Quantitative Ultrasound Biomarkers Research Articles

Lung quantitative ultrasound to stage and monitor interstitial lung diseases

Chronic interstitial lung diseases (ILDs) require frequent point-of-care monitoring. X-ray-based methods lack resolution and are ionizing. Chest computerized tomographic (CT) scans are expensive and provide more radiation. Conventional ultrasound can detect severe lung damage via vertical artifacts (B-lines). However, this information is not quantitative, and the appearance of B-lines is operator- and system-dependent. Here we demonstrate novel ultrasound-based biomarkers to assess severity of ILDs. Lung alveoli scatter ultrasound waves, leading to a complex acoustic signature, which is affected by changes in alveolar density due to ILDs. We exploit ultrasound scattering in the lung and combine quantitative ultrasound (QUS) parameters, to develop ultrasound-based biomarkers that significantly correlate (p = 1e−4 for edema and p = 3e−7 for fibrosis) to the severity of pulmonary fibrosis and edema in rodent lungs. These innovative QUS biomarkers will be very significant for monitoring severity of chronic ILDs and response to treatment, especially in this new era of miniaturized and highly portable ultrasound devices.

Evaluating postpartum cervical remodeling with quantitative ultrasound technology

Having a history of a previous spontaneous preterm birth (sPTB) is the strongest risk factor for recurrent sPTB. It is unknown if there are differences in postpartum cervical remodeling between women who have delivered spontaneous preterm (sPT) and full-term. No studies have evaluated the role of postpartum remodeling between the two groups. Quantitative ultrasound (QUS) is a noninvasive ultrasound technology used to quantify tissue microstructure and function. QUS biomarkers were used to evaluate postpartum cervical microstructure in women who delivered sPT and full-term. Data were collected from 54 women:14 who delivered sPT and 40 who delivered full-term. Transvaginal QUS scans were performed at 6 weeks (±2 weeks) after delivery. Attenuation coefficient (AC), backscatter coefficient (BSC), and shear wave speed (SWS) QUS biomarkers were collected. BSC was significantly higher at six weeks postpartum in women who delivered sPT versus full-term (p = 0.01), while the AC approached statistical significance (p = 0.09). QUS biomarker BSC was able to identify cervical microstructure differences at six weeks postpartum between women who delivered sPT and full-term. QUS technology may improve our understanding of postpartum cervical remodeling and has the potential to noninvasively direct precision-health approaches for recurrent sPTB. [Work supported by NIH 5F31NR019716.]

Quantitative Ultrasound Biomarkers to Assess Nonalcoholic Fatty Liver Disease.

To assess diagnostic performance of quantitative ultrasound (QUS) biomarkers in assessing hepatic steatosis. 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. 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). 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.

3-D-Printed Registration Phantom for Combined Ultrasound and Optical Imaging of Biological Tissues

Efforts to develop quantitative ultrasound biomarkers would benefit from comparisons between ultrasound data and higher-resolution images of the tissue microstructure, such as from optical microscopy. However, only a few studies have used these methods for multiscale imaging because it is difficult to register low-resolution (>100 μm) ultrasound images to high-resolution microscopy images. To address this need, we have designed a 3-D-printed registration phantom that is made of a hard fluorescent resin, fits into a glass-bottom dish and can be used to calculate a coordinate system transform between ultrasound and optical microscopy. We report the phantom design, a registration protocol and an example registration using 18.5-MHz ultrasound and second harmonic generation microscopy. We evaluate the registration precision, achieving standard deviations smaller than the ultrasound resolution across all axes, and illustrate on a mouse mammary gland that this method yields results superior to those of manual landmark registration.

Classification of breast lesions using quantitative ultrasound biomarkers

Quantitative ultrasound (QUS) parameters are gaining attention recently as non-invasive biomarkers for soft tissue characterization. In this work, we use two QUS parameters, namely effective scatterer diameter (ESD) and mean scatterer spacing (MSS), for binary classification of breast lesions. To produce improved classification results, we propose a modified frequency-domain technique for ESD estimation of breast tissues from the diffuse component of backscattered radio-frequency (RF) data. Ensemble empirical mode decomposition (EEMD) is performed to separate the diffuse component from the coherent component of the backscattered RF data. A non-parametric Kolmogorov–Smirnov (K-S) test is employed for automatic selection of the intrinsic mode functions (IMFs). A novel multi-step system effect minimization process is also used. The ESD is estimated using a novel nearest neighborhood average regression line fitting (NNARLF) algorithm. Furthermore, we use an ameliorated EEMD domain autoregressive (AR) spectral estimation technique for MSS estimation. On using the ESD for binary classification of 139 lesions, we obtain high sensitivity, specificity, accuracy values of 95.45%, 95.79%, and 95.68%, respectively. The area under the receiver operating characteristics (ROC) curve is 0.95. On combining ESD with MSS we obtain even more improved sensitivity, specificity, and accuracy values of 97.73%, 95.79%, and 96.40%, respectively. The area under the ROC also increases to 0.97. This high classification performance demonstrates the potential of the use of these QUS parameters as non-invasive biomarkers for breast cancer detection.

Inter-platform reproducibility of ultrasonic attenuation and backscatter coefficients in assessing NAFLD.

