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Distortion product otoacoustic emissions: Introduction Michael P. Gorga, Ph.D. Boys Town National Research Hospital Work supported by the NIH Collaborators on BTNRH OAE Projects • Stephen Neely • Kathy Beauchaine • Darcia Dierking • Tricia Dorn • Cassie Garner • Brenda Hoover • Debra Hussain • Jan Kaminski • Walt Jesteadt • Tiffany Johnson • Doug Keefe • Dawn Konrad-Martin • Danielle Montoya • Jo Peters • Beth Prieve • Joelle Redner • Laura Schulte • Brenda Starnes • Alicia Schmiedt • Lisa Stover Principles behind the use of OAEs to identify hearing loss •normal cochlea behaves nonlinearly •source of nonlinearity is the OHC system •OHCs are physiologically vulnerable •OAEs are byproducts of normal nonlinear function •loss of OAEs indicates damage to the OHCs 1 The clinical Link •OHC damage is closely linked to hearing loss, at least for losses up to about 50-60 dB •loss of OAEs indicates OHC damage, which in turn, indicates the presence of hearing loss Stimuli for eliciting DPOAEs •two primary tones, f1 and f2 •f2 = 1.22(f1) (same as f2/f1 = 1.22) •primary levels may range from 0 to 85 dB SPL •moderate primary levels are in most common clinical use •primary levels may be equal or L1 may be greater than L2 •primary-level differences should increase as overall level decreases Distortion Product Otoacoustic Emission • acoustic response measured using microphone in the sealed ear canal • evoked using two-tone stimulation (f1 and f2; f1 < f2) • response is due to intermodulation distortion in the basilarmembrane response • many DPs are generated, but response typically is measured at the frequency equal to 2f 1-f2 2 Measuring DPOAEs •many distortion products are produced but response typically is measured at a frequency equal to 2f1-f2 because it is the largest one in mammals •noise typically is estimated as the average level in several frequency bins above and below the 2f1-f2 bin. •DPOAE-to-noise ratio (SNR) is estimated as the dB difference between energy at 2f1-f2 and energy in adjacent noise bins DPOAE Measurements •DPGrams - plots of DPOAE level as a function of either f2 frequency or the geometric mean frequency, which is defined as the square root of (f2 x f1), while primary levels are held constant. •DP Input/Output (I/O) functions - plots of DPOAE level as a function of primary level while primary frequencies are held constant. 3 Measurement-Based Stopping Rules •stop test if noise level is reduced to some criterion level, related to the level at which system distortion occurs •stop test if SNR exceeds some criteria •stop test if response level exceeds some criteria •stop test after some amount of test time, even if measurement-based criteria are not met. Why Measurement-Based Stopping Rules? •Increases test efficiency - don’ t waste time •measurements are terminated if high SNR is observed, meaning a response is present •measurements are terminated if low noise is achieved, meaning that, if a response was present, it should have already been measured •measurements are terminated after some time limit, preventing the test from continuing indefinitely. 4 Distortion product otoacoustic emissions in relation to hearing loss Data From Subjects with Hearing Loss •DPgrams tend to mimic the audiogram. That is, there is reduced output (for fixed primary levels) at those f2 frequencies at which hearing loss exists •I/O functions also reflect the pattern of hearing loss. That is, there is less output over most of the range of levels for frequencies at which hearing is impaired. Note: high level responses may be more normal, depending on magnitude of loss 5 from Kemp et al. (1986), Scand. Audiol. 25 (Suppl.), 71-82 Next Slide Kemp et al. (1986) •Top panel: Data from normal ears •Middle panel: DPgrams from three ears with hearing loss •Bottom panel: Audiograms from the same three ears with hearing loss •Note: Frequency is represented on a linear scale 6 from Martin et al. (1990), Ann. Otol. Rhinol.Laryngol. 99 (Suppl. 147), 29-44 Next 3 data slides Martin et al. (1990) •Top row: Audiograms (separate panels for each ear) and DPgrams (different symbols for each ear) •Bottom row: DP I/O functions (different symbols for each ear) •Note: The frequency scale in the audiogram goes from 0.125 to 8 kHz, whereas the DPgram goes from 1 to 10 kHz. Both scales are logarithmic 7 Summary of Case Studies •DPgrams follow the audiogram, showing responses for frequencies where hearing is normal and reduced or absent responses when hearing loss exists. •I/O functions also are consistent with audiometric status. 