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.

Attenuation Compensation and Estimation.

Estimating the loss of ultrasound signal with propagation depth as a function of frequency is essential for quantifying tissue properties. Specifically, ultrasound attenuation is used to correct for spectral distortion prior to estimating quantitative ultrasound parameters to assess the tissue. Ultrasound attenuation can also be used independently to characterize the tissue. In this chapter, we review the primary algorithms for estimating both the local attenuation within a region of interest as well as the total attenuation between a region of interest and an ultrasound source. The strengths and weaknesses of each algorithm are also discussed.

Novel Method for Ultrasound-Derived Fat Fraction Using an Integrated Phantom.

OBJECTIVES: The purpose of this study was to demonstrate the clinical feasibility of an integrated reference phantom method for quantitative ultrasound by creating an ultrasound-derived fat fraction (UDFF) tool. This tool was evaluated with respect to its diagnostic performance as a biomarker for assessing histologic hepatic steatosis and its agreement with the magnetic resonance imaging (MRI) proton density fat fraction (PDFF). METHODS: Adults (n = 101) with known or suspected nonalcoholic fatty liver disease consented to participate in this prospective cross-sectional study. All patients underwent MRI-PDFF and ultrasound scans, whereas 90 underwent liver biopsy. A linear least-squares analysis used the attenuation coefficient and backscatter coefficient to create the UDFF model for predicting MRI-PDFF. RESULTS: The area under the receiver operating characteristic curve values were 0.94 (95% confidence interval [CI], 0.85-0.98) for histologic steatosis grade 0 (n = 6) versus 1 or higher (n = 84), 0.88 (95% CI, 0.8-0.94) for grade 1 or lower (n = 45) versus 2 or higher (n = 45), and 0.83 (95% CI, 0.73-0.9) for grade 2 or lower (n = 78) versus 3 (n = 12). The Pearson correlation coefficient between UDFF and PDFF was ρ = 0.87 with 95% limits of agreement of ±8.5%. Additionally, the diagnosis of steatosis, defined as MRI-PDFF higher than 5% and 10%, had area under the receiver operating characteristic curve values of 0.97 (95% CI, 0.93-0.99) and 0.95 (95% CI, 0.9-0.98), respectively. The body mass index was not correlated with either UDFF or PDFF. CONCLUSIONS: An on-system, integrated UDFF tool provides a simple, noninvasive, accessible, low-cost, and commercially viable clinical tool for quantifying the hepatic fat fraction with a high degree of agreement with histologic biopsy or the MRI-PDFF biomarker.

Inter-sonographer reproducibility of quantitative ultrasound outcomes and shear wave speed measured in the right lobe of the liver in adults with known or suspected non-alcoholic fatty liver disease.

OBJECTIVES: To assess inter-sonographer reproducibility of ultrasound attenuation coefficient (AC), backscatter coefficient (BSC) and shear wave speed (SWS) in adults with known/suspected non-alcoholic fatty liver disease (NAFLD). METHODS: The institutional review board approved this HIPAA-compliant prospective study; informed consent was obtained. Participants with known/suspected NAFLD were recruited and underwent same-day liver examinations with a clinical scanner. Each participant was scanned by two of the six trained sonographers. Each sonographer performed multiple data acquisitions in the right liver lobe using a lateral intercostal approach. A data acquisition was a single operator button press that recorded a B-mode image, radio-frequency data, and the SWS value. AC and BSC were calculated from the radio-frequency data using the reference phantom method. SWS was calculated automatically using product software. Intraclass correlation coefficient (ICC) and within-subject coefficient of variation (wCV) were calculated for applicable metrics. RESULTS: Sixty-one participants were recruited. Inter-sonographer ICC was 0.86 (95% confidence interval: 0.77-0.92) for AC and 0.87 (0.78-0.92) for log-transformed BSC (logBSC = 10log10BSC) using one acquisition per sonographer. ICC was 0.88 (0.80-0.93) for both AC and logBSC averaging 5 acquisitions. ICC for SWS was 0.57 (0.29-0.74) using one acquisition per sonographer, and 0.84 (0.66-0.93) using 10 acquisitions. The wCV was ~7% for AC, and 19-43% for SWS, depending on number of acquisitions. CONCLUSIONS: Hepatic AC, BSC and SWS measures on a clinical scanner have good inter-sonographer reproducibility in adults with known or suspected NAFLD. Multiple acquisitions are required for SWS but not AC or BSC to achieve good inter-sonographer reproducibility. KEY POINTS: • AC, BSC and SWS measurements are reproducible in adults with NAFLD. • Inter-sonographer reproducibility of SWS measurement improves with more acquisitions being averaged. • Multiple acquisitions are required for SWS but not AC or BSC.

Tumor Elastography and Its Association with Collagen and the Tumor Microenvironment.

Purpose: The tumor microenvironment presents with altered extracellular matrix (ECM) and stroma composition, which may affect treatment efficacy and contribute to tissue stiffness. Ultrasound (US) elastography can visualize and quantify tissue stiffness noninvasively. However, the contributions of ECM and stromal components to stiffness are poorly understood. We therefore set out to quantify ECM and stroma density and their relation to tumor stiffness.Experimental Design: A modified clinical ultrasound system was used to measure tumor stiffness and perfusion during tumor growth in preclinical tumor models. In vivo measurements were compared with collagen mass spectroscopy and automatic analysis of matrix and stromal markers derived from immunofluorescence images.Results: US elastography estimates of tumor stiffness were positively correlated with tumor volume in collagen and myofibroblast-rich tumors, while no correlations were found for tumors with low collagen and myofibroblast content. US elastography measurements were strongly correlated with ex vivo mechanical testing and mass spectroscopy-based measurements of total collagen and immature collagen crosslinks. Registration of ultrasound and confocal microscopy data showed strong correlations between blood vessel density and T-cell density in syngeneic tumors, while no correlations were found for genetic tumor models. In contrast to collagen density, which was positively correlated with stiffness, no significant correlations were observed for hyaluronic acid density. Finally, localized delivery of collagenase led to a significant reduction in tumor stiffness without changes in perfusion 24 hours after treatment.Conclusions: US elastography can be used as a potential biomarker to assess changes in the tumor microenvironment, particularly changes affecting the ECM. Clin Cancer Res; 24(18); 4455-67. ©2018 AACR.

Effects of age and pathology on shear wave speed of the human rotator cuff.

Rotator cuff tears are common and often repaired surgically, but post-operative repair tissue healing, and shoulder function can be unpredictable. Tear chronicity is believed to influence clinical outcomes, but conventional clinical approaches for assessing tear chronicity are subjective. Shear wave elastography (SWE) is a promising technique for assessing soft tissue via estimates of shear wave speed (SWS), but this technique has not been used extensively on the rotator cuff. Specifically, the effects of age and pathology on rotator cuff SWS are not well known. The objectives of this study were to assess the association between SWS and age in healthy, asymptomatic subjects, and to compare measures of SWS between patients with a rotator cuff tear and healthy, asymptomatic subjects. SWE images of the supraspinatus muscle and intramuscular tendon were acquired from 19 asymptomatic subjects and 11 patients with a rotator cuff tear. Images were acquired with the supraspinatus under passive and active (i.e., minimal activation) conditions. Mean SWS was positively associated with age in the supraspinatus muscle and tendon under passive and active conditions (p ≤ 0.049). Compared to asymptomatic subjects, patients had a lower mean SWS in their muscle and tendon under active conditions (p ≤ 0.024), but no differences were detected under passive conditions (p ≥ 0.783). These findings identify the influences of age and pathology on SWS in the rotator cuff. These preliminary findings are an important step toward evaluating the clinical utility of SWE for assessing rotator cuff pathology. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:282-288, 2018.

TR-MUSIC inversion of the density and compressibility contrasts of point scatterers.

Time-reversal imaging with multiple signal classification (TR-MUSIC) is a super-resolution ultrasound imaging method for detecting point scatterers. This algorithm assumes that there is no contrast between the density of the point targets and that of the background medium, and that ultrasound scattering is caused only by the compressibility contrast. We modify the TR-MUSIC algorithm to account for ultrasound scattering from point targets with both density and compressibility contrasts. In addition, we develop an inversion method for estimating the density and compressibility contrasts of point scatterers with known locations. This approach is an extension of the inversion method previously developed by Devaney et al. for estimating the scattering strengths of point targets that have no density contrasts relative to the background medium. We use numerical phantom data to demonstrate that our new TR-MUSIC inversion algorithm can reliably estimate the density and compressibility contrasts of point scatterers. The estimates of these properties could be used for distinguishing breast calcifications from other tissue scatterers.

Super-resolution ultrasound imaging using a phase-coherent MUSIC method with compensation for the phase response of transducer elements.

