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sections/04-liver-disease-atlas.Rmd

@@ -110,7 +110,7 @@ knitr::include_graphics(here::here("data/liver_disease_atlas/Figure 3.png"))
 ### Similarities between humans and mice {.unlisted}
 I performed a cross-species analysis to evaluate how well the altered gene expression in the chronic CCl~4~ mouse model reflects the transcriptomic changes in humans that suffer from CLD. For this purpose, I collected genome-wide gene expression data from 5 publicly available patient cohorts with a total of 372 patients and five etiologies (Table \@ref(tab:liver-tab-1), Supplementary Figure \@ref(fig:liver-sfig-1)B). These studies allowed us to calculate a total of 15 contrasts due to different disease stages and phenotypes.
 
-Similar to the acute mouse models I first analyzed inter-study consistency comparing the similarity of the top 500 differentially expressed genes from each signature. Differential genes obtained from studies of the same groups of authors showed a higher degree of similarity (Supplementary Figure \@ref(fig:liver-sfig-14)). The highest similarity of two independent contrasts was observed between NAFLD 7 and HCV 6 (Jaccard Index of 0.154). In summary, the similarity of the top differentially expressed genes in humans appeared to be low. However, the mutual enrichment of the top 500 up-and downregulated genes demonstrated a very high consistency of the direction of regulation within contrasts of the same group of authors but also observed still relatively high accordance across the cohorts reported by different authors (Figure \@ref(fig:liver-fig-4)A). Partially, the direction of regulation of genes from the cohorts of patients with PSC, PBC, and NAFLD did not match well with the other contrasts. However, all other pairwise comparisons yielded convincing consistent results. Similar to the analysis of the mouse studies, this systematic comparison shows that similarities between different studies can better be identified by an enrichment analysis that considers the orientation (up, down) of expression changes than just focussing on the top differentially expressed genes.
+Similar to the acute mouse models I first analyzed inter-study consistency comparing the similarity of the top 500 differentially expressed genes from each signature. Differential genes obtained from studies of the same groups of authors showed a higher degree of similarity (Supplementary Figure \@ref(fig:liver-sfig-14)). The highest similarity of two independent contrasts was observed between NAFLD [@moylan_2014] and HCV [@ramnath_2018] (Jaccard Index of 0.154). In summary, the similarity of the top differentially expressed genes in humans appeared to be low. However, the mutual enrichment of the top 500 up-and downregulated genes demonstrated a very high consistency of the direction of regulation within contrasts of the same group of authors but also observed still relatively high accordance across the cohorts reported by different authors (Figure \@ref(fig:liver-fig-4)A). Partially, the direction of regulation of genes from the cohorts of patients with PSC, PBC, and NAFLD did not match well with the other contrasts. However, all other pairwise comparisons yielded convincing consistent results. Similar to the analysis of the mouse studies, this systematic comparison shows that similarities between different studies can better be identified by an enrichment analysis that considers the orientation (up, down) of expression changes than just focussing on the top differentially expressed genes.
 
 Considering that previous studies reported only very low overlap between differentially expressed genes of humans and mice in CLD [@teufel_2016] and the above-described limitations of this type of comparison I performed a cross-species enrichment analysis between the chronic CCl~4~ model and the set of human data. For this purpose, I enriched the top 500 up-and downregulated genes from each human contrast in the three signatures from the individual time points of the chronic CCl~4~ experiment in mice. I found a high degree of accordance where all human gene sets were significantly and consistently enriched at any time point of the chronic CCl~4~ mouse signatures except for the up- and-downregulated genes of the PBC contrast, the downregulated genes of NAFLD contrast, and the upregulated genes of the NAFLD contrast; instead, I found that even the top 500 upregulated genes of the PBC contrast were significantly enriched among the downregulated genes of the 6-month time point of the chronic CCl~4~ signature (Figure \@ref(fig:liver-fig-4)B).