Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS).

BackgroundFor men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.MethodsUrine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).ResultsSeven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.ConclusionsPCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Clinical tool for disease phenotyping in granulomatous lung disease.

Exposure to beryllium may lead to granuloma formation and fibrosis in those who develop chronic beryllium disease (CBD). Although disease presentation varies from mild to severe, little is known about CBD phenotypes. This study characterized CBD disease phenotypes using longitudinal measures of lung function.Using a case-only study of 207 CBD subjects, subject-specific trajectories over time were estimated from longitudinal pulmonary function and exercise-tolerance tests. To estimate linear combinations of the 30-year values that define underlying patterns of lung function, we conducted factor analysis. Cluster analysis was then performed on all the predicted lung function values at 30 years. These estimates were used to identify underlying features and subgroups of CBD.Two factors, or composite measures, explained nearly 70% of the co-variation among the tests; one factor represented pulmonary function in addition to oxygen consumption and workload during exercise, while the second factor represented exercise tests related to gas exchange. Factors were associated with granulomas on biopsy, exposure, steroid use and lung inflammation. Three clusters of patients (n = 53, n = 59 and, n = 95) were identified based on the collection of test values. Lower levels of each of the factor composite scores and cluster membership were associated with baseline characteristics of patients.Using factor analysis and cluster analysis, we identified disease phenotypes that were associated with baseline patient characteristics, suggesting that CBD is a heterogeneous disease with varying severity. These clinical tools may be used in future basic and clinical studies to help define the mechanisms and risk factors for disease severity

Physical activity and social interaction assessments in schoolyard settings using the System for Observing Outdoor Play Environments in Neighborhood Schools (SOOPEN)

Abstract Background The schoolyard environment provides key opportunities to promote physical activity and socioemotional development for children. Schoolyards can also serve as a community park resource outside of school hours. We aimed to: (i) implement and evaluate reliability of the System for Observing Outdoor Play Environments in Neighborhood Schools (SOOPEN), (ii) assess schoolyard use by children during recess and community members of all ages outside of school hours, and (iii) investigate relationships of schoolyard and children´s group characteristics with physical activity levels and prosocial interactions. Methods In this cross-sectional study, we observed student and community visitor behavior using SOOPEN at three urban elementary schoolyards in Tacoma, Washington, USA, prior to renovations intended to expand each facility’s use as a community park in neighborhoods with poor park access. We assessed interrater reliability using intraclass correlation coefficients and described current levels of schoolyard use (at the group level), physical activity, and prosocial behavior. Physical activity was assessed on a five-point scale and dichotomized to indicate moderate-to-vigorous physical activity (MVPA). Social interactions were coded as prosocial, antisocial, or neutral. We examined associations of selected schoolyard features and group characteristics with group MVPA and prosocial behavior during recess using modified Poisson regression to estimate prevalence ratios (PR) and 95% confidence intervals (CI). Results We observed a total of 981 activity-defined, informal groups in the schoolyards, and achieved good to excellent interrater reliability using SOOPEN. Community use of the schoolyards during evenings and weekends was limited (n = 56 groups). During 26, 25–50 min recess periods (n = 833 groups), 19% of groups were engaged in MVPA. Schoolyard areas with paved surfaces were associated with more MVPA (PR = 1.52, 95% CI: 1.04, 2.23) compared to field/grass areas; supervised groups were associated with less MVPA than groups not directly supervised by an adult (PR = 0.59, 95% CI: 0.36, 0.96). Schoolyard characteristics were not associated with prosocial behavior. Mixed-gender groups were associated with more MVPA and more prosocial behavior. Conclusions Our study using SOOPEN, a reliable new activity observation tool, highlights the multi-dimensional dynamics of physical activity and social interactions in schoolyards, which could be leveraged to promote healthy behaviors during and outside of school hours

Association between lung function and clusters.

<p>Association between lung function and clusters.</p

Comparison of factors between clusters.

<p>Cluster 1 had significantly lower composite scores than Clusters 2 or 3 (p<0.0001). Cluster 3 had significantly lower PFT, VO₂m + WLM composites than Cluster 2 (p<0.0001).</p

Longitudinal models of lung function and current severity proxies.

<p>Longitudinal models of lung function and current severity proxies.</p

Association between patient characteristics and clusters [n(%) or Mean (SD)].

<p>Association between patient characteristics and clusters [n(%) or Mean (SD)].</p

Factors and loadings for standardized outcome estimates at 30 years.

<p>Factors and loadings for standardized outcome estimates at 30 years.</p