Photoacoustic Imaging and Characterization of Bone in Medicine: Overview, Applications, and Outlook.

Photoacoustic techniques have shown promise in identifying molecular changes in bone tissue and visualizing tissue microstructure. This capability represents significant advantages over gold standards (i.e., dual-energy X-ray absorptiometry) for bone evaluation without requiring ionizing radiation. Instead, photoacoustic imaging uses light to penetrate through bone, followed by acoustic pressure generation, resulting in highly sensitive optical absorption contrast in deep biological tissues. This review covers multiple bone-related photoacoustic imaging contributions to clinical applications, spanning bone cancer, joint pathologies, spinal disorders, osteoporosis, bone-related surgical guidance, consolidation monitoring, and transsphenoidal and transcranial imaging. We also present a summary of photoacoustic-based techniques for characterizing biomechanical properties of bone, including temperature, guided waves, spectral parameters, and spectroscopy. We conclude with a future outlook based on the current state of technological developments, recent achievements, and possible new directions.

Ultrasound-Derived Fat Fraction for Hepatic Steatosis Assessment: Prospective Study of Agreement With MRI PDFF and Sources of Variability in a Heterogeneous Population.

BACKGROUND. Metabolic dysfunction-associated steatotic liver disease is a growing global public health concern. Quantitative ultrasound measurements, such as ultrasound-derived fat fraction (UDFF), could provide noninvasive, cost-effective, and portable steatosis evaluation. OBJECTIVE. The purpose of this article was to evaluate utility of UDFF for steatosis assessment using proton density fat fraction (PDFF) as reference in patients undergoing liver MRI for heterogeneous indications and to assess UDFF variability. METHODS. This prospective study included a primary analysis of 187 patients (mean age, 53.8 years; 112 men, 75 women) who underwent 3-T liver MRI for any clinical indication from December 2020 to July 2021. Patients underwent investigational PDFF measurement, including determination of PDFFwhole-liver (mean PDFF of entire liver), and PDFFvoxel (PDFF in single voxel within right lobe, measured by MR spectroscopy), as well as investigational ultrasound with UDFF calculation (mean of five inter-costal measurements) within 1 hour after MRI. In a subanalysis, 21 of these patients underwent additional UDFF measurements 1, 3, and 5 hours after meal consumption. The study also included repeatability and reproducibility analysis of 30 patients (mean age, 26.3 years; 10 men, 20 women) who underwent clinical abdominal ultrasound between November 2022 and January 2023; in these patients, three operators sequentially performed UDFF measurements. RESULTS. In primary analysis, UDFF and PDFFwhole-liver measurements showed intra-class correlation coefficient (ICC) of 0.79. In Bland-Altman analysis, UDFF and PDFFvoxel measurements showed mean difference of 1.5% (95% CI, 0.6-2.4%), with 95% limits of agreement from -11.0% to 14.0%. UDFF measurements exhibited AUC for detecting PDFFvoxel at historic thresholds of 6.5% and greater, 17.4% and greater, and 22.1% and greater of 0.90, 0.95, and 0.95, respectively. In subanalysis, mean UDFF was not significantly different across time points with respect to meal consumption (p = .21). In repeatability and reproducibility analysis, ICC for intraoperator repeatability ranged from 0.98 to 0.99 and for interoperator reproducibility from 0.90 to 0.96. Visual assessment of patient-level data plots indicated increasing variability of mean UDFF measurements across operators and of intercostal measurements within individual patients with increasing steatosis. CONCLUSION. UDFF showed robust agreement with PDFF, diagnostic performance for steatosis grades, and intraoperator repeatability and interoperator reproducibility. Nonetheless, UDFF exhibited bias toward slightly larger values versus PDFF; intraoperator and interoperator variation increased with increasing steatosis. CLINICAL IMPACT. UDFF shows promise for steatosis assessment across diverse populations, although continued optimization remains warranted.

In Vivo Assessment of Bone Quality Without X-rays.

PURPOSE OF REVIEW: This review summarizes recent advances in the assessment of bone quality using non-X-ray techniques. RECENT FINDINGS: Quantitative ultrasound (QUS) provides multiple measurements of bone characteristics based on the propagation of sound through bone, the attenuation of that sound, and different processing techniques. QUS parameters and model predictions based on backscattered signals can discriminate non-fracture from fracture cases with accuracy comparable to standard bone mineral density (BMD). With advances in magnetic resonance imaging (MRI), bound water and pore water, or a porosity index, can be quantified in several long bones in vivo. Since such imaging-derived measurements correlate with the fracture resistance of bone, they potentially provide new BMD-independent predictors of fracture risk. While numerous measurements of mineral, organic matrix, and bound water by Raman spectroscopy correlate with the strength and toughness of cortical bone, the clinical assessment of person's bone quality using spatially offset Raman spectroscopy (SORS) requires advanced spectral processing techniques that minimize contaminating signals from fat, skin, and blood. Limiting exposure of patients to ionizing radiation, QUS, MRI, and SORS has the potential to improve the assessment of fracture risk and track changes of new therapies that target bone matrix and micro-structure.

Osteopenia and Osteoporosis Screening Detection: Calcaneal Quantitative Ultrasound with and without Calibration Factor Comparison to Gold Standard Dual X-ray Absorptiometry.

BACKGROUND: osteoporosis is a worldwide major health problem that normally diagnosed in advanced stages. So, an early detection at preclinical stage is now an interesting issue. A key factor to early diagnosis the disease is the used of noninvasive bone densitometry. Dual energy x-ray absorptiometry (DXA) is the gold standard techniques for the proposed. However, the high cost, non-widely available and exposed to ionizing radiation are still a drawback of the machine. Therefore, a cheaper, smaller and non-ionizing device such quantitative ultrasound (QUS) is now a favor alternative method, but the possibility of used QUS measurement instead of DXA is still limited due to their uncertainties. So, the aim of our study was to calibrated the QUS with the DXA to allowing the possible to establish a calibration factor (CF) to improve the measured value closer to the standard method. METHODOLOGY: 135 healthy men and women aged 30-88 years were recruited for lumbar spine/femoral neck DXA and calcaneal QUS scanning. The Pearson's correlation between T- and Z-score from the two systems were studied. Moreover, the sensitivity, specificity and percentage of diagnosed accuracy for both with and without CF were calculated. RESULTS: The significant correlation between the two systems showed a positive trajectory in highly correlation (r = 0.784-0.899). Analyses showed a higher sensitivity, specificity and reduced the misdiagnosed rates when applied the CF in QUS values. CONCLUSIONS: QUS results showed a significantly correlated with DXA results for both lumbar spine and femoral neck sites with some percentage differences. These differences can be reduced by applied an individual specific machine CF to improve a QUS results. As identification of high risk of osteopenia and osteoporosis to reduce the demand of DXA propose, using a QUS alternative method can be a reliable that provide a cheaper and lack of ionizing radiation.

Characterization of the in vivo transient responses of the femoral cartilage by means of quantitative ultrasound imaging techniques.

BACKGROUND: Quantitative ultrasound (QUS) techniques are new diagnostic tools able to identify changes in structural and material properties of the investigated tissue. For the first time, we evaluated the capability of QUS techniques in determining the in vivo transient changes in knee joint cartilage after a stressful task. METHODS: An ultrasound scanner collecting B-mode and radiofrequency data simultaneously was used to collect data from the femoral cartilage of the right knee in 15 participants. Cartilage thickness (CTK), ultrasound roughness index (URI), average magnitude ratio (AMR), and Nakagami parameters (NA) were evaluated before, immediately after and every 5 min up to 45 min a stressful task (30 min of running on a treadmill with a negative slope of 5%). RESULTS: CTK was affected by time (main effect: p < 0.001). Post hoc test showed significant differences with CTK at rest, which were observed up to 30 min after the run. AMR and NA were affected by time (p < 0.01 for both variables), while URI was unaffected by it. For AMR, post hoc test showed significant differences with rest values in the first 35 min of recovery, while NA was increased compared to rest values in all time points. CONCLUSION: Data suggest that a single running trial is not able to modify the integrity of the femoral cartilage, as reported by URI data. In vivo evaluation of QUS parameters of the femoral cartilage (NA, AMR, and URI) are able to characterize changes in cartilage properties over time.

