Robust Inference for Partially Observed Functional Response Data.

Irregular functional data in which densely sampled curves are observed over different ranges pose a challenge for modeling and inference, and sensitivity to outlier curves is a concern in applications. Motivated by applications in quantitative ultrasound signal analysis, this paper investigates a class of robust M-estimators for partially observed functional data including functional location and quantile estimators. Consistency of the estimators is established under general conditions on the partial observation process. Under smoothness conditions on the class of M-estimators, asymptotic Gaussian process approximations are established and used for large sample inference. The large sample approximations justify a bootstrap approximation for robust inferences about the functional response process. The performance is demonstrated in simulations and in the analysis of irregular functional data from quantitative ultrasound analysis.

Robust probabilistic classification applicable to irregularly sampled functional data.

A robust probabilistic classifier for functional data is developed to predict class membership based on functional input measurements and to provide a reliable probability estimates for class membership. The method combines a Bayes classifier and semi-parametric mixed effects model with robust tuning parameter to make the method robust to outlying curves, and to improve the accuracy of the risk or uncertainty estimates, which is crucial in medical diagnostic applications. The approach applies to functional data with varying ranges and irregular sampling without making parametric assumptions on the within-curve covariance. Simulation studies evaluate the proposed method and competitors in terms of sensitivity to heavy tailed functional distributions and outlying curves. Classification performance is evaluated by both error rate and logloss, the latter of which imposes heavier penalties on highly confident errors than on less confident errors. Runtime experiments on the R implementation indicate that the proposed method scales well computationally. Illustrative applications include data from quantitative ultrasound analysis and phoneme recognition.

Intraoperative optical coherence tomography for assessing human lymph nodes for metastatic cancer.

BACKGROUND: Evaluation of lymph node (LN) status is an important factor for detecting metastasis and thereby staging breast cancer. Currently utilized clinical techniques involve the surgical disruption and resection of lymphatic structure, whether nodes or axillary contents, for histological examination. While reasonably effective at detection of macrometastasis, the majority of the resected lymph nodes are histologically negative. Improvements need to be made to better detect micrometastasis, minimize or eliminate lymphatic disruption complications, and provide immediate and accurate intraoperative feedback for in vivo cancer staging to better guide surgery. METHODS: We evaluated the use of optical coherence tomography (OCT), a high-resolution, real-time, label-free imaging modality for the intraoperative assessment of human LNs for metastatic disease in patients with breast cancer. We assessed the sensitivity and specificity of double-blinded trained readers who analyzed intraoperative OCT LN images for presence of metastatic disease, using co-registered post-operative histopathology as the gold standard. RESULTS: Our results suggest that intraoperative OCT examination of LNs is an appropriate real-time, label-free, non-destructive alternative to frozen-section analysis, potentially offering faster interpretation and results to empower superior intraoperative decision-making. CONCLUSIONS: Intraoperative OCT has strong potential to supplement current post-operative histopathology with real-time in situ assessment of LNs to preserve both non-cancerous nodes and their lymphatic vessels, and thus reduce the associated risks and complications from surgical disruption of lymphoid structures following biopsy.

Contrast Ultrasound Imaging of the Aorta Does Not Affect Progression of Atherosclerosis or Cardiovascular Biomarkers in ApoE-/- Mice.