Time-reversal with multiple signal classification (TR-MUSIC) is an imaging method for locating point-like targets beyond the classic resolution limit. In the presence of noise, however, the super-resolution capability of TR-MUSIC is diminished. Recently a new method, phase-coherent MUSIC (PC-MUSIC), was developed. This algorithm modifies TR-MUSIC to make use of phase information from multiple frequencies to reduce noise effects and preserve the super resolution. PC-MUSIC however, ignores the phase response of the transducer elements. In this paper, we account for the phase response of the transducer elements in the derivation of the PC-MUSIC algorithm. Unfortunately, the phase response of the transducer elements may not be known beforehand. We develop an experimental method to estimate this response using measured signals scattered from a glass microsphere embedded in a tissue-mimicking phantom with a homogeneous background medium of a known sound speed. We use numerical simulations to illustrate that the maximum resolution achieved with PC-MUSIC is limited by the transducer bandwidth and the signal-to-noise ratio. We perform experiments on tissue-mimicking phantoms and compare images obtained with different imaging modalities, including X-ray mammography, synthetic-aperture ultrasound imaging, TR-MUSIC, and PC-MUSIC. We demonstrate the significantly improved resolving power of PC-MUSIC.

Techniques and evaluation from a cross-platform imaging comparison of quantitative ultrasound parameters in an in vivo rodent fibroadenoma model.

This contribution demonstrates that quantitative ultrasound (QUS) capabilities are platform independent, using an in vivo model. Frequency-dependent attenuation estimates, backscatter coefficient, and effective scatterer diameter estimates are shown to be comparable across four different ultrasound imaging systems with varied processing techniques. The backscatter coefficient (BSC) is a fundamental material property from which several QUS parameters are estimated; therefore, consistent BSC estimates among different systems must be demonstrated. This study is an intercomparison of BSC estimates acquired by three research groups (UIUC, UW, ISU) from four in vivo spontaneous rat mammary fibroadenomas using three clinical array systems and a single-element laboratory scanner system. Because of their highly variable backscatter properties, fibroadenomas provided an extreme test case for BSC analysis, and the comparison is across systems for each tumor, not across the highly heterogeneous tumors. RF echo data spanning the 1 to 12 MHz frequency range were acquired in three dimensions from all animals using each system. Each research group processed their RF data independently, and the resulting attenuation, BSC, and effective scatterer diameter (ESD) estimates were compared. The attenuation estimates across all systems showed the same trends and consistently fit the power-law dependence on frequency. BSCs varied among the multiple slices of data acquired by each transducer, with variations between transducers being of a similar magnitude as those from slice to slice. Variation between BSC estimates was assessed via functional signal-to-noise ratios derived from backscatter data. These functional signal-to-noise ratios indicated that BSC versus frequency variations between systems ranged from negligible compared with the noise level to roughly twice the noise level. The corresponding functional analysis of variance (fANOVA) indicated statistically significant differences between BSC curves from different systems. However, root mean squared difference errors of the BSC values (in decibels) between different transducers and imaging platforms were less than half of the BSC magnitudes in most cases. Statistical comparison of the effective scatterer diameter (ESD) estimates resulted in no significant differences in estimates from three of the four transducers used for those estimates, demonstrating agreement among estimates based on the BSC. This technical advance demonstrates that these in vivo measurements can be made in a system-independent manner; the necessary step toward clinical implementation of the technology.

Ultrasound time-reversal MUSIC imaging with diffraction and attenuation compensation.

Time-reversal imaging with multiple signal classification (TR-MUSIC) is an algorithm for imaging point-like scatterers embedded in a homogeneous and non-attenuative medium. We generalize this algorithm to account for the attenuation in the medium and the diffraction effects caused by the finite size of the transducer elements. The generalized algorithm yields higher-resolution images than those obtained with the original TR-MUSIC algorithm. We evaluate the axial and lateral resolutions of the images obtained with the generalized algorithm when noise corrupts the recorded signals and show that the axial resolution is degraded more than the lateral resolution. The TR-MUSIC algorithm is valid only when the number of point-like targets in the imaging plane is fewer than the number of transducer elements used to interrogate the medium. We remedy this shortcoming by dividing the imaging plane into subregions and applying the TR-MUSIC algorithm to the windowed backscattered signals corresponding to each subregion. The images of all subregions are then combined to form the total image. Imaging results of numerical and phantom data show that when the number of scatterers within each subregion is much smaller than the number of transducer elements, the windowing method yields super-resolution images with accurate scatterer localization. We use computer simulations and tissue-mimicking phantom data acquired with a real-time synthetic-aperture ultrasound system to illustrate the algorithms presented in the paper.

