Power calculator for detecting allelic imbalance using hierarchical Bayesian model.
Ontology highlight
ABSTRACT: Objective
Allelic imbalance (AI) is the differential expression of the two alleles in a diploid. AI can vary between tissues, treatments, and environments. Methods for testing AI exist, but methods are needed to estimate type I error and power for detecting AI and difference of AI between conditions. As the costs of the technology plummet, what is more important: reads or replicates?Results
We find that a minimum of 2400, 480, and 240 allele specific reads divided equally among 12, 5, and 3 replicates is needed to detect a 10, 20, and 30%, respectively, deviation from allelic balance in a condition with power > 80%. A minimum of 960 and 240 allele specific reads divided equally among 8 replicates is needed to detect a 20 or 30% difference in AI between conditions with comparable power. Higher numbers of replicates increase power more than adding coverage without affecting type I error. We provide a Python package that enables simulation of AI scenarios and enables individuals to estimate type I error and power in detecting AI and differences in AI between conditions.
SUBMITTER: Sherbina K
PROVIDER: S-EPMC8626927 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundOne method of identifying cis regulatory differences is to analyze allele-specific expression (ASE) and identify cases of allelic imbalance (AI). RNA-seq is the most common way to measure ASE and a binomial test is often applied to determine statistical significance of AI. This implicitly assumes that there is no bias in estimation of AI. However, bias has been found to result from multiple factors including: genome ambiguity, reference quality, the mapping algorithm, and biases in the sequencing process. Two alternative approaches have been developed to handle bias: adjusting for bias using a statistical model and filtering regions of the genome suspected of harboring bias. Existing statistical models which account for bias rely on information from DNA controls, which can be cost prohibitive for large intraspecific studies. In contrast, data filtering is inexpensive and straightforward, but necessarily involves sacrificing a portion of the data.ResultsHere we propose a flexible Bayesian model for analysis of AI, which accounts for bias and can be implemented without DNA controls. In lieu of DNA controls, this Poisson-Gamma (PG) model uses an estimate of bias from simulations. The proposed model always has a lower type I error rate compared to the binomial test. Consistent with prior studies, bias dramatically affects the type I error rate. All of the tested models are sensitive to misspecification of bias. The closer the estimate of bias is to the true underlying bias, the lower the type I error rate. Correct estimates of bias result in a level alpha test.ConclusionsTo improve the assessment of AI, some forms of systematic error (e.g., map bias) can be identified using simulation. The resulting estimates of bias can be used to correct for bias in the PG model, without data filtering. Other sources of bias (e.g., unidentified variant calls) can be easily captured by DNA controls, but are missed by common filtering approaches. Consequently, as variant identification improves, the need for DNA controls will be reduced. Filtering does not significantly improve performance and is not recommended, as information is sacrificed without a measurable gain. The PG model developed here performs well when bias is known, or slightly misspecified. The model is flexible and can accommodate differences in experimental design and bias estimation.
| S-EPMC4230747 | biostudies-literature
Project description:Detecting allelic imbalance at the isoform level requires accounting for inferential uncertainty, caused by multi-mapping of RNA-seq reads. Our proposed method, SEESAW, uses Salmon and Swish to offer analysis at various levels of resolution, including gene, isoform, and aggregating isoforms to groups by transcription start site. The aggregation strategies strengthen the signal for transcripts with high uncertainty. The SEESAW suite of methods is shown to have higher power than other allelic imbalance methods when there is isoform-level allelic imbalance. We also introduce a new test for detecting imbalance that varies across a covariate, such as time.
| S-EPMC10337143 | biostudies-literature
Project description:Methods that integrate population-level sampling from multiple taxa into a single community-level analysis are an essential addition to the comparative phylogeographic toolkit. Detecting how species within communities have demographically tracked each other in space and time is important for understanding the effects of future climate and landscape changes and the resulting acceleration of extinctions, biological invasions, and potential surges in adaptive evolution. Here, we present a statistical framework for such an analysis based on hierarchical approximate Bayesian computation (hABC) with the goal of detecting concerted demographic histories across an ecological assemblage. Our method combines population genetic data sets from multiple taxa into a single analysis to estimate: 1) the proportion of a community sample that demographically expanded in a temporally clustered pulse and 2) when the pulse occurred. To validate the accuracy and utility of this new approach, we use simulation cross-validation experiments and subsequently analyze an empirical data set of 32 avian populations from Australia that are hypothesized to have expanded from smaller refugia populations in the late Pleistocene. The method can accommodate data set heterogeneity such as variability in effective population size, mutation rates, and sample sizes across species and exploits the statistical strength from the simultaneous analysis of multiple species. This hABC framework used in a multitaxa demographic context can increase our understanding of the impact of historical climate change by determining what proportion of the community responded in concert or independently and can be used with a wide variety of comparative phylogeographic data sets as biota-wide DNA barcoding data sets accumulate.
