Abstract FUS-TFCP2-positive rhabdomyosarcoma (FUS-TFCP2+ RMS) is a rare subtype of spindle cell/sclerosing RMS with a craniofacial predilection. These tumors are highly aggressive, quick to metastasize and evade conventional chemotherapies. FUS-TFCP2 fusion results in a gain of function transcription factor that promotes proliferation and activates survival pathways while blocking myogenic differentiation and inhibiting DNA repair. Currently, there is no effective standard of care, surgery can be difficult due to location and patients typically succumb to the disease within 15 months of diagnosis. Overexpression of downstream target, Anaplastic Lymphoma Kinase (ALK), is characteristic of FUS-TFCP2+ RMS. However, while case reports of targeted treatment with ALK inhibitors (ALKi) have shown modest results, resistance always emerges. In collaboration with the Pediatric Cancer Precision Genomics Program at the Riley Hospital for Children, we developed a paired set of FUS-TFCP2+ RMS patient-derived xenografts (PDXs). ALKi-sensitive PDX174 was derived from a patient tumor sample obtained prior to an 11-month ALKi (lorlatinib) regimen. Subsequently, a second sample was acquired following disease progression from which ALKi-resistant PDX199 was established. RT-PCR validated the fusion site in both models. In vivo studies confirmed PDX174 sensitivity and PDX199 resistance to lorlatinib (0.1mg/kg and 1mg/kg). Concordant with FUS-TFCP2+ characterization, transcriptome analysis showed significantly increased expression of ALK in both PDX174 (14.9-fold) and PDX199 (11.1-fold). Western blot analysis revealed robust overexpression of ALK isoforms in PDX174, whereas ALK expression in the ALKi-resistant PDX199 was only barely detectable. Instead, PDX199 exhibited increased levels of TERT, CDK4/6, and BET proteins. To further compare the models, we utilized two complementary approaches to evaluate the activated kinome of ALKi-resistant PDX199 compared to ALKi-sensitive PDX174. Kinase activity profiling using PamGene peptide microarrays revealed a statistically significant increase in kinase activity of components involved in PI3K/AKT pathway and cell cycle CDKs (CDK1,2,4), with concomitant suppression of kinase activity of JNK/p38 MAPKs, indicating a shift toward PI3K/mTOR-driven pro-survival signaling and potential vulnerability to PI3K/AKT and CDK inhibition. Global kinome analysis using multiplexed inhibitor beads also showed an increase in CDK4/6 activation in ALKi-resistant PDX199 versus ALKi-sensitive PDX174. Pre-clinical models such as these provide a platform to connect molecular signatures with targeted therapy, increase our mechanistic understanding of tumor adaptive responses and design therapies that will mitigate the emergence of therapeutic resistance. Citation Format: Erika Dobrota, M. Reza Saadatzadeh, Barbara Bailey, Keiko Kreklau, Gabe Mervis, Kathy Coy, Felicia Kennedy, Melissa Trowbridge, Anthony Sinn, Christopher Davis, Steven Angus, Michael Ferguson, Pankita Pandya, Karen Pollok. Differential sensitivity of paired FUS-TFCP2+ RMS PDX models developed from tumor specimens obtained prior to and after ALK inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6179.

Oysters are ecosystem engineers that restructure their environments through intense filtration and reef-building, known for their ability to remove plankton and particulates from seawater. As microbialization and eutrophication increasingly undermine coastal water quality, understanding how oyster filtration shapes viral and microbial assemblages is essential to evaluate its role in countering these degradation processes. Here, we incubated the eastern oyster, Crassostrea virginica, in natural seawater and conducted a high-resolution 24-hour time-series analysis to track changes in viral and microbial abundances. Oysters preferentially removed autotrophic microbes, skewing community composition toward heterotrophy and altering local carbon and energy fluxes. Understanding the extent to which viral and microbial components contribute to oyster nutrition could provide new insights into these shifts and their broader ecological consequences. Viral abundances displayed Lotka–Volterra-like oscillations, suggesting that phage replication was sustained through lytic cycling rather than integration into microbial genomes, even under reduced microbial availability. Elevated virus-to-microbe ratios (VMRs) in oyster-associated mucus compared to ambient seawater points to a role of bacteriophage adherence-to-mucus (BAM) in modulating host-microbiome interactions within the oyster holobiont. Together, these findings highlight oysters as ecosystem de-microbializers and holobiont viralizers, simultaneously suppressing water-column microbes and stimulating localized viral activity that reshapes microbial interactions and coastal biogeochemistry.

