U.S. payer budget impact of using an AI-augmented cancer risk discrimination digital histopathology platform to identify high-risk of recurrence in women with early-stage invasive breast cancer.

AIMS: Use of gene expression signatures to predict adjuvant chemotherapy benefit in women with early-stage breast cancer is increasing. However, high cost, limited access, and eligibility for these tests results in the adoption of less precise assessment approaches. This study evaluates the cost impact of PreciseDx Breast (PDxBr), an AI-augmented histopathology platform that assesses the 6-year risk of recurrence in early-stage invasive breast cancer patients to help improve informed use of adjuvant chemotherapy. MATERIALS AND METHODS: A decision-tree Markov model was developed to compare the costs of treatment guided by standard of care (SOC) risk assessment (i.e. clinical diagnostic workup with or without Oncotype DX) versus PDxBr with SOC in a hypothetical cohort of U.S. women with early-stage invasive breast cancer. A commercial payer perspective compares costs of testing, adjuvant therapy, recurrence, adverse events, surveillance, and end-of-life care. RESULTS: PDxBr use in prognostic evaluation resulted in savings of $4 million (M) in year one compared to current SOC in 1 M females members. Over 6-years, savings increased to $12.5 M. The per-treated patient costs in year one amounted to $19.5 thousand (K) for SOC and $16.9K for PDxBr. LIMITATIONS: For simplicity, recurrence was not specified. We performed scenario analyses to account for variations in rates for local, regional, and distant recurrence. Second, a recurrent patient incurs the total cost of treated recurrence in the first year and goes back to remission or death. Third, CDK4/6i treatment is only incorporated in the recurrence costs but not in the first line of treatment for early-stage breast cancer due to limited data. CONCLUSIONS: Sensitivity analyses demonstrated robust overall savings to changes in all variables in the model. The use of PDxBr to assess breast cancer recurrence risk has the potential to fill gaps in care and reduce costs when gene expression signatures are not available.

US payer budget impact of a microarray assay with machine learning to evaluate kidney transplant rejection in for-cause biopsies.

AIM: This study evaluates the economic impact to US commercial payers of MMDx-Kidney used in conjunction with histologic evaluation of for-cause kidney transplant biopsies. MATERIALS AND METHODS: An Excel-based model was developed to assess the cost impact of histology plus MMDx-Kidney versus histology alone for the evaluation of potential rejection in kidney transplant patients who receive a for-cause biopsy. Different model time periods were assessed, ranging from 1 to 5 years post-biopsy. A targeted literature review was used to identify parameter estimates, validated by two external clinicians with expertise in managing kidney transplant rejection. A sensitivity analysis was conducted to evaluate the relative impact of key clinical and cost parameters. In particular, the model identified the magnitude of MMDx-Kidney's impact on graft failure from rejection that would be required for MMDx-Kidney to be cost-neutral. RESULTS: By more accurately characterizing rejection, MMDx-Kidney is estimated to increase antirejection treatment costs by $1,126 per test. Nevertheless, a break-even analysis shows that the costs of MMDx-Kidney and anti-rejection medication, as well as the costs associated with an increase in the number of patients with functioning transplants, may be offset by reductions in costs associated with graft failure (i.e. costs of hospitalizations, dialysis, and repeat transplants) over 5 years, assuming MMDx-Kidney reduces annual graft failure from rejection by at least 5%. For the base case, with a 25% relative reduction in annual rate of graft failures from rejection, MMDx-Kidney increases overall costs incurred in the first year of the model but starts generating savings by the second year of the model. CONCLUSIONS: Compared with histologic evaluation of for-cause kidney transplant biopsies alone, the use of MMDx-Kidney in conjunction with histologic evaluation improves the diagnoses of graft dysfunction and may have the potential to generate overall savings from reductions in rejection-related graft failure.

Preserving Wideband Tympanometry Information With Artifact Mitigation.

