Interpreting Graphs in SEA-AD Gene Expression Trajectory Viewer and Comparative Viewer

I am the Scientific Project Manager for the SEA-AD Consortium. I am posting a community question received via email related to working with SEA-AD data:

I have recently started browsing your fantastic dataset on the SEA-AD gene trajectory browser. I am interested in using data from this browser in an upcoming publication but I want to know more information interpreting the graphs.

Specifically, in the cognitive expression dot blots, what exactly is the “^DE in supertype”?

These appear to be the same as the blue lines in the psuedo-progression supertype resolution plots. Is that correct? Also what is meant by “abundance change”? Does this mean statistically significant change over the progression?

I want to know if I can say " Gene X is increased/decreased in Y cells over progression of AD." based on the blue lines.

Thank you

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In the comparative viewer, we added 3 differential expression notations that come from two general linear mixed effects models (NEBULA) with the formulas:
Gene Expression ~ ADNC OR Cognitive Status OR Braak Stage + Sex + Age at death + The number of genes detected
Gene Expression ~ Subclass OR Supertype + Sex + Age at death + The number of genes detected

The first test is to determine if the gene is changed with AD and the second is to determine if the gene is specifically expressed. When the whole taxonomy is selected, both tests are run by subclass. When a subclass is specified, both tests are run on supertypes.

^ DE in supertype means the gene was significantly (FDR=0.05) enriched in that supertype relative to all other supertypes within the subclass.
* DE across X means the gene was significantly changed in that supertype along the covariate specified
# DE in other covariate means the gene was not significantly changed in the covariate you're looking at, but was significantly changed in another.

Take PTPRG in Microglia along ADNC as an example.

The gene has enriched expression in Micro-PVM_3-SEAAD and Micro-PVM_4-SEAAD relative to other Microglia supertypes, AND is significantly changed along ADNC in Micro-PVM_3-SEAAD and Micro-PVM_2.

Compare this to XIST in Microglia along ADNC, where it is not significantly enriched in any types or changed along ADNC, BUT is significantly changed along another covariate in the model. Flipping to XIST in Microglia along sex reveals the covariate it is significantly different in, which we expect as it is a sex-specific gene.

The DE notations in the comparative viewer have nothing to do with the abundances changes/blue lines in the trajectory viewer. The blue lines indicate the populations that were significantly changed in their relative abundance along our pseudo-progression. We add them to alert people to the fact that the expression changes are occurring in a population that is also changing in its relative abundance. To obtain the significance values of genes that change along CPS, I recommend looking at Supplementary Table 6 from the manuscript.

Kyle Travaglini
Human Cell Types