Standard statistical analyses often exclude incomplete observations, which can be particularly problematic when predicting rare outcomes, such as HIV positivity. In the linkage to the HIV care dataset, there were initially 553 complete HIV positive cases, with an additional 554 cases added through imputation. Imputation methods amelia, hmisc, mice and missForest were evaluated. Simulations were conducted across various scenarios using the complete data to guide imputation for the full dataset. A random forest model was used to predict HIV status, assessing imputation precision, overall prediction accuracy, and sensitivity. While missForest produced imputed values closer to the observed ones, this did not translate into better predictive models. Hmisc and mice imputations led to higher prediction accuracy and sensitivity, with median accuracy increasing from 64% to 76% and median sensitivity rising from 0.4 to 0.75. Hmisc and amelia were the fastest imputation methods. Additionally, oversampling the minority class combined with undersampling the majority class did not improve predictions of new HIV positive cases using only the complete observations. However, increasing the minority class information through imputation enhanced sensitivity for predicting cases in this class.

Vaping is marketed as a safe alternative to traditional cigarette smoking, but multiple studies demonstrate deleterious cardiopulmonary effects including cardiac function decline and fibrotic remodeling with alveolar size enlargement. Nicotine, a common constituent of vaping aerosol, stimulates p16 expression in pulmonary tissue but the impact on cardiac tissue remains unclear. In this study, mice were exposed to e-cigarette vape aerosol either containing nicotine (Vape Nicotine; VN) or without nicotine (Vape 0; V0). Non-exposed (No Vape; NoV) mice were used as controls. Cardiac effects were assessed by echocardiography, histology, and immunofluorescence to determine changes in function, morphology, p16, and Discoidin Domain Receptor 2 (DDR2). VN depressed cardiac function and increased collagen deposition relative to V0 and NoV. Interestingly, p16 expression was increased in cardiomyocytes and interstitial cells of male mice while remaining unchanged in females. In contrast to VN, V0 had no significant impact on cardiac function or p16 expression in males. Furthermore, collagen deposition in the V0 group was significantly lower than the VN group. Subsequent cardiac fibroblast analysis using DDR2 revealed increased expression within the V0 group relative to VN and NoV. Collectively, these findings show collagen accumulation as well as p16 expression prompted by vaping is mediated by nicotine as a constituent of vape juice. In contrast, vape aerosol alone promotes accrual of cardiac fibroblasts without concomitant changes in collagen accumulation or p16 expression. These results are the first to identify p16 induction with pathologic collagen deposition by exposure to vape aerosol containing nicotine in male cardiac tissue. The underlying basis for sex-specific differences in cardiac responses to vape aerosol exposure warrant further investigation, particularly those involving cellular and molecular changes that may lead to pathologic changes later in life. ### Competing Interest Statement The authors have declared no competing interest.

OBJECTIVE:The aim of this study was to identify clinical phenotypes using sensor-based measures of posture and movement, pain behavior, and psychological factors in Hispanic/Latino people with chronic low back pain (CLBP). METHODS:Baseline measures from an ongoing clinical trial were analyzed for 81 Hispanic/Latino people with CLBP. Low back posture and movement were measured using commercial sensors during in-person testing and 8 hours of ecological monitoring. Magnitude, frequency, and duration of lumbar movements, sitting and standing postures were measured. Movement-evoked pain was assessed during in-person movement testing. Psychological measures included the Pain Catastrophizing Scale and the Fear Avoidance Beliefs Questionnaire. Random forest analysis was conducted to generate 2 groups and identify important variables that distinguish groups. Group differences in demographics, pain, psychological, and posture and movement variables were examined using t-tests and chi-square analyses. RESULTS:Two subgroups of Hispanic/Latino people with CLBP were identified with minimal error (7.4% misclassification ["out-of-bag" error]). Ecological posture and movement measures best distinguished groups, although most movement-evoked pain and psychological measures did not. Group 1 had greater height and weight, lower movement frequency, more time in sitting, and less time in standing. Group 2 had a greater proportion of women than men, longer low back pain duration, higher movement frequency, more time in standing, and less time in sitting. CONCLUSION:Two distinct clinical phenotypes of Hispanic/Latino people with CLBP were identified. One group was distinguished by greater height and weight and more sedentary posture and movement behavior; the second group had more women, longer duration of low back pain, higher lumbar spine movement frequency, and longer duration of standing postures. IMPACT:Ecological measures of posture and movement are important for identifying 2 clinical phenotypes in Hispanic/Latino people with CLBP and may provide a basis for a more personalized plan of care. LAY SUMMARY:Wearable sensors were used to measure low back posture and movement in Hispanic/Latino people with chronic low back pain. These posture and movement measures helped to identify 2 different clinical subgroups that will give physical therapists more information to better personalize treatment for chronic low back pain in Hispanic/Latino patients.

