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Single-cell approaches have become an increasingly popular way of understanding the genetic factors behind disease. Isolation of DNA and RNA from human tissues is necessary to analyze multi-omic data sets, providing information on the single-cell genome, transcriptome, and epigenome. Here, we isolated high-quality single-nuclei from postmortem human heart tissues for DNA and RNA analysis. Postmortem human tissues were obtained from 106 individuals, 33 with a history of myocardial disease, diabetes, or smoking, and 73 controls without heart disease. We demonstrated that the Qiagen EZ1 instrument and kit consistently isolated genomic DNA of high yield, which can be used for checking DNA quality before conducting single-cell experiments. Here, we provide a method for single-nuclei isolation from cardiac tissue, otherwise known as the SoNIC method, which allows for the isolation of single cardiomyocyte nuclei from postmortem tissue by nuclear ploidy status. We also provide a detailed quality control measure for single-nuclei whole genome amplification and a pre-amplification method for confirming genomic integrity.

Background: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer’s disease (AD); however, findings thus far have been inconsistent. Objective: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). Methods: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. Results: Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = –0.160 [–0.305, –0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = –0.489 [–0.919, –0.058], I2

The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in 56 single cardiomyocytes from 12 individuals (aged from 0.4 to 82 years). Cardiomyocyte sSNVs accumulate with age at rates that are faster than in many dividing cell types and nondividing neurons. Cardiomyocyte sSNVs show distinctive mutational signatures that implicate failed nucleotide excision repair and base excision repair of oxidative DNA damage, and defective mismatch repair. Since age-accumulated sSNVs create many damaging mutations that disrupt gene functions, polyploidization in cardiomyocytes may provide a mechanism of genetic compensation to minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction.

In educational and psychological research, the logit and probit links are often used to fit the binary item response data. The appropriateness and importance of the choice of links within the item response theory (IRT) framework has not been investigated yet. In this paper, we present a family of IRT models with generalized logit links, which include the traditional logistic and normal ogive models as special cases. This family of models are flexible enough not only to adjust the item characteristic curve tail probability by two shape parameters but also to allow us to fit the same link or different links to different items within the IRT model framework. In addition, the proposed models are implemented in the Stan software to sample from the posterior distributions. Using readily available Stan outputs, the four Bayesian model selection criteria are computed for guiding the choice of the links within the IRT model framework. Extensive simulation studies are conducted to examine the empirical performance of the proposed models and the model fittings in terms of “in-sample” and “out-of-sample” predictions based on the deviance. Finally, a detailed analysis of the real reading assessment data is carried out to illustrate the proposed methodology.

PURPOSE Both the performance characteristics of prostate-specific membrane antigen positron emission tomography and insurance approval improves with increasing prostate-specific antigen (PSA) level causing some physicians to delay post-radical prostatectomy salvage radiation therapy (sRT) after PSA failure. Yet, it is unknown for men with at most one high-risk factor (ie, pT3/4 or prostatectomy [p] Gleason score 8-10) whether a PSA level exists above which initiating sRT is associated with increased all-cause mortality (ACM)-risk and was investigated. METHODS Using a multinational database of 25,551 patients with pT2-4N0 or NXM0 prostate cancer, multivariable Cox regression analysis evaluated whether an association with a significant increase in ACM-risk existed when sRT was delivered above a prespecified PSA level beginning at 0.10 ng/mL and in 0.05 increments up to 0.50 ng/mL versus at or below that level. The model was adjusted for age at and year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen deprivation therapy. RESULTS After a median follow-up of 6.00 years, patients who received sRT at a PSA level >0.25 ng/mL had a significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P = .008) compared with men who received sRT when the PSA was ≤0.25 mg/mL. This elevated ACM-risk remained significant for all PSA cutpoints up to 0.50 ng/mL but was not significant at PSA cutpoint values below 0.25 ng/mL. CONCLUSION Among patients with at most one high-risk factor, initiating sRT above a PSA level of 0.25 ng/mL was associated with increased ACM-risk.

