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As imaging technologies and treatment options continue to advance, imaging outcome measures are becoming increasingly utilized as the basis of making major decisions in new drug development and clinical practice. Quantitative imaging biomarkers (QIBs) are now commonly used for subject selection, response assessment, and safety monitoring. Although quantitative measurements can have many advantages compared with subjective, qualitative endpoints, it is important to recognize that QIBs are measured with error. This study uses Monte Carlo simulation to examine the impact of measurement error on a variety of clinical trial designs as well as to test proposed adjustments for measurement error. The focus is on some of the QIBs currently being studied by the Quantitative Imaging Biomarkers Alliance. The results show that the ability of QIBs to discriminate between health states and predict patient outcome is attenuated by measurement error; however, the known technical performance characteristics of QIBs can be used to adjust study sample size, control the misinterpretation rate of imaging findings, and establish statistically valid decision thresholds. We conclude that estimates of the precision and bias of a QIB are important for properly designing clinical trials and establishing the level of imaging standardization required. [ABSTRACT FROM AUTHOR]

Introduction Quantitative imaging biomarkers (QIBs) are being increasingly used in medical practice and clinical trials. An essential first step in the adoption of a quantitative imaging biomarker is the characterization of its technical performance, i.e. precision and bias, through one or more performance studies. Then, given the technical performance, a confidence interval for a new patient's true biomarker value can be constructed. Estimating bias and precision can be problematic because rarely are both estimated in the same study, precision studies are usually quite small, and bias cannot be measured when there is no reference standard. Methods A Monte Carlo simulation study was conducted to assess factors affecting nominal coverage of confidence intervals for a new patient's quantitative imaging biomarker measurement and for change in the quantitative imaging biomarker over time. Factors considered include sample size for estimating bias and precision, effect of fixed and non-proportional bias, clustered data, and absence of a reference standard. Results Technical performance studies of a quantitative imaging biomarker should include at least 35 test-retest subjects to estimate precision and 65 cases to estimate bias. Confidence intervals for a new patient's quantitative imaging biomarker measurement constructed under the no-bias assumption provide nominal coverage as long as the fixed bias is <12%. For confidence intervals of the true change over time, linearity must hold and the slope of the regression of the measurements vs. true values should be between 0.95 and 1.05. The regression slope can be assessed adequately as long as fixed multiples of the measurand can be generated. Even small non-proportional bias greatly reduces confidence interval coverage. Multiple lesions in the same subject can be treated as independent when estimating precision. Conclusion Technical performance studies of quantitative imaging biomarkers require moderate sample sizes in order to provide robust estimates of bias and precision for constructing confidence intervals for new patients. Assumptions of linearity and non-proportional bias should be assessed thoroughly. [ABSTRACT FROM AUTHOR]

ABSTRACT: Cell‐based therapies development for the treatment of osteoarthritis (OA) requires an understanding of the disease progression and attributes of the cells resident in cartilage. This study focused on quantitative assessment of the concentration and biological potential of stem and progenitor cells resident in different zones of cartilage displaying macroscopic Outerbridge grade 1–2 OA, and their correlation with OA progression based on established histologic scoring system. Lateral femoral condyles were collected from 15 patients with idiopathic OA and varus knees undergoing total knee arthroplasty. Superficial(Csp, top ∼ 500 µm) and deep cartilage(Cdp) was separated. Chondrogenic Connective Tissue Progenitors (CTP‐C) were assayed by standardized Colony‐Forming‐Unit assay using automated image analysis (ColonyzeTM) based on ASTM standard F‐2944‐12. Cell concentration (cells/mg) was significantly greater in Csp (median: 7,000; range: 3,440–17,600) than Cdp (median: 5,340; range: 3,393–9,660), p = 0.039. Prevalence (CTPs/million cells) was not different between Csp (median: 1,274; range: 0–3,898) and Cdp (median:1,365; range:0–6,330), p = 0.42. In vitro performance of CTP‐C progeny varied widely within and between patients, manifest by variation in colony size and morphology. Mean histopathological Mankin score was 4.7 (SD = 1.2), representing mild to moderate OA. Tidemark breach by blood vessels was associated with lower Csp cell concentration (p = 0.02). Matrix degradation was associated with lower Cdp cell and CTP‐C concentration (p = 0.015 and p = 0.095, respectively), independent of articular surface changes. These findings suggest that the initiation of OA may occur in either superficial or deep zones. The pathological changes affect CTP‐Cs in Csp and Cdp cartilage zones differently. The heterogeneity among the available CTP‐Cs in Csp and Cdp suggests performance‐based selection to optimize cell‐sourcing strategies for therapy. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1728–1738, 2018. [ABSTRACT FROM AUTHOR]

