Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS

Our new paper on the incorporation of expert knowledge about epigenomics and chromatin looping for modeling epistasis has been published in Human Genetics.

Manduchi E, Williams SM, Chesi A, Johnson ME, Wells AD, Grant SFA, Moore JH. Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS. Hum Genet. 2018 May;137(5):413-425. [PubMed]

Abstract

Although Genome Wide Association Studies (GWAS) have led to many valuable insights into the genetic bases of common diseases over the past decade, the issue of missing heritability has surfaced, as the discovered main effect genetic variants found to date do not account for much of a trait's predicted genetic component. We present a workflow, integrating epigenomics and topologically associating domain data, aimed at discovering trait-associated SNP pairs from GWAS where neither SNP achieved independent genome-wide significance. Each analyzed SNP pair consists of one SNP in a putative active enhancer and another SNP in a putative physically interacting gene promoter in a trait-relevant tissue. As a proof-of-principle case study, we used this approach to identify focused collections of SNP pairs that we analyzed in three independent Type 2 diabetes (T2D) GWAS. This approach led us to discover 35 significant SNP pairs, encompassing both novel signals and signals for which we have found orthogonal support from other sources. Nine of these pairs are consistent with eQTL results, two are consistent with our own capture C experiments, and seven involve signals supported by recent T2D literature.

AI researchers allege that machine learning is alchemy

This is a really nice piece in Science on the limitation and challenges of machine learning. Highly recommended reading.

"Without deep understanding of..basic tools needed to build & train new algorithms, researchers creating AIs resort to hearsay, like medieval alchemists. "People gravitate around cargo-cult practices," relying on "folklore & magic spells"

Improving machine learning reproducibility in genetic association studies with proportional instance cross validation (PICV)

Our new paper on using resampling methods to improve reproducibility of machine learning in the context of cross validation.

Piette ER, Moore JH. Improving machine learning reproducibility in genetic association studies with proportional instance cross validation (PICV). BioData Min. 2018 Apr 19;11:6. [PubMed]

Background: Machine learning methods and conventions are increasingly employed for the analysis of large, complex biomedical data sets, including genome-wide association studies (GWAS). Reproducibility of machine learning analyses of GWAS can be hampered by biological and statistical factors, particularly so for the investigation of non-additive genetic interactions. Application of traditional cross validation to a GWAS data set may result in poor consistency between the training and testing data set splits due to an imbalance of the interaction genotypes relative to the data as a whole. We propose a new cross validation method, proportional instance cross validation (PICV), that preserves the original distribution of an independent variable when splitting the data set into training and testing partitions.

Results: We apply PICV to simulated GWAS data with epistatic interactions of varying minor allele frequencies and prevalences and compare performance to that of a traditional cross validation procedure in which individuals are randomly allocated to training and testing partitions. Sensitivity and positive predictive value are significantly improved across all tested scenarios for PICV compared to traditional cross validation. We also apply PICV to GWAS data from a study of
primary open-angle glaucoma to investigate a previously-reported interaction, which fails to significantly replicate; PICV however improves the consistency of testing and training results.

Conclusions: Application of traditional machine learning procedures to biomedical data may require modifications to better suit intrinsic characteristics of the data, such as the potential for highly imbalanced genotype distributions in the case of epistasis detection. The reproducibility of genetic interaction findings can be improved by considering this variable imbalance in cross validation implementation, such as with PICV. This approach may be extended to problems in other domains in which imbalanced variable distributions are a concern.

Collective feature selection to identify crucial epistatic variants

Nice new paper from Marylyn Ritchie's group on feature selection for epistasis analysis.

Verma SS, Lucas A, Zhang X, Veturi Y, Dudek S, Li B, Li R, Urbanowicz R, Moore JH, Kim D, Ritchie MD. Collective feature selection to identify crucial epistatic variants. BioData Min. 2018 Apr 19;11:5. [Pubmed]

Machine learning methods have gained popularity and practicality in identifying linear and non-linear effects of variants associated with complex disease/traits. Detection of epistatic interactions still remains a challenge due to the large number of features and relatively small sample size as input, thus leading to the so-called "short fat data" problem. The efficiency of machine learning methods can be increased by limiting the number of input features. Thus, it is very important to perform variable selection before searching for epistasis. Many methods have been evaluated and proposed to perform feature selection, but no single method works best in all scenarios. We demonstrate this by conducting two separate simulation analyses to evaluate the proposed collective feature selection approach.

Through our simulation study we propose a collective feature selection approach to select features that are in the "union" of the best performing methods. We explored various parametric, non-parametric, and data mining approaches to perform feature selection. We choose our top performing methods to select the union of the resulting variables based on a user-defined percentage of variants selected from each method to take to downstream analysis. Our simulation analysis shows that non-parametric data mining approaches, such as MDR, may work best under one simulation criteria for the high effect size (penetrance) datasets, while non-parametric methods designed for feature selection, such as Ranger and Gradient boosting, work best under other simulation criteria. Thus, using a collective approach proves to be more beneficial for selecting variables with epistatic effects also in low effect size datasets and different genetic architectures. Following this, we applied our proposed collective feature selection approach to select the top 1% of variables to identify potential interacting variables associated with Body Mass Index (BMI) in ~ 44,000 samples obtained from Geisinger's MyCode Community Health Initiative (on behalf of DiscovEHR collaboration).

In this study, we were able to show that selecting variables using a collective feature selection approach could help in selecting true positive epistatic variables more frequently than applying any single method for feature selection via simulation studies. We were able to demonstrate the effectiveness of collective feature selection along with a comparison of many methods in our simulation analysis. We also applied our method to identify non-linear networks associated with obesity.

