Pitfalls in understanding how multiple long-term conditions cluster: whole population and age-stratified associations in 7,490,874 people in England

Abstract Studies of how multiple long-term conditions (MLTC) cluster together in individuals vary in the populations studied, and whether they age and/or sex stratify, which limits comparison between studies and reproducibility. This study uses a large, UK primary-care dataset to examine how pairwise strength of association between 74 conditions varies by age in both men and women aged 30-99 years, and to explore implications for MLT cluster analyses. Joint prevalence of conditions was lowest in younger age-groups and progressively increased with age, whereas Association Beyond Chance (ABC) was highest in younger age-groups and progressively decreased with age. Condition clustering based on ABC identified different clusters in all men and all women aged 30-99 years, and these clusters differed from those identified in each age-group. Researchers examining how MLTC cluster should consider whether age and sex stratification is appropriate given their study aims and/or would improve comparability and reproducibility, and explicitly justify their choices. Competing Interest Statement The authors have declared no competing interest. Funding Statement The study was funded by the National Institute for Health Research (NIHR) Artificial Intelligence and Multimorbidity: Clustering in Individuals, Space and Clinical Context (NIHR202639). The funder had no role in conduct of the study, interpretation, or the decision to submit for publication. The views expressed are those of the authors and not necessarily those of the NIHR, the Department of Health and Social Care. 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: Provision of anonymized data for research by the Clinical Practice Research Datalink (CPRD) is approved annually by the NHS Research Ethics Service, and study specific NREC review is not required provided the study has been approved by the CPRD Independent Scientific Advisory Committee (ISAC). This study was reviewed by ISAC and approved (protocol 21_000542). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 Data Availability The data controllers do not allow sharing of raw data by the research team, but any researcher can access the same raw data subject to data controller approval (https://www.cprd.com/). Code lists for defining the conditions examined can be found online at Zenodo.38