Feature Pre-Selection for the Development of Epigenetic Biomarkers

Over the last decade, a plethora of blood-based DNA methylation biomarkers have been developed to track differences in ageing, lifestyle, health, and biological outcomes. Typically, penalised regression models are used to generate these predictors, with hundreds or thousands of CpGs included as potential features. However, in such ultra high-dimensional settings, the effectiveness of these methods may be reduced.Here, we introduce Related Trait-based Feature Screening (RTFS), a method for performing CpG pre-selection for incident disease prediction models by utilising associations between CpGs and health-related continuous traits. In a comparison with commonly used CpG pre-selection methods, we evaluate resulting downstream Cox proportional-hazards prediction models for 10-year type 2 diabetes (T2D) onset risk in Generation Scotland (n=18,414). The top performing models utilised incident T2D EWAS (AUC=0.881, PRAUC=0.279) and RTFS (AUC=0.877, PRAUC=0.277). The resulting models also improve prediction over a model using standard risk factors only (AUC=0.841, PRAUC=0.194) and replication was observed in the German-based KORA study (n=4,261)RTFS is a flexible and generalisable framework that can help to refine biomarker development for incident disease outcomes.### Competing Interest StatementR.E.M is an advisor to the Epigenetic Clock Development Foundation and Optima Partners. All other authors declare no competing interests.### Funding StatementThis research was funded in whole, or in part, by the Wellcome Trust [104036/Z/14/Z, 108890/Z/15/Z, 216767/Z/19/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). DNA methylation profiling of the Generation Scotland samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" (STRADL; Reference 104036/Z/14/Z). The DNA methylation data assayed for Generation Scotland was partially funded by a 2018 NARSAD Young Investigator Grant from the Brain \& Behavior Research Foundation (Ref: 27404; awardee: Dr David M Howard) and by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh (Awardee: Dr Heather C Whalley). Y.C. is supported by the University of Edinburgh and University of Helsinki joint PhD program in Human Genomics. C.A.V. is a Chancellor's Fellow funded by the University of Edinburgh. R.E.M. is supported by Alzheimer's Society major project grant AS-PG-19b-010. The KORA study was initiated and financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ and is supported by the DZHK (German Centre for Cardiovascular Research). The KORA study is funded by the Bavarian State Ministry of Health and Care through the research project DigiMed Bayern (www.digimed-bayern.de).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All components of Generation Scotland received ethical approval from the NHS Tayside Committee on Medical Research Ethics (REC Reference Number: 05/S1401/89). Generation Scotland has also been granted Research Tissue Bank status by the East of Scotland Research Ethics Service (REC Reference Number: 20-ES-0021), providing generic ethical approval for a wide range of uses within medical research. Written, informed consent was provided by Generation Scotland participants. The KORA studies were approved by the Ethics Committee of the Bavarian Medical Association (Bayerische Landesärztekammer; S4: \#99186) and were conducted according to the principles expressed in the Declaration of Helsinki. All study participants gave their written informed consent.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.YesI 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).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAccording to the terms of consent for Generation Scotland participants, access to data must be reviewed by the Generation Scotland Access Committee. Applications should be made to access{at}generationscotland.org. The informed consent given by the KORA S4 study participants does not cover data posting in public databases. However, data are available upon request from the KORA Project Application Self-Service Tool. Data requests can be submitted online (https://epi.helmholtz-muenchen.de/) and are subject to approval by the KORA board.