Tips for cloud computing

Epistasis analysis is by nature computationally challenging. Here are some tips for working cloud computing into your analytical pipeline. 

Cole BS, Moore JH. Eleven quick tips for architecting biomedical informatics workflows with cloud computing. PLoS Comput Biol. 2018 Mar 29;14(3):e1005994.doi: 10.1371/journal.pcbi.1005994. [PLOS]

Cloud computing has revolutionized the development and operations of hardware and software across diverse technological arenas, yet academic biomedical research has lagged behind despite the numerous and weighty advantages that cloud computing offers. Biomedical researchers who embrace cloud computing can reap rewards in cost reduction, decreased development and maintenance workload, increased reproducibility, ease of sharing data and software, enhanced security, horizontal and vertical scalability, high availability, a thriving technology partner ecosystem, and much more. Despite these advantages that cloud-based workflows offer, the majority of scientific software developed in academia does not utilize cloud computing and must be migrated to the cloud by the user. In this article, we present 11 quick tips for architecting biomedical informatics workflows on compute clouds, distilling knowledge gained from experience developing, operating, maintaining, and distributing software and virtualized appliances on the world's largest cloud. Researchers who follow these tips stand to benefit immediately by migrating their workflows to cloud computing and embracing the paradigm of abstraction.

Effect of genetic architecture on the prediction accuracy of quantitative traits in samples of unrelated individuals

Nice paper from Trudy Mackay et al. I had the pleasure of talking to her about this paper at the last EDGE workshop.

Morgante F, Huang W, Maltecca C, Mackay TFC. Effect of genetic architecture on the prediction accuracy of quantitative traits in samples of unrelated individuals. Heredity (Edinb). 2018 [PubMed]

Abstract

Predicting complex phenotypes from genomic data is a fundamental aim of animal and plant breeding, where we wish to predict genetic merits of selection candidates; and of human genetics, where we wish to predict disease risk. While genomic prediction models work well with populations of related individuals and high linkage disequilibrium (LD) (e.g., livestock), comparable models perform poorly for populations of unrelated individuals and low LD (e.g., humans). We hypothesized that low prediction accuracies in the latter situation may occur when the genetics architecture of the trait departs from the infinitesimal and additive architecture assumed by most prediction models. We used simulated data for 10,000 lines based on sequence data from a population of unrelated, inbred Drosophila melanogaster lines to evaluate this hypothesis. We show that, even in very simplified scenarios meant as a stress test of the commonly used Genomic Best Linear Unbiased Predictor (G-BLUP) method, using all common variants yields low prediction accuracy regardless of the trait genetic architecture. However, prediction accuracy increases when predictions are informed by the genetic architecture inferred from mapping the top variants affecting main effects and interactions in the training data, provided there is sufficient power for mapping. When the true genetic architecture is largely or partially due to epistatic interactions, the additive model may not perform well, while models that account explicitly for interactions generally increase prediction accuracy. Our results indicate that accounting for genetic architecture can improve prediction accuracy for quantitative traits.

News piece on Gene Medic

Here is a news piece on my new Atari 2600 game Gene Medic that appeared in the Daily Pennsylvanian.

A heuristic method for simulating open-data of arbitrary complexity that can be used to compare and evaluate machine learning methods

A new version of our HIBACHI approach for simulating more realistic data.

Moore JH, Shestov M, Schmitt P, Olson RS. A heuristic method for simulating open-data of arbitrary complexity that can be used to compare and evaluate machine learning methods. Pac Symp Biocomput. 2018;23:259-267. [PDF]

A central challenge of developing and evaluating artificial intelligence and machine learning methods for regression and classification is access to data that illuminates the strengths and weaknesses of different methods. Open data plays an important role in this process by making it easy for computational researchers to easily access real data for this purpose. Genomics has in some examples taken a leading role in the open data effort starting with DNA microarrays. While real data from experimental and observational studies is necessary for developing computational methods it is not sufficient. This is because it is not possible to know what the ground truth is in real data. This must be accompanied by simulated data where that balance between signal and noise is known and can be directly evaluated. Unfortunately, there is a lack of methods and software for simulating data with the kind of complexity found in real biological and biomedical systems. We present here the Heuristic Identification of Biological Architectures for simulating Complex Hierarchical Interactions (HIBACHI) method and prototype software for simulating complex biological and biomedical data. Further, we introduce new methods for developing simulation models that generate data that specifically allows discrimination between different machine learning methods.

Leveraging putative enhancer-promoter interactions to investigate two-way epistasis in Type 2 Diabetes GWAS

We presented this paper at the 2018 Pacific Symposium on Biocomputing. This is an effort to incorporate functional genomics annotations into epistasis analysis in regulatory regions.

Manduchi E, Chesi A, Hall MA, Grant SFA, Moore JH. Leveraging putative enhancer-promoter interactions to investigate two-way epistasis in Type 2 Diabetes GWAS. Pac Symp Biocomput. 2018;23:548-558. [PDF]

We utilized evidence for enhancer-promoter interactions from functional genomics data in order to build biological filters to narrow down the search space for two-way Single Nucleotide Polymorphism (SNP) interactions in Type 2 Diabetes (T2D) Genome Wide Association Studies (GWAS). This has led us to the identification of a reproducible statistically significant SNP pair associated with T2D. As more functional genomics data are being generated that can help identify potentially interacting enhancer-promoter pairs in larger collection of tissues/cells, this approach has implications for investigation of epistasis from GWAS in general.

Gene Medic - a retro edutainment game for the Atari 2600

I am please to announce the release of my new retro edutainment game of genome medicine for the Atari 2600 video computer system (VCS). The game is called Gene Medic and the goal is to edit a patient's mutations to restore health. You can find information about the game along with the binary and source core here.