OBJECTIVE: Absorbance measured using wideband tympanometry (WBT) has been shown to be sensitive to changes in middle and inner ear mechanics, with potential to diagnose various mechanical ear pathologies. However, artifacts in absorbance due to measurement noise can obscure information related to pathologies and increase intermeasurement variability. Published reports frequently present absorbance that has undergone smoothing to minimize artifact; however, smoothing changes the true absorbance and can destroy important narrow-band characteristics such as peaks and notches at different frequencies. Because these characteristics can be unique to specific pathologies, preserving them is important for diagnostic purposes. Here, we identify the cause of artifacts in absorbance and develop a technique to mitigate artifacts while preserving the underlying WBT information. DESIGN: A newly developed Research Platform for the Interacoustics Titan device allowed us to study raw microphone recordings and corresponding absorbances obtained by WBT measurements. We investigated WBT measurements from normal hearing ears and ears with middle and inner ear pathologies for the presence of artifact and noise. Furthermore, it was used to develop an artifact mitigation procedure and to evaluate its effectiveness in mitigating artifacts without distorting the true WBT information. RESULTS: We observed various types of noise that can plague WBT measurements and that contribute to artifacts in computed absorbances, particularly intermittent low-frequency noise. We developed an artifact mitigation procedure that incorporates a high-pass filter and a Tukey window. This artifact mitigation resolved the artifacts from low-frequency noise while preserving characteristics in absorbance in both normal hearing ears and ears with pathology. Furthermore, the artifact mitigation reduced intermeasurement variability. CONCLUSIONS: Unlike smoothing algorithms used in the past, our artifact mitigation specifically removes artifacts caused by noise. It does not change frequency response characteristics, such as narrow-band peaks and notches in absorbance at different frequencies that can be important for diagnosis. Also, by reducing intermeasurement variability, the artifact mitigation can improve the test-retest reliability of these measurements.

Mechanics of Total Drum Replacement Tympanoplasty Studied With Wideband Acoustic Immittance.

OBJECTIVE: Poor hearing outcomes often persist following total drum replacement tympanoplasty. To understand the mechanics of the reconstructed eardrum, we measured wideband acoustic immittance and compared the mechanical characteristics of fascia-grafted ears with the normal tympanic membrane. STUDY DESIGN: Prospective comparison study. SETTING: Tertiary care center. METHODS: Patients who underwent uncomplicated total drum replacement with temporalis fascia grafts were identified. Ears with healed grafts, an aerated middle ear, and no other conductive abnormalities were included. All patients underwent pre- and postoperative audiometry. Wideband acoustic immittance was measured with absorbance and impedance computed. Fascia-grafted ears were compared with normal unoperated ears. RESULTS: Eleven fascia-grafted ears without complications were included. Postoperatively, the median air-bone gap was 15 dB (250-4000 Hz), with variation across frequency and between ears. Fifty-six control ears were included. Absorbance of fascia-grafted ears was significantly lower than that of normal ears at 1 to 4 kHz (P < .05) but similar below 1 kHz. Impedance magnitude demonstrated deeper and sharper resonant notches in fascia-grafted ears than normal ears (P < .05), suggesting lower mechanical resistance of the fascia graft. CONCLUSION: The mechanics of fascia-grafted ears differ from the normal tympanic membrane by having lower absorbance at mid- to high frequencies and thus poor sound transmission. The lower resistance in fascia-grafted ears may be due to poor coupling of the graft to the malleus. To improve sound transmission, grafts for tympanic membrane reconstructions would benefit from refined mechanical properties.

Fracture of the Incus Caused by Digital Manipulation of the Ear Canal and its Diagnosis Using Wideband Acoustic Immittance.

OBJECTIVE: To describe the first reported case of a fracture of the long process of the incus due to digital manipulation of the ear canal and to discuss diagnostic markers for ossicular fractures. PATIENT: A 46-year-old woman with incessant clicking and crunching in her left ear, and hearing loss after digital manipulation of the ear canal. INTERVENTION: Diagnostic evaluation and therapeutic ossiculoplasty. MAIN OUTCOME MEASURE(S): Audiometric and wideband acoustic immittance (WAI) measurements were made before surgery to investigate the cause of clicking sounds and mild conductive hearing loss (CHL). RESULTS: The clinical suspicion of a loose ossicular chain was confirmed by a large narrow-band decrease in power reflectance (calculated from WAI) at frequencies between 600 and 700 Hz, and a mid- to high-frequency air-bone gap. Exploratory tympanotomy revealed an ossicular fracture of the distal aspect of the long process of the incus. Ossiculoplasty with bone cement resolved bothersome clicking sounds. CONCLUSION: A finger inserted into the ear canal can produce an air seal, and subsequent quick removal of the finger can result in the fracture of an ossicle. Clinicians should be cognizant of this form of trauma because insertion of a finger, ear plug, and earphone into the ear canal are common. Ossicular fractures can result in high-frequency CHL, and can be misdiagnosed as sensorineural loss because bone conduction thresholds are not measured above 4 kHz. As in this case, an ossicular fracture may be misdiagnosed and result in inappropriate treatment. Here, WAI, a non-invasive measure of ear mechanics, diagnosed a loose ossicular chain.

