DeepNull models non-linear covariate effects to improve phenotypic prediction and association power.
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ABSTRACT:
SUBMITTER: McCaw ZR
PROVIDER: S-EPMC8752755 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLog-linear association models have been extensively used to investigate the pattern of agreement between ordinal ratings. In 2007, log-linear non-uniform association models were introduced to estimate, from a cross-classification of two independent raters using an ordinal scale, varying degrees of distinguishability between distant and adjacent categories of the scale.MethodsIn this paper, a simple method based on simulations was proposed to estimate the power of non-uniform association models to detect heterogeneities across distinguishabilities between adjacent categories of an ordinal scale, illustrating some possible scale defects.ResultsDifferent scenarios of distinguishability patterns were investigated, as well as different scenarios of marginal heterogeneity within rater. For sample size of N = 50, the probabilities of detecting heterogeneities within the tables are lower than .80, whatever the number of categories. In additition, even for large samples, marginal heterogeneities within raters led to a decrease in power estimates.ConclusionThis paper provided some issues about how many objects had to be classified by two independent observers (or by the same observer at two different times) to be able to detect a given scale structure defect. Our results also highlighted the importance of marginal homogeneity within raters, to ensure optimal power when using non-uniform association models.
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Project description:Statistical models that include random effects are commonly used to analyze longitudinal and correlated data, often with the assumption that the random effects follow a Gaussian distribution. Via theoretical and numerical calculations and simulation, we investigate the impact of misspecification of this distribution on both how well the predicted values recover the true underlying distribution and the accuracy of prediction of the realized values of the random effects. We show that, although the predicted values can vary with the assumed distribution, the prediction accuracy, as measured by mean square error, is little affected for mild-to-moderate violations of the assumptions. Thus, standard approaches, readily available in statistical software, will often suffice. The results are illustrated using data from the Heart and Estrogen/Progestin Replacement Study using models to predict future blood pressure values.
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Project description:Despite the popularity of the general linear mixed model for data analysis, power and sample size methods and software are not generally available for commonly used test statistics and reference distributions. Statisticians resort to simulations with homegrown and uncertified programs or rough approximations which are misaligned with the data analysis. For a wide range of designs with longitudinal and clustering features, we provide accurate power and sample size approximations for inference about fixed effects in linear models we call reversible. We show that under widely applicable conditions, the general linear mixed-model Wald test has non-central distributions equivalent to well-studied multivariate tests. In turn, exact and approximate power and sample size results for the multivariate Hotelling-Lawley test provide exact and approximate power and sample size results for the mixed-model Wald test. The calculations are easily computed with a free, open-source product that requires only a web browser to use. Commercial software can be used for a smaller range of reversible models. Simple approximations allow accounting for modest amounts of missing data. A real-world example illustrates the methods. Sample size results are presented for a multicenter study on pregnancy. The proposed study, an extension of a funded project, has clustering within clinic. Exchangeability among participants allows averaging across them to remove the clustering structure. The resulting simplified design is a single level longitudinal study. Multivariate methods for power provide an approximate sample size. All proofs and inputs for the example are in the Supplementary Materials (available online).
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Project description:BACKGROUND:Power analysis becomes an inevitable step in experimental design of current biomedical research. Complex designs allowing diverse correlation structures are commonly used in RNA-Seq experiments. However, the field currently lacks statistical methods to calculate sample size and estimate power for RNA-Seq differential expression studies using such designs. To fill the gap, simulation based methods have a great advantage by providing numerical solutions, since theoretical distributions of test statistics are typically unavailable for such designs. RESULTS:In this paper, we propose a novel simulation based procedure for power estimation of differential expression with the employment of generalized linear mixed effects models for correlated expression data. We also propose a new procedure for power estimation of differential expression with the use of a bivariate negative binomial distribution for paired designs. We compare the performance of both the likelihood ratio test and Wald test under a variety of simulation scenarios with the proposed procedures. The simulated distribution was used to estimate the null distribution of test statistics in order to achieve the desired false positive control and was compared to the asymptotic Chi-square distribution. In addition, we applied the procedure for paired designs to the TCGA breast cancer data set. CONCLUSIONS:In summary, we provide a framework for power estimation of RNA-Seq differential expression under complex experimental designs. Simulation results demonstrate that both the proposed procedures properly control the false positive rate at the nominal level.
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Project description:The linear logistic test model (LLTM) has been widely applied to investigate the effects of item covariates on item difficulty. The LLTM was extended with random item residuals to account for item differences not explained by the item covariates. This extended LLTM is called the LLTM-R. In this article, statistical inference methods are investigated for these two models. Type I error rates and power are compared via Monte Carlo studies. Based on the simulation results, the use of the likelihood ratio test (LRT) is recommended over the paired-sample t test based on sum scores, the Wald z test, and information criteria, and the LRT is recommended over the profile likelihood confidence interval because of the simplicity of the LRT. In addition, it is concluded that the LLTM-R is the better general model approach. Inferences based on the LLTM while the LLTM-R is the true model appear to be largely biased in the liberal way, while inferences based on the LLTM-R while the LLTM is the true model are only biased in a very minor and conservative way. Furthermore, in the absence of residual variance, Type I error rate and power were acceptable except for power when the number of items is small (10 items) and also the number of persons is small (200 persons). In the presence of residual variance, however, the number of items needs to be large (80 items) to avoid an inflated Type I error and to reach a power level of .90 for a moderate effect.
