Bayesian modeling of ChIP-chip data using latent variables

When rejecting and accepting hypotheses, it is important to determine the risk of false positive conclusions. Hierarchical Bayesian models are frequently applied in cognitive science, psychology, cognitive neuroscience, and psychiatry to reduce the variability of low-level parameters through partial pooling, and to obtain more robust parameter estimates for complex models using limited data. This may lower the risk of false positive inferences from lower-level estimates. In contrast, higher-level (e.g. group-level) estimates may be more affected by modeling choices (e.g. prior distributions), population-level variances in effects, and inference methods, which may in turn affect false positive rates for group-level effects. Here we used simulation and computational modeling to systematically examine false positive rates and effects of specific modeling choices on inferences in a simple hierarchical Bayesian temporal discounting model. To this end, 600 data sets of a temporal discounting task with two conditions were simulated, drawing individual condition effect parameters from a null distribution with varying standard deviations. For each simulated data set, the group-level mean change in the discount rate was modeled with eight different prior variances of the condition effect. Results were subsequently evaluated using several commonly applied Bayesian inference methods: the Savage-Dickey Bayes factor (BF), the directional Bayes factor (dBF), P(effect > 0), and the highest density interval (HDI) against zero decision rule. Results confirm that inference methods that directly depend on the posterior distribution can be used regardless of prior variances, whereas the Savage-Dickey BF should only be used with sufficiently informative priors. Based on the simulation work, decision thresholds that ensure false positive rates below 5% are provided for each inference method. Results are discussed in the context of computational modeling approaches in cognitive (neuro-)science and psychology.

There have been few investigations of cancer prognosis models based on Bayesian hierarchical models. In this study, we used a novel Bayesian method to screen mRNAs and estimate the effects of mRNAs on the prognosis of patients with lung adenocarcinoma. Based on the identified mRNAs, we can build a prognostic model combining mRNAs and clinical features, allowing us to explore new molecules with the potential to predict the prognosis of lung adenocarcinoma. The mRNA data (n = 594) and clinical data (n = 470) for lung adenocarcinoma were obtained from the TCGA database. Gene set enrichment analysis (GSEA), univariate Cox proportional hazards regression, and the Bayesian hierarchical Cox proportional hazards model were used to explore the mRNAs related to the prognosis of lung adenocarcinoma. Multivariate Cox proportional hazard regression was used to identify independent markers. The prediction performance of the prognostic model was evaluated not only by the internal cross-validation but also by the external validation based on the GEO dataset (n = 437). With the Bayesian hierarchical Cox proportional hazards model, a 14-gene signature that included CPS1, CTPS2, DARS2, IGFBP3, MCM5, MCM7, NME4, NT5E, PLK1, POLR3G, PTTG1, SERPINB5, TXNRD1, and TYMS was established to predict overall survival in lung adenocarcinoma. Multivariate analysis demonstrated that the 14-gene signature (HR 3.960, 95% CI 2.710–5.786), T classification (T1, reference; T3, HR 1.925, 95% CI 1.104–3.355) and N classification (N0, reference; N1, HR 2.212, 95% CI 1.520–3.220; N2, HR 2.260, 95% CI 1.499–3.409) were independent predictors. The C-index of the model was 0.733 and 0.735, respectively, after performing cross-validation and external validation, a nomogram was provided for better prediction in clinical application. Bayesian hierarchical Cox proportional hazards models can be used to integrate high-dimensional omics information into a prediction model for lung adenocarcinoma to improve the prognostic prediction and discover potential targets. This approach may be a powerful predictive tool for clinicians treating malignant tumours.

Objective The Bayesian model plays an important role in diagnostic test evaluation in the absence of the gold standard, which used the external prior distribution of a parameter combined with sample data to yield the posterior distribution of the test characteristics. However, the correlation between diagnostic tests has always been a problem that cannot be ignored in the Bayesian model evaluation. This study will discuss how different Bayesian model, correlation scenarios, and prior distribution affect the outcome. MethodsThe data analyzed in this study was gathered during studies of patients presenting to the Nanjing Chest Hospital with suspected tuberculosis. The diagnostic character of T-SPOT.Tb and KD38 tuberculosis antibody test were evaluated in different Bayesian model, and discharge diagnosis as a gold standard was used to verify the model results in the end. Result The comparison of four models under the conditional independence situation found that Bayesian probabilistic constraint model was consistent with the Conditional Covariance Bayesian model. The results were mainly affected by prior information. The sensitivity and specificity of the two tests in Conditional Covariance Bayesian model in prior constraint situation were considerably higher than the Bayesian probabilistic constraint model in prior constraint situation. The results of the four models under the conditional dependence situation were similar to the conditional independence situation; pD was also negative with no prior constraint situation in both model Bayesian probabilistic constraint model and Conditional Covariance Bayesian model. The Deviance Information Criterion of Bayesian probabilistic constraint model was close to model Conditional Covariance Bayesian model, but pD of Conditional Covariance Bayesian model in Prior constraint situation (pD=2.40) was higher than the Bayesian probabilistic constraint model in Prior constraint situation (pD=1.66). Conclusion The result of Conditional Covariance Bayesian model in prior constraint with conditional independence situation was closest to the result of gold standard evaluation in our data. Both of the two Bayesian methods are the feasible way for the evaluation of diagnostic test in the absence of the gold standard diagnostic. Prior source, priority number, and conditional dependencies should be considered in the method selection, the accuracy of posterior estimation mainly depending on the prior distribution.

