Comparison of 5 Thyroid Ultrasound Stratification Systems for Differentiation of Benign and Malignant Nodules and to Avoid Biopsy Using Histology as Reference Standard

ObjectiveWe aimed to compare the thyroid ultrasound risk stratification systems (RSSs) of the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS), European TI-RADS, Korean TI-RADS, and American Thyroid Association (ATA), American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi guidelines to differentiate benign from malignant thyroid nodules and to avoid unnecessary fine needle aspiration (FNA).MethodsThe records of 1143 nodules ≥1 cm that underwent FNA biopsy and thyroidectomy between 2012 and 2020 at our institution were reviewed. Ultrasound categories and FNA recommendation indications of 5 international RSSs were compared with histopathological findings as benign or malignant. The ultrasound categories and recommended FNA indications, the proportion of the avoidable FNA procedures, and false negative rates (FNRs) by different systems were compared with each other.ResultsOf the 1143 nodules, 45% had thyroid malignancy. FNA recommendation and ultrasound risk classification of ATA guidelines had the highest area under curves of 0.619, and 0.715, respectively. ACR TI-RADS, American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi guidelines, European TI-RADS, ATA guidelines, and Korean TI-RADS would have avoided FNA for 34.7%, 31%, 25.7%, 20%, and 6% of nodules with an FNR of 24%, 28.5%, 22%, 7.2%, and 1.9%, respectively.ConclusionOur findings showed that all RSSs classified the nodules appropriately for malignancy. ATA guidelines had the highest area under curves and a low FNR, whereas ACR TI-RADS would have spared more patients from FNA with a high FNR.     

Field‐readable alphanumeric flags are valuable markers for shorebirds: use of double‐marking to identify cases of misidentification

Implicit assumptions for most mark‐recapture studies are that individuals do not lose their markers and all observed markers are correctly recorded. If these assumptions are violated, e.g., due to loss or extreme wear of markers, estimates of population size and vital rates will be biased. Double‐marking experiments have been widely used to estimate rates of marker loss and adjust for associated bias, and we extended this approach to estimate rates of recording errors. We double‐marked 309 Piping Plovers (Charadrius melodus) with unique combinations of color bands and alphanumeric flags and used multi‐state mark recapture models to estimate the frequency with which plovers were misidentified. Observers were twice as likely to read and report an invalid color‐band combination (2.4% of the time) as an invalid alphanumeric code (1.0%). Observers failed to read matching band combinations or alphanumeric flag codes 4.5% of the time. Unlike previous band resighting studies, use of two resightable markers allowed us to identify when resighting errors resulted in reports of combinations or codes that were valid, but still incorrect; our results suggest this may be a largely unappreciated problem in mark‐resight studies. Field‐readable alphanumeric flags offer a promising auxiliary marker for identifying and potentially adjusting for false‐positive resighting errors that may otherwise bias demographic estimates.     

Learning-based biomarker-assisted rules for optimized clinical benefit under a risk constraint

Novel biomarkers, in combination with currently available clinical information, have been sought to improve clinical decision making in many branches of medicine, including screening, surveillance, and prognosis. Statistical methods are needed to integrate such diverse information to develop targeted interventions that balance benefit and harm. In the specific setting of disease detection, we propose novel approaches to construct a multiple-marker-based decision rule by directly optimizing a benefit function, while controlling harm at a maximally tolerable level. These new approaches include plug-in and direct-optimization-based algorithms, and they allow for the construction of both nonparametric and parametric rules. A study of asymptotic properties of the proposed estimators is provided. Simulation results demonstrate good clinical utilities for the resulting decision rules under various scenarios. The methods are applied to a biomarker study in prostate cancer surveillance.     

Identification of glycated and acetylated lysine residues in human α2-antiplasmin

BackgroundThe post-translational protein modification via lysine residues can significantly alter its function. α2-antiplasmin, a key inhibitor of fibrinolysis, contains 19 lysine residues.AimWe sought to identify sites of glycation and acetylation in human α2-antiplasmin and test whether the competition might occur on the lysine residues of α2-antiplasmin.MethodsWe analyzed human α2-antiplasmin (1) untreated; (2) incubated with increasing concentrations of β-d-glucose (0, 5, 10, 50 mM); (3) incubated with 1.6 mM acetylsalicylic acid (ASA) and (4) incubated with 1.6 mM ASA and 50 mM β-d-glucose, using the ultraperformance liquid chromatography system coupled to mass spectrometer.ResultsEleven glycation sites and 10 acetylation sites were found in α2-antiplasmin. Incubation with β-d-glucose was associated with glycation of 4 (K-418, K-427, K-434, K-441) out of 6 lysine residues, known to be important for mediating the interaction with plasmin. Glycation and acetylation overlapped at 9 sites in samples incubated with β-d-glucose or ASA. Incubation with concomitant ASA and β-d-glucose was associated with the decreased acetylation at all sites overlapping with glycation sites. At K-182 and K-448, decreased acetylation was associated with increased glycation when compared with α2-antiplasmin incubated with 50 mM β-d-glucose alone. Although K-24 located in the proximity of the α2-antiplasmin cleavage site, was found to be only acetylated, incubation with ASA and 50 mM β-d-glucose was associated the absence of acetylation at that site.ConclusionHuman α2-antiplasmin is glycated and acetylated at several sites, with the possible competition between acetylation and glycation at K-182 and K-448. Our finding suggests possibly relevant alterations to α2-antiplasmin function at high glycemia and during aspirin use.     

Revisiting the false positive rate in detecting recent positive selection

There is increasing interest in studying the molecular mechanisms of recent adaptations caused by positive selection in the genomics era. Such endeavors to detect recent positive selection, however, have been severely handicapped by false positives due to the confounding impact of demography and the population structure. To reduce false positives, it is critical to conduct a functional analysis to identify the true candidate genes/mutations from those that are filtered through neutrality tests. However, the extremely high cost of such functional analysis may restrict studies within a small number of model species. In particular, when the false positive rate of neutrality tests is high, the efficiency of the functional analysis will also be very low. Therefore, although the recent improvements have been made in the (joint) inference of demography and selection, our ultimate goal, which is to understand the mechanism of adaptation generally in a wide variety of natural populations, may not be achieved using the currently available approaches. More attention should thus be spent on the development of more reliable tests that could not only free themselves from the confounding impact of demography and the population structure but also have reasonable power to detect selection.