We are pleased to launch the first issue of the New England Journal of Statistics in Data Science (NEJSDS). NEJSDS is the official journal of the New England Statistical Society (NESS) under the leadership of Vice President for Journal and Publication and sponsored by the College of Liberal Arts and Sciences, University of Connecticut. The aims of the journal are to serve as an interface between statistics and other disciplines in data science, to encourage researchers to exchange innovative ideas, and to promote data science methods to the general scientific community. The journal publishes high quality original research, novel applications, and timely review articles in all aspects of data science, including all areas of statistical methodology, methods of machine learning, and artificial intelligence, novel algorithms, computational methods, data management and manipulation, applications of data science methods, among others. We encourage authors to submit collaborative work driven by real life problems posed by researchers, administrators, educators, or other stakeholders, and which require original and innovative solutions from data scientists.

Multitype recurrent events are commonly observed in transportation studies, since commercial truck drivers may encounter different types of safety critical events (SCEs) and take different lengths of on-duty breaks in a driving shift. Bayesian nonhomogeneous Poisson process models are a flexible approach to jointly model the intensity functions of the multitype recurrent events. For evaluating and comparing these models, the deviance information criterion (DIC) and the logarithm of the pseudo-marginal likelihood (LPML) are studied and Monte Carlo methods are developed for computing these model assessment measures. We also propose a set of new concordance indices (C-indices) to evaluate various discrimination abilities of a Bayesian multitype recurrent event model. Specifically, the within-event C-index quantifies adequacy of a given model in fitting the recurrent event data for each type, the between-event C-index provides an assessment of the model fit between two types of recurrent events, and the overall C-index measures the model's discrimination ability among multiple types of recurrent events simultaneously. Moreover, we jointly model the incidence of SCEs and on-duty breaks with driving behaviors using a Bayesian Poisson process model with time-varying coefficients and time-dependent covariates. An in-depth analysis of a real dataset from the commercial truck driver naturalistic driving study is carried out to demonstrate the usefulness and applicability of the proposed methodology.

An epidemiological analysis assessing beverage consumption and risk factors for cardiovascular disease was conducted. Participants were 9-16 years old at enrolment, completed food frequency questionnaires in 1996-2001 and self-reported outcomes in 2010-2014. Exclusion criteria included missing data on relevant variables and covariates, prevalent disease before 2005, and implausible/extreme weight or energy intake. Intakes of orange juice, apple/other fruit juice, sugar-sweetened beverages and diet soda were related to the risk of incident hypertension or hyperlipidaemia using Cox proportional hazards regression, adjusting for diet, energy intake, age, smoking, physical activity and body mass index. There were 9,043 participants with 618 cases of hypertension and 850 of hyperlipidaemia in 17 years of mean follow-up. Sugar-sweetened beverage intake but not fruit juice nor diet soda was associated with hypertension (hazard ratio (95% confidence interval): 1.16 (1.03, 1.31)) in males. This study can guide beverage consumption as it relates to early predictors of cardiovascular disease.

Computerized assessment provides rich multidimensional data including trial-by-trial accuracy and response time (RT) measures. A key question in modeling this type of data is how to incorporate RT data, for example, in aid of ability estimation in item response theory (IRT) models. To address this, we propose a joint model consisting of a two-parameter IRT model for the dichotomous item response data, a log-normal model for the continuous RT data, and a normal model for corresponding paper-and-pencil scores. Then, we reformulate and reparameterize the model to capture the relationship between the model parameters, to facilitate the prior specification, and to make the Bayesian computation more efficient. Further, we propose several new model assessment criteria based on the decomposition of deviance information criterion (DIC) the logarithm of the pseudo-marginal likelihood (LPML). The proposed criteria can quantify the improvement in the fit of one part of the multidimensional data given the other parts. Finally, we have conducted several simulation studies to examine the empirical performance of the proposed model assessment criteria and have illustrated the application of these criteria using a real dataset from a computerized educational assessment program.

Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules.Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed.Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity.Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. (Clin Cancer Res 2009;15(18):5902–9)

CCR Translation for the Article from Molecular Target Modulation, Imaging, and Clinical Evaluation of Gastrointestinal Stromal Tumor Patients Treated with Sunitinib Malate after Imatinib Failure

Objectives: The objective of this study is to investigate the impact of early life experiences and gut microbiota on neurobehavioral development in preterm infants during neonatal intensive care unit (NICU) hospitalization. Methods: Preterm infants were followed from NICU admission until their 28th postnatal day or until discharge. Daily stool samples, painful/stressful experiences, feeding patterns, and other clinical and demographic data were collected. Gut microbiota was profiled using 16S rRNA sequencing, and operational taxonomic units (OTUs) were selected to predict the neurobehaviors. The neurobehavioral development was assessed by the Neonatal Neurobehavioral Scale (NNNS) at 36 to 38 weeks of post-menstrual age (PMA). Fifty-five infants who had NNNS measurements were included in the sparse log-contrast regression analysis. Results: Preterm infants who experienced a high level of pain/stress during the NICU hospitalization had higher NNNS stress/abstinence scores. Eight operational taxonomic units (OTUs) were identified to be associated with NNNS subscales after controlling demographic and clinical features, feeding patterns, and painful/stressful experiences. These OTUs and taxa belonging to seven genera, i.e., Enterobacteriaceae_unclassified, Escherichia-Shigella, Incertae_Sedis, Veillonella, Enterococcus, Clostridium_sensu_stricto_1, and Streptococcus with five belonging to Firmicutes and two belonging to Proteobacteria phylum. The enriched abundance of Enterobacteriaceae_unclassified (OTU17) and Streptococcus (OTU28) were consistently associated with less optimal neurobehavioral outcomes. The other six OTUs were also associated with infant neurobehavioral responses depending on days at NICU stay. Conclusions: This study explored the dynamic impact of specific OTUs on neurobehavioral development in preterm infants after controlling for early life experiences, i.e., acute and chronic pain/stress and feeding in the NICU. The gut microbiota and acute pain/stressful experiences dynamically impact the neurobehavioral development in preterm infants during their NICU hospitalization.

During the investigations of macrofungi resources in Zhejiang Province, China, an interesting wood rot fungus was collected. Based on morphological and molecular phylogenetic studies, it was described as a new species Anthracophyllum sinense. A. sinense is characterized by its sessile, charcoal black and pleurotoid pileus; sparse, occasionally branches lamellae; oval basidiospores measuring (8–)9–11.2–13(–14) µm × (5–)6–6.6–8(–9) µm, with obvious spore tips; clavate basidia with obvious sterigmata; and non-heteromorphous cystidium. A. sinense established a separate lineage that was similar to A. archeri and A. lateritium in the phylogenetic tree.

An experimental study was conducted to investigate the effects of loading cycles on seismic behavior and damage properties for flexure-shear critical reinforced concrete columns. Two groups of circular columns (including 8 specimens) with different shear span ratios were tested under quasi-static loads with various cycles, and the numbers of load cycle were designed as 0 (i.e., monotonic loading), 3, 10, and 20 cycles, respectively. The failure modes, load-deformation curves, ductility and energy dissipation capacity of the flexure-shear critical columns with various loading cycles were explored. Test results revealed that the shear effects and cumulative damage effects induced by cyclic loading are intensified with the increase of the loading cycles, which demonstrated that the columns are prone to occur the flexure-shear failure with the increase of the cycles. The study examined that the ultimate deformation is the most crucial factor affecting the damage properties of flexure-shear critical columns. The ultimate displacement diminishes with the loading cycles increase, and it reduces by 38%, 50%, and 62%, respectively, when the loading cycles increase from 0 to 3, 10, and 20 cycles. Additionally, the damage properties of flexure-shear critical columns are also pertinent to cumulative energy dissipation. The cumulative energy dissipation of column specimens increases obviously after yielding and increases with the loading cycles increase. An new two-parameter seismic damage model considering ultimate deformation and energy dissipation that including the effects of loading cycles was proposed, and the model could optimally analyze the damage properties of flexure-shear critical columns subjected to seismic excitation.

The Lowest Radial Distance (LoRaD) method is a modification of the recently introduced Partition-Weighted Kernel method for estimating the marginal likelihood of a model, a quantity important for Bayesian model selection. For analyses involving a fixed tree topology, LoRaD improves upon the Steppingstone or Thermodynamic Integration (Path Sampling) approaches now in common use in phylogenetics because it requires sampling only from the posterior distribution, avoiding the need to sample from a series of ad hoc power posterior distributions, and yet is more accurate than other fast methods such as the Generalized Harmonic Mean (GHM) method. We show that the method performs well in comparison to the Generalized Steppingstone method on an empirical fixed-topology example from molecular phylogenetics involving 180 parameters. The LoRaD method can also be used to obtain the marginal likelihood in the variable-topology case if at least one tree topology occurs with sufficient frequency in the posterior sample to allow accurate estimation of the marginal likelihood conditional on that topology. [Bayesian; marginal likelihood; phylogenetics.]

The complexity of energy infrastructure at large institutions increasingly calls for data-driven monitoring of energy usage. This article presents a hybrid monitoring algorithm for detecting consumption surges using statistical hypothesis testing, leveraging the posterior distribution and its information about uncertainty to introduce randomness in the parameter estimates, while retaining the frequentist testing framework. This hybrid approach is designed to be asymptotically equivalent to the Neyman-Pearson test. We show via extensive simulation studies that the hybrid approach enjoys control over type-1 error rate even with finite sample sizes whereas the naive plug-in method tends to exceed the specified level, resulting in overpowered tests. The proposed method is applied to the natural gas usage data at the University of Connecticut.

Early life stress is commonly experienced by infants, especially preterm infants, and may impact their neurodevelopmental outcomes in their early and later lives. Mitochondrial function/dysfunction may play an important role underlying the linkage of prenatal and postnatal stress and neurodevelopmental outcomes in infants. This review aimed to provide insights on the relationship between early life stress and neurodevelopment and the mechanisms of mitochondrial function/dysfunction that contribute to the neuropathology of stress. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to develop this systematic review. PubMed, Scopus, PsycINFO, and Biosis databases were searched for primary research articles published between 2010 and 2021 that examined the relationships among mitochondrial function/dysfunction, infant stress, and neurodevelopment. Thirty studies were identified. There is evidence to support that mitochondrial function/dysfunction mediates the relationship between prenatal and postnatal stress and neurodevelopmental outcomes in infants. Maternal transgenerational transmission of mitochondrial bioenergetic patterns influenced prenatal stress induced neurodevelopmental outcomes and behavioral changes in infants. Multiple functionally relevant mitochondrial proteins, genes, and polymorphisms were associated with stress exposure. This is the first review of the role that mitochondrial function/dysfunction plays in the association between stress and neurodevelopmental outcomes in full-term and preterm infants. Although multiple limitations were found based on the lack of data on the influence of biological sex, and due to invasive sampling, and lack of longitudinal data, many genes and proteins associated with mitochondrial function/dysfunction were found to influence neurodevelopmental outcomes in the early life of infants.