Audiometric and cVEMP Thresholds Show Little Correlation With Symptoms in Superior Semicircular Canal Dehiscence Syndrome.

OBJECTIVE: Evaluate the relationship between objective audiometric and vestibular tests and patient symptoms in superior canal dehiscence (SCD) syndrome. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care center. PATIENTS: Ninety-eight patients with SCD, preoperative threshold audiograms, cervical vestibular evoked myogenic potential (cVEMP) thresholds, and computed tomography (CT) imaging were included. Clinical reports were reviewed for self-reported SCD symptoms. Twenty-five patients completed the Hearing Handicap Inventory (HHI), Dizziness Handicap Inventory (DHI), Autophony Index (AI), and the 36-item Short Form Survey (SF-36). MAIN OUTCOME MEASURES: Correlations between preoperative low-frequency air-bone gap (ABG), cVEMP thresholds, and symptoms (including HHI, DHI, AI, and SF-36). Symptoms included hearing loss, aural fullness, autophony, hyperacusis, tinnitus, vertigo, imbalance and sound-, pressure and exercise provoked dizziness. Secondary outcome measure: Correlations between changes of objective and subjective measures before and after surgery. RESULTS: Patients who reported hearing loss had larger ABGs at 250 Hz than patients without subjective hearing loss (p = 0.001). ABGs and cVEMP thresholds did not correlate with any other symptom. No significant correlation was found between ABG or cVEMP threshold and the HHI, DHI, AI or Health Utility Value (derived from the SF-36 quality of life score). Following SCD surgery, ABG decreased (p < 0.001), cVEMP thresholds increased (p < 0.001) and overall symptoms, handicap scores and quality-of-life improved; however, there was no significant relationship between these measures. CONCLUSION: While threshold audiometry and cVEMP are important tools to diagnose SCD and monitor surgical outcomes, these measures showed no significant correlation with vestibular and most auditory symptoms or their severity.

Infrasound transmission in the human ear: Implications for acoustic and vestibular responses of the normal and dehiscent inner ear.

The transmission of infrasound within the human ear is not well understood. To investigate infrasound propagation through the middle and inner ear, velocities of the stapes and round window membrane were measured to very low frequencies (down to 0.9 Hz from 2000 Hz) in fresh cadaveric human specimens. Results from ear-canal sound stimulation responses show that below 200 Hz, the middle ear impedance is dominated by its stiffness term, limiting sound transmission to the inner ear. During air-conduction, normal ears have approximately equal volume velocities at the oval (stapes) and round windows, known as a two-window system. However, perturbing the impedance of the inner ear with a superior canal dehiscence (SCD), a pathological opening of the bone surrounding the semicircular canal, breaks down this simple two-window system. SCD changes the volume velocity flow in the inner ear, particularly at low frequencies. The experimental findings and model predictions in this study demonstrate that low-frequency auditory and vestibular sound transmission can be affected by a change in the inner-ear impedance due to a SCD.

Toward Optimizing Cervical Vestibular Evoked Myogenic Potentials (cVEMP): Combining Air-Bone Gap and cVEMP Thresholds to Improve Diagnosis of Superior Canal Dehiscence.

OBJECTIVE: To develop a novel approach combining low-frequency air-bone gap (ABG) and cervical vestibular evoked myogenic potential (cVEMP) thresholds to improve screening for superior canal dehiscence (SCD) syndrome. STUDY DESIGN: Retrospective study. SETTING: Tertiary care center. PATIENTS: One hundred forty patients with SCD and 21 healthy age-matched controls were included. Ears for each patient were divided into three groups based on computed tomography (CT) findings: 1) dehiscent, 2) thin, or 3) unaffected. MAIN OUTCOME MEASURES: cVEMP and audiometric thresholds were analyzed and differences among groups were evaluated. RESULTS: We define the third window indicator (TWI) as the cVEMP thresholds at 500, 750, and 1000 Hz adjusted for the ABG at 250 Hz (i.e., subtracting ABG from cVEMP threshold). The TWI differentiates between dehiscent and nondehiscent control ears with a sensitivity of 82% and specificity of 100%, corresponding to a positive predictive value of 100%. ABGs and cVEMP thresholds were similar for healthy controls and patients with thin bone over the superior canal. CONCLUSION: This is the largest study to date examining the usefulness of cVEMPs in the diagnosis of SCD. Our "third window indicator" (TWI) combines cVEMP thresholds with the ABG at 250 Hz to improve the ability to screen patients with SCD symptoms.

