Rank correlation inferences for clustered data with small sample size.

This paper develops methods to test for associations between two variables with clustered data using a U-Statistic approach with a second-order approximation to the variance of the parameter estimate for the test statistic. The tests that are presented are for clustered versions of: Pearsons χ 2 test, the Spearman rank correlation and Kendall's τ for continuous data or ordinal data and for alternative measures of Kendall's τ that allow for ties in the data. Shih and Fay use the U-Statistic approach but only consider a first-order approximation. The first-order approximation has inflated significance level in scenarios with small sample sizes. We derive the test statistics using the second-order approximations aiming to improve the type I error rates. The method applies to data where clusters have the same number of measurements for each variable or where one of the variables may be measured once per cluster while the other variable may be measured multiple times. We evaluate the performance of the test statistics through simulation with small sample sizes. The methods are all available in the R package cluscor.

Using Prostate Imaging-Reporting and Data System (PI-RADS) Scores to Select an Optimal Prostate Biopsy Method: A Secondary Analysis of the Trio Study.

BACKGROUND: While magnetic resonance imaging (MRI)-targeted biopsy (TBx) results in better prostate cancer (PCa) detection relative to systematic biopsy (SBx), the combination of both methods increases clinically significant PCa detection relative to either Bx method alone. However, combined Bx subjects patients to higher number of Bx cores and greater detection of clinically insignificant PCa. OBJECTIVE: To determine if prebiopsy prostate MRI can identify men who could forgo combined Bx without a substantial risk of missing clinically significant PCa (csPC). DESIGN, SETTING, AND PARTICIPANTS: Men with MRI-visible prostate lesions underwent combined TBx plus SBx. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were detection rates for grade group (GG) ≥2 and GG ≥3 PCa by TBx and SBx, stratified by Prostate Imaging-Reporting and Data System (PI-RADS) score. RESULTS AND LIMITATIONS: Among PI-RADS 5 cases, nearly all csPCs were detected by TBx, as adding SBx resulted in detection of only 2.5% more GG ≥2 cancers. Among PI-RADS 3-4 cases, however, SBx addition resulted in detection of substantially more csPCs than TBx alone (8% vs 7.5%). Conversely, TBx added little to detection of csPC among men with PI-RADS 2 lesions (2%) relative to SBx (7.8%). CONCLUSIONS: While combined Bx increases the detection of csPC among men with MRI-visible prostate lesions, this benefit was largely restricted to PI-RADS 3-4 lesions. Using a strategy of TBx only for PI-RADS 5 and combined Bx only for PI-RADS 3-4 would avoid excess biopsies for men with PI-RADS 5 lesions while resulting in a low risk of missing csPC (1%). PATIENT SUMMARY: Our study investigated an optimized strategy to diagnose aggressive prostate cancer in men with an abnormal prostate MRI (magnetic resonance imaging) scan while minimizing the risk of excess biopsies. We used a scoring system for MRI scan images called PI-RADS. The results show that MRI-targeted biopsies alone could be used for men with a PI-RADS score of 5, while men with a PI-RADS score of 3 or 4 would benefit from a combination of MRI-targeted biopsy and systematic biopsy. This trial is registered at ClinicalTrials.gov as NCT00102544.

Changes in Magnetic Resonance Imaging Using the Prostate Cancer Radiologic Estimation of Change in Sequential Evaluation Criteria to Detect Prostate Cancer Progression for Men on Active Surveillance.

