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* Context.--Despite several studies focusing on the validation of whole slide imaging (WSI) across organ systems or subspecialties, the use of WSI for specific primary diagnosis tasks has been underexamined. Objective.--To assess pathologist performance for the histologic subtyping of individual sections of ovarian carcinomas using a light microscope and WSI. Design.--A panel of 3 experienced gynecologic pathologists provided reference subtype diagnoses for 212 histologic sections from 109 ovarian carcinomas based on optical microscopy review. Two additional attending pathologists provided diagnoses and also identified the presence of a set of 8 histologic features important for ovarian tumor subtyping. Two experienced gynecologic pathologists and 2 fellows reviewed the corresponding WSI images for subtype classification and feature identification. Results.--Across pathologists specialized in gynecologic pathology, concordance with the reference diagnosis for the 5 major ovarian carcinoma subtypes was significantly higher for a pathologist reading on a microscope than each of 2 pathologists reading on WSI. Differences were primarily due to more frequent classification of mucinous carcinomas as endometrioid with WSI. Pathologists had generally low agreement in identifying histologic features important to ovarian tumor subtype classification with either an optical microscopy or WSI. This result suggests the need for refined histologic criteria for identifying such features. Interobserver agreement was particularly low for identifying intracytoplasmic mucin with WSI. Inconsistencies in evaluating nuclear atypia and mitoses with WSI were also observed. Conclusions.--Further research is needed to specify the reasons for these diagnostic challenges and to inform users and manufacturers of WSI technology., More than 90% of ovarian malignancies consist of epithelial cancers, (1) which are further classified into 5 major subtypes, namely high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), clear cell [...]

* Context.--Clinical decision support (CDS) systems could assist less experienced pathologists with certain diagnostic tasks for which subspecialty training or extensive experience is typically needed. The effect of decision support on pathologist performance for such diagnostic tasks has not been examined. Objective.--To examine the impact of a CDS tool for the classification of ovarian carcinoma subtypes by pathology trainees in a pilot observer study using digital pathology. Design.--Histologic review on 90 whole slide images from 75 ovarian cancer patients was conducted by 6 pathology residents using: (1) unaided review of whole slide images, and (2) aided review, where in addition to whole slide images observers used a CDS tool that provided information about the presence of 8 histologic features important for subtype classification that were identified previously by an expert in gynecologic pathology. The reference standard of ovarian subtype consisted of majority consensus from a panel of 3 gynecologic pathology experts. Results.--Aided review improved pairwise concordance with the reference standard for 5 of 6 observers by 3.3% to 17.8% (for 2 observers, increase was statistically significant) and mean interobserver agreement by 9.2% (not statistically significant). Observers benefited the most when the CDS tool prompted them to look for missed histologic features that were definitive for a certain subtype. Observer performance varied widely across cases with unanimous and nonunanimous reference classification, supporting the need for balancing data sets in terms of case difficulty. Conclusions.--Findings showed the potential of CDS systems to close the knowledge gap between pathologists for complex diagnostic tasks. (Arch Pathol Lab Med. 2020;144:869-877; doi: 10.5858/arpa.2019-0390-OA), Advances in whole slide imaging (1) and the recent US Food and Drug Administration clearances of the first 2 whole slide imaging systems for primary diagnosis have accelerated efforts to [...]

The expression of the HER-2/neu (HER2) gene, a member of the epidermal growth factor receptor family, has been shown to be a valuable prognostic indicator for breast cancer. However, interobserver variability has been reported in the evaluation of HER2 with immunohistochemistry. It has been suggested that automated computer-based evaluation can provide a consistent and objective evaluation of HER2 expression. In this manuscript, we present an automated method for the quantitative assessment of HER2 using digital microscopy. The method processes microscopy images from tissue slides with a multistage algorithm, including steps of color pixel classification, nuclei segmentation, and cell membrane modeling, and extracts quantitative, continuous measures of cell membrane staining intensity and completeness. A minimum cluster distance classifier merges the features to classify the slides into HER2 categories. An evaluation based on agreement analysis with pathologist-derived HER2 scores, showed good agreement with the provided truth. Agreement varied within the different classes with highest agreement (up to 90%) for positive (3+) slides, and lowest agreement (72%-78%) for equivocal (2+) slides which contained ambiguous scoring. The developed automated method has the potential to be used as a computer aid for the immunohistochemical evaluation of HER2 expression with the objective of increasing observer reproducibility. Index Terms--Biomarker, breast cancer, computer-aided immunohistochemistry, digital microscopy, HER2/neu, pathology.

