Background: Existing proposed pathogenesis for preeclampsia (PE) was only applied for early-onset PE (EOPE). Our previous work identified the transcriptome to decipher EOPE and late-onset PE (LOPE), but the pathogenesis models were not validated. We developed and validated the pathogenesis models by hierarchical representation learning of interactomes connecting endometrial maturation, placentation, chorioamnionitis, and hemolysis, elevated liver enzyme, and low platelet (HELLP) syndrome. Methods: We utilized 19 gene sets from our previous work to infer interactomes to develop (n=177) and validate (n=352) explainable artificial intelligence models for each PE subtype using deep-insight visible neural network and gradient-weighted class activation mapping. Results: The hierarchically learned representations identified novel genes for LOPE, similar to endometrial maturation (MRPL34, DYNLL1), chorioamnionitis (ANKRD13A, SLA), and HELLP syndrome (FAM43A). We also identified novel genes for EOPE, similar to endometrial maturation (SNAP23, PPL, LRRC32), placentation (GPT2, UBE2H, NIPAL3, NIN, KIAA0232, MT1F, DKK3, SLC24A3), and HELLP syndrome (SWAP70, GREM2, GPR146, PIP5K1B, EZR). Nonetheless, a gene for each subtype was frequently studied, i.e., IGF1 (chorioamnionitis) and PAPPA2 (placentation), including LOPE and EOPE samples. Conclusions: Our pathogenesis models connected both endometrial maturation and HELLP syndrome with LOPE and EOPE. However, they were differently connected with chorioamnionitis and placentation.

HS has signed an expert agreement with Atheneum. The other authors declare that they have no competing interests.

This study was funded by: (1) the Postdoctoral Accompanies Research Project from the National Science and Technology Council (NSTC) of Taiwan (grant nos.: NSTC111-2811-E-038-003-MY2 and NSTC113-2811-E-A49A-003) to HS; and (2) the National Science and Technology Council in Taiwan (grant no. NSTC113-2221-E-A49-193-MY3), the Ministry of Science and Technology (MOST) of Taiwan (grant nos.: MOST110-2628-E-038-001 and MOST111-2628-E-038-001-MY2), the University System of Taipei Joint Research Program (grant no.: USTP-NTOU-TMU-112-04), and the Higher Education Sprout Project from the Ministry of Education (MOE) of Taiwan (grant no.: DP2-111-21121-01-A-05 and DP2-TMU-112-A-13) to ECYS. These funding bodies had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Data are available publicly available in GEO and ArrayExpress, as described in our previous work (https://github.com/herdiantrisufriyana/pec/blob/master/supplementary_material.pdf).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes