Inference of a combinatorial function from multiple independent variables (parents) to a dependent variable (child) in a discrete space can be useful in detecting nonlinear relationships in biological systems. Popular conditional independency measures, heavily used in combinatorial inference, are often insensitive to the direction of functional dependency. To address this issue, we define multivariate and conditional functional chi-squared statistics. We also present an algorithm called CFDF for bivariate discrete function inference via an exclusive-effect strategy, in order to identify a best parent set for a given child. It requires each parent to make sufficient contribution beyond any marginal effect. Simulation studies suggest a marked advantage of our framework over alternatives. Applying the method to transcriptome data in genetically perturbed biological systems, we reproduced combinatorial gene interactions known in the literature. Most importantly, we identified combinatorial patterns from joint RNA and protein data to rebut a dispute on the founding principle of molecular biology.
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Joint Grid Discretization for Biological Pattern Discovery
The complexity, dynamics, and scale of data acquired by modern biotechnology increasingly favor model-free computational methods that make minimal assumptions about underlying biological mechanisms. For example, single-cell transcriptome and proteome data have a throughput several orders more than bulk methods. Many model-free statistical methods for pattern discovery such as mutual information and chi-squared tests, however, require discrete data. Most discretization methods minimize squared errors for each variable independently, not necessarily retaining joint patterns. To address this issue, we present a joint grid discretization algorithm that preserves clusters in the original data. We evaluated this algorithm on simulated data to show its advantage over other methods in maintaining clusters as measured by the adjusted Rand index. We also show it promotes global functional patterns over independent patterns. On single-cell proteome and transcriptome of leukemia and healthy blood, joint grid discretization captured known protein-to-RNA regulatory relationships, while revealing previously unknown interactions. As such, the joint grid discretization is applicable as a data transformation step in associative, functional, and causal inference of molecular interactions fundamental to systems biology. The developed software is publicly available at https://cran.r-project.org/package=GridOnClusters
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- Award ID(s):
- 1661331
- NSF-PAR ID:
- 10236467
- Date Published:
- Journal Name:
- Proceedings. The 11th ACM Int'l Conf on Bioinform, Comput Biol and Health Inform
- Page Range / eLocation ID:
- Article No.: 57
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Intestinal stem cells are non-quiescent, dividing epithelial cells that rapidly differentiate into progenitor cells of the absorptive and secretory cell lineages. The kinetics of this process is rapid such that the epithelium is replaced weekly. To determine how the transcriptome and proteome keep pace with rapid differentiation, we developed a new cell sorting method to purify mouse colon epithelial cells. Here we show that alternative mRNA splicing and polyadenylation dominate changes in the transcriptome as stem cells differentiate into progenitors. In contrast, as progenitors differentiate into mature cell types, changes in mRNA levels dominate the transcriptome. RNA processing targets regulators of cell cycle, RNA, cell adhesion, SUMOylation, and Wnt and Notch signaling. Additionally, global proteome profiling detected >2,800 proteins and revealed RNA:protein patterns of abundance and correlation. Paired together, these data highlight new potentials for autocrine and feedback regulation and provide new insights into cell state transitions in the crypt.
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Abstract Motivation Computer inference of biological mechanisms is increasingly approachable due to dynamically rich data sources such as single-cell genomics. Inferred molecular interactions can prioritize hypotheses for wet-lab experiments to expedite biological discovery. However, complex data often come with unwanted biological or technical variations, exposing biases over marginal distribution and sample size in current methods to favor spurious causal relationships.
Results Considering function direction and strength as evidence for causality, we present an adapted functional chi-squared test (AdpFunChisq) that rewards functional patterns over non-functional or independent patterns. On synthetic and three biology datasets, we demonstrate the advantages of AdpFunChisq over 10 methods on overcoming biases that give rise to wide fluctuations in the performance of alternative approaches. On single-cell multiomics data of multiple phenotype acute leukemia, we found that the T-cell surface glycoprotein CD3 delta chain may causally mediate specific genes in the viral carcinogenesis pathway. Using the causality-by-functionality principle, AdpFunChisq offers a viable option for robust causal inference in dynamical systems.
Availability and implementation The AdpFunChisq test is implemented in the R package ‘FunChisq’ (2.5.2 or above) at https://cran.r-project.org/package=FunChisq. All other source code along with pre-processed data is available at Code Ocean https://doi.org/10.24433/CO.2907738.v1
Supplementary information Supplementary materials are available at Bioinformatics online.
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Kelso, Janet (Ed.)Abstract Motivation Genetic or epigenetic events can rewire molecular networks to induce extraordinary phenotypical divergences. Among the many network rewiring approaches, no model-free statistical methods can differentiate gene-gene pattern changes not attributed to marginal changes. This may obscure fundamental rewiring from superficial changes. Results Here we introduce a model-free Sharma-Song test to determine if patterns differ in the second order, meaning that the deviation of the joint distribution from the product of marginal distributions is unequal across conditions. We prove an asymptotic chi-squared null distribution for the test statistic. Simulation studies demonstrate its advantage over alternative methods in detecting second-order differential patterns. Applying the test on three independent mammalian developmental transcriptome datasets, we report a lower frequency of co-expression network rewiring between human and mouse for the same tissue group than the frequency of rewiring between tissue groups within the same species. We also find secondorder differential patterns between microRNA promoters and genes contrasting cerebellum and liver development in mice. These patterns are enriched in the spliceosome pathway regulating tissue specificity. Complementary to previous mammalian comparative studies mostly driven by first-order effects, our findings contribute an understanding of system-wide second-order gene network rewiring within and across mammalian systems. Second-order differential patterns constitute evidence for fundamentally rewired biological circuitry due to evolution, environment, or disease. Availability The generic Sharma-Song test is available from the R package ‘DiffXTables’ at https://cran.r-project.org/package=DiffXTables. Other code and data are described in Methods. Supplementary information Supplementary data are available at Bioinformatics online.more » « less
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Directional association measured by functional dependency can answer important questions on relationships between variables, for example, in discovery of molecular interactions in biological systems. However, when one has no prior information about the functional form of a directional association, there is not a widely established statistical procedure to detect such an association. To address this issue, here we introduce an exact functional test for directional association by examining the strength of functional dependency. It is effective in promoting functional patterns by reducing statistical power on dependent non-functional patterns. We designed an algorithm to carry out the test using a fast branch-and-bound strategy, which achieved a substantial speedup over brute-force enumeration. On data from an epidemiological study of liver cancer, the test identified the hepatitis status of a subject as the most influential risk factor among others for the cancer phenotype. On human lung cancer transcriptome data, the test selected 1068 transcription start sites of putative noncoding RNAs directionally associated with the presence or absence of lung cancer, stronger than 95 percent transcription start sites of 694 curated cancer genes. These predictions include non-monotonic interaction patterns, to which other routine tests were insensitive. Complementing symmetric (non-directional) association methods such as Fisher’s exact test, the exact functional test is a unique exact statistical test for evaluating evidence for causal relationships.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Conference Paper:
- https://doi.org/10.1145/3388440.3412415