8 Case Studies versus Group Results •Case studies are informative, but what is needed are data from large samples of normal and hearing-impaired subjects •Large sample studies allow for quantitative analyses from which it will be possible to describe how DPOAE tests (or any test, for that matter) perform under clinical conditions Factors affecting DPOAE test performance •f2 frequency (Gorga et al., 1993, 180 subjects) •primary levels (Stover et al., 1996, 210 subjects) •magnitude of hearing loss (Gorga et al., 1997, 806 subjects) Effects of f2 Frequency From Gorga et al. (1993), JASA 93, 2050-2060 9 ROC Curves •Hit rate as a function of false alarm rate •Comparisons are made when f2 = audiometric frequency •Parameter is f2 frequency •In these coordinates, chance performance occurs when ROC curve has a slope of one (line falls on positive diagonal). •Perfect performance occurs when hit rate = 100% and false alarm rate = 0%. Frequency Effects •Performance at 500 Hz is near chance •Performance improves as f2 increases •Best performance observed at 4 kHz •Slight drop in performance when f2 = 8 kHz. 10 Reasons for Frequency Effects •noise decreases as frequency increases •forward (and perhaps reverse) middle ear energy transmission is more efficient for mid to high frequencies compared to lower frequencies •cochlear distortion maybe greater for higher frequencies compared to low frequencies Low-Frequency Limits of DPOAE Measurements •primary source of noise in DPOAE measurements is breathing and movement noise, which are dominated by low-frequency energy •noise increases as frequency decreases, thus making it harder to reliably measure a response at lower frequencies •noise problems are compounded by measuring responses at 2f1-f2 The Problem of Measuring Responses at 2f1-f2 •DPOAEs are generated at the f2 place •cochlear status at the f2 place is being predicted from DPOAE measurements •predictions are based on measurements at 2f1-f2, which is about 1/2 octave below f2, where noise levels are higher, making measurements less reliable 11 Stimulus and Response Representations •Top: Stimuli and response. Note that 2f1f2 is below f1 •Bottom: Idealized representation of stimuli and response along the basilar membrane. Interactions Between Frequency of Interest (f2) and the Frequency of Measurement (2f1-f2) •noise levels reach asymptotic low levels for f2’ s at 4 kHz. Thus, it matters little that 2f1-f2, the frequency of measurement, is about 1/2 octave below f2, the frequency of interest •interaction has a significant negative impact for f2’ s at and below 4 kHz, because 2f1-f2 falls in frequency regions for which noise levels increase 12 Performance at 8 kHz •While noise is the major source of reduced test performance for lower frequencies, noise levels are very low at 8 kHz •Thus, poorer performance at 8 kHz cannot be due to noise •Poorer performance may relate to the need to drive the loudspeakers with a greater voltage in order to get target primary levels. This high voltage may result in an increase in system distortion, resulting in poorer performance Primary Level Effects •Should we use primary levels that result in the largest responses from subjects with normal hearing - that would be the highest possible level •Should we use primary levels close to threshold - that would require several measurements under conditions of poor SNR •Should we use primary levels that result in the greatest separation between the distributions of responses from normal and impaired ears Effects of Primary Level on DPOAE Test Performance From Stover et al. (1996), JASA 100, 956-967 Next 6 data slides 13 I/O Functions to DPgrams •I/O functions plot DPOAE amplitude vs. L2 •Obtain DPOAE I/O functions for several f2 frequencies •From each I/O function, note the DPOAE amplitude when L2 is held constant •DPgrans are plots of these amplitudes as a function of frequency 14 DPgrams and Audiograms in Normal ears •Audiogram –bottom row, middle panel •DPgrams, constructed from I/O functions, for five different L2 levels •High-level –bottom left panel •Low-level –bottom right panel •Moderate levels –top row of panels Results in Normal Ears •Normal ear produces response for most frequencies and most L2 levels •Low-level stimuli sometimes do not produce responses in ears with normal hearing. 