Disentangling Predictors of COPD Mortality with Probabilistic Graphical Models

Background-Research question Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality. Predicting mortality risk in COPD patients can be important for disease management strategies. Although scores for all-cause mortality have been developed previously, there is limited research on factors that may directly affect COPD-specific mortality. Study design-Methods used probabilistic (causal) graphs to analyze clinical baseline COPDGene data, including demographics, spirometry, quantitative chest imaging, and symptom features, as well as gene expression data (from year-5). Results We identified factors linked to all-cause and COPD-specific mortality. Although many were similar, there were differences in certain comorbidities (all-cause mortality model only) and forced vital capacity (COPD-specific mortality model only). Using our results, we developed VAPORED , a 7-variable COPD-specific mortality risk score, which we validated using the ECLIPSE 3-yr mortality data. We showed that the new model is more accurate than the existing ADO, BODE, and updated BODE indices. Additionally, we identified biological signatures linked to all-cause mortality, including a plasma cell mediated component. Finally, we developed a web page to help clinicians calculate mortality risk using VAPORED, ADO, and BODE indices. Interpretation Given the importance of predicting COPD-specific and all-cause mortality risk in COPD patients, we showed that probabilistic graphs can identify the features most directly affecting them, and be used to build new, more accurate models of mortality risk. Novel biological features affecting mortality were also identified. This is an important step towards improving our identification of high-risk patients and potential biological mechanisms that drive COPD mortality. ### Competing Interest Statement TCL, MHR, MJ, PVB have nothing to disclose. PC received grant support from Bayer. FCS has received grant support and consulting fees from Sanofi/Regeneron, AstraZeneca, Verona Pharma, Nuvaira, Gala Therapeutics, GlaxoSmithKline, Boehringer Ingelheim. CPH has received grant support and consulting fees from Alpha-1 Foundation, Bayer, Boehringer Ingelheim, Vertex, AstraZeneca, Takeda, Sanofi. ### Funding Statement This work was supported by NHLBI grants R01HL159805 and R01HL157879 (to PVB) and F31LM013966 (to TCL). This work was also supported by NHLBI U01HL089897 and U01HL089856. The COPDGene study ([NCT00608764][1]) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion. ### 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 data were obtained from COPDGene and ECLIPSE study cohorts before the initiation of this study. All data we used were completely de-identified. Data can be obtained from dbGAP. - COPDGene: - ECLIPSE: or by directly contacting the PIs of these studies. 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 No new data were produced during this study. The COPDGene and ECLIPSE data can be obtained from dbGAP. - COPDGene: - ECLIPSE: * MB : Markov blanket RF : Random Forest [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00608764&atom=%2Fmedrxiv%2Fearly%2F2024%2F02%2F01%2F2024.01.31.24301705.atom