To assess inter-platform reproducibility of ultrasonic attenuation coefficient (AC) and backscatter coefficient (BSC) estimates in adults with known/suspected nonalcoholic fatty liver disease (NAFLD). This HIPAA-compliant prospective study was approved by an institutional review board; informed consent was obtained. Participants with known/suspected NAFLD were recruited and underwent same-day liver examinations with clinical ultrasound scanner platforms from two manufacturers. Each participant was scanned by the same trained sonographer who performed multiple data acquisitions in the right liver lobe using a lateral intercostal approach. Each data acquisition recorded a B-mode image and the underlying radio frequency (RF) data. AC and BSC were calculated using the reference phantom method. Inter-platform reproducibility was evaluated for AC and log-transformed BSC (logBSC = 10log10BSC) by intraclass correlation coefficient (ICC), Pearson's correlation, Bland-Altman analysis with computation of limits of agreement (LOAs), and within-subject coefficient of variation (wCV; applicable to AC). Sixty-four participants were enrolled. Mean AC values measured using the two platforms were 0.90 ± 0.13 and 0.94 ± 0.15dB/cm/MHz while mean logBSC values were - 30.6 ± 5.0 and - 27.9 ± 5.6dB, respectively. Inter-platform ICC was 0.77 for AC and 0.70 for log-transformed BSC in terms of absolute agreement. Pearson's correlation coefficient was 0.81 for AC and 0.80 for logBSC. Ninety-five percent LOAs were - 0.21 to 0.13dB/cm/MHz for AC, and - 9.48 to 3.98dB for logBSC. The wCV was 7% for AC. Hepatic AC and BSC are reproducible across two different ultrasound platforms in adults with known or suspected NAFLD. • Ultrasonic attenuation coefficient and backscatter coefficient are reproducible between two different ultrasound platforms in adults with NAFLD. • This inter-platform reproducibility may qualify quantitative ultrasound biomarkers for generalized clinical application in patients with suspected/known NAFLD.

Quantitative Ultrasound Biomarkers Based on Backscattered Acoustic Power: Potential for Quantifying Remodeling of the Human Cervix during Pregnancy

As pregnancy progresses, the cervix remodels from a rigid structure to one pliable enough to allow delivery of a fetus, a process that involves progressive disorganization of cervical microstructure. Quantitative ultrasound biomarkers that may detect this process include those derived from the backscattered echo signal, namely, acoustic attenuation and backscattered power loss. We recently reported that attenuation and backscattered power loss are affected by tissue anisotropy and heterogeneity in the ex vivo cervix. In this study, we compared attenuation and backscattered power difference in a group of women in early pregnancy (first trimester) with those in a group in late pregnancy (third trimester). We observed a significant decrease in the backscattered power difference in late as compared with early pregnancy, suggesting decreased microstructural organization in late pregnancy, a finding that is consistent with animal models of cervical remodeling. In contrast, we found no difference in attenuation between the time points. These results suggest that the backscattered power difference, but perhaps not attenuation, may be a useful clinical biomarker of cervical remodeling.

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis.

EP22.12: A multi‐biomarker approach to evaluation of the human pregnant cervix using quantitative ultrasound (QUS) imaging biomarkers

To integrate quantitative ultrasound (QUS) biomarkers of changes in cervical softness and extracellular matrix (ECM) organisation from 1st trimester (1T) to 3rd trimester (3T). In pregnant women (n=30) we used shear wave speed estimation (SWS) to measure softness, acoustic backscatter to evaluate ECM microstructural organisation via mean backscattered power difference (mBSPD) and effective scatterer diameter (ESD), and the Nakagami “M” to measure scatterer number density. Parametric and non-parametric tests were used as appropriate to compare differences between parameters and groups. SWS decreased from 1T to 3T [4.09±1.19 m/s (CI: 3.42-4.80) vs 2.13±0.66 m/s (CI: 1.84-2.45), p < 0.0001], suggesting softer tissue in 3T; backscatter anisotropy (mBSPD), was greater in 1T than 3T [4.65±1.72 dB (CI: 3.86-5.62) vs 2.70 ± 1.15 dB(CI: 2.30-3.31), p=0.0061], suggesting less ECM organisation in 3T; effective scatterer diameter (ESD), was larger in 1T than 3T [90±24 μm (CI: 78-97) vs 46±24 μm (CI: 35-56), p < 0.0001], suggesting less ECM organisation in 3T; Nakagami “M” did not vary from 1T to 3T [0.86±0.12, (CI: 0.79-0.92) vs 0.84±0.10, (CI: 0.80-0.89), p=0.80] suggesting no change in collagen concentration from 1T to 3T; and, in 3T ripened cervixes compared to untreated, SWS was lower [1.54±0.31 m/s (CI: 1.37-1.72) vs 2.13±0.66 m/s (CI: 1.84-2.45), p=0.002] but mBSPD unchanged [2.96±1.43 dB (CI: 2.35-3.77) vs 3.14±2.24 dB (CI: 2.51-4.73), p=0.8545], suggesting increased softness without change in ECM organisation. These preliminary results suggest that QUS biomarkers can simultaneously and comprehensively evaluate ECM organisation and tissue softness. They seem consistent with molecular studies in humans and animals that suggest mechanisms of cervical change are different in early compared to late pregnancy. In summary, combined QUS biomarkers may prove valuable for assessing in vivo cervical remodelling in women.

Repeatability and reproducibility of ultrasonic attenuation coefficient and backscatter coefficient measures in adults with non-alcoholic fatty liver disease

The attenuation coefficient (AC) and backscatter coefficient (BSC) are two promising quantitative ultrasound biomarkers, yet their repeatability and reproducibility (RR with and without visible blood vessels) were drawn for each image. AC and BSC were estimated within the FOIs. AC and log-transformed BSC mean values within 2.6-3.0 MHz were used for the R&R analysis based on an unweighted sums of ...