Assessing Bias and Limitations of Clinical Validation Studies of Molecular Diagnostic Tests for Indeterminate Thyroid Nodules: Systematic Review and Meta-Analysis.

Background: Molecular tests for thyroid nodules with indeterminate fine needle aspiration results are increasingly used in clinical practice; however, true diagnostic summaries of these tests are unknown. A systematic review and meta-analysis were completed to (1) evaluate the accuracy of commercially available molecular tests for malignancy in indeterminate thyroid nodules and (2) quantify biases and limitations in studies that validate those tests. Summary: PubMed, EMBASE, and Web of Science were systematically searched through July 2021. English language articles that reported original clinical validation attempts of molecular tests for indeterminate thyroid nodules were included if they reported counts of true-negative, true-positive, false-negative, and false-positive results. We performed screening and full-text review, followed by assessment of eight common biases and limitations, extraction of diagnostic and histopathological information, and meta-analysis of clinical validity using a bivariate linear mixed-effects model. Forty-nine studies were included. Meta-analysis of Afirma Gene expression classifiers (GEC; n = 38 studies) revealed a sensitivity of 0.92 (confidence interval: 0.90-0.94), specificity of 0.26 (0.20-0.32), negative likelihood ratio (LR-) of 0.32 (0.23-0.44), positive LR+ of 1.24 (1.15-1.35), and area under the curve (AUC) of 0.83 (0.74-0.89). Afirma Genomic Sequencing Classifier (GSC; n = 10) had a sensitivity of 0.94 (0.89-0.96), specificity of 0.38 (0.27-0.50), LR- of 0.18 (0.10-0.30), LR+ of 1.52 (1.28-1.87), and AUC of 0.91 (0.62-0.92). ThyroSeq v1 and v2 (n = 10) had a sensitivity of 0.86 (0.82-0.90), specificity of 0.74 (0.59-0.85), LR- of 0.19 (0.13-0.26), LR+ of 3.52 (2.08-5.92), and AUC of 0.86 (0.81-0.90). ThyroSeq v3 (n = 6) had a sensitivity of 0.92 (0.86-0.95), specificity of 0.41 (0.18-0.69), LR- of 0.24 (0.09-0.62), LR+ of 1.67 (1.09-2.98), and AUC of 0.90 (0.63-0.92). Fourteen percent of studies conducted a blinded histopathologic review of excised thyroid nodules, and 8% made the decision to go to surgery blind to molecular test results. Conclusions: Meta-analyses reveal a high diagnostic accuracy of molecular tests for thyroid nodule assessment of malignancy risk; however, these studies are subject to several limitations. Limitations and their potential clinical impacts must be addressed and, when feasible, adjusted for using valid statistical methodologies.

Association of Limited In-Person Attendance in US National Football League and National Collegiate Athletic Association Games With County-Level COVID-19 Cases.

Importance: In 2020 and early 2021, the National Football League (NFL) and National Collegiate Athletic Association (NCAA) opted to host football games in stadiums across the country. The in-person attendance of games varied with time and from county to county. There is currently no evidence on whether limited in-person attendance of games is associated with COVID-19 case numbers on a county-level. Objective: To assess whether NFL and NCAA football games with limited in-person attendance were associated with increased COVID-19 cases in the counties they were held compared with a matched set of counties. Design, Setting, and Participants: In this time-series cross-sectional study, every county hosting NFL or NCAA games with in-person attendance (treated group) in 2020 and 2021 was matched with a county that that did not host a game on the corresponding day but had an identical game history for up to 14 days prior (control group). A standard matching method was used to further refine this matched set so that the treated and matched control counties had similar population size, nonpharmaceutical interventions in place, and COVID-19 trends. The association of hosting games with in-person attendance with COVID-19 cases was assessed using a difference-in-difference estimator. Data were analyzed from August 29 to December 28, 2020. Exposures: Hosting NFL or NCAA games. Main Outcomes and Measures: The main outcome was estimation of new COVID-19 cases per 100 000 residents at the county level reported up to 14 days after a game among counties with NFL and NCAA games with in-person attendance. Results: A total of 528 games with in-person attendance (101 NFL games [19.1%]; 427 NCAA games [80.9%]) were included. The matching algorithm returned 361 matching sets of counties. The median (interquartile range [IQR]) number of attendance for NFL games was 9949 (6000 to 13 797) people. The median number of attendance for NCAA games was not available, and attendance was recorded as a binary variable. The median (IQR) daily new COVID-19 cases in treatment group counties hosting games was 26.14 (10.77-50.25) cases per 100 000 residents on game day. The median (IQR) daily new COVID-19 cases in control group counties where no games were played was 24.11 (9.64-48.55) cases per 100 000 residents on game day. The treatment effect size ranged from -5.17 to 4.72, with a mean (SD) of 1.21 (2.67) cases per 100 000 residents, within the 14-day period in all counties hosting the games, and the daily treatment effect trend remained relatively steady during this period. Conclusions and Relevance: This cross-sectional study did not find a consistent increase in the daily COVID-19 cases per 100 000 residents in counties where NFL and NCAA games were held with limited in-person attendance. These findings suggest that NFL and NCAA football games hosted with limited in-person attendance were not associated with substantial risk for increased local COVID-19 cases.

