Letter to the Editor: on the stability and internal consistency of component-wise sparse mixture regression-based clustering.

Understanding the relationship between molecular markers and a phenotype of interest is often obfuscated by patient-level heterogeneity. To address this challenge, Chang et al. recently published a novel method called Component-wise Sparse Mixture Regression (CSMR), a regression-based clustering method that promises to detect heterogeneous relationships between molecular markers and a phenotype of interest under high-dimensional settings. In this Letter to the Editor, we raise awareness to several issues concerning the assessment of CSMR in Chang et al., particularly its assessment in settings where the number of features, P, exceeds the study sample size, N, and advocate for additional metrics/approaches when assessing the performance of regression-based clustering methodologies.

Improving the accuracy and internal consistency of regression-based clustering of high-dimensional datasets.

Component-wise Sparse Mixture Regression (CSMR) is a recently proposed regression-based clustering method that shows promise in detecting heterogeneous relationships between molecular markers and a continuous phenotype of interest. However, CSMR can yield inconsistent results when applied to high-dimensional molecular data, which we hypothesize is in part due to inherent limitations associated with the feature selection method used in the CSMR algorithm. To assess this hypothesis, we explored whether substituting different regularized regression methods (i.e. Lasso, Elastic Net, Smoothly Clipped Absolute Deviation (SCAD), Minmax Convex Penalty (MCP), and Adaptive-Lasso) within the CSMR framework can improve the clustering accuracy and internal consistency (IC) of CSMR in high-dimensional settings. We calculated the true positive rate (TPR), true negative rate (TNR), IC and clustering accuracy of our proposed modifications, benchmarked against the existing CSMR algorithm, using an extensive set of simulation studies and real biological datasets. Our results demonstrated that substituting Adaptive-Lasso within the existing feature selection method used in CSMR led to significantly improved IC and clustering accuracy, with strong performance even in high-dimensional scenarios. In conclusion, our modifications of the CSMR method resulted in improved clustering performance and may thus serve as viable alternatives for the regression-based clustering of high-dimensional datasets.

PROpwr: a Shiny R application to analyze patient-reported outcomes data and estimate power.

Patient Reported Outcomes (PROs) are widely used in quality of life (QOL) studies, health outcomes research, and clinical trials. The importance of PRO has been advocated by health authorities. We propose this R shiny web application, PROpwr, that estimates power for two-arm clinical trials with PRO measures as endpoints using Item Response Theory (GRM: Graded Response Model) and simulations. PROpwr also supports the analysis of PRO data for convenience of estimating the effect size. There are seven function tabs in PROpwr: Frequentist Analysis, Bayesian Analysis, GRM power, T-test Power Given Sample Size, T-test Sample Size Given Power, Download, and References. PROpwr is user-friendly with point-and-click functions. PROpwr can assist researchers to analyze and calculate power and sample size for PRO endpoints in clinical trials without prior programming knowledge.

Establishing thresholds for meaningful within-individual change using longitudinal item response theory.

PURPOSE: Thresholds for meaningful within-individual change (MWIC) are useful for interpreting patient-reported outcome measures (PROM). Transition ratings (TR) have been recommended as anchors to establish MWIC. Traditional statistical methods for analyzing MWIC such as mean change analysis, receiver operating characteristic (ROC) analysis, and predictive modeling ignore problems of floor/ceiling effects and measurement error in the PROM scores and the TR item. We present a novel approach to MWIC estimation for multi-item scales using longitudinal item response theory (LIRT). METHODS: A Graded Response LIRT model for baseline and follow-up PROM data was expanded to include a TR item measuring latent change. The LIRT threshold parameter for the TR established the MWIC threshold on the latent metric, from which the observed PROM score MWIC threshold was estimated. We compared the LIRT approach and traditional methods using an example data set with baseline and three follow-up assessments differing by magnitude of score improvement, variance of score improvement, and baseline-follow-up score correlation. RESULTS: The LIRT model provided good fit to the data. LIRT estimates of observed PROM MWIC varied between 3 and 4 points score improvement. In contrast, results from traditional methods varied from 2 to 10 points-strongly associated with proportion of self-rated improvement. Best agreement between methods was seen when approximately 50% rated their health as improved. CONCLUSION: Results from traditional analyses of anchor-based MWIC are impacted by study conditions. LIRT constitutes a promising and more robust analytic approach to identifying thresholds for MWIC.

Improvement of Seed Germination under Salt Stress via Overexpressing Caffeic Acid O-methyltransferase 1 (SlCOMT1) in Solanum lycopersicum L.