Ultrasound time-reversal MUSIC imaging of extended targets.

Ultrasound time-reversal imaging with multiple signal classification (TR-MUSIC) can produce images with subwavelength spatial resolution when the targets are point scatterers. In this experimental study, we evaluate the performance of the TR-MUSIC algorithm when the interrogated medium contains extended targets that cannot be considered as point scatterers, i.e., the size of the targets is on the order of the ultrasound wavelength or larger. We construct four tissue-mimicking phantoms, each of which contains glass spheres of a given size. We show that the quality of the phantom images obtained using the TR-MUSIC algorithm decreases with increasing sphere size. However, significant improvement is achieved when the image plane is divided into subregions, where each subregion is imaged separately. In this method, the TR-MUSIC calculations are performed on the windowed backscattered signals originating from each subregion. Our study demonstrates that the TR-MUSIC algorithm with time windowing can accurately locate extended targets but cannot provide the shape and reflectivity of the targets. We scan an inhomogeneous commercial tissue-mimicking phantom using an investigational synthetic-aperture ultrasound system, and show that the TR-MUSIC algorithm is capable of detecting small targets with high spatial resolution in inhomogeneous media.

Optimization of the algorithms for estimating the ultrasonic attenuation along the propagation path.

In this study, we perform statistical analysis on two methods used to estimate the total ultrasound attenuation along the propagation path from the surface of the transducer to a region of interest at a particular depth; namely, the spectral-fit method and the multiple-filter method. We derive mathematical equations for the bias and variance in the attenuation estimates as a function of region of interest (ROI) size, imaging system bandwidth, and number of independent Gaussian filters (for the multiple filter method). We use numerical simulations to validate the mathematical equations and compare the two algorithms. The results show that the variance in the total attenuation coefficient estimates obtained with the two methods are comparable, and that the estimates are unbiased. For the multiple filter method, the optimal number of Gaussian filters is two.

A theoretical comparison of attenuation measurement techniques from backscattered ultrasound echoes.

Accurate characterization of tissue pathologies using ultrasonic attenuation is strongly dependent on the accuracy of the algorithm that is used to obtain the attenuation coefficient estimates. In this paper, computer simulations were used to compare the accuracy and the precision of the three methods that are commonly used to estimate the local ultrasonic attenuation within a region of interest (ROI) in tissue; namely, the spectral log difference method, the spectral difference method, and the hybrid method. The effects of the inhomgeneities within the ROI on the accuracy of the three algorithms were studied, and the optimal ROI size (the number of independent echoes laterally and the number of pulse lengths axially) was quantified for each method. The three algorithms were tested for when the ROI was homogeneous, the ROI had variations in scatterer number density, and the ROI had variations in effective scatterer size. The results showed that when the ROI was homogeneous, the spectral difference method had the highest accuracy and precision followed by the spectral log difference method and the hybrid method, respectively. Also, when the scatterer number density varied, the spectral difference method completely failed, while the log difference method and hybrid method still gave good results. Lastly, when the scatterer size varied, all of the methods failed.

Estimate of the attenuation coefficient using a clinical array transducer for the detection of cervical ripening in human pregnancy.

Premature delivery is the leading cause of infant mortality in the United States. Currently, premature delivery cannot be prevented and new treatments are difficult to develop due to the inability to diagnose symptoms prior to uterine contractions. Cervical ripening is a long period that precedes the active phase of uterine contractions and cervical dilation. The changes in the microstructure of the cervix during cervical ripening suggest that the ultrasonic attenuation should decrease. The objective of this study is to use the reference phantom algorithm to estimate the ultrasonic attenuation in the cervix of pregnant human patients. Prior to applying the algorithm to in vivo human data, two homogeneous phantoms with known attenuation coefficients were used to validate the algorithm and to find the length and the width of the region of interest (ROI) that achieves the smallest error in the attenuation coefficient estimates. In the phantom data, we found that the errors in the attenuation coefficients estimates are less than 12% for ROIs that contain 40 wavelengths or more axially and 30 echo lines or more laterally. The reference phantom algorithm was then used to obtain attenuation maps of the echoes from two human pregnant cervices at different gestational ages. It was observed that the mean of the attenuation coefficient estimates in the cervix of the patient at a more advanced gestational age is smaller than the mean of the attenuation coefficient estimates in the cervix of the patient at an earlier gestational age which suggests that ultrasonic attenuation decreases with increasing gestational age. We also observed a large variance between the attenuation coefficient estimates in the different regions of the cervix due to the natural variation in tissue micro-structures across the cervix. The preliminary results indicate that the algorithm could potentially provide an important diagnostic tool for diagnosing the risk of premature delivery.