Patient Perspectives on the Extent of Surgery and Radioactive Iodine Treatment for Low-Risk Differentiated Thyroid Cancer.

OBJECTIVE: To understand patient perspective regarding recommended changes in the 2015 American Thyroid Association (ATA) guidelines. Specifically, in regard to active surveillance (AS) of some small differentiated thyroid cancer (DTC), performance of less extensive surgery for low-risk DTC, and more selective administration of radioactive iodine (RAI). METHODS: An online survey was disseminated to thyroid cancer patient advocacy organizations and members of the ATA to distribute to the patients. Data were collected on demographic and treatment information, and patient experience with DTC. Patients were asked "what if" scenarios on core topics, including AS, extent of surgery, and indications for RAI. RESULTS: Survey responses were analyzed from 1546 patients with DTC: 1478 (96%) had a total thyroidectomy, and 1167 (76%) underwent RAI. If there was no change in the overall cancer outcome, 606 (39%) of respondents would have considered lobectomy over total thyroidectomy, 536 (35%) would have opted for AS, and 638 (41%) would have chosen to forego RAI. Moreover, (774/1217) 64% of respondents wanted more time with their clinicians when making decisions about the extent of surgery. A total of 621/1167 of patients experienced significant side effects with RAI, and 351/1167 of patients felt that the risks of treatment were not well explained. 1237/1546 (80%) of patients felt that AS would not be overly burdensome, and quality of life was the main reason cited for choosing AS. CONCLUSION: Patient perspective regarding choice in the management of low-risk DTC varies widely, and a large proportion of DTC patients would change aspects of their care if oncologic outcomes were equivalent.

Trends in Thyroid Surgery and Guideline-Concordant Care in the United States, 2007-2018.

Background: The American Thyroid Association (ATA) published the 2015 Management Guidelines for patients with thyroid nodules and differentiated thyroid cancer, recommending a shift to less aggressive diagnostic, surgical, and postoperative treatment strategies. At the same time and perhaps related to the new guidelines, there has been a shift to outpatient thyroid surgery. The aim of the current study was to assess physician adherence to these recommendations by identifying and quantifying temporal trends in the rates and indications for thyroid procedures in the inpatient and outpatient settings. Methods: Using the IBM® MarketScan® Commercial database, we identified employer-insured patients in the United States who underwent outpatient and inpatient thyroid surgery from 2007 to 2018. Thyroid surgery was classified as total thyroidectomy (TT), thyroid lobectomy (TL), or a completion thyroidectomy. The surgical indication diagnosis was also determined and classified as either benign or malignant thyroid disease. We compared outpatient and inpatient trends in surgery between benign and malignant thyroid disease both before and after the release of the 2015 ATA guidelines. Results: A total of 220,088 patients who underwent thyroid surgery were included in the analysis. Approximately 80% of TLs were performed in the outpatient setting versus 70% of TTs. Longitudinal analysis showed a statistically significant changepoint for TT proportion occurring in November 2015. The proportion of TT as compared with TL decreased from 80% in September 2015 to 39% by December 2018. For thyroid cancer, there is an increasing trend in performing TL over TT, increasing from 17% in 2015 to 28% by the end of 2018. Conclusions: There was a significant changepoint occurring in November 2015 in the operative and management trends for benign and malignant thyroid disease.

Practice patterns for surgical management of low-risk papillary thyroid cancer from 2014 to 2019: A CESQIP analysis.

