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Guidance for RNA-seq co-expression network construction and analysis: safety in numbers
Open accessAbstract
Motivation: RNA-seq co-expression analysis is in its infancy and reasonable practices remain poorly defined. We assessed a variety of RNA-seq expression data to determine factors affecting functional connectivity and topology in co-expression networks. Results: We examine RNA-seq co-expression data generated from 1970 RNA-seq samples using a Guilt-By-Association framework, in which genes are assessed for the tendency of co-expression to reflect shared function. Minimal experimental criteria to obtain performance on par with microarrays were >20 samples with read depth >10 M per sample. While the aggregate network constructed shows good performance (area under the receiver operator characteristic curve ∼0.71), the dependency on number of experiments used is nearly identical to that present in microarrays, suggesting thousands of samples are required to obtain ‘gold-standard’ co-expression. We find a major topological difference between RNA-seq and microarray co-expression in the form of low overlaps between hub-like genes from each network due to changes in the correlation of expression noise within each technology. Contact: jgillis@cshl.edu or sballouz@cshl.edu Supplementary information: Networks are available at: http://gillislab.labsites.cshl.edu/supplements/rna-seq-networks/ and supplementary data are available at Bioinformatics online.
Overview
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Written from the paper’s full text.
TL;DR
This paper benchmarks RNA-seq co-expression network construction against microarrays and finds that simple correlation-based networks, especially when aggregated across many datasets, recover known gene function comparably to microarrays. However, RNA-seq and microarray networks differ sharply in topology, largely because low-expression noise creates different hub genes.
Key findings
- Individual RNA-seq co-expression networks performed modestly, with an average AUROC of 0.585; only 0.7% of GO terms averaged above 0.8 AUROC, and only 2% ever exceeded 0.9 AUROC in any assessed network.
- Aggregating networks improved functional connectivity to about 0.71 AUROC for both RNA-seq and microarray data; roughly 20 experiments were enough for AUROC >0.6, while capturing unknown functional information may require more than 50 experiments.
- RNA-seq and microarray aggregate networks had negatively correlated node degrees, and hub-like genes were significantly dissimilar between technologies (P < 1.4e-9), even though both captured individual GO functions similarly.
- Low-expressing transcripts that failed SEQC reliability thresholds in at least 80% of experiments had high node degree in microarrays but low node degree in RNA-seq, explaining much of the topological mismatch.
Methods
- The authors assembled 50 RNA-seq experiments totaling 1970 samples from SRA, Gemma, BrainSpan, and ReCount, plus 43 microarray experiments totaling 5134 arrays from GEO.
- Expression was estimated with Cufflinks, RSEQtools, and RSEM; co-expression networks used rank-transformed correlation edge weights, with comparisons to mutual information, ARACNE, CLR, MRNET, and WGCNA thresholding.
- Functional connectivity was assessed by guilt-by-association using neighbor voting and other machine-learning classifiers, with 3-fold cross-validation and AUROC against GO, KEGG, and Reactome annotations; aggregate networks were built by summing rank-standardized edges across datasets.
Limitations
- Stated: the authors note that their use of GO as the definition of function is the most easily critiqued aspect, although KEGG and Reactome gave nearly identical results; they also state that they cannot readily assess RNA-seq in its most novel applications, such as novel or more diverse transcript assessment.
- Stated: they do not claim to identify an ideal RNA-seq co-expression method, and they note that focused uses such as tissue-specific or developmental analyses may not be higher performing in their framework.
- Evident: the study is limited to human datasets and existing annotations, ignores alternate isoforms in aggregates and performance measures, and uses median values when multiple measures exist, so isoform-level or cross-species generalization is not established.