15 I/O functions in an ear with hearing loss •Noise levels caused variability in I/O functions at lower f2 frequencies •Normal appearing I/O functions at 1, 1.4, and 2 kHz •“ Abnormal”I/O functions at 2.8, 2, and 4 kHz •Probably normal I/O function at 8 kHz DPgrams and Audiograms in an Ear with Hearing Loss •Audiogram - bottom row, middle panel •Abnormal response at high levels, but only for 4 kHz (lower left panel) •Abrnormal responses for moderate level primaries at frequencies for which hearing loss exists (top row of panels) •Abnormal response at 8 kHz for low-level stimuli, even though hearing was normal at this frequency 16 Test Performance Vs. L2 •Area under the ROC curve is an estimate of test performance •Test performance is defined as the test’ s ability to correctly identify both normal and impaired ears •Areas close to 0.5 Represent chance performance •Areas close to 1.0 represent perfect performance •Each function represents data for a different frequency 17 Effects of Primary Level •At all f2 frequencies, test performance increases as L2 increases •An maximum asymptotic value is achieved at moderate L2 levels •Performance decreases slightly at higher L2 levels Reasons for Primary Level Effects •normal ears may not produce a response at low levels - drives up the false positive rate •impaired ears may produce a response at high levels - drives up the false negative rate •moderate levels should minimize errors Laboratory vs. Clinical Observations •Test performance is determined most by f2 frequency. Do the effects of f2 frequency, observed under laboratory conditions, hold when data are obtained under routine clinical conditions •Will the optimal primary levels under laboratory conditions work well in the clinic 18 Large Scale Study in the Clinic •1257 ears of patients seen through the audiology clinic •subjects’ ages covered the life span •all subjects had normal tympanograms on the day of the DPOAE test •audiograms were available for all subjects •65/55 dB SPL primaries were used, given the results of the primary level studies Effects of f2 Frequency under Clinical Conditions From Gorga et al. (1997), Ear & Hearing 18, 440-455 ROC Curves •Plots of hit rate vs. false alarm rate •Triangles: SNR was used •Circles: DPOAE level was used •Each panel shows data for a different f2 •ROC curve areas are given inside each panel 19 Clinical Observations •results under clinical conditions are virtually identical to those seen in the laboratory •test performance is best for frequencies of 4 and 6 kHz •test performance is poorer as f2 decreases and for 8 kHz Summary •DPOAEs accurately identify auditory status at mid and high frequencies •DPOAEs are less accurate for frequencies <1.5 kHz, due primarily to noise levels •DPOAEs are more accurate for moderate level primaries •DPOAEs will miss some ears with mild hearing loss •DPOAEs will incorrectly label some ears with normal hearing as impaired 20 Establishing DPOAE Criteria for Use in the Clinic Gorga et al. (1996) JASA 100, 968-977 Gorga et al., (1997) E&H 18, 440455 Shortcomings of Common Approaches for Selecting DPOAE Test Criteria •Data from normal-hearing subjects can be used to estimate ONLY the false-positive rate (a problem not only for SNR) •a priori SNR criteria, such as 3, 6 or 9 dB SNRs, do NOT result in a 100% hit rate or a 0% false-alarm rate Equal SNRs do not = the Same Auditory Status •DPOAE = 5 dB SPL at 4 kHz •Noise = -4 dB SPL at 4 kHz •SNR = 9 dB, cochlea probably normal •DPOAE = -15 dB SPL at 4 kHz •Noise = -24 dB SPL at 4 kHz •SNR = 9 dB, cochlea probably abnormal •SNR alone would have misdiagnosed the second case as normal hearing 21 Another Problem: Response Distributions Overlap •There are no DPOAE criteria that perfectly separate the responses observed in normal ears from those seen in impaired ears. •Errors are inevitable. The question is, “ which error is more important, falsepositive or false-negative errors” . Which Error is More Important •Prevalence may be important in choosing which error to control •If the incidence of hearing loss is low in the target population, one might want to minimize the false-positive errors •If the incidence is high in the target population, then one might want to minimize the false-negative errors. Cumulative Distributions (CD) •CDs are the proportion of time responses occur that are ≤some criterion value as a function of that value •CDs are another way of plotting a normal distribution. The same data that result in a bell-shaped normal distribution result in a sigmoidal (S) shaped CD. CDs are just a different way of looking at the same data •CDs of responses from both normal and impaired ears are needed whenever the distributions