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Project description:Survival prediction from a large number of covariates is a current focus of statistical and medical research. In this paper, we study a methodology known as the compound covariate prediction performed under univariate Cox proportional hazard models. We demonstrate via simulations and real data analysis that the compound covariate method generally competes well with ridge regression and Lasso methods, both already well-studied methods for predicting survival outcomes with a large number of covariates. Furthermore, we develop a refinement of the compound covariate method by incorporating likelihood information from multivariate Cox models. The new proposal is an adaptive method that borrows information contained in both the univariate and multivariate Cox regression estimators. We show that the new proposal has a theoretical justification from a statistical large sample theory and is naturally interpreted as a shrinkage-type estimator, a popular class of estimators in statistical literature. Two datasets, the primary biliary cirrhosis of the liver data and the non-small-cell lung cancer data, are used for illustration. The proposed method is implemented in R package "compound.Cox" available in CRAN at http://cran.r-project.org/.
| S-EPMC3480451 | biostudies-literature
Project description:Protein kinase inhibitors are one of the most successful targeted therapies to date. Despite this progress, additional kinase inhibitors are needed to expand the target space as well as overcome drug resistance that has emerged in clinical setting. Here, we developed KiDNN (Kinase inhibitor prediction using Deep Neural Networks). KiDNN utilizes non-linear, multilayer feedforward network that mimics complex and dynamic kinase-driven signaling pathways. We used KiDNN to predict the effect of ?200 kinase inhibitors on migration of breast and liver cancer cells. We show that the prediction accuracy of KiDNN outperformed other prediction tools based on linear models. We validated that an inhibitor of tyrosine kinase receptors, and an inhibitor of Src family kinases, decreased migration of triple-negative breast cancer cells, consistent with the role of these kinases in driving motility. Overall, we show that non-linear, DNN-based models provide a powerful approach to in silico screen hundreds of kinase inhibitors.
| S-EPMC7235637 | biostudies-literature
Project description:In genome-enabled prediction, parametric, semi-parametric, and non-parametric regression models have been used. This study assessed the predictive ability of linear and non-linear models using dense molecular markers. The linear models were linear on marker effects and included the Bayesian LASSO, Bayesian ridge regression, Bayes A, and Bayes B. The non-linear models (this refers to non-linearity on markers) were reproducing kernel Hilbert space (RKHS) regression, Bayesian regularized neural networks (BRNN), and radial basis function neural networks (RBFNN). These statistical models were compared using 306 elite wheat lines from CIMMYT genotyped with 1717 diversity array technology (DArT) markers and two traits, days to heading (DTH) and grain yield (GY), measured in each of 12 environments. It was found that the three non-linear models had better overall prediction accuracy than the linear regression specification. Results showed a consistent superiority of RKHS and RBFNN over the Bayesian LASSO, Bayesian ridge regression, Bayes A, and Bayes B models.
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Project description:Background:B-cell epitopes play important roles in vaccine design, clinical diagnosis, and antibody production. Although some models have been developed to predict linear or conformational B-cell epitopes, their performance is still unsatisfactory. Hundreds of thousands of linear B-cell epitope data have accumulated in the Immune Epitope Database (IEDB). These data can be explored using the deep learning methods, in order to create better predictive models for linear B-cell epitopes. Results:After data cleaning, we obtained 240,563 peptide samples with experimental evidence from the IEDB database, including 25,884 linear B-cell epitopes and 214,679 non-epitopes. Based on the peptide center, we adapted each peptide to the same length by trimming or extending. A random portion of the data, with the same amount of epitopes and non-epitopes, were set aside as test dataset. Then a same number of epitopes and non-epitopes were randomly selected from the remaining data to build a classifier with the feedforward deep neural network. We built eleven classifiers to form an ensemble prediction model. The model will report a peptide as an epitope if it was classified as epitope by all eleven classifiers. Then we used the test data set to evaluate the performance of the model using the area value under the receiver operating characteristic (ROC) curve (AUC) as an indicator. We established 40 models to predict linear B-cell epitopes of length from 11 to 50 separately, and found that the AUC value increased with the length and tended to be stable when the length was 38. Repeated results showed that the models constructed by this method were robust. Tested on our and two public test datasets, our models outperformed current major models available. Conclusions:We applied the feedforward deep neural network to the large amount of linear B-cell epitope data with experimental evidence in the IEDB database, and constructed ensemble prediction models with better performance than the current major models available. We named the models as DLBEpitope and provided web services using the models at http://ccb1.bmi.ac.cn:81/dlbepitope/.
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