Noninvasive Evaluation of Breast Tumor Response to Combined Ultrasound-Stimulated Microbubbles and Hyperthermia Therapy Using Quantitative Ultrasound-Based Texture Analysis Method.

OBJECTIVES: Quantitative ultrasound (QUS) is a noninvasive imaging technique that can be used for assessing response to anticancer treatment. In the present study, tumor cell death response to the ultrasound-stimulated microbubbles (USMB) and hyperthermia (HT) treatment was monitored in vivo using QUS. METHODS: Human breast cancer cell lines (MDA-MB-231) were grown in mice and were treated with HT (10, 30, 50, and 60 minutes) alone, or in combination with USMB. Treatment effects were examined using QUS with a center frequency of 25 MHz (bandwidth range: 16 to 32 MHz). Backscattered radiofrequency (RF) data were acquired from tumors subjected to treatment. Ultrasound parameters such as average acoustic concentration (AAC) and average scatterer diameter (ASD), were estimated 24 hours prior and posttreatment. Additionally, texture features: contrast (CON), correlation (COR), energy (ENE), and homogeneity (HOM) were extracted from QUS parametric maps. All estimated parameters were compared with histopathological findings. RESULTS: The findings of our study demonstrated a significant increase in QUS parameters in both treatment conditions: HT alone (starting from 30 minutes of heat exposure) and combined treatment of HT plus USMB finally reaching a maximum at 50 minutes of heat exposure. Increase in AAC for 50 minutes HT alone and USMB +50 minutes was found to be 5.19 ± 0.417% and 5.91 ± 1.11%, respectively, compared to the control group with AAC value of 1.00 ± 0.44%. Furthermore, between the treatment groups, ΔASD-ENE values for USMB +30 minutes HT significantly reduced, depicting 0.00062 ± 0.00096% compared to 30 minutes HT only group, showing 0.0058 ± 0.0013%. Further, results obtained from the histological analysis indicated greater cell death and reduced nucleus size in both HT alone and HT combined with USMB. CONCLUSION: The texture-based QUS parameters indicated a correlation with microstructural changes obtained from histological data. This work demonstrated the use of QUS to detect HT treatment effects in breast cancer tumors in vivo.

Unsupervised Learning-Based Measurement of Ultrasonic Axial Transmission Velocity in Neonatal Bone.

OBJECTIVES: To develop a robust algorithm for estimating ultrasonic axial transmission velocity from neonatal tibial bone, and to investigate the relationships between ultrasound velocity and neonatal anthropometric measurements as well as clinical biochemical markers of skeletal health. METHODS: This study presents an unsupervised learning approach for the automatic detection of first arrival time and estimation of ultrasonic velocity from axial transmission waveforms, which potentially indicates bone quality. The proposed method combines the ReliefF algorithm and fuzzy C-means clustering. It was first validated using an in vitro dataset measured from a Sawbones phantom. It was subsequently applied on in vivo signals collected from 40 infants, comprising 21 males and 19 females. The extracted neonatal ultrasonic velocity was subjected to statistical analysis to explore correlations with the infants' anthropometric features and biochemical indicators. RESULTS: The results of in vivo data analysis revealed significant correlations between the extracted ultrasonic velocity and the neonatal anthropometric measurements and biochemical markers. The velocity of first arrival signals showed good associations with body weight (ρ = 0.583, P value <.001), body length (ρ = 0.583, P value <.001), and gestational age (ρ = 0.557, P value <.001). CONCLUSION: These findings suggest that fuzzy C-means clustering is highly effective in extracting ultrasonic propagating velocity in bone and reliably applicable in in vivo measurement. This work is a preliminary study that holds promise in advancing the development of a standardized ultrasonic tool for assessing neonatal bone health. Such advancements are crucial in the accurate diagnosis of bone growth disorders.

In-vivo high-frequency quantitative ultrasound-derived parameters of the anterior sclera correlated with level of myopia and presence of staphyloma.

BACKGROUND: A high-frequency point-of-care (POC) ultrasound instrument was used to evaluate the microstructural and biomechanical properties of the anterior sclera in vivo using parameters computed from quantitative ultrasound (QUS) methods. METHODS: In this cross-sectional study, both eyes of 85 enrolled patients were scanned with the POC instrument and ultrasound data were processed to obtain QUS parameters. Pearson correlation and multi-linear regression were used to identify relationships between QUS parameters and refractive error (RE) or axial length. After categorising eyes based on RE, binary support vector machine (SVM) classifiers were trained using the QUS or ophthalmic parameters (anterior chamber depth, central corneal thickness, corneal power, and intraocular pressure) to classify each eye. Classifier performance was evaluated by computing the area under the receiver-operating characteristic curve (AUC). RESULTS: Individual QUS parameters correlated with RE and axial length (p < 0.05). Multi-linear regression revealed significant correlation between the set of QUS parameters and both RE (R = 0.49, p < 0.001) and axial length (R = 0.46, p = 0.001). Classifiers trained with QUS parameters achieved higher AUC (𝑝 = 0.06) for identifying myopic eyes (AUC = 0.71) compared to classifiers trained with ophthalmic parameters (AUC = 0.63). QUS-based classifiers attained the highest AUC when identifying highly myopic eyes (AUC = 0.77). CONCLUSIONS: QUS parameters correlate with progressing myopia and may be indicative of myopia-induced microstructural and biomechanical changes in the anterior sclera. These methods may provide critical clinical information complementary to standard ophthalmic measurements for predicting myopia progression and risk assessment for posterior staphyloma formation.

Spectral-based Quantitative Ultrasound Imaging Processing Techniques: Comparisons of RF Versus IQ Approaches.

Quantitative ultrasound (QUS) is an imaging technique which includes spectral-based parameterization. Typical spectral-based parameters include the backscatter coefficient (BSC) and attenuation coefficient slope (ACS). Traditionally, spectral-based QUS relies on the radio frequency (RF) signal to calculate the spectral-based parameters. Many clinical and research scanners only provide the in-phase and quadrature (IQ) signal. To acquire the RF data, the common approach is to convert IQ signal back into RF signal via mixing with a carrier frequency. In this study, we hypothesize that the performance, that is, accuracy and precision, of spectral-based parameters calculated directly from IQ data is as good as or better than using converted RF data. To test this hypothesis, estimation of the BSC and ACS using RF and IQ data from software, physical phantoms and in vivo rabbit data were analyzed and compared. The results indicated that there were only small differences in estimates of the BSC between when using the original RF, the IQ derived from the original RF and the RF reconverted from the IQ, that is, root mean square errors (RMSEs) were less than 0.04. Furthermore, the structural similarity index measure (SSIM) was calculated for ACS maps with a value greater than 0.96 for maps created using the original RF, IQ data and reconverted RF. On the other hand, the processing time using the IQ data compared to RF data were substantially less, that is, reduced by more than a factor of two. Therefore, this study confirms two things: (1) there is no need to convert IQ data back to RF data for conducting spectral-based QUS analysis, because the conversion from IQ back into RF data can introduce artifacts. (2) For the implementation of real-time QUS, there is an advantage to convert the original RF data into IQ data to conduct spectral-based QUS analysis because IQ data-based QUS can improve processing speed.

High-frequency Quantitative Ultrasound Imaging of Human Rotator Cuff Muscles: Assessment of Repeatability and Reproducibility.

This study evaluated the repeatability and reproducibility of using high-frequency quantitative ultrasound (QUS) measurement of backscatter coefficient (BSC), grayscale analysis, and gray-level co-occurrence matrix (GLCM) textural analysis, to characterize human rotator cuff muscles. The effects of varying scanner settings across two different operators and two US systems were investigated in a healthy volunteer with normal rotator cuff muscles and a patient with chronic massive rotator cuff injury and substantial muscle degeneration. The results suggest that BSC is a promising method for assessing rotator cuff muscles in both control and pathological subjects, even when operators were free to adjust system settings (depth, level of focus, and time-gain compensation). Measurements were repeatable and reproducible across the different operators and ultrasound imaging platforms. In contrast, grayscale and GLCM analyses were found to be less reliable in this setting, with significant measurement variability. Overall, the repeatability and reproducibility measurements of BSC indicate its potential as a diagnostic tool for rotator cuff muscle evaluation.

Are there associations between hip geometry and bone quality? An analysis on 3074 adults from a general population.

