with cisplatin, carboplatin, or ototoxic antibiotic therapies? (2) Do commonly reported treatment or subject factors confound or modify the incidence of tinnitus onset? DATA COLLECTION AND ANALYSIS: A prospective observational study design was used to evaluate occurrence of significant otologic changes in 488 veterans (962 ears) receiving chemotherapeutic agents (cisplatin, carboplatin), ototoxic antibiotics (primarily aminoglycoside), or nonototoxic drugs (control medications). A subset of 260 veterans lacking tinnitus prior to drug exposure was used to compare rates of tinnitus onset. Subjects were tested prior to, during, and following their treatment. Planned comparisons using logistic regression, analysis of variance (ANOVA), and chi(2) statistics were made among groups by the type of medication taken, age, presence of preexisting hearing loss, days on drug, and cumulative dose of drug. RESULTS: Baseline tinnitus rates were high (nearly 47%) relative to the general population of a similar age. Subjects with exposure to ototoxic medications had significantly increased risk for developing tinnitus. Those on chemotherapeutic agents were found to have the greatest risk. Cisplatin elevated the risk by 5.53 times while carboplatin increased the risk by 3.75 over nonototoxic control medications. Ototoxic antibiotics resulted in borderline risk (2.81) for new tinnitus. Contrary to other reports, we did not find that subject factors (increased age or pre-existing hearing loss) or treatment factors (days on drug or cumulative dose) contributed to rates of tinnitus onset during treatment. CONCLUSIONS: This large prospective study confirms that new tinnitus during treatment is associated with chemotherapy and with certain ototoxic antibiotic treatment. Cisplatin and carboplatin were found to be the most potent ototoxic agents causing tinnitus at much greater numbers than the other drugs studied. Implications for counseling and audiological resource allocation are discussed.