OBJECTIVES: Ultrasound contrast agents (UCAs) enhance cardiovascular ultrasound imaging. Adverse biological effects have occurred after administration of UCAs, and more research is needed for a comprehensive understanding of the risks involved. We used the ApoE(-/-) mouse model of atherosclerosis to characterize the effects of ultrasound and UCAs on atherosclerosis and plasma biomarkers. METHODS: Male ApoE(-/-) mice (8 weeks old; n = 24) were intravenously infused with a UCA (2 × 10(10) Definity microbubbles per hour; Lantheus Medical Imaging, North Billerica, MA) and exposed to 2.8-MHz center frequency ultrasound (10 Hz pulse repetition frequency, 1.4 microseconds pulse duration, 2 minutes exposure duration, and 2 sites) at 1 of 3 derated peak rarefactional pressure amplitudes (0, 1.9, or 3.8 MPa), and then consumed either a chow or Western diet for 4 weeks (n = 4 per group). Blood plasma samples were collected before ultrasound exposure and at 2 and 4 weeks after exposure and assayed for total cholesterol and von Willebrand Factor (vWF). A pathologist measured atheroma thickness in formalin-fixed, hematoxylin-eosin-stained transverse aorta sections and scored them for severity of atherosclerosis. RESULTS: Plasma total cholesterol initially averaged 286 mg/dL in the Western diet group and increased to 861 mg/dL after 4 weeks on the diet (P < .0001). Total cholesterol did not increase significantly in the chow diet group. Plasma vWF increased after 2 weeks on the Western diet (P < .0001). Atheroma thickness was greater in animals consuming the Western diet than in chow-fed animals (P < .05). Ultrasound had no significant effect on plasma total cholesterol, plasma vWF, or atheroma thickness. CONCLUSIONS: Contrast ultrasound did not increase the severity of atherosclerosis or alter cardiovascular biomarkers in the ApoE(-/-) mouse model.

Contrast Ultrasound Imaging Does Not Affect Heat Shock Protein 70 Expression in Cholesterol-Fed Rabbit Aorta.

OBJECTIVES: Diagnostic ultrasound imaging is enhanced by the use of circulating microbubble contrast agents (UCAs), but the interactions between ultrasound, UCAs, and vascular tissue are not fully understood. We hypothesized that ultrasound with a UCA would stress the vascular tissue and increase levels of heat shock protein 70 (Hsp70), a cellular stress protein. METHODS: Male New Zealand White rabbits (n = 32) were fed a standard chow diet (n = 4) or a 1% cholesterol, 10% fat, and 0.11% magnesium diet (n = 28). At 21 days, 24 rabbits on the cholesterol diet were either exposed to ultrasound (3.2-MHz f/3 transducer; 2.1 MPa; mechanical index, 1.17; 10 Hz pulse repetition frequency; 1.6 microseconds pulse duration; 2 minutes exposure duration at 4 sites along the aorta) with the UCA Definity (1× concentration, 1 mL/min; Lantheus Medical Imaging, North Billerica, MA) or sham exposed with a saline vehicle injection (n = 12 per group). Four rabbits on the cholesterol diet and 4 on the chow diet served as cage controls and were not exposed to ultrasound or restrained for blood sample collection. Animals were euthanized 24 hours after exposure, and aortas were quickly isolated and frozen in liquid nitrogen. Aorta lysates from the area of ultrasound exposure were analyzed for Hsp70 level by Western blot. Blood plasma was analyzed for cholesterol, Hsp70, and von Willebrand factor, a marker of endothelial function. RESULTS: Plasma total cholesterol levels increased to an average of 705 mg/dL. Ultrasound did not affect plasma von Willebrand factor, plasma Hsp70, or aorta Hsp70. Restraint increased Hsp70 (P < .001, analysis of variance). CONCLUSIONS: Restraint, but not ultrasound with the UCA or cholesterol feeding, significantly increased Hsp70.

Quantitative Ultrasound Comparison of MAT and 4T1 Mammary Tumors in Mice and Rats Across Multiple Imaging Systems.

