Glutamate indicators with improved activation kinetics and localization for imaging synaptic transmission.

The fluorescent glutamate indicator iGluSnFR enables imaging of neurotransmission with genetic and molecular specificity. However, existing iGluSnFR variants exhibit low in vivo signal-to-noise ratios, saturating activation kinetics and exclusion from postsynaptic densities. Using a multiassay screen in bacteria, soluble protein and cultured neurons, we generated variants with improved signal-to-noise ratios and kinetics. We developed surface display constructs that improve iGluSnFR's nanoscopic localization to postsynapses. The resulting indicator iGluSnFR3 exhibits rapid nonsaturating activation kinetics and reports synaptic glutamate release with decreased saturation and increased specificity versus extrasynaptic signals in cultured neurons. Simultaneous imaging and electrophysiology at individual boutons in mouse visual cortex showed that iGluSnFR3 transients report single action potentials with high specificity. In vibrissal sensory cortex layer 4, we used iGluSnFR3 to characterize distinct patterns of touch-evoked feedforward input from thalamocortical boutons and both feedforward and recurrent input onto L4 cortical neuron dendritic spines.

A Bayesian nonparametric meta-analysis model for estimating the reference interval.

A reference interval represents the normative range for measurements from a healthy population. It plays an important role in laboratory testing, as well as in differentiating healthy from diseased patients. The reference interval based on a single study might not be applicable to a broader population. Meta-analysis can provide a more generalizable reference interval based on the combined population by synthesizing results from multiple studies. However, the assumptions of normally distributed underlying study-specific means and equal within-study variances, which are commonly used in existing methods, are strong and may not hold in practice. We propose a Bayesian nonparametric model with more flexible assumptions to extend random effects meta-analysis for estimating reference intervals. We illustrate through simulation studies and two real data examples the performance of our proposed approach when the assumptions of normally distributed study means and equal within-study variances do not hold.

Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.

Flexible bivariate correlated count data regression.

Multivariate count data are common in many disciplines. The variables in such data often exhibit complex positive or negative dependency structures. We propose three Bayesian approaches to modeling bivariate count data by simultaneously considering covariate-dependent means and correlation. A direct approach utilizes a bivariate negative binomial probability mass function developed in Famoye (2010, Journal of Applied Statistics). The second approach fits bivariate count data indirectly using a bivariate Poisson-gamma mixture model. The third approach is a bivariate Gaussian copula model. Based on the results from simulation analyses, the indirect and copula approaches perform better overall than the direct approach in terms of model fitting and identifying covariate-dependent association. The proposed approaches are applied to two RNA-sequencing data sets for studying breast cancer and melanoma (BRCA-US and SKCM-US), respectively, obtained through the International Cancer Genome Consortium.

Estimation of sensitivity and specificity of multiple repeated binary tests without a gold standard.

A model for multiple diagnostic tests, applied repeatedly over time on each subject, is proposed; gold standard data are not required. The model is identifiable with as few as three tests, and correlation among tests at each time point in the diseased and nondiseased populations, as well as across time points, is explicitly included. An efficient Markov chain Monte Carlo scheme allows for straightforward posterior inference; sample R code is available in the Supporting Web Materials for this paper. The proposed model is broadly illustrated via simulations and an analysis of scaphoid fracture data from a prospective study. In addition, omnibus tests constructed from individual tests in parallel and serial are considered.

Bayes factors for choosing among six common survival models.

A super model that includes proportional hazards, proportional odds, accelerated failure time, accelerated hazards, and extended hazards models, as well as the model proposed in Diao et al. (Biometrics 69(4):840-849, 2013) accounting for crossed survival as special cases is proposed for the purpose of testing and choosing among these popular semiparametric models. Efficient methods for fitting and computing fast, approximate Bayes factors are developed using a nonparametric baseline survival function based on a transformed Bernstein polynomial. All manner of censoring is accommodated including right, left, and interval censoring, as well as data that are observed exactly and mixtures of all of these; current status data are included as a special case. The method is tested on simulated data and two real data examples. The approach is easily carried out via a new function in the spBayesSurv R package.

Chronic, wireless recordings of large-scale brain activity in freely moving rhesus monkeys.

Advances in techniques for recording large-scale brain activity contribute to both the elucidation of neurophysiological principles and the development of brain-machine interfaces (BMIs). Here we describe a neurophysiological paradigm for performing tethered and wireless large-scale recordings based on movable volumetric three-dimensional (3D) multielectrode implants. This approach allowed us to isolate up to 1,800 neurons (units) per animal and simultaneously record the extracellular activity of close to 500 cortical neurons, distributed across multiple cortical areas, in freely behaving rhesus monkeys. The method is expandable, in principle, to thousands of simultaneously recorded channels. It also allows increased recording longevity (5 consecutive years) and recording of a broad range of behaviors, such as social interactions, and BMI paradigms in freely moving primates. We propose that wireless large-scale recordings could have a profound impact on basic primate neurophysiology research while providing a framework for the development and testing of clinically relevant neuroprostheses.