Coordinated regulation of acid resistance in Escherichia coli.

BACKGROUND: Enteric Escherichia coli survives the highly acidic environment of the stomach through multiple acid resistance (AR) mechanisms. The most effective system, AR2, decarboxylates externally-derived glutamate to remove cytoplasmic protons and excrete GABA. The first described system, AR1, does not require an external amino acid. Its mechanism has not been determined. The regulation of the multiple AR systems and their coordination with broader cellular metabolism has not been fully explored. RESULTS: We utilized a combination of ChIP-Seq and gene expression analysis to experimentally map the regulatory interactions of four TFs: nac, ntrC, ompR, and csiR. Our data identified all previously in vivo confirmed direct interactions and revealed several others previously inferred from gene expression data. Our data demonstrate that nac and csiR directly modulate AR, and leads to a regulatory network model in which all four TFs participate in coordinating acid resistance, glutamate metabolism, and nitrogen metabolism. This model predicts a novel mechanism for AR1 by which the decarboxylation enzymes of AR2 are used with internally derived glutamate. This hypothesis makes several testable predictions that we confirmed experimentally. CONCLUSIONS: Our data suggest that the regulatory network underlying AR is complex and deeply interconnected with the regulation of GABA and glutamate metabolism, nitrogen metabolism. These connections underlie and experimentally validated model of AR1 in which the decarboxylation enzymes of AR2 are used with internally derived glutamate.

Individual differences reveal correlates of hidden hearing deficits.

Clinical audiometry has long focused on determining the detection thresholds for pure tones, which depend on intact cochlear mechanics and hair cell function. Yet many listeners with normal hearing thresholds complain of communication difficulties, and the causes for such problems are not well understood. Here, we explore whether normal-hearing listeners exhibit such suprathreshold deficits, affecting the fidelity with which subcortical areas encode the temporal structure of clearly audible sound. Using an array of measures, we evaluated a cohort of young adults with thresholds in the normal range to assess both cochlear mechanical function and temporal coding of suprathreshold sounds. Listeners differed widely in both electrophysiological and behavioral measures of temporal coding fidelity. These measures correlated significantly with each other. Conversely, these differences were unrelated to the modest variation in otoacoustic emissions, cochlear tuning, or the residual differences in hearing threshold present in our cohort. Electroencephalography revealed that listeners with poor subcortical encoding had poor cortical sensitivity to changes in interaural time differences, which are critical for localizing sound sources and analyzing complex scenes. These listeners also performed poorly when asked to direct selective attention to one of two competing speech streams, a task that mimics the challenges of many everyday listening environments. Together with previous animal and computational models, our results suggest that hidden hearing deficits, likely originating at the level of the cochlear nerve, are part of "normal hearing."

Bottom-up influences of voice continuity in focusing selective auditory attention.

Selective auditory attention causes a relative enhancement of the neural representation of important information and suppression of the neural representation of distracting sound, which enables a listener to analyze and interpret information of interest. Some studies suggest that in both vision and in audition, the "unit" on which attention operates is an object: an estimate of the information coming from a particular external source out in the world. In this view, which object ends up in the attentional foreground depends on the interplay of top-down, volitional attention and stimulus-driven, involuntary attention. Here, we test the idea that auditory attention is object based by exploring whether continuity of a non-spatial feature (talker identity, a feature that helps acoustic elements bind into one perceptual object) also influences selective attention performance. In Experiment 1, we show that perceptual continuity of target talker voice helps listeners report a sequence of spoken target digits embedded in competing reversed digits spoken by different talkers. In Experiment 2, we provide evidence that this benefit of voice continuity is obligatory and automatic, as if voice continuity biases listeners by making it easier to focus on a subsequent target digit when it is perceptually linked to what was already in the attentional foreground. Our results support the idea that feature continuity enhances streaming automatically, thereby influencing the dynamic processes that allow listeners to successfully attend to objects through time in the cacophony that assails our ears in many everyday settings.