Background and purpose — A better understanding of the patterns and variation in initiation and progression of osteoarthritis (OA) in the knee may influence the design of therapies to prevent or slow disease progression. By studying cartilage from the human lateral femoral condyle (LFC), we aimed to: (1) assess specimen distribution into early, mild, moderate, and severe OA as per the established histopathological scoring systems (HHGS and OARSI); and (2) evaluate whether these 2 scoring systems provide sufficient tools for characterizing all the features and variation in patterns of OA. Patients and methods — 2 LFC osteochondral specimens (4 x 4 x 8 mm) were collected from 50 patients with idiopathic OA varus knee and radiographically preserved lateral compartment joint space undergoing total knee arthroplasty. These were fixed, sectioned, and stained with HE and Safranin O-Fast Green (SafO). Results — The histopathological OA severity distribution of the 100 specimens was: 6 early, 62 mild, 30 moderate, and 2 severe. Overall, 45/100 specimens were successfully scored by both HHGS and OARSI: 12 displayed low OA score and 33 displayed cartilage surface changes associated with other histopathological features. However, 55/100 samples exhibited low surface structure scores, but were deemed to be inadequately scored by HHGS and OARSI because of anomalous features in the deeper zones not accounted for by these systems: 27 exhibited both SafO and tidemark abnormal features, 16 exhibited only SafO abnormal features, and 12 exhibited tidemark abnormal features. Interpretation — LFC specimens were scored as mild to moderate OA by HHGS and OARSI. Yet, several specimens exhibited deep zone anomalies while maintaining good surface structure, inconsistent with mild OA. Overall, a better classification of these anomalous histopathological features could help better understand idiopathic OA and potentially recognize different subgroups of disease. [ABSTRACT FROM AUTHOR]

Background: Anterior cruciate ligament (ACL) reconstruction can effectively return athletes to the playing field, but they are still at risk of developing posttraumatic osteoarthritis (PTOA). No studies have used multivariable analysis to evaluate the predictors of radiographic PTOA in the lateral compartment of the knee at short-term follow-up after ACL reconstruction. Purpose: To determine the predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in a young, active cohort. Study Design: Cohort study; Level of evidence, 2. Methods: A nested cohort of 358 patients from the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort who were aged ≤33 years, were injured playing a sport, and had never undergone surgery on the contralateral knee were followed up 2 years after ACL reconstruction with questionnaires and with weightbearing knee radiographs using the metatarsophalangeal (MTP) joint technique. The joint space width in the lateral compartment was measured using a semiautomatic computerized method, and multivariable predictive modeling was used to evaluate the relationship between meniscus treatment, cartilage injury, graft type, and joint space while adjusting for age, sex, body mass index, and Marx activity score. Results: The mean lateral joint space width was 0.11 mm narrower on the ACL-reconstructed knee compared with the contralateral healthy knee (7.69 mm vs 7.80 mm, respectively; P < .01). Statistically significant predictors of a narrower joint space width on the ACL-reconstructed knee included lateral meniscectomy (P < .001) and a Marx activity score less than 16 points (P < .001). Conclusion: This study identifies lateral meniscectomy and a lower baseline Marx activity score to be predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in young, active patients without a prior knee injury. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Quantitative imaging biomarkers (QIBs) are becoming increasingly adopted into clinical practice to monitor changes in patients' conditions. The repeatability coefficient (RC) is the clinical cut-point used to discern between changes in a biomarker's measurements due to measurement error and changes that exceed measurement error, thus indicating real change in the patient. Imaging biomarkers have characteristics that make them difficult for estimating the repeatability coefficient, including nonconstant error, non-Gaussian distributions, and measurement error that must be estimated from small studies.Methods: We conducted a Monte Carlo simulation study to investigate how well three statistical methods for estimating the repeatability coefficient perform under five settings common for QIBs.Results: When the measurement error is constant and replicates are normally distributed, all of the statistical methods perform well. When the measurement error is proportional to the true value, approaches that use the log transformation or coefficient of variation perform similarly. For other common settings, none of the methods for estimating the repeatability coefficient perform adequately.Conclusion: Many of the common approaches to estimating the repeatability coefficient perform well for only limited scenarios. The optimal approach depends strongly on the pattern of the within-subject variability; thus, a precision profile is critical in evaluating the technical performance of QIBs. Asymmetric bounds for detecting regression vs progression can be implemented and should be used when clinically appropriate. [ABSTRACT FROM AUTHOR]