BACKGROUND: The ability of serial magnetic resonance imaging (MRI) to capture pathologic progression during active surveillance (AS) remains in question. OBJECTIVE: To determine whether changes in MRI are associated with pathologic progression for patients on AS. DESIGN, SETTING, AND PARTICIPANTS: From July 2007 through January 2020, we identified all patients evaluated for AS at our institution. Following confirmatory biopsy, a total of 391 patients who underwent surveillance MRI and biopsy at least once were identified (median follow-up of 35.6 mo, interquartile range 19.7-60.6). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All MRI intervals were scored using the "Prostate Cancer Radiologic Estimation of Change in Sequential Evaluation" (PRECISE) criteria, with PRECISE scores =4 considered a positive change in MRI. A generalized estimating equation-based logistic regression analysis was conducted for all intervals with a PRECISE score of <4 to determine the predictors of Gleason grade group (GG) progression despite stable MRI. RESULTS AND LIMITATIONS: A total of 621 MRI intervals were scored by PRECISE and validated by biopsy. The negative predictive value of stable MRI (PRECISE score <4) was greatest for detecting GG1 to?=?GG3 disease (0.94 [0.91-0.97]). If 2-yr surveillance biopsy were performed exclusively for a positive change in MRI, 3.7% (4/109) of avoided biopsies would have resulted in missed progression from GG1 to?=?GG3 disease. Prostate-specific antigen (PSA) density (odds ratio 1.95 [1.17-3.25], p?=? 0.01) was a risk factor for progression from GG1 to =GG3 disease despite stable MRI. CONCLUSIONS: In patients with GG1 disease and stable MRI (PRECISE score <4) on surveillance, grade progression to?=?GG3 disease is not common. In patients with grade progression detected on biopsy despite stable MRI, elevated PSA density appeared to be a risk factor for progression to?=?GG3 disease. PATIENT SUMMARY: For patients with low-risk prostate cancer on active surveillance, the risk of progressing to grade group 3 disease is low with a stable magnetic resonance image (MRI) after 2?yr. Having higher prostate-specific antigen density increases the risk of progression, despite having a stable MRI.

Clinical Utility of Targeted Next-Generation Sequencing Assay to Detect Copy Number Variants Associated with Myelodysplastic Syndrome in Myeloid Malignancies.

Copy number variants (CNVs) and gene mutations are important for diagnosis and treatment of myeloid malignancies. In a routine clinical setting, somatic gene mutations are detected by targeted next-generation sequencing (NGS) assay, but CNVs are commonly detected by conventional chromosome analysis and fluorescence in situ hybridization (FISH). The aim of this proof-of-principle study was to investigate the feasibility of using targeted NGS to simultaneously detect both somatic mutations and CNVs. Herein, we sequenced 406 consecutive patients with myeloid malignancies by targeted NGS and performed a head-to-head comparison with the results from a myelodysplastic syndrome (MDS) FISH and conventional chromosome analysis to detect CNVs. Among 91 patients with abnormal MDS FISH results, the targeted NGS revealed all 120 CNVs detected by MDS FISH (including -5/5q-, -7/7q-, +8, and 20q-) and 193 extra CNVs detected by conventional chromosome analysis. The targeted NGS achieved 100% concordance with the MDS FISH. The lower limit of detection of MDS CNVs by the targeted NGS was generally 5% variant allele fraction for DNA, based on the lowest percentages of abnormal cells detected by MDS FISH in this study. This proof-of-principle study demonstrated that the targeted NGS assay can simultaneously detect both MDS CNVs and somatic mutations, which can provide a more comprehensive genetic profiling for patients with myeloid malignancies using a single assay in a clinical setting.

Magnetic Resonance Imaging-Targeted and Systematic Biopsy for Detection of Grade Progression in Patients on Active Surveillance for Prostate Cancer.

PURPOSE: Active surveillance for patients with low and intermediate risk prostate cancers is becoming a more utilized option in recent years. However, the use of magnetic resonance imaging and imaging-targeted biopsy for monitoring grade progression has been poorly studied in this population. We aim to define the utility of magnetic resonance imaging-targeted biopsy and systematic biopsy in an active surveillance population. MATERIALS AND METHODS: Between July 2007 and January 2020, patients with diagnosed prostate cancer who elected active surveillance were monitored with prostate magnetic resonance imaging, imaging-targeted biopsy and standard systematic biopsy. Patients were eligible for surveillance if diagnosed with any volume Gleason grade 1 disease and select Gleason grade 2 disease. Grade progression (Gleason grade 1 to ≥2 disease and Gleason grade 2 to ≥3 disease) for each biopsy modality was measured at 2 years, 4 years and 6+ years. RESULTS: In total, 369 patients had both magnetic resonance imaging-targeted and systematic biopsy and were surveilled for at least 1 year. At 2 years, systematic biopsy, magnetic resonance imaging-targeted biopsy and combined biopsy (systematic+imaging-targeted) detected grade progression in 44 patients (15.9%), 73 patients (26.4%) and 90 patients (32.5%), respectively. Magnetic resonance imaging-targeted biopsy detected more cancer grade progression compared to systematic biopsy in both the low and intermediate risk populations (p <0.001). Of all 90 grade progressions at the 2-year time point 46 (51.1%) were found by magnetic resonance imaging-targeted biopsy alone and missed by systematic biopsy. CONCLUSIONS: Magnetic resonance imaging-targeted biopsy detected significantly more grade progressions in our active surveillance cohort compared to systematic biopsy at 2 years. Our results provide compelling evidence that prostate magnetic resonance imaging and imaging-targeted biopsy should be included in contemporary active surveillance protocols.