of normal and impaired responses overlap 22 Possible DPOAE criteria that can be used in the clinic •DPOAE Level •DPOAE SNR •DPOAE Threshold •Multivariate Scores •Other, as yet, undetermined DPOAE measure, such as latency or slope of the I/O function Developing an Approach for Use in the Clinic (Gorga et al., 1996, 1997) •We need CDs of the measurement variable of interest (i.e., DPOAE level or SNR). •CDs from normal-hearing ears can be used to determine criteria associated with specific falsepositive rates •CDs from impaired ears can be used to determine criteria associated with specific hit rates Selecting a Hit Rate from CDs •One approach for selecting a criterion DPOAE value is to first decide on an acceptable hit rate or test sensitivity •Draw a horizontal line at that hit rate until it intersects the distribution of responses from impaired ears •Drop a vertical line to the X-axis to find the criterion value that provides that hit rate 23 Selecting a False-Alarm Rate •Decide on an acceptable false-positive rate •Draw a horizontal line at the false-positive rate until it intersects the distribution of responses from normal ears •Draw a vertical line from this intersection to the X axis to find the criterion DPOAE value associated with that false-alarm rate Cumulative Distributions in Normal and Impaired Ears Note: As examples, criteria are selected that resulted in a 95% hit rate (impaired CD) and a 5% false alarm rate (normal CD) 24 Figure showing DPOAE Levels for Fixed False Alarm and Hit Rates •DPOAE level as a function of f2 •Data from normal (left panel) and impaired (right panel) ears are shown •Parameter is percentage, from 5th to 95th percentiles •Filled symbols represent the DPOAE levels at the median (50th) percentile Evidence of Overlap Between Normal and Impaired Responses •No criterion can be selected for which the hit rate is 100% AND the false alarm rate is 0%. All of the functions in the right panel are not below all of the functions in the left panel. •Some impaired ears produce bigger responses (or lower thresholds) than some normal ears •Or, stated differently, some normal ears produce smaller responses (or higher thresholds) than some impaired ears 25 Constructing a Useful Clinical Form (Gorga et al.,1997, 2002) •Select 1 or 2 hit rates (say 90th & 95th %) and find the DPOAE criteria associated with them •Select 1 or 2 false-alarm rates (say, 5th & 10th %) and find the DPOAE criteria associated with them •Plot these values (DPOAE criteria vs. f2) to create a form for clinical use Basis for Developing a Clinical Form •Right: Schematic showing overlap between DPOAE levels from normal and impaired ears •Left: top line = 95th percentile (hit rate = 95%) from impaired distribution, second line = 90th percentile from impaired distribution (hit rate = 90%), third line = 10th percentile from normal distribution (false-alarm rate = 10%), bottom line = 5th percentile from normal distribution (false-alarm rate = 5%) 26 Interpreting DPOAE Data, Using the Left Panel of the Previous Figure •Responses above highest values from impaired CDs would be consistent with normal hearing because few impaired ears produced responses this big or bigger •Responses below lowest values from normal CDs would be consistent with hearing loss because few normal ears produced responses this small or smaller •Diagnosis is uncertain for responses between these values (i.e., in shaded regions), where normal and impaired responses overlap Large Sample Study figure and data from Gorga et al. (1997, E&H) and Gorga et al. (2002) in Robinette and Glattke, 2nd Ed. •Data from 1257 normal and impaired ears •L1/L2 = 65/55 dB SPL •All data collected under clinical conditions •Measurement-based stopping rules were used BTNRH Clinical Form NOTE: Baljit Rehal, Au.D. was instrumental in developing this form 27 Caveats when using this form • SNR should be ≥6 dB IF noise floor is not below the lower limit of graph in order to use this form to help interpret responses • Large DPOAE levels cannot be plotted on this form if DPOAE ≈ noise floor (i.e., SNR≈0 dB); such “ responses”are uninterpretable because they could be just noise • If noise is reduced below lower limits of graph AND response is not above the noise floor (SNR=0 dB), the results are interpretable (i.e., consistent with hearing loss) because the reason no response was observed was because the response was so small, not because the noise was too high • Diagnosis is uncertain for responses in shaded area (SNR≥6 dB but responses from normal and