INTRODUCTION: Patients with reduced bone mineral density and altered hip geometry are susceptible for hip pathologies. Knowledge on associations between bone properties and hip geometric parameters might facilitate identification of patients at risk for hip pathologies. The aim of the present study was to identify associations of bone properties assessed by quantitative ultrasound (QUS) at the heel and hip geometric parameters like center-edge angle (CE), neck-shaft angle (NSA) and alpha angle. MATERIALS AND METHODS: Hip geometric parameters (CE, NSA and alpha angle) of 3074 participants from the population-based Study of Health in Pomerania were assessed on magnetic resonance imaging. QUS was performed on both calcanei providing broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness-index. Based on the stiffness-index the individual osteoporotic fracture risk (low, moderate or high) was determined. Associations between QUS-based and hip geometric parameters were calculated in linear regression models adjusted for age, sex, body height and weight. Interactions of QUS markers with age and sex on hip geometric parameters were tested. RESULTS: Significant inverse associations between BUA (ß = - 0.068), SOS (ß = - 0.024) as well as stiffness-index (ß = - 0.056) and CE were present, while fracture risk was positively associated with CE (ß for high = 1.28 and moderate = 2.54 vs. low fracture risk). Interactions between BUA and sex as well as between SOS and age were detected in the models for CE. Furthermore, there was an inverse relation between fracture risk and NSA that was restricted to the moderate risk (ß for moderate vs. low fracture risk = - 0.60). There were no significant associations between QUS parameters and alpha angle. CONCLUSIONS: In the general population, several associations between QUS-based bone properties or fracture risk and hip geometry are present. Less dysplastic hips had a lower stiffness-index and a higher fracture risk, whereas more valgus hips had a lower fracture risk.

Heel quantitative ultrasound (QUS) predicts incident fractures independently of trabecular bone score (TBS), bone mineral density (BMD), and FRAX: the OsteoLaus Study.

This study aimed to better define the role of heel-QUS in fracture prediction. Our results showed that heel-QUS predicts fracture independently of FRAX, BMD, and TBS. This corroborates its use as a case finding/pre-screening tool in osteoporosis management. INTRODUCTION: Quantitative ultrasound (QUS) characterizes bone tissue based on the speed of sound (SOS) and broadband ultrasound attenuation (BUA). Heel-QUS predicts osteoporotic fractures independently of clinical risk factors (CRFs) and bone mineral density (BMD). We aimed to investigate whether (1) heel-QUS parameters predict major osteoporotic fractures (MOF) independently of the trabecular bone score (TBS) and (2) the change of heel-QUS parameters over 2.5 years is associated with fracture risk. METHODS: One thousand three hundred forty-five postmenopausal women from the OsteoLaus cohort were followed up for 7 years. Heel-QUS (SOS, BUA, and stiffness index (SI)), DXA (BMD and TBS), and MOF were assessed every 2.5 years. Pearson's correlation and multivariable regression analyses were used to determine associations between QUS and DXA parameters and fracture incidence. RESULTS: During a mean follow-up of 6.7 years, 200 MOF were recorded. Fractured women were older, more treated with anti-osteoporosis medication; had lower QUS, BMD, and TBS; higher FRAX-CRF risk; and more prevalent fractures. TBS was significantly correlated with SOS (0.409) and SI (0.472). A decrease of one SD in SI, BUA or SOS increased the MOF risk by (OR(95%CI)) 1.43 (1.18-1.75), 1.19 (0.99-1.43), and 1.52 (1.26-1.84), respectively, after adjustment for FRAX-CRF, treatment, BMD, and TBS. We found no association between the change of QUS parameters in 2.5 years and incident MOF. CONCLUSION: Heel-QUS predicts fracture independently of FRAX, BMD, and TBS. Thus, QUS represents an important case finding/pre-screening tool in osteoporosis management. The change in QUS over time was not associated with future fractures, making it inappropriate for patient monitoring.

Diminished cortical bone density of long bones among children with haemophilic arthropathy.