A multistage algorithm for the automated classification of fluorescent in situ hybridization (FISH) images from breast carcinomas is presented. The algorithm focuses on the detection of FISH dots per image and also on the combining results from multiple images taken from a slice for overall case classification.

Variance stabilization is an important step in the statistical assessment of quantitative imaging biomarkers. The objective of this study is to compare the Log and the Box-Cox transformations for variance stabilization in the context of assessing the performance of a particular quantitative imaging biomarker, the estimation of lung nodule volume from computed tomography images. First, a model is developed to generate and characterize repeated measurements typically observed in computed tomography lung nodule volume estimation. Given this model, we derive the parameter of the Box-Cox transformation that stabilizes the variance of the measurements across lung nodule volumes. Second, simulated, phantom, and clinical datasets are used to compare the Log and the Box-Cox transformations. Two metrics are used for quantifying the stability of the measurements across the transformed lung nodule volumes: the coefficient of variation for the standard deviation and the repeatability coefficient. The results for simulated, phantom, and clinical datasets show that the Box-Cox transformation generally had better variance stabilization performance compared to the Log transformation for lung nodule volume estimates from computed tomography scans. [ABSTRACT FROM AUTHOR]

* Context.--The use of computer aids has been suggested as a way to reduce interobserver variability that is known to exist in the interpretation of immunohistochemical staining in pathology. Such computer aids should be automated in their usage but also they should be trained in an automated and reproducible fashion. Objective.--To present a computer aid for the quantitative analysis of tissue-based biomarkers, based on color content analysis. Design.--The developed system incorporates an automated algorithm to allow retraining based on the color properties of different training sets. The algorithm first generates a color palette containing the colors present in a training subset. Based on the palette, color histograms are derived and are used as feature vectors to a pattern recognition system, which returns an output proportional to biomarker continuous expression or a categorical classification. The method was evaluated on a database of HER2/neu digital breast cancer slides, for which expression scores from a pathologist panel were available. The system was retrained and evaluated on different transformations of the database, including compression, blurring, and changes in illumination, to examine its robustness to different imaging conditions frequently met in digital pathology. Results.--Results showed high agreement between the results of the algorithm and the truth from the pathologist panel as well as robustness to image transformations. Conclusions.--The results of the study are encouraging for the potential of this method as a computer aid to assess biomarker expression in a consistent and reproducible manner. (Arch Pathol Lab Med. 2012; 136:539-550; doi:10.5858/arpa.2011-0195-OA), Tissue-based molecular biomarkers have been increasingly used in clinical practice to aid in disease diagnosis, in assessing patient prognosis, and in treatment planning by predicting individual patient response to therapy. [...]