Melatonin (MT) is a phytohormone-like substance and is profoundly involved in modulating nearly all aspects of plant development and acclimation to environmental stressors. However, there remain no studies about the effects of MT on tomato seed germination under salt stress. Here we reported that the overexpression of caffeic acid O-methyltransferase 1 (SlCOMT1) significantly increased both MT content and salt tolerance in the germinated seeds of a transgenic tomato relative to wild type (WT) samples. Physiological investigation showed higher amylase activity in the stressed overexpression seeds than WT, leading to the promoted starch decomposition and enhanced soluble sugar content. The stimulated production of osmolytes and enhanced activities of SOD, POD, and CAT, together with the significant reduction in H2O2 and O2·- accumulation, were revealed in the stressed overexpression seeds relative to WT, largely accounting for their lower membrane lipid peroxidation. qPCR assay showed that, upon salt stress, the transcript abundance of hub genes related to germination (SlCYP707A1, SlABA1, SlGA3ox2 and SlGA2ox4) and stress tolerance (SlCDPK1, SlWRKY33 and SlMAPK1) were distinctly altered in the overexpression samples when compared to WT, providing a molecular basis for MT-mediated improvement of seed salt tolerance. Altogether, our observations shed new insights into biological functions of SlCOMT1 and could expand its utilization in genetic improvement of tomato salt tolerance in future.

Factors Associated with Musculoskeletal Injuries While Hiking with a Backpack at Philmont Scout Ranch.

INTRODUCTION: Participants at Philmont Scout Ranch embark on 12-d treks with pre-trek physical conditioning and medical clearance by their primary care physician. In this study, we investigated potential contributing factors to self-reported musculoskeletal injuries during a backpack trek. METHODS: This study was a prospective cohort study that used a 3-part survey administered to participants before, during, and after their trek from June through August 2019. Health history and demographic information were retrieved from each hiker's medical record. A logistic regression model was used to assess factors associated with injuries, and odds ratios and 95% confidence intervals were reported. RESULTS: There were 1206 individuals enrolled in this study, and none withdrew from participation. The median age of the participants was 17 y (interquartile range 15-47); 1130 were male, 75 were female, and 1 was of unknown sex. Injuries were reported by 7% (n=88) of participants while in the backcountry, with injuries occurring in various anatomic locations (knee, ankle, leg, foot, hand, arm). Participants without missing data (74%; n=897) were included in the logistical regression analysis to describe factors significantly associated with injury. Factors significantly associated with injury included greater backpack weight to body weight ratio, body mass index greater than 30 kg·m-2, and past injuries that required a doctor visit. CONCLUSIONS: Self-reported injuries while hiking at Philmont Scout Ranch are infrequent and do not often require evacuation or advanced medical care. Camp policies to maintain appropriate backpack weight and counseling of obese and previously injured individuals may mitigate injury occurrence.

A comparison between manual and artificial intelligence-based automatic positioning in CT imaging for COVID-19 patients.

OBJECTIVE: To analyze and compare the imaging workflow, radiation dose, and image quality for COVID-19 patients examined using either the conventional manual positioning (MP) method or an AI-based automatic positioning (AP) method. MATERIALS AND METHODS: One hundred twenty-seven adult COVID-19 patients underwent chest CT scans on a CT scanner using the same scan protocol except with the manual positioning (MP group) for the initial scan and an AI-based automatic positioning method (AP group) for the follow-up scan. Radiation dose, patient positioning time, and off-center distance of the two groups were recorded and compared. Image noise and signal-to-noise ratio (SNR) were assessed by three experienced radiologists and were compared between the two groups. RESULTS: The AP operation was successful for all patients in the AP group and reduced the total positioning time by 28% compared with the MP group. Compared with the MP group, the AP group had significantly less patient off-center distance (AP 1.56 cm ± 0.83 vs. MP 4.05 cm ± 2.40, p < 0.001) and higher proportion of positioning accuracy (AP 99% vs. MP 92%), resulting in 16% radiation dose reduction (AP 6.1 mSv ± 1.3 vs. MP 7.3 mSv ± 1.2, p < 0.001) and 9% image noise reduction in erector spinae and lower noise and higher SNR for lesions in the pulmonary peripheral areas. CONCLUSION: The AI-based automatic positioning and centering in CT imaging is a promising new technique for reducing radiation dose and optimizing imaging workflow and image quality in imaging the chest. KEY POINTS: • The AI-based automatic positioning (AP) operation was successful for all patients in our study. • AP method reduced the total positioning time by 28% compared with the manual positioning (MP). • AP method had less patient off-center distance and higher proportion of positioning accuracy than MP method, resulting in 16% radiation dose reduction and 9% image noise reduction in erector spinae.