INTRODUCTION: Children with haemophilia (CwH) have lower bone mineral density in the spine (trabecular bone) than healthy children. There are few studies focusing on bone mineral density in long bones (cortical bone). AIM: To evaluate bi-laterally the distal third of radius and midshaft tibias using quantitative ultrasound (QUS) and assess the speed of sound (SoS). METHODS: A cross-sectional study where 91 CwH and 91 age-matched healthy boys were included. Joint evaluation was determined with the Haemophilia Joint Health Score 2.1 and SoS values. The Z scores were measured with the Sunlight Omnisense 8000 S equipment. RESULTS: Ninety-one CwH (haemophilia A) were evaluated (26 mild form, 26 moderate, and 39 severe). Most patients were treated with on-demand factor replacement and had higher total HJHS scores according to severity (4.8, 14.8 and 14.1, respectively). Patients with moderate and severe disease showed a statistical difference in SoS values for both radius and tibias compared to controls. QUS Z-scores ≥-2 were more frequent in radius and tibias in CwH, but were statistically significant only in tibias when compared to controls (in 30% mild, 46% moderate, 28% severe, respectively). CONCLUSIONS: There was diminished cortical bone density in radius and tibias of CwH compared to healthy controls. Changes predominated in tibias, more frequently affected according to the severity of haemophilia. Early intervention with factor replacement combined with physical activity are key aspects to promote bone health.

Three-dimensional quantitative muscle ultrasound in patients with facioscapulohumeral dystrophy and myotonic dystrophy.

INTRODUCTION/AIMS: Ultrasound imaging of muscle tissue conventionally results in two-dimensional sampling of tissue. For heterogeneously affected muscles, a sampling error using two-dimensional (2D) ultrasound can therefore be expected. In this study, we aimed to quantify and extend ultrasound imaging findings in neuromuscular disorders by using three-dimensional quantitative muscle ultrasound (3D QMUS). METHODS: Patients with facioscapulohumeral dystrophy (n = 31) and myotonic dystrophy type 1 (n = 16) were included in this study. After physical examination, including Medical Research Council (MRC) scores, the tibialis anterior muscle was scanned with automated ultrasound. QMUS parameters were calculated over 15 cm of the length of the tibialis anterior muscle and were compared with a healthy reference data set. RESULTS: With 3D QMUS local deviations from the healthy reference could be detected. Significant Pearson correlations (P < .01) between MRC score and QMUS parameters in male patients (n = 23) included the mean echo intensity (EI) (0.684), the standard deviation of EI (0.737), and the residual attenuation (0.841). In 91% of all patients, mean EI deviated by more than 1 standard deviation from the healthy reference. In general, the proportion of muscle tissue with a Z score >1 was about 50%. DISCUSSION: In addition to mean EI, multiple QMUS parameters reported in this study are potential biomarkers for pathology. Besides a moderate correlation of mean EI with muscle weakness, two other parameters showed strong correlations: standard deviation of EI and residual attenuation. Local detection of abnormalities makes 3D QMUS a promising method that can be used in research and potentially for clinical evaluation.

Association between walking speed and calcaneus stiffness index in older adults.

INTRODUCTION: The aim here is to examine the association between objectively measured usual walking speed (UWS) and bone status in community-dwelling older Chinese. MATERIALS AND METHODS: This is a cross-sectional study of a population of 1528 adults (817 females, mean age 68.5 ± 5.3; 711 males, mean age 69.1 ± 5.2) aged 60-79, living in communities in Shanghai. Walking speed was assessed using a 4-m walk test at a usual-pace walking speed a walking speed at which the subject felt relaxed-and bone status measured by quantitative ultrasound (QUS). The health-related characteristics of participants include family background, physical activity level, chronic disease, smoking and alcohol consumption, frequency of falls, vitamin intake, and hormone therapy. RESULTS: Multiple linear regression is used to analyses any association between UWS and bone status, adjusting for confounding factors showing a significant association between faster UWS and a higher calcaneal stiffness index (SI) (p < 0.01). Comparing the lowest quartile of the data set with the highest at UWS, a high SI is achieved with 5.34 (95% CI = 3.22, 7.46) (p < 0.01), after adjusting for confounders. An increase of 1 dm/s was associated with a 0.91 (95% CI = 0.53, 1.29) increase in SI. This relationship for most subgroups is consistent. CONCLUSION: Our findings suggest that UWS can be a sensitive indicator of calcaneal bone loss among an older population.