Estimating the total ultrasound attenuation along the propagation path by using a reference phantom.

In this study, an algorithm previously developed for estimating the total ultrasonic attenuation along the propagation path from the surface of the transducer to a region of interest (ROI) in tissue, was modified to make it more practical for use in clinical settings. Specifically, the algorithm was re-derived for when a tissue mimicking phantom rather than a planar reflector is used to obtain the reference power spectrum. The reference power spectrum is needed to compensate for the transfer function of the transmitted pulse, the transfer function of transducer, and the diffraction effects that result from focusing/beam forming. The modified algorithm was tested on simulated radio frequency (RF) echo lines obtained from two samples that have different scatterer sizes and different attenuation coefficient slopes, one of which was used as a reference. The mean and standard deviation of the percent errors in the attenuation coefficient estimates (ACEs) were less than 5% and 10%, respectively, for ROIs that contain more than 10 pulse lengths and more than 25 independent echo lines. The proposed algorithm was also tested on two tissue mimicking phantoms that have attenuation coefficient slopes of 0.7 dB/cm-MHz and 0.5 dB/cm-MHz respectively, the latter being the reference phantom. When a single element spherically focused source was used, the mean and standard deviation of the percent errors in the ACEs were less than 5% and 10% respectively for windows that contain more than 10 pulse lengths and more than 17 independent echo lines. When a clinical array transducer was used, the mean and standard deviation of the percent errors in the ACEs were less than 5% and 25%, respectively, for windows that contain more than 12 pulse lengths and more than 45 independent echo lines.

An improved 1-D gel electrophoresis image analysis system.

Images obtained through the gel electrophoresis technique contain important genetic information. However, due to degradations and abnormalities from which these images suffer, extracting this information can be a tedious task and may lead to reproducibility issues. Image processing techniques that are commonly used to analyze gel electrophoresis images require three main steps: band detection, band matching, and quantification. Although several techniques were proposed to automate all steps fully, gel image analysis still requires researchers to extract information manually. This type of extraction is time consuming and subject to human errors. This paper proposes a fully automated system to analyze the gel electrophoresis images. This system involves four main steps: lane separation, lane segmentation, band detection, and data quantification.

Cross-imaging platform comparison of ultrasonic backscatter coefficient measurements of live rat tumors.

OBJECTIVE: To translate quantitative ultrasound (QUS) from the laboratory into the clinic, it is necessary to demonstrate that the measurements are platform independent. Because the backscatter coefficient (BSC) is the fundamental estimate from which additional QUS estimates are calculated, agreement between BSC results using different systems must be demonstrated. This study was an intercomparison of BSCs from in vivo spontaneous rat mammary tumors acquired by different groups using 3 clinical array systems and a single-element laboratory scanner system. METHODS: Radio frequency data spanning the 1- to 14-MHz frequency range were acquired in 3 dimensions from all animals using each system. Each group processed their radio frequency data independently, and the resulting BSCs were compared. The rat tumors were diagnosed as either carcinoma or fibroadenoma. RESULTS: Carcinoma BSC results exhibited small variations between the multiple slices acquired with each transducer, with similar slopes of BSC versus frequency for all systems. Somewhat larger variations were observed in fibroadenomas, although BSC variations between slices of the same tumor were of comparable magnitude to variations between transducers and systems. The root mean squared (RMS) errors between different transducers and imaging platforms were highly variable. The lowest RMS errors were observed for the fibroadenomas between 4 and 5 MHz, with an average RMS error of 4 x 10(-5) cm(-1)Sr(-1) and an average BSC value of 7.1 x 10(-4) cm(-1)Sr(-1), or approximately 5% error. The highest errors were observed for the carcinoma between 7 and 8 MHz, with an RMS error of 1.1 x 10(-1) cm(-1)Sr(-1) and an average BSC value of 3.5 x 10(-2) cm(-1)Sr(-1), or approximately 300% error. CONCLUSIONS: This technical advance shows the potential for QUS technology to function with different imaging platforms.