BACKGROUND: Patients with low-risk-PTC who undergo thyroid lobectomy (TL) have comparable disease-specific survival with lower morbidity than total thyroidectomy (TT). We aim to describe the surgical management of low-risk-PTC using the Collaborative Endocrine Surgery Quality Improvement Program (CESQIP). METHOD: CESQIP thyroidectomies of PTC tumors <4 cm were analyzed from 2014 to 2019 (n = 740). Postoperative outcomes were compared. Subgroup analysis examined temporal and institutional trends, and stratified for tumor size. Statistics utilized t-test, ANOVA, and Chi-squared. RESULTS: TT patients had greater hypoparathyroidism, operative time, and length-of-stay (all p < 0.001). Incidence of TL decreased with increasing tumor size (24.2% for <1 cm, 15.8% for 1-2 cm, 6.1% for 2-4 cm). TL rates increased from 2.0% in 2014 to 21.2% in 2018-19. Completion thyroidectomy was recommended in 12.0% of TL subjects. There was significant variation in TL rate by institution (p < .001). CONCLUSIONS: For low-risk-PTC, TT remained the most commonly utilized operation. TL rates increased following release of the new ATA guidelines. TT was associated with higher perioperative morbidity. Further insight is needed to understand factors influencing operative approach.

Reduction of COVID-19 Incidence and Nonpharmacologic Interventions: Analysis Using a US County-Level Policy Data Set.

BACKGROUND: Worldwide, nonpharmacologic interventions (NPIs) have been the main tool used to mitigate the COVID-19 pandemic. This includes social distancing measures (closing businesses, closing schools, and quarantining symptomatic persons) and contact tracing (tracking and following exposed individuals). While preliminary research across the globe has shown these policies to be effective, there is currently a lack of information on the effectiveness of NPIs in the United States. OBJECTIVE: The purpose of this study was to create a granular NPI data set at the county level and then analyze the relationship between NPI policies and changes in reported COVID-19 cases. METHODS: Using a standardized crowdsourcing methodology, we collected time-series data on 7 key NPIs for 1320 US counties. RESULTS: This open-source data set is the largest and most comprehensive collection of county NPI policy data and meets the need for higher-resolution COVID-19 policy data. Our analysis revealed a wide variation in county-level policies both within and among states (P<.001). We identified a correlation between workplace closures and lower growth rates of COVID-19 cases (P=.004). We found weak correlations between shelter-in-place enforcement and measures of Democratic local voter proportion (R=0.21) and elected leadership (R=0.22). CONCLUSIONS: This study is the first large-scale NPI analysis at the county level demonstrating a correlation between NPIs and decreased rates of COVID-19. Future work using this data set will explore the relationship between county-level policies and COVID-19 transmission to optimize real-time policy formulation.

Quality of Care and Outcomes Among Hospitalized Inflammatory Bowel Disease Patients: A Multicenter Retrospective Study.

BACKGROUND: Half of patients with inflammatory bowel disease (IBD) require hospitalization. We sought to characterize inpatient quality indicators of care and outcomes during IBD-related hospitalizations at 4 major IBD referral centers in Canada. METHODS: We conducted a multicenter retrospective cohort study of patients with IBD admitted from 2011 to 2013 to tertiary centers in Toronto, Montreal, Ottawa, and Vancouver. We assessed the following inpatient indicators of care: pharmacological venous thromboembolism (VTE) prophylaxis, Clostridium difficile testing, and medical rescue therapy for steroid-refractory ulcerative colitis (UC). We also evaluated rates of VTE, C. difficile infection, and IBD-related surgery. RESULTS: There were 837 patients hospitalized for IBD (Crohn's disease, 59%; UC, 41%). The proportion of patients with IBD who received VTE prophylaxis and C. difficile testing were 77% and 82%, respectively, although these indicators varied significantly by center and admitting specialty. Patients admitted under surgeons were more likely than those admitted under gastroenterologists to receive VTE prophylaxis (84% versus 74%, P = 0.016) but less likely to be tested for C. difficile (41% versus 88%, P < 0.0001). The rate of VTE was the same for those who did and did not receive VTE prophylaxis (2.2 per 1000 hospital-days). Among the 14 VTE events, 79% had received prophylaxis, but only 36% within 24 hours of admission. Among steroid-refractory UC patients, 70% received rescue therapy within 7 days of steroid initiation. The proportion of patients with UC and CD who required respective bowel surgery was 18% and 20%, respectively. CONCLUSIONS: There are opportunities to optimize quality of care among hospitalized patients with IBD.