| S-EPMC4137712 | biostudies-literature
Project description:BACKGROUND:The basket trial evaluates the treatment effect of a targeted therapy in patients with the same genetic or molecular aberration, regardless of their cancer types. Bayesian hierarchical modeling has been proposed to adaptively borrow information across cancer types to improve the statistical power of basket trials. Although conceptually attractive, research has shown that Bayesian hierarchical models cannot appropriately determine the degree of information borrowing and may lead to substantially inflated type I error rates. METHODS:We propose a novel calibrated Bayesian hierarchical model approach to evaluate the treatment effect in basket trials. In our approach, the shrinkage parameter that controls information borrowing is not regarded as an unknown parameter. Instead, it is defined as a function of a similarity measure of the treatment effect across tumor subgroups. The key is that the function is calibrated using simulation such that information is strongly borrowed across subgroups if their treatment effects are similar and barely borrowed if the treatment effects are heterogeneous. RESULTS:The simulation study shows that our method has substantially better controlled type I error rates than the Bayesian hierarchical model. In some scenarios, for example, when the true response rate is between the null and alternative, the type I error rate of the proposed method can be inflated from 10% up to 20%, but is still better than that of the Bayesian hierarchical model. LIMITATION:The proposed design assumes a binary endpoint. Extension of the proposed design to ordinal and time-to-event endpoints is worthy of further investigation. CONCLUSION:The calibrated Bayesian hierarchical model provides a practical approach to design basket trials with more flexibility and better controlled type I error rates than the Bayesian hierarchical model. The software for implementing the proposed design is available at http://odin.mdacc.tmc.edu/~yyuan/index_code.html.
| S-EPMC5891374 | biostudies-literature
Project description:The multilevel item response theory (MLIRT) models have been increasingly used in longitudinal clinical studies that collect multiple outcomes. The MLIRT models account for all the information from multiple longitudinal outcomes of mixed types (e.g., continuous, binary, and ordinal) and can provide valid inference for the overall treatment effects. However, the continuous outcomes and the random effects in the MLIRT models are often assumed to be normally distributed. The normality assumption can sometimes be unrealistic and thus may produce misleading results. The normal/independent (NI) distributions have been increasingly used to handle the outlier and heavy tail problems in order to produce robust inference. In this article, we developed a Bayesian approach that implemented the NI distributions on both continuous outcomes and random effects in the MLIRT models and discussed different strategies of implementing the NI distributions. Extensive simulation studies were conducted to demonstrate the advantage of our proposed models, which provided parameter estimates with smaller bias and more reasonable coverage probabilities. Our proposed models were applied to a motivating Parkinson's disease study, the DATATOP study, to investigate the effect of deprenyl in slowing down the disease progression.
| S-EPMC5064853 | biostudies-literature
Project description:Detecting disease-associated genomic outcomes is one of the key steps in precision medicine research. Cutting-edge high-throughput technologies enable researchers to unbiasedly test if genomic outcomes are associated with disease of interest. However, these technologies also include the challenges associated with the analysis of genome-wide data. Two big challenges are (1) how to reduce the effects of technical noise; and (2) how to handle the curse of dimensionality (i.e., number of variables are way larger than the number of samples). To tackle these challenges, we propose a constrained mixture of Bayesian hierarchical models (MBHM) for detecting disease-associated genomic outcomes for data obtained from paired/matched designs. Paired/matched designs can effectively reduce effects of confounding factors. MBHM does not involve multiple testing, hence does not have the problem of the curse of dimensionality. It also could borrow information across genes so that it can be used for whole genome data with small sample sizes.