Impact of the Scientific Registry of Transplant Recipients’ New Bayesian Method on Estimating Center Effects and Flagging of Centers as Worse Than Expected

My dissertation is motivated by the need for improved statistical approaches for understanding differences in cancer risk in rural vs. urban areas. To accomplish this goal, we develop three statistical methods that can be used to model and explain differences in age-adjusted rates between small areas with differing characteristics. These methods allow researchers to draw meaningful inferences from sparse spatial or spatio-temporal datasets at the ZIP code or county levels. Furthermore, they can be used to identify regions that might require public health interventions and to motivate costly data collection efforts at the individual level. The statistical methods we propose in this dissertation can be classified into two categories: estimation and mediation. Chapter 2 focuses on precisely estimating age-adjusted cancer mortality rates for small areas from spatio-temporal datasets with an excessive number of zeros. A large proportion of zeros are often present in datasets involving low-prevalence diseases and in datasets that include rural regions with small population sizes. When stratifying counts for each region and year by age group in the process of estimating age-adjusted rates, the proportion of zeros in the dataset is further inflated. We propose a novel Bayesian hierarchical hurdle model with spatial and temporal random effects for estimating age-adjusted rates in these settings. Via a simulation study and two data examples, we study the performance of this model and make recommendations as to when it should be used over a Bayesian hierarchical Poisson regression model for age-adjusted rates. Chapters 3 and 4 address the goal of mediation. Specifically, Chapter 3 focuses on a method for performing a mediation analysis and Chapter 4 introduces a method for performing a decomposition analysis. Both chapters aim to explain a difference in age-adjusted rates at the ZIP code level based on either a ZIP code-level exposure (mediation) or a fixed characteristic (decomposition). We develop flexible statistical methods that use Bayesian hierarchical models with spatial random effects and a Bayesian version of the g-computation technique from causal inference. Both methods were designed to create counterfactual small area estimates of age-adjusted rates within the analysis and consequently stable estimates of the effects of interest. Through a simulation study, we illustrate a high level of precision and minimal bias in the total, direct, and indirect effects when using our proposed mediation analysis method. We also compare our proposed mediation method to two methods used in the medical literature and show that our method exhibits the best trade-off of bias and variance. To demonstrate the performance of our decomposition method, we perform a data analysis to understand whether park access explains the disparity in age-adjusted colorectal cancer incidence rates in rural vs. urban ZIP codes in Iowa. We illustrate that precise inferences can be made from sparse ZIP code-level datasets when incorporating small area estimation techniques into each analysis.

Appropriate inference for stocks or species with low-quality data (poor data) or limited data (data poor) is extremely important. Hierarchical Bayesian methods are especially applicable to small-area, small-sample-size estimation problems because they allow poor-data species to borrow strength from species with good-quality data. We used a hammerhead shark complex as an example to investigate the advantages of using hierarchical Bayesian models in assessing the status of poor-data and data-poor exploited species. The hammerhead shark complex (Sphyrna spp.) along the Atlantic and Gulf of Mexico coasts of the United States is composed of three species: the scalloped hammerhead (S. lewini), the great hammerhead (S. mokarran), and the smooth hammerhead (S. zygaena) sharks. The scalloped hammerhead comprises 70-80% of the catch and has catch and relative abundance data of good quality, whereas great and smooth hammerheads have relative abundance indices that are both limited and of low quality presumably because of low stock density and limited sampling. Four hierarchical Bayesian state-space surplus production models were developed to simulate variability in population growth rates, carrying capacity, and catchability of the species. The results from the hierarchical Bayesian models were considerably more robust than those of the nonhierarchical models. The hierarchical Bayesian approach represents an intermediate strategy between traditional models that assume different population parameters for each species and those that assume all species share identical parameters. Use of the hierarchical Bayesian approach is suggested for future hammerhead shark stock assessments and for modeling fish complexes with species-specific data, because the poor-data species can borrow strength from the species with good data, making the estimation more stable and robust.