High-frequency ultrasound point-of-care device to quantify myopia-induced microstructural changes in the anterior sclera.

PURPOSE: To develop a point-of-care (POC) device using high-frequency ultrasound (US) for evaluating microstructural changes in the anterior sclera associated with myopia. METHODS: The proposed POC device must satisfy four primary requirements for effective clinical use: the measurement component is handheld; the software must be simple and provide real-time feedback; patient safety and health data security requirements set forth by relevant governing bodies must be satisfied and the measurement data must have sufficient signal-to-noise ratio (SNR) and repeatability. Radiofrequency (RF) echo data acquired by the POC device will be processed using our quantitative US methods to characterise tissue microstructure and biomechanical properties. RESULTS: All stated requirements have been met in the developed POC device. The high-frequency transducer is housed in a custom, 3D-printed, pen-like holder that allows for easy measurements of the anterior sclera. Custom software provides a simple interface for data acquisition, real-time data display and secure data storage. Exposimetry measurements of the US pressure field indicate device compliance with United States Food and Drug Administration limits for ophthalmic US. In vivo measurements on a volunteer suggest the RF data SNR and acquisition consistency are suitable for quantitative analysis. CONCLUSIONS: A fully functioning POC device using high-frequency US has been created for evaluating the microstructure of the anterior sclera. Planned studies using the POC device to scan the eyes of myopia patients will help clarify how the anterior sclera microstructure may be affected by myopia. If effective, this portable, inexpensive and user-friendly system could be an important part of routine eye examinations.

Inter- and Intra-Operator Variability of Regularized Backscatter Quantitative Ultrasound for the Characterization of Breast Masses.

OBJECTIVES: Here we report on the intra- and inter-operator variability of the backscatter coefficient (BSC) estimated with a new low-variance quantitative ultrasound (QUS) approach applied to breast lesions in vivo. METHODS: Radiofrequency (RF) echo signals were acquired from 29 BIRADS 4 and 5 breast lesions in 2 sequential cohorts following 2 imaging protocols: cohort 1) radial and antiradial views, and cohort 2) short- and long-axis views. Protocol 2 was implemented after retraining and discussion on how to improve reproducibility. Each patient was scanned by at least 2 of 3 radiologists; each performed 3 acquisitions with transducer and patient repositioning in between acquisitions. BSC was estimated using a low-variance QUS approach based on regularization. Intra- and inter-operator variability of the intra-lesion median BSC was evaluated with a multifactorial ANOVA test (P-values) and the intraclass correlation coefficient (ICC). RESULTS: Inter-operator variability was only significant in the first protocol (P < .007); ICCinter = .77 (95% CI .71-.82), indicating good inter-operator agreement. In the second protocol, the inter-operator variability was not significant (P > .05) and agreement was excellent (ICCinter = .92 [.89-.94]). In both protocols, the intra-operator variability was not significant. CONCLUSIONS: Our findings demonstrate the need for standardizing image acquisition protocols for backscatter-based QUS to reduce inter-operator variability and ensure its successful translation to the characterization of suspicious breast masses.

Interobserver Variability in Ultrasound-Based Liver Fat Quantification.

OBJECTIVES: To assess interobserver variability in ultrasound-based quantitative liver fat content measurements and to determine how much time these quantitative ultrasound (QUS) techniques require. METHODS: One hundred patients with known or suspected of having nonalcoholic fatty liver disease were included in this prospective study. Two observers who were blinded to each other measurements performed tissue attenuation imaging (TAI) and tissue scatter distribution imaging (TSI) techniques independently. Both observers assessed hepatic steatosis visually and obtained 5 measurements for each QUS technique and the median values of the measurements were recorded. Spearman's correlation test was used to assess the correlation between QUS measurements and visual hepatic stetaosis grades. Intraclass correlation coefficient (ICC) test was used to assess interobserver variability in QUS measurements. RESULTS: The median values of TAI measurements for the observers 1 and 2 were 0.75 and 0.74 dB/cm/MHz, respectively. The median values of TSI measurements for the observers 1 and 2 were 93.53 and 92.58, respectively. The interobserver agreement in TAI (ICC: 0.970) and TSI (ICC: 0.938) measurements were excellent. The mean of the required time period for TAI technique were 55.1 ± 7.8 and 59.9 ± 6.6 seconds for the observers 1 and 2, respectively. The mean of the required time period for TSI technique were 49.1 ± 5.8 and 54.1 ± 5.4 seconds for the observers 1 and 2, respectively. CONCLUSION: The current study revealed that both TAI and TSI techniques are highly reproducible and can be implemented into daily practice with little additional time requirement.

