Population-wide analysis of laboratory tests to assess seasonal variation and the relevance of temporal reference interval modification

We identified mortality-, age-, and sex-associated differences in relation to reference intervals (RI) for laboratory tests in population-wide data from nearly two million hospital patients in Denmark and comprising of more than 300 million measurements. A low-parameter mathematical wave-based modification method was developed to adjust for dietary and environment influences during the year. The resulting mathematical fit allowed for improved association rates between re-classified abnormal laboratory tests, patient diagnoses and mortality. The study highlights the need for seasonally modified RIs and presents an approach that has the potential to reduce over- and underdiagnosis, impacting both physician-patient interactions and EHR research as a whole. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We thank the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594) as well as the Danish Innovation Fund (5184-00102B) for providing funding for the study. V. Muse is the recipient of a fellowship from the Novo Nordisk Foundation as part of the Copenhagen Bioscience Ph.D. Programme, supported through grant NNF19SA0035440. ### 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: This study has been approved by The Danish Data Protection Agency (ref: 514-0255/18-3000, 514-0254/18-3000, SUND-2016-50), The Danish Health Data Authority (ref: FSEID-00003724 and FSEID-00003092) and The Danish Patient Safety Authority (3-3013-1731/1/). The study has been approved as a registry study where patient consent is not needed in Denmark. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 The Danish National Patient Registry (DNPR) and laboratory data used can only be accessed by researchers authorized by the Danish health authorities. Approvals are listed in the manuscript. * BCC : B-Data Clinical Chemistry Laboratory System CRP : c-reactive protein CVD : Coronary Vascular Disease DNK : code for Denmark DL : Deep Learning DNPR : Danish National Patient Registry EHR : Electronic Health Record FDR : false discovery rate HDL Cholesterol : High Density Lipoprotein Cholesterol ICD : International Statistical Classification of Diseases IFCC : International Federation of Clinical Chemistry LABKA : The Clinical Laboratory Information System LOINC : Logical Observation Identifiers Names and Codes ML : Machine Learning NPU : Nomenclature, Properties and Units NLS : non-linear least-squares RI : Reference Interval PSA : Prostate Specific Antigen TSH : Thyroid Stimulating Hormone.