* Context.--Observer variability in digital microscopy and the effect of computer-aided digital microscopy are underexamined areas in need of further research, considering the increasing use and future role of digital imaging in pathology. A reduction in observer variability using computer aids could enhance the statistical power of studies designed to determine the utility of new biomarkers and accelerate their incorporation in clinical practice. Objectives.--To quantify interobserver and intraobserver variability in immunohistochemical analysis of HER2/ neu with digital microscopy and computer-aided digital microscopy, and to test the hypothesis that observer agreement in the quantitative assessment of HER2/neu immunohistochemical expression is increased with the use of computer-aided microscopy. Design.--A set of 335 digital microscopy images extracted from 64 breast cancer tissue slides stained with a HER2 antibody, were read by 14 observers in 2 reading modes: the unaided mode and the computer-aided mode. In the unaided mode, HER2 images were displayed on a calibrated color monitor with no other information, whereas in the computer-aided mode, observers were shown a HER2 image along with a corresponding feature plot showing computer-extracted values of membrane staining intensity and membrane completeness for the particular image under examination and, at the same time, mean feature values of the different HER2 categories. In both modes, observers were asked to provide a continuous score of HER2 expression. Results.--Agreement analysis performed on the output of the study showed significant improvement in both interobserver and intraobserver agreement when the computer-aided reading mode was used to evaluate preselected image fields. Conclusion.--The role of computer-aided digital microscopy in reducing observer variability in immunohistochemistry is promising., Immunohistochemistry (IHC) has evolved during the past 40 years to become central to both diagnostic pathology and clinical research. (1) Advances in molecular biology leading to the discovery of numerous [...]

Purpose: To evaluate the performance of lesion volumetry in hepatic CT as a function of various imaging acquisition parameters. Methods: An anthropomorphic abdominal phantom with removable liver inserts was designed for this study. Two liver inserts, each containing 19 synthetic lesions with varying diameter (6-40 mm), shape, contrast (10-65 HU), and both homogenous and mixed-density were designed to have background and lesion CT values corresponding to arterial and portal-venous phase imaging, respectively. The two phantoms were scanned using two commercial CT scanners (GE 750 HD and Siemens Biograph mCT) across a set of imaging protocols (four slice thicknesses, three effective mAs, two convolution kernels, two pitches). Two repeated scans were collected for each imaging protocol. All scans were analyzed using a matched-filter estimator for volume estimation, resulting in 6080 volume measurements across all of the synthetic lesions in the two liver phantoms. A subset of portal venous phase scans was also analyzed using a semi-automatic segmentation algorithm, resulting in about 900 additional volume measurements. Lesions associated with large measurement error (quantified by root mean square error) for most imaging protocols were considered not measurable by the volume estimation tools and excluded for the statistical analyses. Imaging protocols were grouped into distinct imaging conditions based on ANOVA analysis of factors for repeatability testing. Statistical analyses, including overall linearity analysis, grouped bias analysis with standard deviation evaluation, and repeatability analysis, were performed to assess the accuracy and precision of the liver lesion volume biomarker. Results: Lesions with lower contrast and size ≤10 mm were associated with higher measurement error and were excluded from further analysis. Lesion size, contrast, imaging slice thickness, dose, and scanner were found to be factors substantially influencing volume estimation. Twenty-four distinct repeatable imaging conditions were determined as protocols for each scanner with a fixed slice thickness and dose. For the matched-filter estimation approach, strong linearity was observed for all imaging data for lesions ≥20 mm. For the Siemens scanner with 50 mAs effective dose at 0.6 mm slice thickness, grouped bias was about -10%. For all other repeatable imaging conditions with both scanners, grouped biases were low (-3%-3%). There was a trend of increasing standard deviation with decreasing dose. For each fixed dose, the standard deviations were similar among the three larger slice thicknesses (1.25, 2.5, 5 mm for GE, 1.5, 3, 5 mm for Siemens). Repeatability coefficients ranged from about 8% to 75% and showed similar trend to grouped standard deviation. For the segmentation approach, the results led to similar conclusions for both lesion characteristic factors and imaging factors but with increasing magnitude in all the error metrics assessed. Conclusions: Results showed that liver lesion volumetry was strongly dependent on lesion size, contrast, acquisition dose, and their interactions. The overall performances were similar for images reconstructed with larger slice thicknesses, clinically used pitches, kernels, and doses. Conditions that yielded repeatable measurements were identified and they agreed with the Quantitative Imaging Biomarker Alliance's (QIBA) profile requirements in general. The authors' findings also suggest potential refinements to these guidelines for the tumor volume biomarker, especially for soft-tissue lesions. [ABSTRACT FROM AUTHOR]