OBJECTIVES: Quantitative ultrasound estimates such as the frequency-dependent backscatter coefficient (BSC) have the potential to enhance noninvasive tissue characterization and to identify tumors better than traditional B-mode imaging. Thus, investigating system independence of BSC estimates from multiple imaging platforms is important for assessing their capabilities to detect tissue differences. METHODS: Mouse and rat mammary tumor models, 4T1 and MAT, respectively, were used in a comparative experiment using 3 imaging systems (Siemens, Ultrasonix, and VisualSonics) with 5 different transducers covering a range of ultrasonic frequencies. RESULTS: Functional analysis of variance of the MAT and 4T1 BSC-versus-frequency curves revealed statistically significant differences between the two tumor types. Variations also were found among results from different transducers, attributable to frequency range effects. At 3 to 8 MHz, tumor BSC functions using different systems showed no differences between tumor type, but at 10 to 20 MHz, there were differences between 4T1 and MAT tumors. Fitting an average spline model to the combined BSC estimates (3-22 MHz) demonstrated that the BSC differences between tumors increased with increasing frequency, with the greatest separation above 15 MHz. Confining the analysis to larger tumors resulted in better discrimination over a wider bandwidth. CONCLUSIONS: Confining the comparison to higher ultrasonic frequencies or larger tumor sizes allowed for separation of BSC-versus-frequency curves from 4T1 and MAT tumors. These constraints ensure that a greater fraction of the backscattered signals originated from within the tumor, thus demonstrating that statistically significant tumor differences were detected.

Enhanced identification of women at risk for preterm birth via quantitative ultrasound: a prospective cohort study.

BACKGROUND: Historically, clinicians have relied on medical risk factors and clinical symptoms for preterm birth risk assessment. In nulliparous women, clinicians may rely solely on reported symptoms to assess for the risk of preterm birth. The routine use of ultrasound during pregnancy offers the opportunity to incorporate quantitative ultrasound scanning of the cervix to potentially improve assessment of preterm birth risk. OBJECTIVE: This study aimed to investigate the efficiency of quantitative ultrasound measurements at relatively early stages of pregnancy to enhance identification of women who might be at risk for spontaneous preterm birth. STUDY DESIGN: A prospective cohort study of pregnant women was conducted with volunteer participants receiving care from the University of Illinois Hospital in Chicago, Illinois. Participants received a standard clinical screening followed by 2 research screenings conducted at 20±2 and 24±2 weeks. Quantitative ultrasound scans were performed during research screenings by registered diagnostic medical sonographers using a standard cervical length approach. Quantitative ultrasound features were computed from calibrated raw radiofrequency backscattered signals. Full-term birth outcomes and spontaneous preterm birth outcomes were included in the analysis. Medically indicated preterm births were excluded from the analysis. Using data from each visit, logistic regression with Akaike information criterion feature selection was conducted to derive predictive models for each time frame based on historical clinical and quantitative ultrasound features. Model evaluations included a likelihood ratio test of quantitative ultrasound features, cross-validated receiver operating characteristic curve analysis, sensitivity, and specificity. RESULTS: On the basis of historical clinical features alone, the best predictive model had an estimated receiver operating characteristic area under the curve of 0.56±0.03. By the time frame of Visit 1, a predictive model using both historical clinical and quantitative ultrasound features provided a modest improvement in the area under the curve (0.63±0.03) relative to that of the predictive model using only historical clinical features. By the time frame of Visit 2, the predictive model using historical clinical and quantitative ultrasound features provided significant improvement (likelihood ratio test, P<.01), with an area under the curve of 0.69±0.03. CONCLUSION: Accurate identification of women at risk for spontaneous preterm birth solely through historical clinical features has been proven to be difficult. In this study, a history of preterm birth was the most significant historical clinical predictor of preterm birth risk, but the historical clinical predictive model performance was not statistically significantly better than the no-skill level. According to our study results, including quantitative ultrasound yields a statistically significant improvement in risk prediction as the pregnancy progresses.

Automated Field of Interest Determination for Quantitative Ultrasound Analyses of Cervical Tissues: Toward Real-time Clinical Translation in Spontaneous Preterm Birth Risk Assessment.