The most prevalent spatial data setting is, arguably, that of so-called geostatistical data, data that arise as random variables observed at fixed spatial locations. Collection of such data in space and in time has grown enormously in the past two decades. With it has grown a substantial array of methods to analyze such data. Here, we attempt a review of a fully model-based perspective for such data analysis, the approach of hierarchical modeling fitted within a Bayesian framework. The benefit, as with hierarchical Bayesian modeling in general, is full and exact inference, with proper assessment of uncertainty. Geostatistical modeling includes univariate and multivariate data collection at sites, continuous and categorical data at sites, static and dynamic data at sites, and datasets over very large numbers of sites and long periods of time. Within the hierarchical modeling framework, we offer a review of the current state of the art in these settings.

Conventional ground survey data are very accurate, but expensive. Airborne lidar data can reduce the costs and effort required to conduct large-scale forest surveys. It is critical to improve biomass estimation and evaluate carbon stock when we use lidar data. Bayesian methods integrate prior information about unknown parameters, reduce the parameter estimation uncertainty, and improve model performance. This study focused on predicting the independent tree aboveground biomass (AGB) with a hierarchical Bayesian model using airborne LIDAR data and comparing the hierarchical Bayesian model with classical methods (nonlinear mixed effect model, NLME). Firstly, we chose the best diameter at breast height (DBH) model from several widely used models through a hierarchical Bayesian method. Secondly, we used the DBH predictions together with the tree height (LH) and canopy projection area (CPA) derived by airborne lidar as independent variables to develop the AGB model through a hierarchical Bayesian method with parameter priors from the NLME method. We then compared the hierarchical Bayesian method with the NLME method. The results showed that the two methods performed similarly when pooling the data, while for small sample sizes, the Bayesian method was much better than the classical method. The results of this study imply that the Bayesian method has the potential to improve the estimations of both DBH and AGB using LIDAR data, which reduces costs compared with conventional measurements.

Intensity-duration-frequency curves in the Guangdong-Hong Kong-Macao Greater Bay Area inferred from the Bayesian hierarchical model

Childhood acute lymphoblastic leukemia (ALL) is a condition that arises from complex etiologies. The absence of consistent environmental risk factors and the presence of modest familial associations suggest ALL is a complex trait with an underlying genetic component. The identification of genetic factors associated with disease is complicated by complex genetic covariance structures and multiple testing issues. Both issues can be resolved with appropriate Bayesian variable selection methods. The present study was undertaken to extend our hierarchical Bayesian model for case-parent triads to incorporate single nucleotide polymorphisms (SNPs) and incorporate the biological grouping of SNPs within genes. Based on previous evidence that genetic variation in the folate metabolic pathway influences ALL risk, we evaluated 128 tagging SNPs in 16 folate metabolic genes among 118 ALL case-parent triads recruited from the Texas Children’s Cancer Center (Houston, TX) between 2003 and 2010. We used stochastic search gene suggestion (SSGS) in hierarchical Bayesian models to evaluate the association between folate metabolic SNPs and ALL. Using Bayes factors among these variants in childhood ALL case-parent triads, two SNPs were identified with a Bayes factor greater than 1. There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1 rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL. Our findings are suggestive of the role of inherited genetic variation in the folate metabolic pathway on childhood ALL risk, and they also suggest the utility of Bayesian variable selection methods in the context of case-parent triads for evaluating the role of SNPs on disease risk.

BackgroundAlthough frequentist paradigm has been the predominant approach to clinical studies for decades, some limitations associated with the frequentist null hypothesis significance testing have been recognized. Bayesian approaches can provide additional insights into data interpretation and inference by deriving posterior distributions of model parameters reflecting the clinical interest. In this article, we sought to demonstrate how Bayesian approaches can improve the data interpretation by reanalyzing the Rural Engagement in Primary Care for Optimizing Weight Reduction (REPOWER).MethodsREPOWER is a cluster randomized clinical trial comparing three care delivery models: in-clinic individual visits, in-clinic group visits, and phone-based group visits. The primary endpoint was weight loss at 24 months and the secondary endpoints included the proportions of achieving 5 and 10% weight loss at 24 months. We reanalyzed the data using a three-level Bayesian hierarchical model. The posterior distributions of weight loss at 24 months for each arm were obtained using Hamiltonian Monte Carlo. We then estimated the probability of having a higher weight loss and the probability of having greater proportion achieving 5 and 10% weight loss between groups. Additionally, a four-level hierarchical model was used to assess the partially nested intervention group effect which was not investigated in the original REPOWER analyses.ResultsThe Bayesian analyses estimated 99.5% probability that in-clinic group visits, compared with in-clinic individual visits, resulted in a higher percent weight loss (posterior mean difference: 1.8%[95% CrI: 0.5,3.2%]), a greater probability of achieving 5% threshold (posterior mean difference: 9.2% [95% CrI: 2.4, 16.0%]) and 10% threshold (posterior mean difference: 6.6% [95% CrI: 1.7, 11.5%]). The phone-based group visits had similar result. We also concluded that including intervention group did not impact model fit significantly.ConclusionsWe unified the analyses of continuous (the primary endpoint) and categorical measures (the secondary endpoints) of weight loss with one single Bayesian hierarchical model. This approach gained statistical power for the dichotomized endpoints by leveraging the information in the continuous data. Furthermore, the Bayesian analysis enabled additional insights into data interpretation and inference by providing posterior distributions for parameters of interest and posterior probabilities of different hypotheses that were not available with the frequentist approach.Trial registrationClinicalTrials.gov Identifier NCT02456636; date of registry: May 28, 2015.