impaired ears overlap). Interpreting Responses in the Shaded Areas •There should be a minimum SNR of 6 dB •Between 90th (impaired distributions and 5th (normal distributions) percentiles, responses fall in the region of uncertainty because there is overlap in responses from normal and impaired ears 28 Five Case Studies, in which Clinical Form was Used to Assist in Interpretation First step in interpreting results is to determine if DPOAE level was reliably measured. SNR helps to determine that. A related issue is to determine whether the noise floor was sufficiently reduced. Case #1 Frequency 750 1000 1500 2000 3000 4000 6000 8000 DPOAE 7 8 6 3 1 2 3 -5 Noise - 8 -10 -11 -13 -15 -20 -21 -20 Signal/Noise 15 18 17 16 16 22 24 15 29 Case 1: Results Consistent with Normal Hearing •Low noise levels even for lower f2’ s •Large DPOAEs •Positive SNR at all f2’ s •Levels above 90th percentile for impaired ears •Results consistent with normal hearing because few impaired ears produce such large responses Case #2 30 Frequency 750 1000 1500 2000 3000 4000 6000 8000 DPOAE 7 8 5 0 1 0 1 -5 Noise 6 8 3 -1 2 0 0 -7 Signal/Noise 1 0 2 1 -1 0 1 2 Case #2: High Noise Levels = Uninterpretable Responses •“ Large”DPOAEs •High noise levels •Low SNR •Results are uninterpretable because “ large”DPOAEs may be nothing more than noise •Note that the levels were the same as for Case #1 31 Case #3 Frequency 750 1000 1500 2000 3000 4000 6000 8000 DPOAE -15 -14 -16 -18 -17 -18 -20 -26 Noise -16 -15 -17 -17 -17 -20 -20 -25 Signal/Noise 1 1 1 1 0 2 0 -1 32 Case #3: Low SNR & Low Noise Levels can be Interpreted •DPOAEs below the lower limits of graph •Noise levels also are low •Low SNR (i.e., DPOAE level was not measured reliably above the noise floor) •Results are consistent with hearing loss because the reason a response was not measured was NOT due to high levels of noise, but to low level of response. Case #4 Frequency 750 1000 1500 2000 3000 4000 6000 8000 DPOAE 0 0 -5 -6 -8 -6 -7 -15 Noise -10 -11 -14 -14 -19 -20 -22 -25 Signal/Noise 10 11 9 8 11 14 15 10 33 Case #4: DPOAEs in the region of uncertainty •DPOAE levels in shaded region •Noise levels well below DPOAE levels •Positive SNR, meaning DPOAEs were measured reliably •Results cannot be assigned to normal or impaired distribution Responses between 90th (Impaired) and 5th (Normal) Percentiles (Gorga et al., 2002) •This is the region where overlap occurs between the responses produced by normal and impaired ears. One might conclude that these responses are completely uninterpretable •If SNR ≥6 dB, we can exploit the relation between audiometric threshold and DPOAE level to help interpret the response 34 Audiometric Threshold vs. DPOAE Level •Audiometric threshold (dB HL) as a function of DPOAE level (dB SPL) •Data for a different f2 shown in each panel •Solid line = 50th percentile (median) •Shaded areas = interquartile range (25th to 75th percentile) Audiometric Threshold vs. DPOAE Level •Audiometric threshold decreases as DPOAE level increases •Although variable (note that the shaded area only covers the middle 50% of the distribution at each audiometric threshold), relation exists for audiometric thresholds from -5 to about 50-60 dB HL •No relation above 55 dB HL, related to the range of levels over which outer hair cells operate 35 Caveats For This Form •The SNR should be ≥6 dB •The shaded area covers only the 25th to the 75th percentile •Thus, there are still cases when interpretations will be wrong •However, using this form provides limited but still useful information for interpretation, especially when no other data are available to assign a response to either normal or impaired groups Interpreting Data in the Region of Uncertainty •DPOAE levels reliably measured •All DPOAEs are in region of uncertainty; thus, they cannot be assigned to normal or impaired distributions •Given the measured levels, one would anticipate that these responses were coming from an ear with either normal hearing or mild hearing loss (see previous figure). It would be less likely that these responses were coming from an ear with moderate, severe or profound hearing loss. Case #5 36 Frequency 750 1000 1500 2000 3000 4000 6000 8000 DPOAE -2 0 -3 -5 -7 -6 -7 -15 Noise -1 -2 -4 -5 -8 -5 -7 -16 Signal/Noise -1 2 1 0 1 -1 0 1 Case #5: Uninterpretable DPOAEs in Region of Uncertainty •DPOAEs in shaded region •Noise levels = DPOAE level (SNR ≈0) •DPOAEs, therefore, are not reliable •Results cannot be interpreted (cannot use either form) because measured “ responses” may be just