OBJECTIVE: Quantitative ultrasound (QUS) analysis of the human cervix is valuable for predicting spontaneous preterm birth risk. However, this approach currently requires an offline processing step wherein a medically trained analyst manually draws a free-hand field of interest (Manual FOI) for QUS computation. This offline step hinders the clinical adoption of QUS. To address this challenge, we developed a method to determine automatically the cervical FOI (Auto FOI). This study's objective is to evaluate the agreement between QUS results obtained from the Auto and Manual FOIs and assess the feasibility of using the Auto FOI to replace the Manual FOI for cervical QUS computation. METHODS: The auto FOI method was developed and evaluated using cervical ultrasound data from 527 pregnant women, using Manual FOIs as the reference. A deep learning model was developed using the cervical B-mode image as the input to determine automatically the FOI. RESULTS: Quantitative comparison between the Auto and Manual FOIs yielded a high pixel accuracy of 97% and a Dice coefficient of 87%. Further, the Auto FOI yielded QUS biomarker values that were highly correlated with those obtained from the Manual FOIs. For example, the Pearson correlation coefficient was 0.87 between attenuation coefficient values obtained using Auto and Manual FOIs. Further, Bland-Altman analyses showed negligible bias between QUS biomarker values computed using the Auto and Manual FOIs. CONCLUSION: The results support the feasibility of using Auto FOIs to replace Manual FOIs in QUS computation, an important step toward the clinical adoption of QUS technology.

Trajectory of Postpartum Cervical Remodeling in Women Delivering Full-Term and Spontaneous Preterm: Sensitivity to Quantitative Ultrasound Biomarkers.

OBJECTIVE: Women with a history of spontaneous preterm birth (sPTB) face an increased risk of recurrence. Yet, the factors contributing to the increased risk are unknown, hampering the development of targeted interventions. Noninvasive quantitative ultrasound (QUS) has been validated in the characterization of cervical tissue and has the potential to provide information about postpartum cervical remodeling. The objective of this study was to determine the postpartum cervical remodeling trajectories of women over 12 mo post-delivery and to determine whether there were differences between women who delivered full-term and spontaneous preterm that were sensitive to QUS biomarkers. METHODS: Data were collected prospectively from 55 women: 41 who delivered full-term and 14 who delivered spontaneously preterm at 6 wk, 3, 6, 9 and 12 mo (±2 wk) postpartum. Data from QUS biomarkers: Attenuation Coefficient; Backscatter Coefficient; Shear Wave Speed; and Lizzi-Feleppa Slope, Intercept and Midband were analyzed from the acquired radiofrequency data using a Siemens S2000 ultrasound system with a transvaginal MC 9-4 MHz probe. The biomarkers were analyzed using descriptive statistics and linear mixed-effects models. RESULTS: QUS biomarkers, Backscatter Coefficient and Lizzi-Feleppa Intercept showed significant differences during the year after delivery between women who had a full-term birth and sPTB (p < 0.05), suggesting that there are differences in the cervical remodeling trajectories between the two groups. All QUS biomarkers demonstrated significant variations between the full-term birth and sPTB groups over time (p < 0.05), indicating ongoing cervical remodeling for both groups during the 12-mo postpartum period. CONCLUSION: QUS biomarkers identified cervical microstructure differences and trajectories in the year after delivery between women who delivered full-term and spontaneous preterm.

Testing Linear Operator Constraints in Functional Response Regression with Incomplete Response Functions.

Hypothesis testing procedures are developed to assess linear operator constraints in function-on-scalar regression when incomplete functional responses are observed. The approach enables statistical inferences about the shape and other aspects of the functional regression coefficients within a unified framework encompassing three incomplete sampling scenarios: (i) partially observed response functions as curve segments over random sub-intervals of the domain; (ii) discretely observed functional responses with additive measurement errors; and (iii) the composition of former two scenarios, where partially observed response segments are observed discretely with measurement error. The latter scenario has been little explored to date, although such structured data is increasingly common in applications. For statistical inference, deviations from the constraint space are measured via integrated L 2 -distance between the model estimates from the constrained and unconstrained model spaces. Large sample properties of the proposed test procedure are established, including the consistency, asymptotic distribution and local power of the test statistic. Finite sample power and level of the proposed test are investigated in a simulation study covering a variety of scenarios. The proposed methodologies are illustrated by applications to U.S. obesity prevalence data, analyzing the functional shape of its trends over time, and motion analysis in a study of automotive ergonomics.

Predicting Spontaneous Pre-term Birth Risk Is Improved When Quantitative Ultrasound Data Are Included With Historical Clinical Data.