The need to study rural cancer outcome disparities at the local level: a retrospective cohort study in Kansas and Missouri.

BACKGROUND: Rural residence is commonly thought to be a risk factor for poor cancer outcomes. However, a number of studies have reported seemingly conflicting information regarding cancer outcome disparities with respect to rural residence, with some suggesting that the disparity is not present and others providing inconsistent evidence that either urban or rural residence is associated with poorer outcomes. We suggest a simple explanation for these seeming contradictions: namely that rural cancer outcome disparities are related to factors that occur differentially at a local level, such as environmental exposures, lack of access to care or screening, and socioeconomic factors, which differ by type of cancer. METHODS: We conducted a retrospective cohort study examining ten cancers treated at the University of Kansas Medical Center from 2011 to 2018, with individuals from either rural or urban residences. We defined urban residences as those in a county with a U.S. Department of Agriculture Urban Influence Code (UIC) of 1 or 2, with all other residences defines a rural. Inverse probability of treatment weighting was used to create a pseudo-sample balanced for covariates deemed likely to affect the outcomes modeled with cumulative link and weighted Cox-proportional hazards models. RESULTS: We found that rural residence is not a simple risk factor but rather appears to play a complex role in cancer outcome disparities. Specifically, rural residence is associated with higher stage at diagnosis and increased survival hazards for colon cancer but decreased risk for lung cancer compared to urban residence. CONCLUSION: Many cancers are affected by unique social and environmental factors that may vary between rural and urban residents, such as access to care, diet, and lifestyle. Our results show that rurality can increase or decrease risk, depending on cancer site, which suggests the need to consider the factors connected to rurality that influence this complex pattern. Thus, we argue that such disparities must be studied at the local level to identify and design appropriate interventions to improve cancer outcomes.

The Process and Product of Coherence Monitoring in Young Readers: Effects of Reader and Text Characteristics.

We examined sixth graders' detection of inconsistencies in narrative and expository passages, contrasting participants who were monolingual speakers (N = 85) or Spanish-English DLLs (N = 94) when recruited in pre-kindergarten (PK). We recorded self-paced reading times and judgments about whether the text made sense, and took an independent measure of word reading. Main findings were that inconsistency detection was better for narratives, for participants who were monolingual speakers in PK, and for those who were better word readers. When the text processing demands were increased by separating the inconsistent sentence and its premise with filler sentences there was a stronger signal for inconsistency detection during reading for better word readers. Reading patterns differed for texts for which children reported an inconsistency compared to those for which they did not, indicating a failure to adequately monitor for coherence while reading. Our performance measures indicate that narrative and expository texts make different demands on readers.

Utilization of Technology to Improve Efficiency in Investigational Drug Management Processes.

Background: Background: An investigational pharmacy is responsible for all tasks related to receiving, storing, and dispensing of any investigational drugs. Traditional methods of inventory and protocol tracking on paper binders are very tedious and could be error-prone. Objective: To evaluate the utilization of the IDS to efficiently manage the inventory within an investigational Pharmacy. We hypothesize that the IDS will reduce the drug processing time. Methods: Our pharmacy tracked the drug processing time before and after using the IDS including the receiving, dispensing, and inventory. As part of the receiving the study drug pharmacists tracked the time it took a pharmacist to complete the tasks of logging the study drug before and after the implementation of the IDS system. In addition, the pharmacy also timed the process for drug dispensing and a full investigational drug inventory check. Wilcoxon signed-rank test was used to compare the difference in the meantime of total processing before and after the IDS. Results: Utilization of the IDS system showed significant reduction in processing time, and improvement of efficiency in inventory management. Additionally, the usability survey of the IDS demonstrated that the IDS system helped pharmacists capture data consistently across every clinical trial. Conclusion: Our results demonstrates how technology helps pharmacists to focus on their actual day to day medication-related tasks rather than worrying about other operational aspects. Informatics team continues to further enhance the features such as monitor portal, and features related to finance - generation of invoices, billing reconciliation, etc.

Preferential activation for emotional Western classical music versus emotional environmental sounds in motor, interoceptive, and language brain areas.

