Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models

<p>Abstract</p> <p>Background</p> <p>Growing interest on biological pathways has called for new statistical methods for modeling and testing a genetic pathway effect on a health outcome. The fact that genes within a pathway tend to interact with each other and relate to the outcome in a complicated way makes nonparametric methods more desirable. The kernel machine method provides a convenient, powerful and unified method for multi-dimensional parametric and nonparametric modeling of the pathway effect.</p> <p>Results</p> <p>In this paper we propose a logistic kernel machine regression model for binary outcomes. This model relates the disease risk to covariates parametrically, and to genes within a genetic pathway parametrically or nonparametrically using kernel machines. The nonparametric genetic pathway effect allows for possible interactions among the genes within the same pathway and a complicated relationship of the genetic pathway and the outcome. We show that kernel machine estimation of the model components can be formulated using a logistic mixed model. Estimation hence can proceed within a mixed model framework using standard statistical software. A score test based on a Gaussian process approximation is developed to test for the genetic pathway effect. The methods are illustrated using a prostate cancer data set and evaluated using simulations. An extension to continuous and discrete outcomes using generalized kernel machine models and its connection with generalized linear mixed models is discussed.</p> <p>Conclusion</p> <p>Logistic kernel machine regression and its extension generalized kernel machine regression provide a novel and flexible statistical tool for modeling pathway effects on discrete and continuous outcomes. Their close connection to mixed models and attractive performance make them have promising wide applications in bioinformatics and other biomedical areas.</p

Adaptive Cluster Thresholding with Spatial Activation Guarantees Using All-resolutions Inference

Classical cluster inference is hampered by the spatial specificity paradox. Given the null-hypothesis of no active voxels, the alternative hypothesis states that there is at least one active voxel in a cluster. Hence, the larger the cluster the less we know about where activation in the cluster is. Rosenblatt et al. (2018) proposed a post-hoc inference method, All-resolutions Inference (ARI), that addresses this paradox by estimating the number of active voxels of any brain region. ARI allows users to choose arbitrary brain regions and returns a simultaneous lower confidence bound of the true discovery proportion (TDP) for each of them, retaining control of the family-wise error rate. ARI does not, however, guide users to regions with high enough TDP. In this paper, we propose an efficient algorithm that outputs all maximal supra-threshold clusters, for which ARI gives a TDP lower confidence bound that is at least a chosen threshold, for any number of thresholds that need not be chosen a priori nor all at once. After a preprocessing step in linearithmic time, the algorithm only takes linear time in the size of its output. We demonstrate the algorithm with an application to two fMRI datasets. For both datasets, we found several clusters whose TDP confidently meets or exceeds a given threshold in less than a second

Simultaneous confidence intervals for ranks with application to ranking institutions

When a ranking of institutions such as medical centers or universities is based on a numerical measure of performance provided with a standard error, confidence intervals (CIs) should be calculated to assess the uncertainty of these ranks. We present a novel method based on Tukey's honest significant difference test to construct simultaneous CIs for the true ranks. When all the true performances are equal, the probability of coverage of our method attains the nominal level. In case the true performance measures have no exact ties, our method is conservative. For this situation, we propose a rescaling method to the nominal level that results in shorter CIs while keeping control of the simultaneous coverage. We also show that a similar rescaling can be applied to correct a recently proposed Monte-Carlo based method, which is anticonservative. After rescaling, the two methods perform very similarly. However, the rescaling of the Monte-Carlo based method is computationally much more demanding and becomes infeasible when the number of institutions is larger than 30-50. We discuss another recently proposed method similar to ours based on simultaneous CIs for the true performance. We show that our method provides uniformly shorter CIs for the same confidence level. We illustrate the superiority of our new methods with a data analysis for travel time to work in the United States and on rankings of 64 hospitals in the Netherlands.Development and application of statistical models for medical scientific researc

Simultaneous confidence intervals for ranks using the partitioning principle

We consider the problem of constructing simultaneous confidence intervals (CIs) for the ranks of n means based on their estimates together with the (known) standard errors of those estimates. We present a generic method based on the partitioning principle in which the parameter space is partitioned into disjoint subsets and then each one of them is tested at level a. The resulting CIs have then a simultaneous coverage of 1 - alpha. We show that any procedure which produces simultaneous CIs for ranks can be written as a partitioning procedure. We present a first example where we test the partitions using the likelihood ratio (LR) test. Then, in a second example we show that a recently proposed method for simultaneous CIs for ranks using Tukey's honest significant difference test has an equivalent procedure based on the partitioning principle. By embedding these two methods inside our generic partitioning procedure, we obtain improved variants. We illustrate the performance of these methods through simulations and real data analysis on hotel ratings. While the novel method that uses the LR test and its variant produce shorter CIs when the number of means is small, the Tukey-based method and its variant produce shorter CIs when the number of means is high.Development and application of statistical models for medical scientific researc

ProbCD: enrichment analysis accounting for categorization uncertainty

As in many other areas of science, systems biology makes extensive use of statistical association and significance estimates in contingency tables, a type of categorical data analysis known in this field as enrichment (also over-representation or enhancement) analysis. In spite of efforts to create probabilistic annotations, especially in the Gene Ontology context, or to deal with uncertainty in high throughput-based datasets, current enrichment methods largely ignore this probabilistic information since they are mainly based on variants of the Fisher Exact Test. We developed an open-source R package to deal with probabilistic categorical data analysis, ProbCD, that does not require a static contingency table. The contingency table for&#xd;&#xa;the enrichment problem is built using the expectation of a Bernoulli Scheme stochastic process given the categorization probabilities. An on-line interface was created to allow usage by non-programmers and is available at: http://xerad.systemsbiology.net/ProbCD/. We present an analysis framework and software tools to address the issue of uncertainty in categorical data analysis. In particular, concerning the enrichment analysis, ProbCD can accommodate: (i) the stochastic nature of the high-throughput experimental techniques and (ii) probabilistic gene annotation