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Claims the paper makes
65 Own result · 37 Own interpretation · 10 Not checked yet · 3 Own method · 3 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Network topology was not fully robust to the methods used (Supplementary Fig. S1A), with the correlations of node degree between the networks created ranging between q ¼ À0.39 and q ¼ 0.88.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.1 RNA-seq expression estimates and co-expression measures affect network topology but not functional connectivity
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Samples assayed by microarrays show a linear relationship between sample size and network performance (Fig. 3A, q ¼ 0.66)”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.2 Many samples and greater read depth increases the functional connectivity of the networks
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In the paper
“A similar, albeit weaker trend is visible with increasing read depth (Supplementary Fig. S2C)”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.2 Many samples and greater read depth increases the functional connectivity of the networks
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In the paper
“A notable point is that both RNA-seq and microarray networks appear to converge to similar performance measures (average AUROC $0.7).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.3 Aggregating across many networks improves performance and removes noise
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In the paper
“We observe a particularly strong role for number of samples and aggregation (Sections 3.2 and 3.3) in GBA assessments while mapping and machine learning methods (Sections 3.1 and 3.4) affect primarily topology and not GBA.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 1 Introduction
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In the paper
“Networks constructed using more samples were generally higher performing, and the trend is surprisingly consistent in strength between microarrays and RNA-seq (Fig. 3A and B).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.2 Many samples and greater read depth increases the functional connectivity of the networks
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In the paper
“While in theory it is possible that individual networks work well for different functions, this did not occur to any substantial extent.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.2 Many samples and greater read depth increases the functional connectivity of the networks
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Networks constructed using more samples were generally higher performing, and the trend is surprisingly consistent in strength between microarrays and RNA-seq (Fig. 3A and B).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.2 Many samples and greater read depth increases the functional connectivity of the networks
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, for any given experiment, the fraction of its GO terms which outperform the aggregate is very small, reaching a maximum of 17% only in very large experiments and averaging only 5% of GO terms (again, those with low performance, Fig. 5B).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.3 Aggregating across many networks improves performance and removes noise
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In the paper
“The top group had the highest performance (average AUROC ¼ 0.71), only just above the range of the random sampled”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 33
- Probably not a substantial claim. 6
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In the paper
“Taking all the protein complex subgroups in GO in our analyses, their performance on average in the aggregate was AUROC $0.77, significantly greater than the remaining terms (Wilcoxon test, p $ 5.423eÀ7)”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similarly, for any given experiment, the fraction of its GO terms which outperform the aggregate is very small, reaching a maximum of 17% only in very large experiments and averaging only 5% of GO terms (again, those with low performance, Fig. 5B).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.3 Aggregating across many networks improves performance and removes noise
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The MI network performs below the correlation coefficients, and closer to the networks generated including the negative correlation (average AUROC ¼ 0.56).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.1 RNA-seq expression estimates and co-expression measures affect network topology but not functional connectivity
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In the paper
“## 3.3 Aggregating across many networks improves performance and removes noise”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.3 Aggregating across many networks improves performance and removes noise
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Inset shows the correlation between the two GO AUROCs distributions plotted (q ¼ 0.84, P < 1eÀ16), showing that GO groups that perform well in one, perform equally well in the other network”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The average AUROC varied slightly between methods (Supplementary Table S4), with the neighbor voting, logistic regres- sion and stochastic gradient descent giving the highest performance (average AUROC ¼ 0.69), and the random forest performing the worst of the six methods (average AUROC ¼ 0.63).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.4 Machine learning methods do not confound network performance results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, all the methods perform well on similar GO groups as neighbor voting (performances correlated at q ¼ 0.87-0.96, P < 2.2eÀ16)”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.4 Machine learning methods do not confound network performance results
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the aggregate, almost half (47%) of the gene pairs exhibit high ranking (top 10%) co-expression, while a proportionately smaller fraction ($2%) exhibit very highly ranked (top 1%) co-expression.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we verified by removing the connections ranked in the top 1% and seeing no significant drop in performance whereas removal of the connections in the top 10% had a large effect (AUROC $0.6).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In co-expression analysis, increasing depth past 100 M aligned reads per sample and even thousands of samples continue to add value if our focus is on genome-wide functional inference for a given dataset.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RNA-seq coexpression and microarray co-expression are very similar in their functional properties but very dissimilar in their overall topology (Fig. 6A).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.6 Noisy expression variation dominates topology outside of functional connectivity
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“a simple rank-andsummate aggregation across multiple datasets generates a more robust network, capturing known biology with high efficacy.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our study suggests that 1 M reads per sample (with many samples) is sufficient to build a network that is slightly divergent from random and adding such networks has no negative impact on the performance of the aggregate network.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
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It may state two separate claims as one.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“simple, basic approaches were among the highest performing, from measuring network connectivity (Spearman correlation) to functional inference (neighbor voting).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, again, performances are similar in microarray and RNA-seq (mean GO AUROCs of 0.64 and 0.65, respectively), but topology is starkly different with a correlation of q ¼ À0.66 between the node degrees of the two networks constructed.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.6 Noisy expression variation dominates topology outside of functional connectivity
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, the computationally simplest and most transparent method for calculating co-expression-simple correlation-was also the highest performing.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.1 RNA-seq expression estimates and co-expression measures affect network topology but not functional connectivity
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It may state two separate claims as one.
In the paper
“These include dependencies on library preparation, sequencing depth, gene lengths, GC content and transcript lengths, as well as other laboratory-specific practices (Hitzemann et al., 2013).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 1 Introduction
What the sources say
- Not checked yetcites Hitzemann et al., 2013 source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is characteristic of groups benefiting from aggregation in exhibiting moderate performance even before aggregation and, interestingly, in being a protein complex.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Altogether, our examination of the collagen complex supports the view that aggregation will work best in functions where pairwise relationships are expected to be distributed (e.g. protein complexes rather than dynamic pathways) and weak aggregate effects can summate to provide a strong total signal.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
None of the sources cited for this claim have been checked yet.
In the paper
“Node degree is central to network topology and a major factor in numerous other properties (Gillis and Pavlidis, 2011b;Newman, 2003).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 1 Introduction
What the sources say
- Not checked yetcites Gillis and Pavlidis, 2011b
- Not checked yetcites Newman, 2003 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Even though this is lower than the random sets of experiments, it still outperforms almost all of the individual networks (equal to the best performing), indicating that even the weakest networks are useful in aggregate (Supplementary Fig. S5B).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The apparent performance dependencies suggest that to move from an AUROC ¼ 0.55-0.6 requires either thousands of samples, or millions of more sequenced reads, which is likely not feasible in a single experiment.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.2 Many samples and greater read depth increases the functional connectivity of the networks
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We also resampled across datasets to ensure the aggregated network exhibited robust properties.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 2.4 Co-expression networks and network aggregation
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, RNA-seq offers unique virtues but is not a technical panacea.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Users of co-expression data cannot naively apply those recommendations because the minimum number of samples is already relatively high, and robustly measuring correlations may require an even greater increase.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This indicates that the negative correlation between microarrays and RNA-seq data is a recurring feature of the individual networks, and not just the aggregates, and suggests a feature due to technological biases (in conjunction with network construction methods, Supplementary Fig. S5C).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.5 Microarray and RNA-seq-derived networks have different hub genes
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This dissimilarity suggests again that while inference methods average away topological noise, the actual networks exhibit it to a substantial degree and this could be easily altered by varying methodology in other ways.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.5 Microarray and RNA-seq-derived networks have different hub genes
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this may reflect our reliance on GO as a reference, even for narrowly defined functions.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unsupervised interpretation of RNA-seq data connectivity is unlikely to be robust to underlying methodological choices without careful filtering, while methods that extract signals using training data (supervised or semi-supervised methods) appear to safely recover known information.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, the low impact of variation in node degree on semisupervised learning (e.g. through GBA) suggests that even without the appropriate filtering, many methods adequately identify the absence of learnable features in noisy expression.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the machine learning algorithm selected has little influence on the results, which also implies that the features being selected to make predictions, determine connectivity and assess the networks are adequate for the task at hand.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“So profound is the performance difference between aggregate and individual networks that it is difficult to recommend any minimum depth or sample count which is adequate; certainly none in our case come close to producing the same apparent performance.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our analysis suggests that the reordering reflects the tendency for low-expressing genes to be correlated in microarray data, but that RNA-seq allows us to identify which genes are 'too' low to be trusted with much greater specificity.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and in not generating spurious correlation among these noisy values (low node degree).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.6 Noisy expression variation dominates topology outside of functional connectivity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Co-expression analyses will still require many samples and a reliable quality reference network as a control and comparative measure.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because of our reliance on pre-existing knowledge (GO) or data (microarray) to provide reference knowledge, we cannot readily assess RNA-seq where its application is likely to prove most novel and exciting, e.g.novel or more diverse transcript assessment.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: The GO reference data adequately represents biological function for evaluating co-expression network performance.
- Rests on an assumption: The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
The paper relies on this without support.
RNA-seq co-expression analysis is in its infancy and reasonable practices remain poorly defined.
“RNA-seq co-expression analysis is in its infancy and reasonable practices remain poorly defined.”
The paper relies on this without support.
The GO, KEGG, and Reactome annotations used as labels accurately reflect gene function and are sufficiently complete for evaluating functional connectivity.
“By using known annotations as labels for the genes (here we used GO, KEGG and Reactome labeled gene sets), one can determine how well the network recapitulates this information”
The paper relies on this without support.
The 10 RNA-seq experiments selected for method comparisons are representative of the broader corpus.
“We used a sample of 10 representative experiments, comparing the estimation expressions of Cufflinks, RSEQtools and RSEM and constructed co-expression networks using our default procedures”
The paper relies on this without support.
The aggregate network's performance on GO terms is a valid proxy for capturing unknown functional information.
“to comprehensively capture unknown functional information may require >50 separate experiments.”
The paper relies on this without support.
The RNA-seq and microarray datasets used are comparable enough that observed differences in network topology and sample-size dependency reflect technology rather than dataset composition.
“In a similar fashion, we generated an aggregate of the microarrays on a random sample of 30 datasets using 3320 individual microarrays.”
The paper relies on this without support.
GO slim's 109 terms are broadly representative of the ontology overall.
“For our machine learning analysis, we used GO slim, a version of GO that filters analyses to 109 GO terms, broadly representative of the ontology overall.”
The paper relies on this without support.
The GO reference data adequately represents biological function for evaluating co-expression network performance.
“our use of the GO as a way of defining 'function' is perhaps the most easily critiqued, albeit hard to avoid and common.”
The paper relies on this without support.
The 50 RNA-seq and 30 microarray datasets are representative of their respective technologies.
“We used the 30 networks from the microarray aggregate, and the 50 networks of the RNA-seq aggregates”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“While differential co-expression methods are sensitive to noise [21], they are becoming more effective with the increase in RNA-seq data quantity and quality.”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Co-expression networks constructed using this cut-off have been suggested to have a similar quality to microarray-based co-expression networks if constructed from the same number of samples [21], but decreasing in quality with fewer reads.”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A higher total read depth for RNA-seq samples increases the accuracy of the expression measurements, especially for genes with low expression [21, 59].”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“At currently available sample sizes, networks are most reproducible at a module level35,38,39, then at the hub gene level41,223 and, last, at the level of precise gene connectivity rankings or precise module memberships of genes40,49.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [40]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“To create co-expression networks from RNA-seq data, a 20-sample minimum has been suggested [21, 54], and increased sample sizes produce networks with a higher functional connectivity [21, 59].”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“To create co-expression networks from RNA-seq data, a 20-sample minimum has been suggested [21, 54], and increased sample sizes produce networks with a higher functional connectivity [21, 59].”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [21]
The cited source says what the claim attributes to it.
In the citing paper
“Not surprisingly, higher quality data tend to result in more accurate co-expression networks [21, 59].”
From Gene co-expression analysis for functional classification and gene–disease predictions (2017) · cites this paper as [21]
In the citing paper
“To obtain module-level reproducibility, 20 independent samples are usually sufficient40, but systematic and accurate reconstruction of specific edges, particularly for systematic regulatory relationship discovery, may require hundreds of samples49.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [40]
In the citing paper
“For DGE and network analysis, there are many studies with guidelines that are based on theoretical models and empirical assessments40,173–176, but most studies use data from experiments that do not have the spatial, temporal or disease-relevant complexities that occur in studies of the CNS or post-mortem tissue.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [40]
In the citing paper
“To obtain module-level reproducibility, 20 independent samples are typically considered adequate; however, systematic consistency at the more granular hub and module membership levels may require hundreds of samples [61, 93, 94].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [93]
In the citing paper
“To obtain module-level reproducibility, 20 independent samples are typically considered adequate; however, systematic consistency at the more granular hub and module membership levels may require hundreds of samples [61, 93, 94].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [93]
In the citing paper
“Network analyses of AD brain tissue demonstrate the most reproducibility at the module level, followed by the hub protein level, and then finally at the level of precise protein connectivity rankings and module protein membership [61, 89–94].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [93]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > Abstract
“Minimal experimental criteria to obtain performance on par with microarrays were >20 samples with read depth >10 M per sample.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.2 Many samples and greater read depth increases the functional connectivity of the networks
“suggests using RNA-seq co-expression to obtain even modest performance (AUROC >0.55) requires sample sizes >20 and read depth per sam- ple close to 100 M reads.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.4 Machine learning methods do not confound network performance results
“implying that the results are not strongly method independent.”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 4 Discussion
“the machine learning algorithm selected has little influence on the results”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > 3.5 Microarray and RNA-seq-derived networks have different hub genes
“Even so, both networks capture individual GO functions in a similar way (P ¼ 0.84, Fig. 4B and inset).”
§ Gene expression Guidance for RNA-seq co-expression network construction and analysis: safety in numbers > A B
“Inset shows the correlation between the two GO AUROCs distributions plotted (q ¼ 0.84, P < 1eÀ16)”
Citations
Cites
Breiman, L. (2001) · Machine Learning · doi:10.1023/a:1010933404324 · Cited by 133,538
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400
Gene Ontology: tool for the unification of biology
Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., Davis, A. P., Dolinski, K., Dwight, S. S., Eppig, J. T., et al. (2000) · Nature Genetics · doi:10.1038/75556 · Cited by 43,206
KEGG: Kyoto Encyclopedia of Genes and Genomes
Kanehisa, M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.27 · Cited by 37,077
KEGG: Kyoto Encyclopedia of Genes and Genomes
Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., & Kanehisa, M. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.1.29 · Cited by 31,232
RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome
Li, B., & Dewey, C. N. (2011) · BMC Bioinformatics · doi:10.1186/1471-2105-12-323 · Cited by 22,179
The Structure and Function of Complex Networks
Newman, M. E. J. (2003) · SIAM Review · doi:10.1137/s003614450342480 · Cited by 18,719
Cluster analysis and display of genome-wide expression patterns
Eisen, M. B., Spellman, P. T., Brown, P. O., & Botstein, D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14863 · Cited by 16,184
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556
Mapping and quantifying mammalian transcriptomes by RNA-Seq
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L., & Wold, B. (2008) · Nature Methods · doi:10.1038/nmeth.1226 · Cited by 13,696
Cited by
Sorted by citations
Gene co-expression analysis for functional classification and gene–disease predictions
van Dam, S., Võsa, U., van der Graaf, A., Franke, L., & de Magalhães, J. P. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbw139 · Cited by 995
Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression
Schmiedel, B. J., Singh, D., Madrigal, A., Valdovino-Gonzalez, A. G., White, B. M., Zapardiel-Gonzalo, J., Ha, B., Altay, G., Greenbaum, J. A., McVicker, G., et al. (2018) · Cell · doi:10.1016/j.cell.2018.10.022 · Cited by 867
Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders
Parikshak, N. N., Gandal, M. J., & Geschwind, D. H. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3934 · Cited by 430
Crow, M., Paul, A., Ballouz, S., Huang, Z. J., & Gillis, J. (2018) · Nature Communications · doi:10.1038/s41467-018-03282-0 · Cited by 365
Self-citationCEMiTool: a Bioconductor package for performing comprehensive modular co-expression analyses
Russo, P. S. T., Ferreira, G. R., Cardozo, L. E., Bürger, M. C., Arias‐Carrasco, R., Maruyama, S. R., Hirata, T. D. C., de Lima, D. S., Passos, F. M., Fukutani, K. F., et al. (2018) · BMC Bioinformatics · doi:10.1186/s12859-018-2053-1 · Cited by 313
“around 20 samples (which is in accordance to previous findings [26]), indicating that the β x R(2) curve, and thus”
Result
Metadata
- Authors
- Ballouz, S., Verleyen, W., & Gillis, J.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Ballouz, S.
- Gillis, J.
- Venue
- Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-28
- Volume
- 31
- Issue
- 13
- Pages
- 2123-2130
- ISSN
- 1367-4803 (ISSN-L)
- 1367-4811
- OpenAlex
- W2104724027
- Cited by
- 215
- References
- 47
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 7 · 2023: 21 · 2022: 15 · 2021: 31 · 2020: 18 · 2019: 27 · 2018: 24 · 2017: 23 · 2016: 20 · 2015: 6
- FWCI
- 10.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Bioinformatics (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- guilt by association, gene co-expression, network topology, hub genes, sample size requirements, sequencing depth, stochastic gene expression, microarray comparison, functional connectivity, gene function prediction
- MeSH terms
- Algorithms, Brain, Humans, Models, Theoretical, Sequence Analysis, RNA, Computational Biology, Gene Expression Profiling, Gene Regulatory Networks, High-Throughput Nucleotide Sequencing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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