Recent meta analyses suggest there is a common brain network involved in processing emotion in music and sounds. However, no studies have directly compared the neural substrates of equivalent emotional Western classical music and emotional environmental sounds. Using functional magnetic resonance imaging we investigated whether brain activation in motor cortex, interoceptive cortex, and Broca's language area during an auditory emotional appraisal task differed as a function of stimulus type. Activation was relatively greater to music in motor and interoceptive cortex - areas associated with movement and internal physical feelings - and relatively greater to emotional environmental sounds in Broca's area. We conclude that emotional environmental sounds are appraised through verbal identification of the source, and that emotional Western classical music is appraised through evaluation of bodily feelings. While there is clearly a common core emotion-processing network underlying all emotional appraisal, modality-specific contextual information may be important for understanding the contribution of voluntary versus automatic appraisal mechanisms.

Testing the construct validity of a health transition question using vignette-guided patient ratings of health.

BACKGROUND: A single-item transition question is often used to assess improvement or worsening in health, but its validity has not been tested extensively. The purpose of this study was to test the construct validity of a transition question by relating it to qualitative changes in patient's self-rating of health guided by clinical vignettes. METHODS: We studied 169 patients with active rheumatoid arthritis (RA) before and after treatment escalation. At both assessments, patients scored their current health on a rating scale after first rating three vignettes describing mild, moderate, or severe RA. We classified patients into one of these three RA categories using a nearest-neighbor match. We then related the change in these self-rated categories between visits to responses to a transition question on visit 2. RESULTS: Sixty patients improved their RA vignette category after treatment, 86 remained in the same vignette category, and 23 worsened categories. On the transition question, 101 patients reported improvement, 48 reported no change, and 20 reported worsening, representing a modest association with changes in RA vignette categories (polychoric correlation r = 0.19). The association was stronger if patients who were in the mild RA category at both visits were also classified as improved if their self-rating changed from below to above their mild vignette rating (r = 0.23) and when incorporating the importance of changes on the transition question (r = 0.26). CONCLUSION: Changes in health states, guided by clinical vignettes, support the construct validity of the transition question.

Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016.

OBJECTIVE: To determine trends in survival among adult and paediatric patients with systemic lupus erythematosus (SLE) from 1950 to the present. METHODS: We performed a systematic literature review to identify all published cohort studies on survival in patients with SLE. We used Bayesian methods to derive pooled survival estimates separately for adult and paediatric patients, as well as for studies from high-income countries and low/middle-income countries. We pooled contemporaneous studies to obtain trends in survival over time. We also examined trends in major causes of death. RESULTS: We identified 125 studies of adult patients and 51 studies of paediatric patients. Among adults, survival improved gradually from the 1950s to the mid-1990s in both high-income and low/middle-income countries, after which survival plateaued. In 2008-2016, the 5-year, 10-year and 15-year pooled survival estimates in adults from high-income countries were 0.95, 0.89 and 0.82, and in low/middle-income countries were 0.92, 0.85 and 0.79, respectively. Among children, in 2008-2016, the 5-year and 10-year pooled survival estimates from high-income countries were 0.99 and 0.97, while in low/middle-income countries were 0.85 and 0.79, respectively. The proportion of deaths due to SLE decreased over time in studies of adults and among children from high-income countries. CONCLUSIONS: After a period of major improvement, survival in SLE has plateaued since the mid-1990s. In high-income countries, 5-year survival exceeds 0.95 in both adults and children. In low/middle-income countries, 5-year and 10-year survival was lower among children than adults.

Vengeance, Condomless Sex and HIV Disclosure Among Men Who Have Sex with Men Living with HIV.

Vengeance has been shown to be a risk factor for HIV nondisclosure. Research examining the associations between vengeance, condomless sex, and HIV nondisclosure is lacking. The aim of the current study was to explore the association between vengeance, condomless sex and disclosure (behavior, attitude and intention) among men who have sex with men (MSM) living with HIV. Participants included 266 MSM who were a part of a disclosure intervention study. Men were recruited from local and state AIDS service organizations (ASOs), HIV-related venues and forums, and at local eating and drinking establishments in Tampa, Florida, and Columbus and Dayton, Ohio metropolitan statistical areas (MSAs). Advertisements were also placed in local daily newspapers. Vengeance was operationalized into three groups based on percentiles (least, more, and most vengeful) and as a continuous variable. Crude and multivariable logistic regression models were used to examine the association between vengeance and condomless sex in the past 30 days. Simple and multiple linear regression models were used to determine the association between vengeance and HIV disclosure. After adjusting for demographic and geographic characteristics, participants who were "most vengeful" had, on average, an approximate six-point decrease (ß: -5.46; 95% CI -9.55, -1.36) in disclosure intention compared to MSM who were "least vengeful." Prevention and intervention programs geared towards improving disclosure among MSM should address vengeance.

Psychometric Evaluation of the HIV Disclosure Belief Scale: A Rasch Model Approach.