noise, but this cannot be known 37 Univariate vs. Multivariate Analyses •Univariate approach compares data from one measurement (say DPOAE & noise level at one f2) to predict cochlear status at the same frequency. •Multivariate analyses use data from many variables (in our case, DPOAE level and noise for many f2’ s) to predict cochlear status at a single frequency. What Do Multivariate Analyses Do? •Use many variables as inputs to generate a single dimensionless number •select variables and coefficients that result in the greatest separation between the means of two distributions of the new dimensionless variable •Select variables and coefficients that minimize the variance of each distribution One Kind of Multivariate Analysis Discriminant Analysis 38 Developing Multivariate Solutions •Because many variables are being used, the solutions can be irregular and may not generalize to a new set of data •Multivariate solutions should be validated on an independent set of data Validating Multivariate Analyses (Dorn et al., 1999) •Obtained large data set •randomly divided data set in half •use the first half to develop (train) the algorithm •do not change the training algorithm •apply training algorithm to the other half of the data set 39 Relative Operating Characteristic Curve Areas (AROC) •AROCs can be used to describe test performance for dichotomous clinical decisions (i.e., normal versus impaired hearing) •AROCs range from 0.5 (chance performance) to 1.0 (perfect performance) •No audiological tests have AROCs equaling 1.0. Univariate vs. Multivariate Results •Multivariate solutions provide better test performance than univariate analyses •greatest differences between univariate and multivariate approaches occurs in the lower frequencies •Multivariate solutions do nearly as well on validation set as they did on training set. Thus, the solutions appear to be robust •Validation from studies by other investigators would be useful 40 Problems with Validation in Original Work •Both ears of many subjects were tested •Ears were randomly assigned to either training or validation sets •The two ears of the same subject are not independent •A completely independent data set are needed to evaluate the generalizability of the multivariate solutions A Better Validation of Multivariate Analyses (Gorga et al., 2005) •An entirely new set of subjects: –345 ears of 187 subjects, 2 to 86 years of age –No middle-ear dysfunction –Pure-tone audiograms measured for each subject •DPOAE Stimuli: –f2 = 0.75 to 8 kHz, half-octave steps –f2/f1 = 1.22 –L1 = 65 dB SPL; L2 = 55 dB SPL •Previously described multivariate solution, without modification, were applied to these new data. •Clinical decision theory (AROCs) used to assess test performance 41 SNR & DPOAE Level Versus Multivariate Solution •AROCs are larger for SNR compared to DPOAE level at lowest frequency, while AROCs are larger for DPOAE level at most mid and high frequencies •AROCs for multivariate analyses exceed those for both DPOAE level and SNR, with the exception of 4 kHz, a frequency for which areas are about the same. Conclusions •Previously described multivariate solutions were robust and generalized to an entirely new set of data. •Improved DPOAE test performance can be achieved by using the multivariate solutions. •The improved test performance does not require any additional test time. Case Studies Comparing… •Pure tone audiograms •DP-Level form (univariate analysis) •P(N) form (multivariate analysis) •NOTE: Probability of normal (P(N)) is derived from the dimensionless number generated by the multivariate analysis 42 Normal hearing subjects with high P(N) Hearing impaired subjects with low P(N) Hearing Impaired Subjects with Flat and Sloping Losses 43 Test performance is not perfect: Example of a false negative Test performance is not perfect: Example of a False Positive Summary •DPOAEs do not perform perfectly •Test performance can be improved by using multivariate analyses •Multivariate solutions are robust and appear to generalize •Even with these improvements, perfect performance is never achieved 44 Bad News - Good News •The bad news is that errors in diagnoses are inevitable when DPOAEs are used to identify hearing loss. •This is true for other tests, not just DPOAE tests. •The good news is that, when auditory status is uncertain, it is more likely that we are confusing normal or mild hearing losses or mild and moderate hearing losses. It is much less likely that we are confusing normal hearing with moderate or greater losses. 45