PI-RADS® Category as a Predictor of Progression to Unfavorable Risk Prostate Cancer in Men on Active Surveillance.

PURPOSE: We identified baseline imaging and clinical characteristics of patients that may improve risk stratification among patients being evaluated for active surveillance. MATERIALS AND METHODS: From July 2007 to January 2020 patients referred to our institution for prostate cancer were evaluated and those who remained on active surveillance were identified. Men underwent multiparametric magnetic resonance imaging upon entry into our active surveillance protocol during which baseline demographic and imaging data were documented. Patients were then followed and outcomes, specifically progression to Gleason Grade Group (GG)3 or greater disease, were recorded. RESULTS: Of the men placed on active surveillance 344 had at least 1 PI-RADS score documented. For those with an index lesion PI-RADS category of 5, 33% (17/51) had progression to GG3 or greater on active surveillance with a median time to progression of 31 months. When comparing the progression-free survival times and progression rates in each category, PI-RADS category was found to be associated with progression to GG3 or greater on active surveillance (p <0.01). On univariable analysis factors associated with progression included an index lesion PI-RADS category of 5, prostate specific antigen density and the size of the largest lesion. On multivariable analysis only PI-RADS category of 5 and prostate specific antigen density were associated with progression on active surveillance. CONCLUSIONS: PI-RADS lesion categories at baseline multiparametric magnetic resonance imaging during active surveillance enrollment can be used to predict cancer progression to GG3 or greater on active surveillance. This information, along with other clinical data, can better assist urologists in identifying and managing patients appropriate for active surveillance.

Promoting Social Learning at Recess for Children with ASD and Related Social Challenges.

The school playground provides an ideal opportunity for social inclusion; however, children with autism spectrum disorder (ASD) often struggle to engage in appropriate social interactions in this unstructured environment. Thus, they may spend recess time alone. The FRIEND Playground Program is a structured, play-based intervention aimed at improving social interactions of children with ASD and other social challenges during recess. The current research study employed a multiple baseline across participant design to systematically evaluate whether this intervention yields increased social engagement and initiations with peers during recess. Seven participants with ASD or other social challenges received 20 min of direct intervention from trained playground facilitators during school recess each day. Results suggest that the FRIEND Playground Program produced meaningful increases in social engagement and social initiations from baseline among participants with ASD and other social challenges.

Production of pharmaceutical-grade recombinant aprotinin and a monoclonal antibody product using plant-based transient expression systems.

Plants have been proposed as an attractive alternative for pharmaceutical protein production to current mammalian or microbial cell-based systems. Eukaryotic protein processing coupled with reduced production costs and low risk for mammalian pathogen contamination and other impurities have led many to predict that agricultural systems may offer the next wave for pharmaceutical product production. However, for this to become a reality, the quality of products produced at a relevant scale must equal or exceed the predetermined release criteria of identity, purity, potency and safety as required by pharmaceutical regulatory agencies. In this article, the ability of transient plant virus expression systems to produce a wide range of products at high purity and activity is reviewed. The production of different recombinant proteins is described along with comparisons with established standards, including high purity, specific activity and promising preclinical outcomes. Adaptation of transient plant virus systems to large-scale manufacturing formats required development of virus particle and Agrobacterium inoculation methods. One transient plant system case study illustrates the properties of greenhouse and field-produced recombinant aprotinin compared with an US Food and Drug Administration-approved pharmaceutical product and found them to be highly comparable in all properties evaluated. A second transient plant system case study demonstrates a fully functional monoclonal antibody conforming to release specifications. In conclusion, the production capacity of large quantities of recombinant protein offered by transient plant expression systems, coupled with robust downstream purification approaches, offers a promising solution to recombinant protein production that compares favourably to cell-based systems in scale, cost and quality.