OBJECTIVE: Predicting women at risk for spontaneous pre-term birth (sPTB) has been medically challenging because of the lack of signs and symptoms of pre-term birth until interventions are too late. We hypothesized that prediction of the sPTB risk level is enhanced when using both historical clinical (HC) data and quantitative ultrasound (QUS) data compared with using only HC data. HC data defined herein included birth history prior to that of the current pregnancy as well as, from the current pregnancy, a clinical cervical length assessment and physical examination data. METHODS: The study population included 248 full-term births (FTBs) and 26 sPTBs. QUS scans (Siemens S2000 and MC9-4) were performed by registered diagnostic medical sonographers using a standard cervical length approach. Two cervical QUS scans were conducted at 20 ± 2 and 24 ± 2 wk of gestation. Multiple QUS features were evaluated from calibrated raw radiofrequency backscattered ultrasonic signals. Two statistical models designed to determine sPTB risk were compared: (i) HC data alone and (ii) combined HC and QUS data. Model comparisons included a likelihood ratio test, cross-validated receiver operating characteristic area under the curve, sensitivity and specificity. The study's birth outcomes were only FTBs and sPTBs; medically induced pre-term births were not included. DISCUSSION: Combined HC and QUS data identified women at risk of sPTB with better AUC (0.68, 95% confidence interval [CI]: 0.57-0.78) compared with HC data alone (0.53, 95% CI: 0.40-0.66) and HC data + cervical length at 18-20 wk of gestation (average AUC = 0.51, 95% CI: 0.38-0.64). A likelihood ratio test for significance of QUS features in the classification model was highly statistically significant (p < 0.01). CONCLUSION: Even with only 26 sPTBs among 274 births, value was added in predicting sPTB when QUS data were included with HC data.

Contrast ultrasound imaging of the aorta alters vascular morphology and circulating von Willebrand factor in hypercholesterolemic rabbits.

OBJECTIVES: Ultrasound contrast agents (UCAs) are intravenously infused microbubbles that add definition to ultrasonic images. Ultrasound contrast agents continue to show clinical promise in cardiovascular imaging, but their biological effects are not known with confidence. We used a cholesterol-fed rabbit model to evaluate these effects when used in conjunction with ultrasound (US) to image the descending aorta. METHODS: Male New Zealand White rabbits (n = 41) were weaned onto an atherogenic diet containing 1% cholesterol, 10% fat, and 0.11% magnesium. At 21 days, rabbits were exposed to contrast US at 1 of 4 pressure levels using either the UCA Definity (Lantheus Medical Imaging, Inc, North Billerica, MA) or a saline control (n = 5 per group). Blood samples were collected and analyzed for lipids and von Willebrand factor (vWF), a marker of endothelial function. Animals were euthanized at 42 days, and tissues were collected for histologic analysis. RESULTS: After adjustment for pre-exposure vWF, high-level US (in situ [at the aorta] peak rarefactional pressure of 1.4 or 2.1 MPa) resulted in significantly lower vWF 1 hour post exposure (P = .0127; P(adj) < .0762). This difference disappeared within 24 hours. Atheroma thickness in the descending aorta was lower in animals receiving the UCA compared to animals receiving saline. CONCLUSIONS: Contrast US affected the descending aorta, as evidenced by two separate outcome measures. These results may be a first step in elucidating a previously unknown biological effect of UCAs. Further research is warranted to characterize the effects of this procedure.

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.

Statistical evaluation of reader variability in assessing the diagnostic performance of optical coherence tomography.