A Bayesian approach to model the trends and variability in urban stormwater quality associated with catchment and hydrologic parameters

Meta-analyses are frequently performed on adverse event data and are primarily used for improving statistical power to detect safety signals. However, in the evaluation of drug safety for New Drug Applications, simple pooling of adverse event data from multiple clinical trials is still commonly used. We sought to propose a new Bayesian hierarchical meta-analytic approach based on consideration of a hierarchical structure of reported individual adverse event data from multiple randomized clinical trials. To develop our meta-analysis model, we extended an existing three-stage Bayesian hierarchical model by including an additional stage of the clinical trial level in the hierarchical model; this generated a four-stage Bayesian hierarchical model. We applied the proposed Bayesian meta-analysis models to published adverse event data from three premarketing randomized clinical trials of tadalafil and to a simulation study motivated by the case example to evaluate the characteristics of three alternative models. Comparison of the results from the Bayesian meta-analysis model with those from Fisher's exact test after simple pooling showed that 6 out of 10 adverse events were the same within a top 10 ranking of individual adverse events with regard to association with treatment. However, more individual adverse events were detected in the Bayesian meta-analysis model than in Fisher's exact test under the body system "Musculoskeletal and connective tissue disorders." Moreover, comparison of the overall trend of estimates between the Bayesian model and the standard approach (odds ratios after simple pooling methods) revealed that the posterior median odds ratios for the Bayesian model for most adverse events shrank toward values for no association. Based on the simulation results, the Bayesian meta-analysis model could balance the false detection rate and power to a better extent than Fisher's exact test. For example, when the threshold value of the posterior probability for signal detection was set to 0.8, the false detection rate was 41% and power was 88% in the Bayesian meta-analysis model, whereas the false detection rate was 56% and power was 86% in Fisher's exact test. Adverse events under the same body system were not necessarily positively related when we used "system organ class" and "preferred term" in the Medical Dictionary for Regulatory Activities as a hierarchical structure of adverse events. For the Bayesian meta-analysis models to be effective, the validity of the hierarchical structure of adverse events and the grouping of adverse events are critical. Our proposed meta-analysis models considered trial effects to avoid confounding by trial and borrowed strength from both within and across body systems to obtain reasonable and stable estimates of an effect measure by considering a hierarchical structure of adverse events.

Myocardial T1 mapping using an instantaneous signal loss simulation modeling and a Bayesian estimation method: A robust T1 extraction method free of tuning parameters

PurposeDevelop a hierarchical longitudinal regression model for estimating local rates of change of macular ganglion cell complex (GCC) measurements with optical coherence tomography (OCT).MethodsWe enrolled 112 eyes with four or more macular OCT images and ≥2 years of follow-up. GCC thickness measurements within central 6 × 6 superpixels were extracted from macular volume scans. We fit data from each superpixel separately with several hierarchical Bayesian random-effects models. Models were compared with the Watanabe–Akaike information criterion. For our preferred model, we estimated population and individual slopes and intercepts (baseline thickness) and their correlation.ResultsMean (SD) follow-up time and median (interquartile range) baseline 24-2 visual field mean deviation were 3.6 (0.4) years and −6.8 (−12.2 to −4.3) dB, respectively. The random intercepts and slopes model with random residual variance was the preferred model. While more individual and population negative slopes were observed in the paracentral and papillomacular superpixels, superpixels in the superotemporal and inferior regions displayed the highest correlation between baseline thickness and rates of change (r = –0.43 to –0.50 for the top five correlations).ConclusionsA Bayesian linear hierarchical model with random intercepts/slopes and random variances is an optimal initial model for estimating GCC slopes at population and individual levels. This novel model is an efficient method for estimating macular rates of change and probability of glaucoma progression locally.Translational RelevanceThe proposed Bayesian hierarchical model can be applied to various macular outcomes from different OCT devices and to superpixels of variable sizes to estimate local rates of change and progression probability.