Determinants of Ascending Aortic Morphology: Cross-sectional Deep Learning-Based Analysis on 25,073 Non-Contrast-enhanced MRI of NAKO

Background: Pathologies of the thoracic aorta are associated with chronic cardiovascular disease and can be of life-threatening nature. Understanding determinants of thoracic aortic morphology is crucial for precise diagnostics and preventive and therapeutic approaches. This study aimed to automatically characterize ascending aortic morphology based on 3D non-contrast-enhanced magnetic resonance angiography (NE-MRA) data from the large epidemiological cross-sectional German National Cohort (NAKO) and to investigate possible determinants of mid-ascending aortic diameter (mid-AAoD). Methods: Deep learning was used to automatically segment the thoracic aorta and extract ascending aortic length, volume, and diameter from 25,073 NE-MRAs. Descriptive statistics, correlation analyses, and multivariable regression were used to investigate statistical relationships between mid-AAoD and demographic factors, hypertension, diabetes, alcohol, and tobacco consumption. Additionally, automated causal discovery analysis using the Peter-Clark algorithm was performed to identify possible causal interactions. Results: Males exhibited significantly larger mid-AAoD than females (M: 35.5±4.8 mm, F: 33.3±4.5 mm). Age and body surface area (BSA) were positively correlated with mid-AAoD. Hypertensive and diabetic subjects showed higher mid-AAoD. Hypertension was linked to higher mid-AAoD regardless of age and BSA, while diabetes and mid-AAoD were uncorrelated across age-stratified subgroups. Daily alcohol consumption and smoking history exceeding 16.5 pack-years exhibited highest mid-AAoD. Causal analysis revealed that age, BSA, hypertension, and alcohol consumption are possibly causally related to mid-AAoD, while diabetes and smoking are likely spuriously correlated. Conclusions: Mid-AAoD varies significantly within the unique large-scale NAKO population depending on demographic factors, individual health, and lifestyle. This work provides a proof-of-concept for automated causal analysis which can help disentangle observed correlations and identify potential causal determinants of ascending aortic morphology. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was conducted with data from the German National Cohort (NAKO) (www.nako.de). The NAKO is funded by the Federal Ministry of Education and Research (BMBF) [project funding reference numbers: 01ER1301A/B/C, 01ER1511D and 01ER1801A/B/C/D], federal states of Germany and the Helmholtz Association, the participating universities, and the institutes of the Leibniz Association. We thank all participants who took part in the German National Cohort and the staff in this research program. This project was partially funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project number 428219130 and supported under Germany?s Excellence Strategy ? EXC 2064/1 ? project number 390727645. ### 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 responsible ethics committees of individual studies approved all study-related analyses: GUIDE: 202/22 approved by the Ethics Committee of the Medical Faculty of the Rheinische Friedrich-Wilhelm-University Bonn ELISA: University of Luebeck (Az. 20-150) NAKO: The study is continuously approved by the responsible local ethics committees of the German Federal States where all study centers are located in (original ethics approvals of the leading ethics committee of the Bayerische Landesaerztekammer (protocol code 13023, Approval Date: 27 March 2013 and 14 February 2014 (rectification of documents, study protocol, consent form)). An external ethics advisory board has been established that accompanies NAKO over the full study period. A 'Code of Ethics' of NAKO (Ethikkodex) has been developed and the study is under steady surveillance by the ethics committees of the regional study centers (8). STAAB: Ethics committee of the Medical Faculty of the University Wuerzburg (STAAB: #98/13) MuSPAD: Ethics committee of Hannover Medical School (9086\_BO\_S\_2020 for MuSPAD), Dresden paedSAXCOVID: Ethics Committee of the Technische University (TU) Dresden (BO-EK-156042020). Bochum CorKID: Ethics Committee of the Ruhr University Bochum (Nr. 20-6927\_7) Wuerzburg Wue-KITa-CoV: Wuerzburg, Kennzeichen 105/21 IMMUNEBRIDGE_ED: Ethics Committee of University Medical Center Goettingen (21/6/22) 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 The data that support the findings of this study are available from the German National Cohort but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.