| S-EPMC5373614 | biostudies-literature
Project description:The detection of T cell activation is critical in many immunological assays. However, detecting T cell activation in live tissues remains a challenge due to highly noisy data. We developed a Bayesian probabilistic model to identify T cell activation based on calcium flux, a dramatic increase in intracellular calcium concentration that occurs during T cell activation. Because a T cell has unknown number of flux events, the implementation of posterior inference requires trans-dimensional posterior simulation. The model is able to detect calcium flux events at the single cell level from simulated data, as well as from noisy biological data.
| S-EPMC5796679 | biostudies-literature
Project description:BACKGROUND:Group structures among genes encoded in functional relationships or biological pathways are valuable and unique features in large-scale molecular data for survival analysis. However, most of previous approaches for molecular data analysis ignore such group structures. It is desirable to develop powerful analytic methods for incorporating valuable pathway information for predicting disease survival outcomes and detecting associated genes. RESULTS:We here propose a Bayesian hierarchical Cox survival model, called the group spike-and-slab lasso Cox (gsslasso Cox), for predicting disease survival outcomes and detecting associated genes by incorporating group structures of biological pathways. Our hierarchical model employs a novel prior on the coefficients of genes, i.e., the group spike-and-slab double-exponential distribution, to integrate group structures and to adaptively shrink the effects of genes. We have developed a fast and stable deterministic algorithm to fit the proposed models. We performed extensive simulation studies to assess the model fitting properties and the prognostic performance of the proposed method, and also applied our method to analyze three cancer data sets. CONCLUSIONS:Both the theoretical and empirical studies show that the proposed method can induce weaker shrinkage on predictors in an active pathway, thereby incorporating the biological similarity of genes within a same pathway into the hierarchical modeling. Compared with several existing methods, the proposed method can more accurately estimate gene effects and can better predict survival outcomes. For the three cancer data sets, the results show that the proposed method generates more powerful models for survival prediction and detecting associated genes. The method has been implemented in a freely available R package BhGLM at https://github.com/nyiuab/BhGLM .
| S-EPMC6391807 | biostudies-other
Project description:In longitudinal studies in which a medical device is used to monitor outcome repeatedly and frequently on the same patients over a prespecified duration of time, two clustering goals can arise. One goal is to assess the degree of heterogeneity among patient profiles. A second yet equally important goal unique to such studies is to determine frequency and duration of monitoring sufficient to identify longitudinal changes. Considering these goals jointly would identify clusters of patients who share similar patterns over time and characterize temporal stability within each cluster. We use a biclustering approach, allowing simultaneous clustering of observations at both patient and time levels and using a nonparametric hierarchical Bayesian model. Because clustering units at the time level (i.e., time points) are ordered and hence unexchangeable, we utilize a multivariate Dirichlet process mixture model by specifying a Dirichlet process prior at the patient level whose base measure employs change points at the time level to achieve the desired joint clustering. We consider structured covariance between consecutive time points and assess model performance through simulation studies. We apply the model to data on 24-hr ambulatory blood pressure monitoring and examine the relationship between diastolic blood pressure and pediatric obstructive sleep apnoea.
| S-EPMC9355390 | biostudies-literature
Project description:In proteomics, identification of proteins from complex mixtures of proteins extracted from biological samples is an important problem. Among the experimental technologies, Mass-Spectrometry (MS) is the most popular one. Protein identification from MS data typically relies on a "two-step" procedure of identifying the peptide first followed by the separate protein identification procedure next. In this setup, the interdependence of peptides and proteins are neglected resulting in relatively inaccurate protein identification. In this article, we propose a Markov chain Monte Carlo (MCMC) based Bayesian hierarchical model, a first of its kind in protein identification, which integrates the two steps and performs joint analysis of proteins and peptides using posterior probabilities. We remove the assumption of independence of proteins by using clustering group priors to the proteins based on the assumption that proteins sharing the same biological pathway are likely to be present or absent together and are correlated. The complete conditionals of the proposed joint model being tractable, we propose and implement a Gibbs sampling scheme for full posterior inference that provides the estimation and statistical uncertainties of all relevant parameters. The model has better operational characteristics compared to two existing "one-step" procedures on a range of simulation settings as well as on two well-studied datasets.
| S-EPMC6519717 | biostudies-literature