This study provides psychometric assessment of an HIV disclosure belief scale (DBS) among men who have sex with men (MSM). This study used baseline data from a clinical trial evaluating the effectiveness of an HIV serostatus disclosure intervention of 338 HIV-positive MSM. The Rasch model was used after unidimensionality and local independence assumptions were tested for application of the model. Results suggest that there was only one item that did not fit the model well. After removing the item, the DBS showed good model-data fit and high item and person reliabilities. This instrument showed measurement invariance across two different age groups, but some items showed differential item functioning between Caucasian and other minority groups. The findings suggest that the DBS is suitable for measuring the HIV disclosure beliefs, but it should be cautioned when the DBS is used to compare the disclosure beliefs between different racial/ethnic groups.

Screening for depression in arthritis populations: an assessment of differential item functioning in three self-reported questionnaires.

PURPOSE: To determine if persons with arthritis differ systematically from persons without arthritis in how they respond to questions on three depression questionnaires, which include somatic items such as fatigue and sleep disturbance. METHODS: We extracted data on the Centers for Epidemiological Studies Depression (CES-D) scale, the Patient Health Questionnaire-9 (PHQ-9), and the Kessler-6 (K-6) scale from three large population-based national surveys. We assessed items on these questionnaires for differential item functioning (DIF) between persons with and without self-reported physician-diagnosed arthritis using multiple indicator multiple cause models, which controlled for the underlying level of depression and important confounders. We also examined if DIF by arthritis status was similar between women and men. RESULTS: Although five items of the CES-D, one item of the PHQ-9, and five items of the K-6 scale had evidence of DIF based on statistical comparisons, the magnitude of each difference was less than the threshold of a small effect. The statistical differences were a function of the very large sample sizes in the surveys. Effect sizes for DIF were similar between women and men except for two items on the Patient Health Questionnaire-9. For each questionnaire, DIF accounted for 8% or less of the arthritis-depression association, and excluding items with DIF did not reduce the difference in depression scores between those with and without arthritis. CONCLUSIONS: Persons with arthritis respond to items on the CES-D, PHQ-9, and K-6 depression scales similarly to persons without arthritis, despite the inclusion of somatic items in these scales.

An evaluation of the use of covariates to assist in class enumeration in linear growth mixture modeling.

This study examined whether the inclusion of covariates that predict class membership improves class identification in a growth mixture modeling (GMM). We manipulated the degree of class separation, sample size, the magnitude of covariate effect on class membership, the covariance between the intercept and the slope, and fit two models with covariates and an unconditional model. We concluded that correct class identification in GMM requires large sample sizes and class separation, and that unconditional GMM performs better than GMM with covariates if the sample size and class separation are sufficiently large. With small sample sizes, GMM with covariates outperformed unconditional GMM, but the percentage of correct class enumeration was low across different fit criteria.

Psychological reactance and HIV-related stigma among women living with HIV.

Psychological reactance is defined as the drive to re-establish autonomy after it has been threatened or constrained. People living with HIV may have high levels of psychological reactance due to the restrictions that they may perceive as a result of living with HIV. People living with HIV may also exhibit levels of HIV-related stigma. The relationship between psychological reactance and HIV-related stigma is complex yet understudied. Therefore, the main aim of this study was to examine the association between psychological reactance and HIV-related stigma among women living with HIV. Data were obtained from one time-point (a cross-sectional assessment) of a longitudinal HIV disclosure study. Psychological reactance was measured using the 18-item Questionnaire for the Measurement of Psychological Reactance. HIV-related stigma was measured using the HIV Stigma Scale, which has four domains: personalized, disclosure concerns, negative self-image, and concerns with public attitudes. Principal component analysis was used to derive components of psychological reactance. Linear regression models were used to determine the association between overall psychological reactance and its components, and stigma and its four domains, and depressive and anxiety symptoms. The associations between stigma and mental health were also examined. Three components of psychological reactance were derived: Opposition, Irritability, and Independence. Overall psychological reactance and irritability were associated with all forms of stigma. Opposition was linked to overall and negative self-image stigma. Overall psychological reactance, opposition, and irritability were positively associated with anxiety symptoms while opposition was also associated with Centers for Epidemiologic Studies-Depression depressive symptoms. There were also positive associations between all forms of stigma, and depressive and anxiety symptoms. Health-care providers and counselors for women living with HIV addressing feelings of irritability and opposition toward others may reduce HIV-related stigma. Future research should examine the link between psychological reactance, mental health, and HIV-related stigma among other populations living with HIV.