Students with brain tumors: their post-treatment perceptions of teachers, peers, and academics and retrospective views on school during treatment.

The purpose of this pilot study was: (1) to determine how students surviving brain tumors (BTs) perceive their teachers' responses to them, their own academic performance, and their interactions with peers at school using a new measure; and (2) to describe students' retrospective perceptions of schooling while undergoing treatment. Using a sample of 22 students treated for a BT (ages 9-18) and 22 comparison (ages 8-19), no significant BT-control group differences regarding perceptions of teacher response, academic performance, and interactions with peers at school were found. Generally, students with BTs reported positive school experiences during treatment including favorable perceptions of their teachers' effectiveness, enjoyment of schoolwork, and the quality of their schooling. Additionally, they felt that completing schoolwork during treatment was important. The results of this study may provide insight into the perceived psychosocial adjustment and academic performance of students with BTs during and after treatment.

The influence of dietary vitamin E, fat, and methionine on blood cholesterol profile, homocysteine levels, and oxidizability of low density lipoprotein in the gerbil.

A 90-day feeding study with gerbils was conducted to evaluate the influence of dietary vitamin E levels (25 mg/kg diet, 75 mg/kg, 300 mg/kg, and 900 mg/kg), two levels of dietary methionione (casein or casein+L-methionine (1% w/w)) and two sources of lipid (soybean oil [20%] or soybean oil [4%]+coconut oil [16%, 1:4 w/w]) upon serum lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol). In addition, this study examined the effects of diet-induced hyperhomocysteinemia and supplemental dietary vitamin E on the oxidation of low density lipoproteins. Tissue vitamin E (heart, liver, and plasma) demonstrated a dose response (P< or =0.001) following the supplementation with increasing dietary vitamin E (25, 75, 300, and 900 mg/kg). In addition, tissue vitamin E levels were found to be higher (P< or =0.001) in those animals receiving a combination of coconut oil+soybean oil as compared to the group receiving soybean oil solely. Blood cholesterol profiles indicated an increase (P< or =0.001) in total cholesterol and LDL cholesterol by the influence of saturated fat and supplemental methionine. Low-density lipoprotein cholesterol profile demonstrated a reduction (P< or =0.001) at the higher dietary vitamin E levels (300 and 900 mg/kg) as compared to the 25 mg/kg and 75 mg/kg dietary vitamin E. Plasma protein carbonyls were not influenced by dietary vitamin E nor by supplemental methionine intake. In vitro oxidation of LDL showed that vitamin E delayed the lag time of the oxidation phase (P< or =0.001) and reduced total diene production (P< or =0.001). On the contrary, supplemental methionine decreased (P< or =0.001) the delay time of the lag phase, whereas total diene production was increased (P< or =0.001). Plasma lipid hydroperoxides were significantly reduced (P< or =0.05) with supplemental dietary vitamin E, whereas supplemental L-methionine (1%) resulted in a significant (P< or =0.05) increase in lipid plasma hydroperoxide formation. Plasma homocysteine was elevated (P< or =0.001) with supplemental dietary L-methionine (1%) as well as the inclusion of dietary saturated fat. The present data showed that 1) a combination of dietary lipids (saturated and unsaturated fatty acids) as well as vitamin E and methionine supplementation altered blood cholesterol lipoprotein profiles; 2) in vitro oxidation parameters including LDL (lag time and diene production) and plasma hydroperoxide formations were affected by vitamin E and methionine supplementation; and 3) plasma homocysteine concentrations were influenced by supplemental methionine and the inclusion of dietary saturated fat.