Similar gene expression profiles of sporadic, PGL2-, and SDHD-linked paragangliomas suggest a common pathway to tumorigenesis

Contains fulltext : 81540.pdf (publisher's version ) (Open Access)BACKGROUND: Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. A significant number of cases (10-50%) are proven to be familial. Multiple genes encoding subunits of the mitochondrial succinate-dehydrogenase (SDH) complex are associated with hereditary paraganglioma: SDHB, SDHC and SDHD. Furthermore, a hereditary paraganglioma family has been identified with linkage to the PGL2 locus on 11q13. No SDH genes are known to be located in the 11q13 region, and the exact gene defect has not yet been identified in this family. METHODS: We have performed a RNA expression microarray study in sporadic, SDHD- and PGL2-linked head and neck paragangliomas in order to identify potential differences in gene expression leading to tumorigenesis in these genetically defined paraganglioma subgroups. We have focused our analysis on pathways and functional gene-groups that are known to be associated with SDH function and paraganglioma tumorigenesis, i.e. metabolism, hypoxia, and angiogenesis related pathways. We also evaluated gene clusters of interest on chromosome 11 (i.e. the PGL2 locus on 11q13 and the imprinted region 11p15). RESULTS: We found remarkable similarity in overall gene expression profiles of SDHD -linked, PGL2-linked and sporadic paraganglioma. The supervised analysis on pathways implicated in PGL tumor formation also did not reveal significant differences in gene expression between these paraganglioma subgroups. Moreover, we were not able to detect differences in gene-expression of chromosome 11 regions of interest (i.e. 11q23, 11q13, 11p15). CONCLUSION: The similarity in gene-expression profiles suggests that PGL2, like SDHD, is involved in the functionality of the SDH complex, and that tumor formation in these subgroups involves the same pathways as in SDH linked paragangliomas. We were not able to clarify the exact identity of PGL2 on 11q13. The lack of differential gene-expression of chromosome 11 genes might indicate that chromosome 11 loss, as demonstrated in SDHD-linked paragangliomas, is an important feature in the formation of paragangliomas regardless of their genetic background.1 p

Adaptive Cluster Thresholding with Spatial Activation Guarantees Using All-resolutions Inference

Classical cluster inference is hampered by the spatial specificity paradox. Given the null-hypothesis of no active voxels, the alternative hypothesis states that there is at least one active voxel in a cluster. Hence, the larger the cluster the less we know about where activation in the cluster is. Rosenblatt et al. (2018) proposed a post-hoc inference method, All-resolutions Inference (ARI), that addresses this paradox by estimating the number of active voxels of any brain region. ARI allows users to choose arbitrary brain regions and returns a simultaneous lower confidence bound of the true discovery proportion (TDP) for each of them, retaining control of the family-wise error rate. ARI does not, however, guide users to regions with high enough TDP. In this paper, we propose an efficient algorithm that outputs all maximal supra-threshold clusters, for which ARI gives a TDP lower confidence bound that is at least a chosen threshold, for any number of thresholds that need not be chosen a priori nor all at once. After a preprocessing step in linearithmic time, the algorithm only takes linear time in the size of its output. We demonstrate the algorithm with an application to two fMRI datasets. For both datasets, we found several clusters whose TDP confidently meets or exceeds a given threshold in less than a second

MOVING PICTURES: RAISING AWARENESS OF DEMENTIA IN CALD COMMUNITIES THROUGH MULTIMEDIA

Abstract Limited awareness of dementia in people from culturally and linguistically diverse (CALD) backgrounds often results in delayed diagnosis, poorer prognosis, and a higher burden of care on families and health systems. Given the rapidly ageing and multicultural populations in migrant-receiving countries such as Australia and the United States, this disparity needs to be addressed urgently. This project aimed to inform and educate people from five linguistically diverse backgrounds – Hindi, Tamil, Mandarin, Cantonese, and Arabic – about dementia. A mixed methods, multimedia design comprising video-interviews with 76 participants including carers from the five language groups and key service providers was employed. Data were gathered nationally across Australia in 2018 and thematically analysed. Data were used to co-produce 15 short films, comics, and a mobile-optimised website from which data analytics were measured. The films and comics focused on dementia detection and timely diagnosis, how to navigate the aged care system, and the importance of self-care. Analytics data is currently being collected online and via community forums. In conclusion, co-production methods in tandem with digital multimedia are fundamental to developing culturally salient interventions to address dementia disparities in CALD populations in Australia and internationally.</jats:p

Classes of Multiple Decision Functions Strongly Controlling FWER and FDR

This paper provides two general classes of multiple decision functions where each member of the first class strongly controls the family-wise error rate (FWER), while each member of the second class strongly controls the false discovery rate (FDR). These classes offer the possibility that an optimal multiple decision function with respect to a pre-specified criterion, such as the missed discovery rate (MDR), could be found within these classes. Such multiple decision functions can be utilized in multiple testing, specifically, but not limited to, the analysis of high-dimensional microarray data sets.Comment: 19 page

Integrated analysis of DNA copy number and gene expression microarray data using gene sets

Background: Genes that play an important role in tumorigenesis are expected to show association between DNA copy number and RNA expression. Optimal power to find such associations can only be achieved if analysing copy number and gene expression jointly. Furthermore, some copy number changes extend over larger chromosomal regions affecting the expression levels of multiple resident genes.