Assessment of DPOAE test-retest difference curves via hierarchical Gaussian processes.

Distortion product otoacoustic emissions (DPOAE) testing is a promising alternative to behavioral hearing tests and auditory brainstem response testing of pediatric cancer patients. The central goal of this study is to assess whether significant changes in the DPOAE frequency/emissions curve (DP-gram) occur in pediatric patients in a test-retest scenario. This is accomplished through the construction of normal reference charts, or credible regions, that DP-gram differences lie in, as well as contour probabilities that measure how abnormal (or in a certain sense rare) a test-retest difference is. A challenge is that the data were collected over varying frequencies, at different time points from baseline, and on possibly one or both ears. A hierarchical structural equation Gaussian process model is proposed to handle the different sources of correlation in the emissions measurements, wherein both subject-specific random effects and variance components governing the smoothness and variability of each child's Gaussian process are coupled together.

Bayesian regression for group testing data.

Group testing involves pooling individual specimens (e.g., blood, urine, swabs, etc.) and testing the pools for the presence of a disease. When individual covariate information is available (e.g., age, gender, number of sexual partners, etc.), a common goal is to relate an individual's true disease status to the covariates in a regression model. Estimating this relationship is a nonstandard problem in group testing because true individual statuses are not observed and all testing responses (on pools and on individuals) are subject to misclassification arising from assay error. Previous regression methods for group testing data can be inefficient because they are restricted to using only initial pool responses and/or they make potentially unrealistic assumptions regarding the assay accuracy probabilities. To overcome these limitations, we propose a general Bayesian regression framework for modeling group testing data. The novelty of our approach is that it can be easily implemented with data from any group testing protocol. Furthermore, our approach will simultaneously estimate assay accuracy probabilities (along with the covariate effects) and can even be applied in screening situations where multiple assays are used. We apply our methods to group testing data collected in Iowa as part of statewide screening efforts for chlamydia, and we make user-friendly R code available to practitioners.

Flexible parametrization of variance functions for quantal response data derived from counts.

Although the Poisson model has been widely used to fit count data, a well-known drawback is that the Poisson mean equals its variance. Many alternative models for counts that are overdispersed relative to Poisson have been developed to solve this issue, including the negative binomial model. In this article, the negative binomial model with a four-parameter logistic mean is proposed to handle these types of counts, with variance that flexibly depends on the mean. Various parameterizations for the variance are considered, including extra-Poisson variability modeled as an exponentiated B-spline. Thus, the proposed model ably captures the leveling off of the mean, i.e., the "lazy-S" shape often encountered for overdispersed dose-response counts, simultaneously taking into account both overdispersion and natural mortality. Two real datasets illustrate the merits of the proposed approach: media colony counts after tuberculosis decontamination, and the number of monkeys killed by Ache hunters over several hunting trips in the Paraguayan tropical forest.

Generalized accelerated failure time spatial frailty model for arbitrarily censored data.

Flexible incorporation of both geographical patterning and risk effects in cancer survival models is becoming increasingly important, due in part to the recent availability of large cancer registries. Most spatial survival models stochastically order survival curves from different subpopulations. However, it is common for survival curves from two subpopulations to cross in epidemiological cancer studies and thus interpretable standard survival models can not be used without some modification. Common fixes are the inclusion of time-varying regression effects in the proportional hazards model or fully nonparametric modeling, either of which destroys any easy interpretability from the fitted model. To address this issue, we develop a generalized accelerated failure time model which allows stratification on continuous or categorical covariates, as well as providing per-variable tests for whether stratification is necessary via novel approximate Bayes factors. The model is interpretable in terms of how median survival changes and is able to capture crossing survival curves in the presence of spatial correlation. A detailed Markov chain Monte Carlo algorithm is presented for posterior inference and a freely available function frailtyGAFT is provided to fit the model in the R package spBayesSurv. We apply our approach to a subset of the prostate cancer data gathered for Louisiana by the surveillance, epidemiology, and end results program of the National Cancer Institute.

Association of green tea consumption with mortality from all-cause, cardiovascular disease and cancer in a Chinese cohort of 165,000 adult men.

Tea is the most ancient and popular beverage in the world, and its beneficial health effects has attracted tremendous attention worldwide. However, the prospective evidence relating green tea consumption to total and cause-specific mortality is still limited and inconclusive. We recruited 164,681 male participants free of pre-existing disease during 1990-1991, with green tea consumption and other covariates assessed by the standardized questionnaire and mortality follow up continued until 2006 (mean 11 years; total person-years: 1,961,791). Cox regression analyses were used to quantify the associations of green tea consumption with all-cause (n = 32,700), CVD (n = 11,839) and cancer (n = 7002) mortality, adjusting simultaneously for potential confounders. At baseline, 18 % reported regular consumption of green tea. Compared with non-green tea drinkers, regular drinkers had significantly lower all-cause mortality, with adjusted hazard ratios (HRs) being 0.94 (95 % CI 0.89, 0.99) for ≤5 g/day, 0.95 (0.91, 0.99) for 5-10 g/day and 0.89 (0.85, 0.93) for >10 g/day. For CVD mortality, the corresponding HRs were 0.93 (0.85, 1.01) 0.91 (0.85, 0.98) and 0.86 (0.79, 0.93), respectively, while for cancer they were 0.86 (0.78, 0.98), 0.92 (0.83, 1.00) and 0.79 (0.71, 0.88), respectively. The patterns of these associations varied by smoking, alcohol drinking and locality. This large prospective study shows that regular green tea consumption is associated with significantly reduced risk of death from all-cause, CVD and cancer among Chinese adults.

Spatial extended hazard model with application to prostate cancer survival.

This article develops a Bayesian semiparametric approach to the extended hazard model, with generalization to high-dimensional spatially grouped data. County-level spatial correlation is accommodated marginally through the normal transformation model of Li and Lin (2006, Journal of the American Statistical Association 101, 591-603), using a correlation structure implied by an intrinsic conditionally autoregressive prior. Efficient Markov chain Monte Carlo algorithms are developed, especially applicable to fitting very large, highly censored areal survival data sets. Per-variable tests for proportional hazards, accelerated failure time, and accelerated hazards are efficiently carried out with and without spatial correlation through Bayes factors. The resulting reduced, interpretable spatial models can fit significantly better than a standard additive Cox model with spatial frailties.

Marginal Bayesian nonparametric model for time to disease arrival of threatened amphibian populations.

The global emergence of Batrachochytrium dendrobatidis (Bd) has caused the extinction of hundreds of amphibian species worldwide. It has become increasingly important to be able to precisely predict time to Bd arrival in a population. The data analyzed herein present a unique challenge in terms of modeling because there is a strong spatial component to Bd arrival time and the traditional proportional hazards assumption is grossly violated. To address these concerns, we develop a novel marginal Bayesian nonparametric survival model for spatially correlated right-censored data. This class of models assumes that the logarithm of survival times marginally follow a mixture of normal densities with a linear-dependent Dirichlet process prior as the random mixing measure, and their joint distribution is induced by a Gaussian copula model with a spatial correlation structure. To invert high-dimensional spatial correlation matrices, we adopt a full-scale approximation that can capture both large- and small-scale spatial dependence. An efficient Markov chain Monte Carlo algorithm with delayed rejection is proposed for posterior computation, and an R package spBayesSurv is provided to fit the model. This approach is first evaluated through simulations, then applied to threatened frog populations in Sequoia-Kings Canyon National Park.

Flexible regression models for ROC and risk analysis, with or without a gold standard.

A novel semiparametric regression model is developed for evaluating the covariate-specific accuracy of a continuous medical test or biomarker. Ideally, studies designed to estimate or compare medical test accuracy will use a separate, flawless gold-standard procedure to determine the true disease status of sampled individuals. We treat this as a special case of the more complicated and increasingly common scenario in which disease status is unknown because a gold-standard procedure does not exist or is too costly or invasive for widespread use. To compensate for missing data on disease status, covariate information is used to discriminate between diseased and healthy units. We thus model the probability of disease as a function of 'disease covariates'. In addition, we model test/biomarker outcome data to depend on 'test covariates', which provides researchers the opportunity to quantify the impact of covariates on the accuracy of a medical test. We further model the distributions of test outcomes using flexible semiparametric classes. An important new theoretical result demonstrating model identifiability under mild conditions is presented. The modeling framework can be used to obtain inferences about covariate-specific test accuracy and the probability of disease based on subject-specific disease and test covariate information. The value of the model is illustrated using multiple simulation studies and data on the age-adjusted ability of soluble epidermal growth factor receptor - a ubiquitous serum protein - to serve as a biomarker of lung cancer in men. SAS code for fitting the model is provided. Copyright © 2015 John Wiley & Sons, Ltd.

Bayesian Models for Detecting Difference Boundaries in Areal Data.

With increasing accessibility to Geographical Information Systems (GIS) software, researchers and administrators in public health routinely encounter areal data compiled as aggregates over areal regions, such as counts or rates across counties in a state. Spatial models for areal data attempt to deliver smoothed maps by accounting for high variability in certain regions. Subsequently, inferential interest is focused upon formally identifying the "diffrence edges" or " difference boundaries" on the map, which delineate adjacent regions with vastly disparate outcomes, perhaps caused by latent risk factors. We propose nonparametric Bayesian models for areal data that can formally identify boundaries between disparate neighbors. After elucidating these models and their estimation methods, we conduct simulation experiments to assess their effectiveness and subsequently analyze Pneumonia and Influenza hospitalization maps from the SEER-Medicare program in Minnesota, where we detect and report highly disparate neighboring counties.