Purpose: Traditional ways to estimate 2D CT noise power spectrum (NPS) involve an ensemble average of the power spectrums of many noisy scans. When only a few scans are available, regions of interest are often extracted from different locations to obtain sufficient samples to estimate the NPS. Using image samples from different locations ignores the nonstationarity of CT noise and thus cannot accurately characterize its local properties. The purpose of this work is to develop a method to estimate local NPS using only a few fan-beam CT scans. Methods: As a result of FBP reconstruction, the CT NPS has the same radial profile shape for all projection angles, with the magnitude varying with the noise level in the raw data measurement. This allows a 2D CT NPS to be factored into products of a 1D angular and a 1D radial function in polar coordinates. The polar separability of CT NPS greatly reduces the data requirement for estimating the NPS. The authors use this property and derive a radial NPS estimation method: in brief, the radial profile shape is estimated from a traditional NPS based on image samples extracted at multiple locations. The amplitudes are estimated by fitting the traditional local NPS to the estimated radial profile shape. The estimated radial profile shape and amplitudes are then combined to form a final estimate of the local NPS. We evaluate the accuracy of the radial NPS method and compared it to traditional NPS methods in terms of normalized mean squared error (NMSE) and signal detectability index. Results: For both simulated and real CT data sets, the local NPS estimated with no more than six scans using the radial NPS method was very close to the reference NPS, according to the metrics of NMSE and detectability index. Even with only two scans, the radial NPS method was able to achieve a fairly good accuracy. Compared to those estimated using traditional NPS methods, the accuracy improvement was substantial when a few scans were available. Conclusions: The radial NPS method was shown to be accurate and efficient in estimating the local NPS of FBP-reconstructed 2D CT images. It presents strong advantages over traditional NPS methods when the number of scans is limited and can be extended to estimate the in-plane NPS of cone-beam CT and multislice helical CT scans. [ABSTRACT FROM AUTHOR]

Purpose: To determine inter-related factors that contribute substantially to measurement error of pulmonary nodule measurements with CT by assessing a large-scale dataset of phantom scans and to quantitatively validate the repeatability and reproducibility of a subset containing nodules and CT acquisitions consistent with the Quantitative Imaging Biomarker Alliance (QIBA) metrology recommendations. Methods: The dataset has about 40 000 volume measurements of 48 nodules (5-20 mm, four shapes, three radiodensities) estimated by a matched-filter estimator from CT images involving 72 imaging protocols. Technical assessment was performed under a framework suggested by QIBA, which aimed to minimize the inconsistency of terminologies and techniques used in the literature. Accuracy and precision of lung nodule volume measurements were examined by analyzing the linearity, bias, variance, root mean square error (RMSE), repeatability, reproducibility, and significant and substantial factors that contribute to the measurement error. Statistical methodologies including linear regression, analysis of variance, and restricted maximum likelihood were applied to estimate the aforementioned metrics. The analysis was performed on both the whole dataset and a subset meeting the criteria proposed in the QIBA Profile document. Results: Strong linearity was observed for all data. Size, slice thickness×collimation, and randomness in attachment to vessels or chest wall were the main sources of measurement error. Grouping the data by nodule size and slice thickness×collimation, the standard deviation (3.9%-28%), and RMSE (4.4%-68%) tended to increase with smaller nodule size and larger slice thickness. For 5, 8, 10, and 20 mm nodules with reconstruction slice thickness ≤0.8, 3, 3, and 5 mm, respectively, the measurements were almost unbiased (-3.0% to 3.0%). Repeatability coefficients (RCs) were from 6.2% to 40%. Pitch of 0.9, detail kernel, and smaller slice thicknesses yielded better (smaller) RCs than those from pitch of 1.2, medium kernel, and larger slice thicknesses. Exposure showed no impact on RC. The overall reproducibility coefficient (RDC) was 45%, and reduced to about 20%-30% when the slice thickness and collimation were fixed. For nodules and CT imaging complying with the QIBA Profile (QIBA Profile subset), the measurements were highly repeatable and reproducible in spite of variations in nodule characteristics and imaging protocols. The overall measurement error was small and mostly due to the randomness in attachment. The bias, standard deviation, and RMSE grouped by nodule size and slice thickness×collimation in the QIBA Profile subset were within ±3%, 4%, and 5%, respectively. RCs are within 11% and the overall RDC is equal to 11%. Conclusions: The authors have performed a comprehensive technical assessment of lung nodule volumetry with a matched-filter estimator from CT scans of synthetic nodules and identified the main sources of measurement error among various nodule characteristics and imaging parameters. The results confirm that the QIBA Profile set is highly repeatable and reproducible. These phantom study results can serve as a bound on the clinical performance achievable with volumetric CT measurements of pulmonary nodules. [ABSTRACT FROM AUTHOR]