SIGNIFICANCE: Optical coherence tomography (OCT) is widely used as a potential diagnostic tool for a variety of diseases including various types of cancer. However, sensitivity and specificity analyses of OCT in different cancers yield results varying from 11% to 100%. Hence, there is a need for more detailed statistical analysis of blinded reader studies. AIM: Extensive statistical analysis is performed on results from a blinded study involving OCT of breast tumor margins to assess the impact of reader variability on sensitivity and specificity. APPROACH: Five readers with varying levels of experience reading OCT images assessed 50 OCT images of breast tumor margins collected using an intraoperative OCT system. Statistical modeling and analysis was performed using the R language to analyze reader experience and variability. RESULTS: Statistical analysis showed that the readers' prior experience with OCT images was directly related to the probability of the readers' assessment agreeing with histology. Additionally, results from readers with prior experience specific to OCT in breast cancer had a higher probability of agreement with histology compared to readers with experience with OCT in other (noncancer) diseases. CONCLUSIONS: The results from this study demonstrate the potential impact of reader training and experience in the assessment of sensitivity and specificity. They also demonstrate even greater potential improvement in diagnostic performance by combining results from multiple readers. These preliminary findings suggest valuable directions for further study.

A Phantom-Based Assessment of Repeatability and Reproducibility of Transvaginal Quantitative Ultrasound.

This article evaluated the repeatability and reproducibility (R&R) of quantitative ultrasound (QUS) biomarkers attenuation coefficient (AC) and backscatter coefficient (BSC) in transvaginal QUS reference phantoms for obstetric applications. Five phantoms were scanned by three sonographers according to the scanning protocol. Each sonographer scanned each phantom with four transvaginal transducers of the same model (MC9-4) and three probe cover types (latex cover, nonlatex cover, and no cover). The AC and BSC were estimated by using a reference phantom method. The R&R analysis was performed for the frequency-averaged AC and logBSC (= 10log10BSC) (5.4-5.8 MHz) by using three-factor random effects Analysis of Variance with interaction. The total R&R variabilities for AC and logBSC are small (AC: 0.042-0.065 dB/cm-MHz; logBSC: 0.50-0.68 dB), indicating high measurement precision. These values are small compared to the ranges of AC (0.28-0.99 dB/cm-MHz) and logBSC (-33.16 to -20.35 dB) of the five phantoms. The AC and logBSC biomarkers measured on transvaginal QUS phantoms using the reference phantom method are repeatable, and reproducible between sonographers, transducers, and probe covers.

Threshold estimation of ultrasound-induced lung hemorrhage in adult rabbits and comparison of thresholds in mice, rats, rabbits and pigs.

The objective of this study was to assess the threshold and superthreshold behavior of ultrasound (US)-induced lung hemorrhage in adult rabbits to gain greater understanding about species dependency. A total of 99 76 +/- 7.6-d-old 2.4 +/- 0.14-kg New Zealand White rabbits were used. Exposure conditions were 5.6-MHz, 10-s exposure duration, 1-kHz PRF and 1.1-micros pulse duration. The in situ (at the pleural surface) peak rarefactional pressure, p(r(in situ)), ranged between 1.5 and 8.4 MPa, with nine acoustic US exposure groups plus a sham exposure group. Rabbits were assigned randomly to the 10 groups, each with 10 rabbits, except for one group that had nine rabbits. Rabbits were exposed bilaterally with the order of exposure (left then right lung, or right then left lung) and acoustic pressure both randomized. Individuals involved in animal handling, exposure and lesion scoring were blinded to the exposure condition. Probit regression analysis was used to examine the dependence of the lesion occurrence on in situ peak rarefactional pressure and order of exposure (first vs. second). Likewise, lesion depth and lesion root surface area were analyzed using Gaussian tobit regression analysis. Neither probability of a lesion nor lesion size measurements was found to be statistically dependent on the order of exposure after the effect of p(r(in situ)) was considered. Also, a significant correlation was not detected between the two exposed lung sides on the same rabbit in either lesion occurrence or size measures. The p(r(in situ)) threshold estimates (in MPa) were similar to each other across occurrence (3.54 +/- 0.78), depth (3.36 +/- 0.73) and surface area (3.43 +/- 0.77) of lesions. Using the same experimental techniques and statistical approach, great consistency of thresholds was demonstrated across three species (mouse, rat and rabbit). Further, there were no differences in the biologic mechanism of injury induced by US and US-induced lesions were similar in morphology in all species and age groups studied. The extent of US-induced lung damage and the ability of the lung to heal led to the conclusion that, although US can produce lung damage at clinical levels, the degree of damage does not appear to be a significant medical problem.

Beyond Cervical Length: A Pilot Study of Ultrasonic Attenuation for Early Detection of Preterm Birth Risk.

The purpose of this study was to determine whether cervical ultrasonic attenuation could identify women at risk of spontaneous preterm birth. During pregnancy, women (n = 67) underwent from one to five transvaginal ultrasonic examinations to estimate cervical ultrasonic attenuation and cervical length. Ultrasonic data were obtained with a Zonare ultrasound system with a 5- to 9-MHz endovaginal transducer and processed offline. Cervical ultrasonic attenuation was lower at 17-21 wk of gestation in the SPTB group (1.02 dB/cm-MHz) than in the full-term birth groups (1.34 dB/cm-MHz) (p = 0.04). Cervical length was shorter (3.16 cm) at 22-26 wk in the SPTB group than in the women delivering full term (3.68 cm) (p = 0.004); cervical attenuation was not significantly different at this time point. These findings suggest that low attenuation may be an additional early cervical marker to identify women at risk for SPTB.

Evaluation of unscanned-mode soft-tissue thermal index for rectangular sources and proposed new indices.

The monopole-source solution was used to calculate the three-dimensional complex acoustic pressure field for one-dimensional focused rectangular apertures in a medium having homogeneous acoustic and thermal properties. For each of six frequencies (1, 3, 5, 7, 9 and 12 MHz) and three focuses (f/1, f/2 and f/4), 33 rectangular aperture cases were investigated, for a total of 594 cases. For these focused field geometries, the three-dimensional temperature distribution was calculated using the bioheat transfer equation in homogeneous perfused media (attenuation = absorption: 0.3 dB/cm-MHz; perfusion length: 1.0 cm). For each of the 594 cases, the acoustic field was normalized to the derated spatial-peak temporal-average intensity (ISPTA.3) of 720 mW/cm2, the maximum value condition allowed based on the U.S. Food and Drug Administration (FDA) regulatory limit for most diagnostic ultrasound (US) equipment. Using the normalized acoustic field, the axial temperature increase profiles and the maximum temperature increases (DeltaTmax) were determined for each case. Also, from the normalized acoustic field, the unscanned-mode soft-tissue thermal index (TIS) for the rectangular sources was determined according to the procedures of the Standard for Real-Time Display of Thermal and Mechanical Indices on Diagnostic Ultrasound Equipment, commonly called the output display standard, ODS. The DeltaTmax:TIS ratio of the 594 cases yielded a mean value of 0.22, a median value of 0.16, a maximum value of 1.04 and a minimum value of 0.039. For all but one of the cases, TIS was greater than DeltaTmax. Also, two new unscanned-mode soft-tissue thermal indices (denoted TIS(new1) and TIS(new2)) were proposed. For new model 1, the DeltaTmax: TIS(new1) ratio yielded a mean value of 1.02, a median value of 1.01, a maximum value of 1.83 and a minimum value of 0.44. For new model 2, the DeltaTmax: TIS(new2) ratio yielded a mean value of 1.04, a median value of 0.99, a maximum value of 2.31 and a minimum value of 0.34. Further, both new models fit more closely to DeltaTmax than does the ODS-determined TIS and have the potential of being easier for manufacturers to implement because only the source power and frequency need to be measured.

Threshold estimates and superthreshold behavior of ultrasound-induced lung hemorrhage in adult rats: role of pulse duration.