In this paper, we propose a new partial borrowing-by-parts power prior for carrying out the analysis of co-longitudinal and survival data within the joint modeling framework. The borrowing-by-parts power prior facilitates borrowing the information from a subset of the data, from a subset of the model parameters, or from the different parts of the joint model. The deviance information criterion is used to quantify the gain in the fit of the current longitudinal and survival data when leveraging external co-data. A Markov chain Monte Carlo sampling algorithm is developed for carrying out Bayesian computations. The proposed methodology is motivated by two large concurrent clinical trials: Selenium and Vitamin E Cancer Prevention Trial (SELECT) and Prostate, Lung, Colon, Ovarian (PLCO) prevention trial. In both trials, the longitudinal biomarkers and competing risks survival data were collected. A detailed analysis of the PLCO and SELECT data is conducted to demonstrate the usefulness of the proposed methodology.

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ImportanceMesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to anti-seizure medications. While most MTLE patients do not have pathogenic germline genetic variants, the contribution of post-zygotic (i.e., somatic) variants in the brain is unknown.ObjectiveTo test the association between pathogenic somatic variants in the hippocampus and MTLE.DesignThis case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically-treated patients with MTLE and age- and sex-matched neurotypical controls. Participants were enrolled from 1988 through 2019 and clinical data was collected retrospectively. Whole-exome and gene-panel sequencing (depth>500X) were used to identify candidate pathogenic somatic variants. A subset of novel variants were functionally evaluated using cellular and molecular assays.SettingLevel 4 epilepsy centers, multi-center study.ParticipantsNon-lesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE patients who underwent anterior medial temporal lobectomy. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks.ExposuresDrug-resistant MTLE.Main Outcomes and MeasuresPresence and abundance of pathogenic somatic variants in the hippocampus versus the unaffected temporal neocortex.ResultsSamples were obtained from 105 MTLE patients (52 male, 53 female; age: MED [IQR], 32 [26-44]) and 30 neurotypical controls (19 male, 11 female; age: MED [IQR], 37 [18-53]). Eleven pathogenic somatic variants, enriched in the hippocampus relative to the unaffected temporal neocortex (MED [IQR], 1.92 [1.5-2.7] vs 0.3 [0-0.9], pPTPN11, SOS1, KRAS, BRAF, andNF1, all predicted to constitutively activate Ras/Raf/MAPK signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for thePTPN11variants as a possible dominant gain-of-function mechanism.Conclusions and RelevanceHippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in single cardiomyocytes from individuals across the human lifespan. Aged cardiomyocytes were found to have a higher burden of sSNVs and show mutational signatures that suggest failed repair of oxidative DNA damage.

Purpose: an association with a reduction in the risk of all-cause mortality (ACM) and the use of adjuvant as compared with early postradical prostatectomy salvage radiation therapy (sRT) in men with pN1 prostate cancer (PC) has been observed. Yet, whether this finding applies irrespective of the number of positive lymph nodes (LNs) after adjusting for the time-dependent use and duration of androgen deprivation therapy is unknown and is addressed in the current study. Methods: univariable and multivariable Cox regression was used to evaluate whether the ACM risk ratio for time-dependent use of adjuvant versus early sRT per unit increase in positive pelvic LNs was significantly reduced. Adjusted ACM estimates were calculated among men who received adjuvant, early salvage, or no RT stratified by one to three or four or more positive pelvic LNs. Results: after a median follow-up of 7.02 years, 986 (5.50%) men died, with 223 (22.62%) of PC. Adjuvant compared with early sRT was associated with a significantly lower ACM risk per unit increase in positive pelvic LNs (adjusted hazard ratio: 0.92; 95% CI, 0.85 to 0.99; P = .03). A significant difference in the 7-year adjusted ACM estimates favoring aRT versus early sRT was observed in men with four or more positive LNs (7.74% v 23.36%) in that the 95% CI for the 15.62% difference (5.90 to 25.35) excluded 0.00, but this was not true for men with 1-3 positive LNs (14.27% v 13.89%; 95% CI for the 0.38% difference [–7.02 to 7.79]). Conclusion: adjuvant compared with early sRT in men with pN1 PC was associated with a decreased ACM risk, and this reduction increased with each additional positive pelvic LN., Janssen