Symbolic regression analysis of interactions between first trimester maternal serum adipokines in pregnancies which develop pre-eclampsia

Objectives Pre-eclampsia (PE) is an important cause of perinatal morbidity and mortality. Despite an elusive pathophysiology, PE has been associated with changes in maternal serum concentrations of adipokines in early pregnancy. We hypothesized, that symbolic regression might identify interactions between adipokines and PE, which may have eluded regression and Bayesian models. Methods In this nested case-control sub-study, of the Copenhagen First Trimester Screening Study, data regarding maternal weight and serum concentrations of PAPP-A, leptin (Lp), soluble leptin receptor (sLR), adiponectin, and resistin (Re) was available from 423 first trimester pregnancies (gestational week 10+3– 13+6), 126 of which developed PE. Symbolic regression with QLattice/Feyn 2.1 was used to identify models comprising two-interactions between up-to three markers. Results The optimal mathematical model exhibited a non-linear relation between Re and the combined effect of sLR and Lp. The model was dependent, in a Gaussian way, on the level of Re. The receiver operating characteristic (ROC) curve of the model viz. identification of PE cases in first trimester had an AUC of 0.81 and a modelled DR of 40 % for a FPR of 4 %. Symbolic regression outperformed logistic regression of the same parameters with a ROC with AUC = 0.77, and a DR of 7 % for a 3 % FPR. Conclusions Symbolic regression identified non-linear interactions between Lp, sLR and Re concentrations in first trimester pregnancy serum of pregnancies which later developed PE. Non-linear interactions suggest new pathophysiological pathways and may help in designing more efficient screening protocols for PE. ### Competing Interest Statement Casper Wilstrup is founder and CEO of Abzu, a company providing AI solutions. None of the author authors have any interests to report. ### Funding Statement The study did not recieve any funding. ### Author Declarations 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: The study was approved by the Scientific Ethics Committee for Copenhagen and Frederiksberg Counties. No.(KF) 01-288/97. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript