{"paper_id":"3cda3e90-e214-4c7d-9621-20296dcf6a4d","body_text":"Abstract\nCurrent long read sequencing (LRS) platforms allow the simultaneous detection of both genetic variation and epigenetic modification, yet in most cases only genetic variation is utilised. Here we demonstrate the additional potential utility of methylation-based cell type deconvolution and outlier detection, using LRS data from two different platforms. This approach could reliably estimate the proportions of the most abundant cellular constituents of human blood and peripheral blood mononuclear cells, using either primary samples or synthetic mixtures of data from purified cells. Using samples from patients with a hematological malignancy (B cell chronic lymphocytic leukemia) or immunodeficiency (X-linked agammaglobulinemia), LRS resolved both the disease-associated variant and primary cellular phenotype in a single assay. The LRS approach yielded similar cell proportion estimates to orthogonal scRNAseq data generated on the same samples. LRS-derived methylation data therefore represents an incidental source of phenotypic data, with potential future utility in genomic discovery in population-scale biobanks, and in the investigation of inherited and acquired genetic disease.\nCompeting Interest Statement\nI.W.D. has previously received conference travel and accommodation expenses from ONT, and has a paid consultant role with Sequin Pty Ltd. A.W.H. and O.M.S. are cofounders, directors, and equity holders in Seonix Pty Ltd.\nFunding Statement\nThis research was supported by the Snow Medical Research Foundation (Grant No. PF2019-040). The funders were not involved in the design of the study, collection, analysis, and interpretation of the data, the writing of this report, or the decision to submit the article for publication. The authors express their sincere appreciation to the Snow Medical Research Foundation for their generous support of this work.\nAuthor Declarations\nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.\nYes\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\nHuman Research Ethics Committee of Western Sydney Local Health District gave ethical approval for this work (HREC 17/5449) Human Research Ethics Committee of The University of Tasmania gave ethical approval for this work (HREC 2020/ETH02479) Human Research Ethics Committee of Northern Sydney Local Health District gave ethics approval for this work (HREC 17/HAWKE/343) Human Research Ethics Committee of The Sydney Children's Hospitals Network gave ethics approval for this work (HREC/18/SCHN/140)\nI 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.\nYes\nI 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).\nYes\nI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.\nYes\nData Availability\nAll data referred to in the present study will be available at the time of publication if allowable by their respective ethics protocols","source_license":"CC-BY-4.0","license_restricted":false}