skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: dICC: distance-based intraclass correlation coefficient for metagenomic reproducibility studies
Abstract SummaryDue to the sparsity and high dimensionality, microbiome data are routinely summarized into pairwise distances capturing the compositional differences. Many biological insights can be gained by analyzing the distance matrix in relation to some covariates. A microbiome sampling method that characterizes the inter-sample relationship more reproducibly is expected to yield higher statistical power. Traditionally, the intraclass correlation coefficient (ICC) has been used to quantify the degree of reproducibility for a univariate measurement using technical replicates. In this work, we extend the traditional ICC to distance measures and propose a distance-based ICC (dICC). We derive the asymptotic distribution of the sample-based dICC to facilitate statistical inference. We illustrate dICC using a real dataset from a metagenomic reproducibility study. Availability and implementationdICC is implemented in the R CRAN package GUniFrac. Supplementary informationSupplementary data are available at Bioinformatics online.  more » « less
Award ID(s):
2113359 2113360
PAR ID:
10372004
Author(s) / Creator(s):
; ;
Publisher / Repository:
Oxford University Press
Date Published:
Journal Name:
Bioinformatics
ISSN:
1367-4803
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract MotivationLearning associations of traits with the microbial composition of a set of samples is a fundamental goal in microbiome studies. Recently, machine learning methods have been explored for this goal, with some promise. However, in comparison to other fields, microbiome data are high-dimensional and not abundant; leading to a high-dimensional low-sample-size under-determined system. Moreover, microbiome data are often unbalanced and biased. Given such training data, machine learning methods often fail to perform a classification task with sufficient accuracy. Lack of signal is especially problematic when classes are represented in an unbalanced way in the training data; with some classes under-represented. The presence of inter-correlations among subsets of observations further compounds these issues. As a result, machine learning methods have had only limited success in predicting many traits from microbiome. Data augmentation consists of building synthetic samples and adding them to the training data and is a technique that has proved helpful for many machine learning tasks. ResultsIn this paper, we propose a new data augmentation technique for classifying phenotypes based on the microbiome. Our algorithm, called TADA, uses available data and a statistical generative model to create new samples augmenting existing ones, addressing issues of low-sample-size. In generating new samples, TADA takes into account phylogenetic relationships between microbial species. On two real datasets, we show that adding these synthetic samples to the training set improves the accuracy of downstream classification, especially when the training data have an unbalanced representation of classes. Availability and implementationTADA is available at https://github.com/tada-alg/TADA. Supplementary informationSupplementary data are available at Bioinformatics online. 
    more » « less
  2. Abstract Motivationmetal-binding proteins have a central role in maintaining life processes. Nearly one-third of known protein structures contain metal ions that are used for a variety of needs, such as catalysis, DNA/RNA binding, protein structure stability, etc. Identifying metal-binding proteins is thus crucial for understanding the mechanisms of cellular activity. However, experimental annotation of protein metal-binding potential is severely lacking, while computational techniques are often imprecise and of limited applicability. Resultswe developed a novel machine learning-based method, mebipred, for identifying metal-binding proteins from sequence-derived features. This method is over 80% accurate in recognizing proteins that bind metal ion-containing ligands; the specific identity of 11 ubiquitously present metal ions can also be annotated. mebipred is reference-free, i.e. no sequence alignments are involved, and is thus faster than alignment-based methods; it is also more accurate than other sequence-based prediction methods. Additionally, mebipred can identify protein metal-binding capabilities from short sequence stretches, e.g. translated sequencing reads, and, thus, may be useful for the annotation of metal requirements of metagenomic samples. We performed an analysis of available microbiome data and found that ocean, hot spring sediments and soil microbiomes use a more diverse set of metals than human host-related ones. For human microbiomes, physiological conditions explain the observed metal preferences. Similarly, subtle changes in ocean sample ion concentration affect the abundance of relevant metal-binding proteins. These results highlight mebipred’s utility in analyzing microbiome metal requirements. Availability and implementationmebipred is available as a web server at services.bromberglab.org/mebipred and as a standalone package at https://pypi.org/project/mymetal/. Supplementary informationSupplementary data are available at Bioinformatics online. 