The study objective was to estimate the pressure threshold (ED(05), effective dose, or in situ peak rarefactional pressure associated with 5% probability of lesions) of ultrasound (US)-induced lung hemorrhage as a function of pulse duration (PD) in adult rats. A total of 220 10- to 11-week-old 250-g female Sprague-Dawley rats (Harlan) were randomly divided into 20 ultrasonic exposure groups (10 rats/group) and one sham group (20 rats). The 20 ultrasonic exposure groups (2.8-MHz; 10-s exposure duration; 1-kHz PRF; -6-dB pulse-echo focal beam width of 470 microm) were divided into four PD groups (1.3, 4.4, 8.2 and 11.6 micros) and, for each PD group, there were five in situ peak rarefactional pressures (range between 4 and 9 MPa). Rats were weighed, anesthetized, depilated, exposed, and euthanized under anesthesia. The left lung was removed and scored for the occurrence of hemorrhage. If hemorrhage was present, the lesion surface area and depth were measured. Individuals involved in animal handling, exposure and lesion scoring were "blinded" to the exposure conditions. Logistic regression analysis was used to examine the dependence of the lesion occurrences, and Gaussian tobit regression analysis was used to examine the dependence of the lesion surface areas and depths on in situ peak rarefactional pressure and PD. Threshold results are reported in terms of ED(05). For PDs of 1.3, 4.4, 8.2 and 11.6 micros, respectively, lesion occurrence ED(05)s were 3.1, 2.8, 2.3 and 2.0 MPa with standard errors around 0.6 MPa. Lesion size ED(05)s showed similar values. A mechanical index (MI) of 1.9, the US Food and Drug Administration (FDA) regulatory limit of diagnostic US equipment, is equivalent to the adult rat's in situ peak rarefactional pressure of 4.0 MPa. PDs of 8.2 and 11.6 micros had ED(05)s more than 2 standard errors below 4.0 MPa, indicating that the ED(05)s of these two PDs are statistically significantly different from 4.0 MPa. The ED(05) threshold levels for a PD of 1.3 micros are consistent with previous US-induced lung hemorrhage studies. As the PD increases, the ED(05) levels decrease, suggesting greater likelihood of lung damage as the PD increases. All of the ED(05)s are less than the FDA limit.

Excess risk thresholds in ultrasound safety studies: statistical methods for data on occurrence and size of lesions.

Concerns about the safe use of clinical ultrasound (US) at diagnostic pressure levels (below a mechanical index, or MI, = 1.9) have stimulated considerable research in US risk assessment. The objective of the present study was to develop probability-based risk thresholds for US safety studies, to present statistical methods for estimating the thresholds and their standard errors and to compare these methods with the analysis based on a piecewise linear ("hockey stick") model. The excess risk at exposure level x > 0 was defined as the relative increase in the probability of a lesion at that level compared with the background probability of a lesion at exposure x = 0. The risk threshold was then defined as the exposure level at which the excess risk exceeded a specified level (e.g. 5% or 50%). Thus, given pressure-dependent estimates of the excess risk, the thresholds were estimated by solving the risk equation to obtain the pressure at which the target level of excess risk occurs. Threshold estimates of this type have been developed extensively in the literature for incidence (presence or absence) data. Only recently, however, have excess risk threshold estimates been derived for data in which lesion size (depth, surface area) is measured if present and a zero is recorded if the lesion is absent. Tobit regression was used to estimate pressure-dependent percentiles of the size distribution, and the excess risks were estimated from the tobit probability of a positive-valued response. The tobit model provides a well-established approach to modeling data constrained to be nonnegative. Solving the risk equation for the tobit model leads to risk threshold estimates that incorporate the information on size of observed lesions. Results using these probability-based risk estimates were compared with results for a piecewise linear ("hockey stick") model, which has also been used in the US safety literature, although it does not explicitly address the nonnegativity constraint in the sampling model. The comparisons were carried out for data from two previously published studies, from different laboratories, on US-induced lung hemorrhage. The thresholds derived from logistic regression of lesion occurrence and tobit regression of lesion size were quite consistent with each other and within sampling error. The hockey stick thresholds, defined as the exposure level at which the piecewise linear model for the probability of the expected size of a lesion bends upward, corresponded to quite different excess risk values for incidence (lesion occurrence) compared with size (lesion surface area or depth), although these methods have been developed previously for both types of data. The use of probability-based excess risk thresholds is recommended to obtain consistent incidence vs. size thresholds and to ensure that the thresholds are well-defined and interpretable independent of the details of the statistical model.