29,656 research outputs found
Multiple tests of association with biological annotation metadata
We propose a general and formal statistical framework for multiple tests of
association between known fixed features of a genome and unknown parameters of
the distribution of variable features of this genome in a population of
interest. The known gene-annotation profiles, corresponding to the fixed
features of the genome, may concern Gene Ontology (GO) annotation, pathway
membership, regulation by particular transcription factors, nucleotide
sequences, or protein sequences. The unknown gene-parameter profiles,
corresponding to the variable features of the genome, may be, for example,
regression coefficients relating possibly censored biological and clinical
outcomes to genome-wide transcript levels, DNA copy numbers, and other
covariates. A generic question of great interest in current genomic research
regards the detection of associations between biological annotation metadata
and genome-wide expression measures. This biological question may be translated
as the test of multiple hypotheses concerning association measures between
gene-annotation profiles and gene-parameter profiles. A general and rigorous
formulation of the statistical inference question allows us to apply the
multiple hypothesis testing methodology developed in [Multiple Testing
Procedures with Applications to Genomics (2008) Springer, New York] and related
articles, to control a broad class of Type I error rates, defined as
generalized tail probabilities and expected values for arbitrary functions of
the numbers of Type I errors and rejected hypotheses. The resampling-based
single-step and stepwise multiple testing procedures of [Multiple Testing
Procedures with Applications to Genomics (2008) Springer, New York] take into
account the joint distribution of the test statistics and provide Type I error
control in testing problems involving general data generating distributions
(with arbitrary dependence structures among variables), null hypotheses, and
test statistics.Comment: Published in at http://dx.doi.org/10.1214/193940307000000446 the IMS
Collections (http://www.imstat.org/publications/imscollections.htm) by the
Institute of Mathematical Statistics (http://www.imstat.org
Generating Labels for Regression of Subjective Constructs using Triplet Embeddings
Human annotations serve an important role in computational models where the
target constructs under study are hidden, such as dimensions of affect. This is
especially relevant in machine learning, where subjective labels derived from
related observable signals (e.g., audio, video, text) are needed to support
model training and testing. Current research trends focus on correcting
artifacts and biases introduced by annotators during the annotation process
while fusing them into a single annotation. In this work, we propose a novel
annotation approach using triplet embeddings. By lifting the absolute
annotation process to relative annotations where the annotator compares
individual target constructs in triplets, we leverage the accuracy of
comparisons over absolute ratings by human annotators. We then build a
1-dimensional embedding in Euclidean space that is indexed in time and serves
as a label for regression. In this setting, the annotation fusion occurs
naturally as a union of sets of sampled triplet comparisons among different
annotators. We show that by using our proposed sampling method to find an
embedding, we are able to accurately represent synthetic hidden constructs in
time under noisy sampling conditions. We further validate this approach using
human annotations collected from Mechanical Turk and show that we can recover
the underlying structure of the hidden construct up to bias and scaling
factors.Comment: 9 pages, 5 figures, accepted journal pape
Predicting continuous conflict perception with Bayesian Gaussian processes
Conflict is one of the most important phenomena of social life, but it is still largely neglected by the computing community. This work proposes an approach
that detects common conversational social signals (loudness, overlapping speech,
etc.) and predicts the conflict level perceived by human observers in continuous,
non-categorical terms. The proposed regression approach is fully Bayesian and it
adopts Automatic Relevance Determination to identify the social signals that influence most the outcome of the prediction. The experiments are performed over the SSPNet Conflict Corpus, a publicly available collection of 1430 clips extracted from televised political debates (roughly 12 hours of material for 138 subjects in total). The results show that it is possible to achieve a correlation close to 0.8 between actual and predicted conflict perception
Current advances in systems and integrative biology
Systems biology has gained a tremendous amount of interest in the last few years. This is partly due to the realization that traditional approaches focusing only on a few molecules at a time cannot describe the impact of aberrant or modulated molecular environments across a whole system. Furthermore, a hypothesis-driven study aims to prove or disprove its postulations, whereas a hypothesis-free systems approach can yield an unbiased and novel testable hypothesis as an end-result. This latter approach foregoes assumptions which predict how a biological system should react to an altered microenvironment within a cellular context, across a tissue or impacting on distant organs. Additionally, re-use of existing data by systematic data mining and re-stratification, one of the cornerstones of integrative systems biology, is also gaining attention. While tremendous efforts using a systems methodology have already yielded excellent results, it is apparent that a lack of suitable analytic tools and purpose-built databases poses a major bottleneck in applying a systematic workflow. This review addresses the current approaches used in systems analysis and obstacles often encountered in large-scale data analysis and integration which tend to go unnoticed, but have a direct impact on the final outcome of a systems approach. Its wide applicability, ranging from basic research, disease descriptors, pharmacological studies, to personalized medicine, makes this emerging approach well suited to address biological and medical questions where conventional methods are not ideal
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Meta-analysis of massively parallel reporter assays enables prediction of regulatory function across cell types.
Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data-driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta-analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell-type-specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation "Regulation Saturation" Challenge for predicting effects of single-nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest
Using functional annotation to characterize genome-wide association results
Genome-wide association studies (GWAS) have successfully identified thousands of variants robustly associated with hundreds of complex traits, but the biological mechanisms driving these results remain elusive. Functional annotation, describing the roles of known genes and regulatory elements, provides additional information about associated variants. This dissertation explores the potential of these annotations to explain the biology behind observed GWAS results.
The first project develops a random-effects approach to genetic fine mapping of trait-associated loci. Functional annotation and estimates of the enrichment of genetic effects in each annotation category are integrated with linkage disequilibrium (LD) within each locus and GWAS summary statistics to prioritize variants with plausible functionality. Applications of this method to simulated and real data show good performance in a wider range of scenarios relative to previous approaches. The second project focuses on the estimation of enrichment by annotation categories. I derive the distribution of GWAS summary statistics as a function of annotations and LD structure and perform maximum likelihood estimation of enrichment coefficients in two simulated scenarios. The resulting estimates are less variable than previous methods, but the asymptotic theory of standard errors is often not applicable due to non-convexity of the likelihood function. In the third project, I investigate the problem of selecting an optimal set of tissue-specific annotations with greatest relevance to a trait of interest. I consider three selection criteria defined in terms of the mutual information between functional annotations and GWAS summary statistics. These algorithms correctly identify enriched categories in simulated data, but in the application to a GWAS of BMI the penalty for redundant features outweighs the modest relationships with the outcome yielding null selected feature sets, due to the weaker overall association and high similarity between tissue-specific regulatory features.
All three projects require little in the way of prior hypotheses regarding the mechanism of genetic effects. These data-driven approaches have the potential to illuminate unanticipated biological relationships, but are also limited by the high dimensionality of the data relative to the moderate strength of the signals under investigation. These approaches advance the set of tools available to researchers to draw biological insights from GWAS results
An automated identification and analysis of ontological terms in gastrointestinal diseases and nutrition-related literature provides useful insights
With an unprecedented growth in the biomedical literature, keeping up to date with
the new developments presents an immense challenge. Publications are often studied
in isolation of the established literature, with interpretation being subjective and
often introducing human bias. With ontology-driven annotation of biomedical data
gaining popularity in recent years and online databases offering metatags with rich
textual information, it is now possible to automatically text-mine ontological terms
and complement the laborious task of manual management, interpretation, and
analysis of the accumulated literature with downstream statistical analysis. In this
paper, we have formulated an automated workflow through which we have identified
ontological information, including nutrition-related terms in PubMed abstracts
(from 1991 to 2016) for two main types of Inflammatory Bowel Diseases: Crohn’s
Disease and Ulcerative Colitis; and two other gastrointestinal (GI) diseases, namely,
Coeliac Disease and Irritable Bowel Syndrome. Our analysis reveals unique clustering
patterns as well as spatial and temporal trends inherent to the considered GI diseases
in terms of literature that has been accumulated so far. Although automated
interpretation cannot replace human judgement, the developed workflow shows
promising results and can be a useful tool in systematic literature reviews. The
workflow is available at https://github.com/KociOrges/pytag
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