    more » « less
  3. Abstract MotivationGenome annotations are a common way to represent genomic features such as genes, regulatory elements or epigenetic modifications. The amount of overlap between two annotations is often used to ascertain if there is an underlying biological connection between them. In order to distinguish between true biological association and overlap by pure chance, a robust measure of significance is required. One common way to do this is to determine if the number of intervals in the reference annotation that intersect the query annotation is statistically significant. However, currently employed statistical frameworks are often either inefficient or inaccurate when computing P-values on the scale of the whole human genome. ResultsWe show that finding the P-values under the typically used ‘gold’ null hypothesis is NP-hard. This motivates us to reformulate the null hypothesis using Markov chains. To be able to measure the fidelity of our Markovian null hypothesis, we develop a fast direct sampling algorithm to estimate the P-value under the gold null hypothesis. We then present an open-source software tool MCDP that computes the P-values under the Markovian null hypothesis in O(m2+n) time and O(m) memory, where m and n are the numbers of intervals in the reference and query annotations, respectively. Notably, MCDP runtime and memory usage are independent from the genome length, allowing it to outperform previous approaches in runtime and memory usage by orders of magnitude on human genome annotations, while maintaining the same level of accuracy. Availability and implementationThe software is available at https://github.com/fmfi-compbio/mc-overlaps. All data for reproducibility are available at https://github.com/fmfi-compbio/mc-overlaps-reproducibility. Supplementary informationSupplementary data are available at Bioinformatics online. 
    more » « less
  4. Abstract MotivationSingle-cell RNA sequencing (scRNA-seq) has revolutionized biological sciences by revealing genome-wide gene expression levels within individual cells. However, a critical challenge faced by researchers is how to optimize the choices of sequencing platforms, sequencing depths and cell numbers in designing scRNA-seq experiments, so as to balance the exploration of the depth and breadth of transcriptome information. ResultsHere we present a flexible and robust simulator, scDesign, the first statistical framework for researchers to quantitatively assess practical scRNA-seq experimental design in the context of differential gene expression analysis. In addition to experimental design, scDesign also assists computational method development by generating high-quality synthetic scRNA-seq datasets under customized experimental settings. In an evaluation based on 17 cell types and 6 different protocols, scDesign outperformed four state-of-the-art scRNA-seq simulation methods and led to rational experimental design. In addition, scDesign demonstrates reproducibility across biological replicates and independent studies. We also discuss the performance of multiple differential expression and dimension reduction methods based on the protocol-dependent scRNA-seq data generated by scDesign. scDesign is expected to be an effective bioinformatic tool that assists rational scRNA-seq experimental design and comparison of scRNA–seq computational methods based on specific research goals. Availability and implementationWe have implemented our method in the R package scDesign, which is freely available at https://github.com/Vivianstats/scDesign. Supplementary informationSupplementary data are available at Bioinformatics online. 
    more » « less
  5. Schwartz, Russell (Ed.)
    Abstract Summary PERMANOVA (permutational multivariate analysis of variance based on distances) has been widely used for testing the association between the microbiome and a covariate of interest. Statistical significance is established by permutation, which is computationally intensive for large sample sizes. As large-scale microbiome studies, such as American Gut Project (AGP), become increasingly popular, a computationally efficient version of PERMANOVA is much needed. To achieve this end, we derive the asymptotic distribution of the PERMANOVA pseudo-F statistic and provide analytical P-value calculation based on chi-square approximation. We show that the asymptotic P-value is close to the PERMANOVA P-value even under a moderate sample size. Moreover, it is more accurate and an order-of-magnitude faster than the permutation-free method MDMR. We demonstrated the use of our procedure D-MANOVA on the AGP dataset. Availability and implementation D-MANOVA is implemented by the dmanova function in the CRAN package GUniFrac. Supplementary information Supplementary data are available at Bioinformatics online. 
    more » « less