Background Vaping is touted as a safer alternative to traditional cigarette smoking, but the full spectrum of harm reduction versus comparable risk remains unresolved. Elevated bioavailability of nicotine in vape aerosol together with known risks of nicotine exposure may result in previously uncharacterized cardiovascular consequences of vaping. The objective of this study is to assess the impact of nicotine exposure via vape aerosol inhalation upon myocardial response to infarction injury. Methods and Results Flavored vape juice containing nicotine (5 mg/mL) or vehicle alone (0 mg) was delivered using identical 4‐week treatment protocols. Mice were subjected to acute myocardial infarction injury and evaluated for outcomes of cardiac structure and function. Findings reveal that nicotine exposure leads to worse outcomes with respect to contractile performance regardless of sex. Nonmyocyte interstitial cell accumulation following infarction significantly increased with exposure to vape aerosol alone, but a comparable increase was not present when nicotine was included. Conclusions Myocardial function after infarction is significantly decreased after exposure to nicotine vape aerosol irrespective of sex. Comparable loss of contractile function was not observed in mice exposed to vape aerosol alone, highlighting the essential role of nicotine in loss of contractile function. Increased vimentin immunoreactivity was observed in the vape alone group compared with control and vape nicotine. The correlation between vaping, interstitial cell responses, and cardiac remodeling leading to impaired contractility warrants further investigation. Public health experts seeking to reduce vaping‐related health risks should consider messaging that highlights the increased cardiovascular risk especially with nicotine‐containing aerosols.

Background Predation pressure and herbivory exert cascading effects on coral reef health and stability. However, the extent of these cascading effects can vary considerably across space and time. This variability is likely a result of the complex interactions between coral reefs’ biotic and abiotic dimensions. A major biological component that has been poorly integrated into the reefs' trophic studies is the microbial community, despite its role in coral death and bleaching susceptibility. Viruses that infect bacteria can control microbial densities and may positively affect coral health by controlling microbialization. We hypothesize that viral predation of bacteria has analogous effects to the top-down pressure of macroorganisms on the trophic structure and reef health. Results Here, we investigated the relationships between live coral cover and viruses, bacteria, benthic algae, fish biomass, and water chemistry in 110 reefs spanning inhabited and uninhabited islands and atolls across the Pacific Ocean. Statistical learning showed that the abundance of turf algae, viruses, and bacteria, in that order, were the variables best predicting the variance in coral cover. While fish biomass was not a strong predictor of coral cover, the relationship between fish and corals became apparent when analyzed in the context of viral predation: high coral cover (> 50%) occurred on reefs with a combination of high predator fish biomass (sum of sharks and piscivores > 200 g m −2 ) and high virus-to-bacteria ratios (> 10), an indicator of viral predation pressure. However, these relationships were non-linear, with reefs at the higher and lower ends of the coral cover continuum displaying a narrow combination of abiotic and biotic variables, while reefs at intermediate coral cover showed a wider range of parameter combinations. Conclusions The results presented here support the hypothesis that viral predation of bacteria is associated with high coral cover and, thus, coral health and stability. We propose that combined predation pressures from fishes and viruses control energy fluxes, inhibiting the detrimental accumulation of ecosystem energy in the microbial food web.

Abstract Background: Incomplete observation units may contain important information about the population being studied, analysis conducted with the complete portion of the dataset, done in most standard statistical software, may produce biased or low statistical power results. In this paper we investigate the behavior of imputation methods for a linkage to HIV care study dataset with more than 60% incomplete cases. Methods: Missing data imputation algorithms amelia , missForest , mice and hmisc were considered. Two sets of simulations were conducted: first with the subset of data containing only complete observations and second with the whole dataset. Imputation accuracy and general behavior for each imputation algorithm were accessed in the first set. Random forest models were fit to evaluate overall prediction accuracy and sensitivity in both sets of simulations. Results: The imputed values by missForest, a single imputation method, were more accurate for all incomplete variables and scenarios. Median overall prediction accuracy of HIV status, a three levels outcome, was slightly higher after imputations with missForest and amelia ( approximately 52%, 61% and 65% for samples of 350, 700 and 1050 units respectively). In general, different missing percentages (20%, 40% and 60%) did not result in large changes in prediction or imputation accuracy and larger sample sizes performance improved for imputation and overall prediction accuracy but mixed results were observed with sensitivity. For the second set of simulations, missForest and amelia produced better overall prediction accuracy with larger samples (1200 versus 350 units). For new HIV positive HIV class, hmisc and mice presented better sensitivity, with median sensitivity 65% versus 50% and approximately 90% versus 20% for samples with 350 and 1200 units respectively, compared to incomplete samples. Conclusions: Imputation with mice and hmisc may be used for imputation when the main interest is to increase sensitivity in predicting new HIV positive. Furthermore, it is interesting to investigate which method gives more advantage for other performance measures of interest. Trial registration: NCT02545673

BACKGROUND: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and occupational purposes, but inclusion of race is under scrutiny.RESEARCH QUESTION: Does including self-identified race in spirometry reference equation formation improve the ability of predicted FEV1 values to explain quantitative chest CT abnormalities, dyspnea, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification?STUDY DESIGN AND METHODS: Using data from healthy adults who have never smoked in both the National Health and Nutrition Survey (2007-2012) and COPDGene study cohorts, race-neutral, race-free, and race-specific prediction equations were generated for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, these equations were applied in a cross-sectional analysis to populations of individuals who currently smoke and individuals who formerly smoked to determine how they affected GOLD classification and the fit of models predicting quantitative chest CT phenotypes or dyspnea.RESULTS: Race-specific equations showed no advantage relative to race-neutral or race-free equations in models of quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified up to 19% of Black participants into more severe GOLD classes, while race-neutral/race-free equations may improve model fit for dyspnea symptoms relative to race-specific equations.INTERPRETATION: Race-specific equations offered no advantage over race-neutral/race-free equations in three distinct explanatory models of dyspnea and chest CT scan abnormalities. Race-neutral/race-free reference equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease.

Abstract Temozolomide remains the lone pharmacotherapeutic option for glioblastoma (GBM), yet the development of resistance to temozolomide has been a major challenge contributing to the persistent median < 2-year survival for patients after diagnosis. Tumor heterogeneity and induction of treatment response networks, such as the DNA damage response (DDR), are major contributors to temozolomide resistance in GBM. Targeting DDR treatment response networks, such as the MDM2/p53/p73 and PI3K/AKT/mTOR networks, with small-molecule inhibitors (SMIs) presents an opportunity to disrupt resistance mechanisms and enhance temozolomide efficacy. We utilized a triple drug combination of clinically relevant concentrations of the blood-brain-barrier penetrant SMIs of AKT (ipatasertib; GDC-0068) and MDM2 (idasanutlin; RG7388) with temozolomide to evaluate this targeted strategy using the recurrent, temozolomide-resistant, p53wt GBM10 xenoline. Proliferation studies demonstrated dose-related additive to synergistic inhibition of proliferation at clinically relevant concentrations of ipatasertib and idasanutlin. Further, IncuCyte live-cell imaging demonstrated dose-and time-related growth inhibition of these GBM cells and apoptosis marked by increased cleaved caspase 3 expression following the temozolomide+idasanutlin+ipatasertib triple combination treatment. Cells treated with temozolomide+idasanutlin+ipatasertib also displayed senescence phenotypes, with increased cell cycle arrest and elevated expression of SPiDER β-Gal expression and cell-cycle inhibitors such as p53 and p21. Experiments are in progress to determine the extent to which the effects of temozolomide+idasanutlin+ipatasertib combination therapy are dependent on p53 using siRNA knockdown of p53. In the present study, targeting the temzolomide-induced DNA damage response with idasanutlin+ipatasertib increased the effectiveness of temozolomide. These results indicate that this triple combination may be a promising approach to improving patient outcomes in temozolomide-resistant GBM.

Functional connectivity MRI (fcMRI) is a technique used to study the functional connectedness of distinct regions of the brain by measuring the temporal correlation between their blood oxygen level-dependent (BOLD) signals. fcMRI is typically measured with the Pearson correlation (PC), which assumes that there is no lag between time series. Dynamic time warping (DTW) is an alternative measure of similarity between time series that is robust to such time lags. We used PC fcMRI data and DTW fcMRI data as predictors in machine learning models for classifying autism spectrum disorder (ASD). When combined with dimension reduction techniques, such as principal component analysis, functional connectivity estimated with DTW showed greater predictive ability than functional connectivity estimated with PC. Our results suggest that DTW fcMRI can be a suitable alternative measure that may be characterizing fcMRI in a different, but complementary, way to PC fcMRI that is worth continued investigation. In studying different variants of cross validation (CV), our results suggest that, when it is necessary to tune model hyperparameters and assess model performance at the same time, a K-fold CV nested within leave-one-out CV may be a competitive contender in terms of performance and computational speed, especially when sample size is not large.

Long-term atmospheric CO2 concentration records have suggested a reduction in the positive effect of warming on high-latitude carbon uptake since the 1990s. A variety of mechanisms have been proposed to explain the reduced net carbon sink of northern ecosystems with increased air temperature, including water stress on vegetation and increased respiration over recent decades. However, the lack of consistent long-term carbon flux and in situ soil moisture data has severely limited our ability to identify the mechanisms responsible for the recent reduced carbon sink strength. In this study, we used a record of nearly 100 site-years of eddy covariance data from 11 continuous permafrost tundra sites distributed across the circumpolar Arctic to test the temperature (expressed as growing degree days, GDD) responses of gross primary production (GPP), net ecosystem exchange (NEE), and ecosystem respiration (ER) at different periods of the summer (early, peak, and late summer) including dominant tundra vegetation classes (graminoids and mosses, and shrubs). We further tested GPP, NEE, and ER relationships with soil moisture and vapor pressure deficit to identify potential moisture limitations on plant productivity and net carbon exchange. Our results show a decrease in GPP with rising GDD during the peak summer (July) for both vegetation classes, and a significant relationship between the peak summer GPP and soil moisture after statistically controlling for GDD in a partial correlation analysis. These results suggest that tundra ecosystems might not benefit from increased temperature as much as suggested by several terrestrial biosphere models, if decreased soil moisture limits the peak summer plant productivity, reducing the ability of these ecosystems to sequester carbon during the summer.

Thousands of buildings in Cleveland, Ohio were demolished or rehabilitated since the Great Recession in the 2000s. Recent evidence suggests removing vacant and decaying buildings reduces violent and firearm-involved crime. This study examines the dose-response relationship between demolitions, rehabilitations, and crime. We use Bayesian spatiotemporal models to estimate the association of interest for five types of crime outcomes: violent crimes, violent crimes involving a firearm, drug crimes, and crimes often associated with building vacancy. We estimate associations in quarterly time periods from 2012 through 2017 in 569 hexagons approximately the size of a neighborhood (2000 feet, approximately 610 m, in diameter), stratified by vacancy level. Across vacancy levels, the majority of our models do not identify statistically significant associations between demolition and rehabilitation dose and crime incidence. However, in some cases, we identify positive associations between demolition and crime. These associations generally appeared at higher levels of demolition (2 or 3 or more demolitions) in areas characterized by medium to high levels of vacancy. We also find that the presence of a property rehabilitation is associated with an increase in drug crimes in areas with medium levels of vacancy.

Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO 2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO 2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO 2 later in the season.

Background: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and social purposes, but inclusion of race is under scrutiny. In this study, we we examined how the percent predicted forced expiratory volume in one second (FEV1) values calculated from race-specific, race-neutral, and race-free reference equations differentially affect COPD classification or predict radiographic or symptom phenotypes in two large cohorts of smokers. Methods: Using data from healthy never-smoking adults in both the National Health and Nutrition Survey (NHANES, 2007-12) and COPD Genetic Epidemiology study (COPDGene) cohorts, we generated race-neutral, race-free and race-specific prediction equations for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, we applied these equations in a cross-sectional analysis to populations of smokers to determine how they affected the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification and predicted quantitative chest computed tomography (CT) phenotypes and dyspnea. Findings: Race-specific equations showed no advantage relative to race-neutral or race-free equations in predicting quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified Black participants into more severe GOLD classes from 13.8% up to 19.2% across datasets, and race-neutral/free equations modestly improved prediction of dyspnea symptoms relative to race-specific equations. Interpretation: Race-neutral over race-specific equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease. Funding Information: This work was supported by NHLBI U01 HL089897 and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Bayer Pharmaceuticals, Boehringer- Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion. ALN was additionally supported by UCSD Academic Senate Grant and UCSD Division of Social Sciences Research Grant. Declaration of Interests: ALN is supported by UCSD Academic Senate Grant and UCSD Division of Social Sciences Research Grant. AAD declares speaker fees from Boehringer-Ingelheim, outside of the submitted work. AKD is funded by NIH grants KL2TR002492 and UL1TR002494, unrelated to present work. SPB is supported by NIH R01 HL151421 and NIH UH3HL155806, Nuvaira, Sanofi, has received royalties from Springer Humana, consulting fees from Boehringer Ingelheim, Sanofi/Regeneron, and IntegrityCE, unrelated to present work. RC has been supported by grants from AstraZeneca, Regeneron, Genentech, consulting fees from Regeneron, Genentech, Inogen, and Boehringer Ingelheim, and honoraria from Glaxo Smith Kline, unrelated to current work. RC is also on the Board of Directors for the COPD Foundation and President of the Pulmonary Education and Research Foundation. All other authors declare no competing interests. Ethics Approval Statement: The NHANES survey and consent documents were approved by the CDC Institutional Review Board.