Background. We conducted a validation study of digital pathology for the quantitative assessment of tissue-based biomarkers with immunohistochemistry. Objective. To examine observer agreement as a function of viewing modality (digital versus optical microscopy), whole slide versus tissue microarray (TMA) review, biomarker type (HER2 incorporating membranous staining and Ki-67 with nuclear staining), and data type (continuous and categorical). Methods. Eight pathologists reviewed 50 breast cancer whole slides (25 stained with HER2 and 25 with Ki-67) and 2 TMAs (1 stained with HER2, 1 with Ki-67, each containing 97 cores), using digital and optical microscopy. Results. Results showed relatively high overall interobserver and intermodality agreement, with different patterns specific to biomarker type. For HER2, there was better interobserver agreement for optical compared to digital microscopy for whole slides as well as better interobserver and intermodality agreement for TMAs. For Ki-67, those patterns were not observed. Conclusions. The differences in agreement patterns when examining different biomarkers and different scoring methods and reviewing whole slides compared to TMA stress the need for validation studies focused on specific pathology tasks to eliminate sources of variability that might dilute findings. The statistical uncertainty observed in our analyses calls for adequate sampling for each individual task rather than pooling cases. [ABSTRACT FROM AUTHOR]

Originally, the aim of the present study was to investigate the psychometric properties and the appropriateness of the Greek version of the PSQI for a non-clinical sample. However, the scale was deemed not to be appropriate and results suggested some major modifications (study 1). The modified scale was administered to a second sample of Cypriots and was shown to be unidimensional and to have a high degree of reliability (study 2). The items define a theoretical linear quality of sleep continuum of increasing difficulty and cover a wide range of that continuum. Furthermore, a 3-point (instead of the original 4-point) Likert scale was shown to be optimal and the scale was found to be appropriate for a non-clinical sample. The resulting scale is suitable for research purposes in studies regarding quality of sleep in academia, medicine and marketing. It could be used either for individuals or for large scale samples. [ABSTRACT FROM AUTHOR]

This work is a part of our more general effort to probe the interrelated factors impacting the accuracy and precision of lung nodule measurement tasks. For such a task a low-bias size estimator is needed so that the true effect of factors such as acquisition and reconstruction parameters, nodule characteristics and others can be assessed. Towards this goal, we have developed a matched filter based on an adaptive model of the object acquisition and reconstruction process. Our model derives simulated reconstructed data of nodule objects (templates) which are then matched to computed tomography data produced from imaging the actual nodule in a phantom study using corresponding imaging parameters. This approach incorporates the properties of the imaging system and their effect on the discrete 3-D representation of the object of interest. Using a sum of absolute differences cost function, the derived matched filter demonstrated low bias and variance in the volume estimation of spherical synthetic nodules ranging in density from -630 to +100~HU and in size from 5 to 10 mm. This work could potentially lead to better understanding of sources of error in the task of lung nodule size measurements and may lead to new techniques to account for those errors. [ABSTRACT FROM PUBLISHER]