Pulse-Echo Technique to Compensate for Laminate Membrane Transmission Loss in Phantom-Based Ultrasonic Attenuation Coefficient Measurements.

OBJECTIVES: Accurately measuring the attenuation coefficient (AC) of reference phantoms is critical in clinical applications of quantitative ultrasound. Phantom AC measurement requires proper compensation of membrane transmission loss. Conventional methods require separate membrane samples to obtain membrane transmission loss. Unfortunately, separate membrane samples are often unavailable. A pulse-echo approach is proposed herein to compensate for membrane transmission loss without requiring separate membrane samples. METHODS: The proposed method consists of the following steps. First, the insertion loss, caused by phantom attenuation and membrane transmission loss, is measured. Second, the membrane reflection coefficient is measured. Third, the unknown acoustic parameters of the membrane and phantom material are estimated by fitting theoretical reflection coefficient to the measured one. Finally, the fitted parameters are used to estimate membrane transmission loss and phantom AC. The proposed method was validated through k-Wave simulations and phantom experiments. Experimental AC measurements were repeated on 5 distinct phantoms by 2 operators to assess the repeatability and reproducibility of the proposed method. Five transducers were used to cover a broad bandwidth (0.7-16 MHz). RESULTS: The acquired AC in the simulations had a maximum error of 0.06 dB/cm-MHz for simulated phantom AC values ranging from 0.5 to 1 dB/cm-MHz. The acquired AC in the experiments had a maximum error of 0.045 dB/cm-MHz for phantom AC values ranging from 0.28 to 1.48 dB/cm-MHz. Good repeatability and cross-operator reproducibility were observed with a mean coefficient of variation below 0.054. CONCLUSION: The proposed method simplifies phantom AC measurement while providing satisfactory accuracy and precision.

Quantitative Ultrasound Biomarkers to Assess Nonalcoholic Fatty Liver Disease.

PURPOSE: To assess diagnostic performance of quantitative ultrasound (QUS) biomarkers in assessing hepatic steatosis. METHODS: We prospectively recruited 125 participants (mean age 54 years) who underwent liver QUS, magnetic resonance imaging (MRI), and laboratory tests within 30 days in this IRB approved study. Based on MRI-proton density fat fraction (MRI-PDFF) and MRE, we divided 125 participants into normal liver, nonalcoholic fatty liver (NAFL) and liver fibrosis (≥F1) groups. We examined diagnostic performance of ultrasound attenuation coefficient (AC), normalized local variance (NLV), superb microvascular imaging-based vascularity index (SMI-VI), and shear wave velocity (SWV) for determining hepatic steatosis and fibrosis using area under receiver operating characteristic curve (AUC). We also analyzed correlations of QUS biomarkers to MRI using Spearman correlation coefficient. RESULTS: We observed significant differences in AC, NLV, and SMI-VI among the three groups (22 participants with normal liver, 78 with NAFL, and 25 with liver fibrosis). AUC of AC, NLV, and SMI-VI for determining ≥ mild steatotic livers (MRI-PDFF ≥5%) was 0.95, 0.90, and 0.92, respectively. AUC of SWV for determining ≥ F1 liver fibrosis was 0.93. The correlation of MRI-PDFF was positive to AC (r = 0.91) and negative to NLV (r = -0.74), SMI-VI (r = -0.8) in NAFL group. There was a significant difference in regression slope of AC to MRI-PDFF in livers with and without ≥F1 (0.84 vs 0.91, P = .02). CONCLUSIONS: QUS biomarkers have high sensitivity and specificity to determine and grade hepatic steatosis and detect liver fibrosis. The effect of liver fibrosis on the performance of QUS biomarkers in quantifying liver fat content warrants further investigation.