Background: Cystic Fibrosis (CF) is a multi-systemic disorder resulting from genetic variation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which can result in bronchiectasis, chronic sinusitis, pancreatic malabsorption, cholestatic liver disease and distal intestinal obstructive syndrome. This study generates multi-dimensional clinical phenotypes that capture the complexity and spectrum of the disease manifestations seen in adult CF patients using statistically robust techniques. Methods: Pre-transplant clinical data from adult (age >= 18 years) CF patients (n = 992) seen in six regionally distinct US CF centers between 1/1/2014 and 6/30/2015 were included. Demographic, spirometry, nutritional, microbiological and therapy data were used to generate clusters using the Random Forests statistical-learning and Partitioning around Medoids (PAM) clustering algorithms. Five commonly measured demographic, physiological and nutritional parameters were needed to create the final phenotypes that are highly similar to a regionally matched group of patients from the CF Foundation Patient Registry Results: This approach identified high-risk phenotypes with expected characteristics including high rates of pancreatic insufficiency, diabetes and Pseudomonas aeruginosa colonization. It also identified unexpected populations including a) a male-dominated, well-nourished group with good lung function with a high prevalence of severe genotypes (i.e. 60% subjects had two minimal function CFTR variations), b) and an older, "survivor" phenotype that had high rates of chronic P. aeruginosa infection. Conclusions: This study identified recognizable phenotypes that capture the clinical complexity in a statistically robust manner and which may aide in the identification of specific genetic and environmental factors responsible for these disease manifestation patterns. (C) 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Scientific interest often centers on characterizing the effect of one or more variables on an outcome.While data mining approaches such as random forests are flexible alternatives to conventional parametric models, they suffer from a lack of interpretability because variable effects are not quantified in a substantively meaningful way.In this paper we describe a method for quantifying variable effects using partial dependence, which produces an estimate that can be interpreted as the effect on the response for a one unit change in the predictor, while averaging over the effects of all other variables.Most importantly, the approach avoids problems related to model misspecification and challenges to implementation in high dimensional settings encountered with other approaches (e.g., multiple linear regression).We propose and evaluate through simulation a method for constructing a point estimate of this effect size.We also propose and evaluate interval estimates based on a non-parametric bootstrap.The method is illustrated on data used for the prediction of the age of abalone.

Reef-building corals are ecosystem engineers that compete with other benthic organisms for space and resources. Corals harvest energy through their surface by photosynthesis and heterotrophic feeding, and they divert part of this energy to defend their outer colony perimeter against competitors. Here, we hypothesized that corals with a larger space-filling surface and smaller perimeters increase energy gain while reducing the exposure to competitors. This predicted an association between these two geometric properties of corals and the competitive outcome against other benthic organisms. To test the prediction, fifty coral colonies from the Caribbean island of Curaçao were rendered using digital 3D and 2D reconstructions. The surface areas, perimeters, box-counting dimensions (as a proxy of surface and perimeter space-filling), and other geometric properties were extracted and analyzed with respect to the percentage of the perimeter losing or winning against competitors based on the coral tissue apparent growth or damage. The increase in surface space-filling dimension was the only significant single indicator of coral winning outcomes, but the combination of surface space-filling dimension with perimeter length increased the statistical prediction of coral competition outcomes. Corals with larger surface space-filling dimensions (Ds > 2) and smaller perimeters displayed more winning outcomes, confirming the initial hypothesis. We propose that the space-filling property of coral surfaces complemented with other proxies of coral competitiveness, such as life history traits, will provide a more accurate quantitative characterization of coral competition outcomes on coral reefs. This framework also applies to other organisms or ecological systems that rely on complex surfaces to obtain energy for competition.