Purpose: To compare diagnostic performance of a 5-min knee MRI protocol to that of a standard knee MRI.Materials and Methods: One hundred 3 T (100 patients, mean 38.8 years) and 50 1.5 T (46 patients, mean 46.4 years) MRIs, consisting of 5 fast, 2D multi-planar fast-spin-echo (FSE) sequences and five standard multiplanar FSE sequences, from two academic centers (1/2015-1/2016), were retrospectively reviewed by four musculoskeletal radiologists. Agreement between fast and standard (interprotocol agreement) and between standard (intraprotocol agreement) readings for meniscal, ligamentous, chondral, and bone pathology was compared for interchangeability. Frequency of major findings, sensitivity, and specificity was also tested for each protocol.Results: Interprotocol agreement using fast MRI was similar to intraprotocol agreement with standard MRI (83.0-99.5%), with no excess disagreement (≤ 1.2; 95% CI, -4.2 to 3.8%), across all structures. Frequency of major findings (1.1-22.4% across structures) on fast and standard MRI was not significantly different (p ≥ 0.215), except more ACL tears on fast MRI (p = 0.021) and more cartilage defects on standard MRI (p < 0.001). Sensitivities (59-100%) and specificities (73-99%) of fast and standard MRI were not significantly different for meniscal and ligament tears (95% CI for difference, -0.08-0.08). For cartilage defects, fast MRI was slightly less sensitive (95% CI for difference, -0.125 to -0.01) but slightly more specific (95% CI for difference, 0.01-0.5) than standard MRI.Conclusion: A fast 5-min MRI protocol is interchangeable with and has similar accuracy to a standard knee MRI for evaluating internal derangement of the knee. [ABSTRACT FROM AUTHOR]

Background Venous sinus stenting for dural sinus stenoses is an emerging alternative to cerebrospinal fluid diversion in cases of medically refractory idiopathic intracranial hypertension. Juxta-stent 're-stenoses' have been reported and managed alternatively with ventricular shunting or stent revision. Identification of factors that might predispose patients to recurrent narrowing may help to select or exclude patients with idiopathic intracranial hypertension for venous sinus stenting. Methods We retrospectively reviewed a prospectively maintained database spanning December 2011 to May 2015 of all patients with idiopathic intracranial hypertension who were screened for possible venous sinus stenting, including only patients who received a stent, noting symptomatic improvements, changes in opening lumbar puncture pressure, demographic characteristics, and any subsequent intervention after stent placement. Fisher's exact test and logistic regression were used to test each of seven potential predictors for retreatment. Results There were eight revisions in 31 patients (25.8%). Among Caucasians, 8.0% required a revision compared with 100% of African-Americans (p<0.001). The c-index for race was 0.857. Body mass index (BMI) was also a significant predictor of revision (p=0.031): among class III obese patients the revision rate was 46.2% compared with 16.7% among class I and II obese patients and 0% among overweight to normal weight patients. Conclusions BMI was a significant predictor of revision, suggesting that higher BMI may have a higher risk of revision. The small number of African-Americans in the study makes interpretation of the practical significance of the revision rate in these patients uncertain. None of the other studied factors was statistically significant. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The purpose of this study was to characterize analytic performance of software-aided arterial vessel structure measurements across a range of scanner settings for computed tomography angiography where ground truth is known. We characterized performance for measurands that may be efficiently measured for clinical cases without use of software, as well as those that may be done manually but which is generally not done due to the effort level required unless software is employed.Materials and Methods: Four measurands (lumen area, stenosis, wall area, wall thickness) were evaluated using tissue-mimicking phantoms to estimate bias, heteroscedasticity, and limits of quantitation both pooled across scanner settings and individually for eight different settings. Reproducibility across scanner settings was also estimated.Results: Measurements of lumen area have a near constant bias of +1.3 mm for measurements ranging from 3 mm2 to 40 mm2; stenosis bias is +7% across a 30%-70% range; wall area bias is +14% across a 50-450 mm2 range; and wall thickness bias is +1.2 mm across a 3-9 mm range. All measurements possess properties that make them suitable for measuring longitudinal change. Lumen area demonstrates the most sensitivity to scanner settings (bias from as low as +.1 mm to as high as +2.7 mm); wall thickness demonstrates negligible sensitivity.Conclusions: Variability across scanner settings for lumen measurands was generally higher than bias for a given setting. The converse was true for the wall measurands, where variability due to scanner settings was very low. Both bias and variability due to scanner settings of vessel structure were within clinically useful levels. [ABSTRACT FROM AUTHOR]