Accelerated hazards model based on parametric families generalized with Bernstein polynomials.

A transformed Bernstein polynomial that is centered at standard parametric families, such as Weibull or log-logistic, is proposed for use in the accelerated hazards model. This class provides a convenient way towards creating a Bayesian nonparametric prior for smooth densities, blending the merits of parametric and nonparametric methods, that is amenable to standard estimation approaches. For example optimization methods in SAS or R can yield the posterior mode and asymptotic covariance matrix. This novel nonparametric prior is employed in the accelerated hazards model, which is further generalized to time-dependent covariates. The proposed approach fares considerably better than previous approaches in simulations; data on the effectiveness of biodegradable carmustine polymers on recurrent brain malignant gliomas is investigated.

Sample size requirements for establishing clinical test-retest standards.

OBJECTIVE: To define sample size requirements for establishing clinical serial monitoring protocols. DESIGN: The 95% confidence bound of a critical difference score is defined and used to identify false-negative regions suitable for sample size calculation. RESULTS: Reference subject sample sizes vary from about 40 to 480 subjects, depending on the minimum acceptable error rates of the clinical protocol. CONCLUSIONS: Sample size requirements for establishing test-retest standards are generally defined and suitable for any serial monitoring protocol.

Subcortical neuronal ensembles: an analysis of motor task association, tremor, oscillations, and synchrony in human patients.

Deep brain stimulation (DBS) has expanded as an effective treatment for motor disorders, providing a valuable opportunity for intraoperative recording of the spiking activity of subcortical neurons. The properties of these neurons and their potential utility in neuroprosthetic applications are not completely understood. During DBS surgeries in 25 human patients with either essential tremor or Parkinson's disease, we acutely recorded the single-unit activity of 274 ventral intermediate/ventral oralis posterior motor thalamus (Vim/Vop) neurons and 123 subthalamic nucleus (STN) neurons. These subcortical neuronal ensembles (up to 23 neurons sampled simultaneously) were recorded while the patients performed a target-tracking motor task using a cursor controlled by a haptic glove. We observed that modulations in firing rate of a substantial number of neurons in both Vim/Vop and STN represented target onset, movement onset/direction, and hand tremor. Neurons in both areas exhibited rhythmic oscillations and pairwise synchrony. Notably, all tremor-associated neurons exhibited synchrony within the ensemble. The data further indicate that oscillatory (likely pathological) neurons and behaviorally tuned neurons are not distinct but rather form overlapping sets. Whereas previous studies have reported a linear relationship between power spectra of neuronal oscillations and hand tremor, we report a nonlinear relationship suggestive of complex encoding schemes. Even in the presence of this pathological activity, linear models were able to extract motor parameters from ensemble discharges. Based on these findings, we propose that chronic multielectrode recordings from Vim/Vop and STN could prove useful for further studying, monitoring, and even treating motor disorders.

A Bayesian goodness of fit test and semiparametric generalization of logistic regression with measurement data.

Logistic regression is a popular tool for risk analysis in medical and population health science. With continuous response data, it is common to create a dichotomous outcome for logistic regression analysis by specifying a threshold for positivity. Fitting a linear regression to the nondichotomized response variable assuming a logistic sampling model for the data has been empirically shown to yield more efficient estimates of odds ratios than ordinary logistic regression of the dichotomized endpoint. We illustrate that risk inference is not robust to departures from the parametric logistic distribution. Moreover, the model assumption of proportional odds is generally not satisfied when the condition of a logistic distribution for the data is violated, leading to biased inference from a parametric logistic analysis. We develop novel Bayesian semiparametric methodology for testing goodness of fit of parametric logistic regression with continuous measurement data. The testing procedures hold for any cutoff threshold and our approach simultaneously provides the ability to perform semiparametric risk estimation. Bayes factors are calculated using the Savage-Dickey ratio for testing the null hypothesis of logistic regression versus a semiparametric generalization. We propose a fully Bayesian and a computationally efficient empirical Bayesian approach to testing, and we present methods for semiparametric estimation of risks, relative risks, and odds ratios when parametric logistic regression fails. Theoretical results establish the consistency of the empirical Bayes test. Results from simulated data show that the proposed approach provides accurate inference irrespective of whether parametric assumptions hold or not. Evaluation of risk factors for obesity shows that different inferences are derived from an analysis of a real data set when deviations from a logistic distribution are permissible in a flexible semiparametric framework.