Rational and Objectives: This study aims to evaluate the diagnostic utility of breast imaging using transmission ultrasound. We present readers' accuracy in determining whether a breast lesion is a cyst versus a solid using transmission ultrasound as an adjunct to mammography.Materials and Methods: This retrospective multi-reader, multi-case receiver operating characteristic study included 37 lesions seen on mammography and transmission ultrasound. Cyst cases were confirmed as cysts using their appearance on handheld ultrasound. Solid cases were confirmed as solids with pathology results. Fourteen readers performed blinded, randomized reads with mammography + quantitative transmission scan images, assigning both a confidence score (0-100) and a binary classification of cyst or solid. A 95% percentile bootstrap confidence interval (CI) was computed for the readers' mean receiver operating characteristic area, sensitivity, and specificity.Results: Using the readers' binary classification of cyst or solid lesions, the mean sensitivity and specificity were 0.933 [95% CI: 0.837, 0.995] and 0.858 [95% CI: 0.701, 0.985], respectively. When the readers' confidence scores were used to distinguish a cyst versus solid, the mean receiver operating characteristic area was 0.920 [95% CI: 0.827, 0.985].Conclusions: Transmission ultrasound can provide an accurate assessment of a cyst versus a solid lesion in the breast. Prospective clinical trials will further delineate the role of transmission ultrasound as an adjunct to mammography to increase specificity in breast evaluation. [ABSTRACT FROM AUTHOR]

Background: Accurate and consistent regional lymph node classification is an important element in the staging and multidisciplinary management of lung cancer. Regional lymph node definition sets-lymph node maps-have been created to standardize regional lymph node classification. In 2009, the International Association for the Study of Lung Cancer (IASLC) introduced a lymph node map to supersede all preexisting lymph node maps. Our aim was to study if and how lung cancer specialists apply the IASLC lymph node map when classifying thoracic lymph nodes encountered on CT scans during lung cancer staging.Methods: From April 2013 through July 2013, invitations were distributed to all members of the Fleischner Society, Society of Thoracic Radiology, General Thoracic Surgical Club, and the American Association of Bronchology and Interventional Pulmonology to participate in an anonymous online image-based and text-based 20-question survey regarding lymph node classification for lung cancer staging on CT imaging.Results: Three hundred thirty-seven people responded (approximately 25% participation). Respondents consisted of self-reported thoracic radiologists (n = 158), thoracic surgeons (n = 102), and pulmonologists who perform endobronchial ultrasonography (n = 77). Half of the respondents (50%; 95% CI, 44%-55%) reported using the IASLC lymph node map in daily practice, with no significant differences between subspecialties. A disparity was observed between the IASLC definition sets and their interpretation and application on CT scans, in particular for lymph nodes near the thoracic inlet, anterior to the trachea, anterior to the tracheal bifurcation, near the ligamentum arteriosum, between the bronchus intermedius and esophagus, in the internal mammary space, and adjacent to the heart.Conclusions: Use of older lymph node maps and inconsistencies in interpretation and application of definitions in the IASLC lymph node map may potentially lead to misclassification of stage and suboptimal management of lung cancer in some patients. [ABSTRACT FROM AUTHOR]